• Provide written informed consent.
• Age ≥ 18 years old.
• Histologically and/or cytologically documented metastatic colorectal adenocarcinoma. RAS, BRAF, and microsatellite instability (MSI)/mismatch repair (MMR) status must be documented, according to country guidelines.
• Subjects must have progressed on or been intolerant to treatment with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are considered intolerant to TAS-102 or regorafenib if they have received at least 1 dose of either agent and were discontinued from therapy for reasons other than disease progression. Subjects who have been treated with both TAS-102 and regorafenib are permitted. Subjects must also have been previously treated with:
  • standard approved therapies: fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy;
  • an anti-VEGF biological therapy (eg, bevacizumab, aflibercept, ramucirumab). [Please note that regorafenib is NOT an anti-VEGF biologic]; and
  • if RAS wild-type, an anti-EGFR therapy (e.g., cetuximab, panitumumab);
• Subjects with microsatellite-high (MSI-H) or mismatch repair deficient (dMMR) tumors must have been treated with immune checkpoint inhibitors if approved and available in the subject’s country unless the subject is ineligible for treatment with a checkpoint inhibitor.
• Subjects who received oxaliplatin in the adjuvant setting and developed metastatic disease during or within 6 months of completing adjuvant therapy are considered eligible without receiving oxaliplatin in the metastatic setting. Subjects who developed metastatic disease more than 6 months after completion of oxaliplatin-containing adjuvant treatment must be treated with oxaliplatin-based therapy in the metastatic setting to be eligible.
• Body weight ≥ 40kg.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Have measurable disease according to RECIST Version 1.1, assessed locally. Tumors that were treated with radiotherapy are not measurable per RECIST Version 1.1, unless there has been documented progression of those lesions.
• Expected survival > 12 weeks.
• For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement to use a highly effective form(s) of contraception, that results in a low failure rate (< 1% per year) when used consistently and correctly, starting during the screening period, continuing throughout the entire study period, and for 90 days after taking the last dose of study drug. Such methods include: oral hormonal contraception (combined estrogen/ progestogen, or progestogen-only) associated with inhibition of ovulation intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal ligation, vasectomized partner, or true sexual abstinence in line with the preferred and usual lifestyle of the subject. Highly effective contraception should always be combined with an additional barrier method (e.g., diaphragm, with a spermacide).The same criteria are applicable to male subjects involved in this clinical trial if they have a partner of childbirth potential, and male subjects must always use a condom.
• Subjects with BRAF-mutant tumors must have been treated with a BRAF inhibitor if approved and available in the subject’s country unless the patient is ineligible for treatment with a BRAF inhibitor.

• Absolute neutrophil count (ANC) < 1.5×10^9/L.
• Platelet count < 100 × 10^9/L.
• Hemoglobin < 9.0 g/dL.
• Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed.
• Serum total bilirubin > 1.5 × the upper limit of normal (ULN).
• ALT or AST > 2.5 × ULN in subjects without hepatic metastases; ALT or AST > 5 × ULN in subjects with hepatic metastases.
• Serum creatinine > 1.5 × ULN or creatinine clearance < 60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation.
• Urine dipstick or urinalysis with protein ≥ 2+ or 24-hour urine protei ≥ 1.0 g/24-h. Subjects with greater than 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level. 
• Uncontrolled hypertension, defined as: systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mm Hg despite optimal medical management. The subject must have blood pressures below both limits. Repeated assessments are permitted.
• International Normalized Ratio (INR) > 1.5 x ULN or activated partial thromboplastin time (aPTT) > 1.5 × ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes.
• History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator’s judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening.
• History or presence of hemorrhage from any other site (eg, hemoptysis or hematemesis) within 2 months prior to screening.
• History of a thromboembolic event, including deep vein thrombosis (DVT), pulmonary embolism (PE), or arterial embolism within 6 months prior to screening.
• Stroke and/or transient ischemic attack within 12 months prior to screening;
• Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) 480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in a first-degree relative.
• Concomitant medications with a known risk of causing QT prolongation and/or torsades de pointes (Source list is continuously updated online at www.crediblemeds.org).
• Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy.
• Systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors) within 5 halflives or 4 weeks (whichever is shorter) prior to the first dose of study drug.
• Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug.
• Brachytherapy (i.e., implantation of radioactive seeds) within 60 days prior to the first dose of study drug;
• Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug.
• Surgery or invasive procedure (i.e., a procedure that includes a biopsy; central venous catheter placement is allowed) within 60 days prior to the first dose of study drug or unhealed surgical incision.
• Any unresolved toxicities from a previous antitumor treatment greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) v5.0 grade 1 (except for alopecia or neurotoxicity grade ≤ 2).
• Known human immunodeficiency virus (HIV) infection.
• Known history of active viral hepatitis. For subjects with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Subjects with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load.
• Clinically uncontrolled active infection requiring IV antibiotics.
• Tumor invasion of a large vascular structure (eg, pulmonary artery, superior or inferior vena cava).
• Women who are pregnant or lactating.
• Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; subjects requiring steroids within 4 weeks prior to start of study treatment are excluded.
• Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening.
• Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (e.g., gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product.
• Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (e.g., current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the subject at undue risk of harm based on the investigator’s assessment.
• Known hypersensitivity to fruquintinib or any of its (or placebo) inactive ingredients including the azo dyes Tartrazine
  •FD&C Yellow 5 and Sunset yellow FCF
  •FD&C Yellow 6.
• Subjects who have received prior fruquintinib.
• Live vaccine ≤ 28 days before the first dose of study drug(s). Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.

Eligibility last updated 10/1/21. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Pre-registration: 

• Age ≥ 18 years.
• Disease characteristics.
• Histological confirmation of adenocarcinoma of the stomach or gastroesophageal junction (GEJ).
• Currently receiving first-line therapy with FOLFOX and nivolumab without evidence of disease progression OR planning to start first-line therapy with FOLFOX and nivolumab.
• No radiographic or histological evidence of non-peritoneal metastasis.
• ECOG Performance Status (PS) 0, 1 or 2.
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Inclusion Criteria
•Registration:

• Peritoneal Carcinomatosis Index (PCI) ≥ 1 and ≤ 24 obtained ≤ 30 days prior to registration.
• Clinical, pathological, or radiographic evidence of peritoneal metastasis per PCI (Appendix II) and PGRS.
• The following laboratory values obtained ≤ 15 days prior to registration:
• • Hemoglobin ≥ 8.0 g/dL;
  • Absolute neutrophil count (ANC) ≥ 1000/mm^3;
  • Platelet count ≥ 75,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN;
  • Alanine aminotransferase (ALT) AND aspartate transaminase (AST) ≤ 1.5 x ULN;
  • PT/INR/aPTT ≤ 1.5 x ULN;
    OR if patient is receiving anticoagulant therapy, then INR or aPTT is within target range of therapy;
• • Calculated creatinine clearance ≥ 45 ml/min using the Cockcroft-Gault formula below:
    • Creatinine clearance for males = (140-age) (weight in kg) (72) (serum creatinine inmgdL);
    • Creatinine clearance for females = (140-age) (weight in kg) (0.85 )(72)(serum creatinine inmgdL).
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Provide written informed consent.
• Willingness to provide mandatory blood specimens for correlative research.
• Willingness to provide mandatory tissue specimens for correlative research.
• Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

Exclusion Criteria
•Pre-registration:

• Any of the following because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects:
• • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception.
• Any of the following prior therapies: IL-2 or chronic corticosteroids, or immunosuppressive agents:
  • NOTE: Inhaled corticosteroids are allowed.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• Uncontrolled intercurrent illness including, but not limited to:
• • Ongoing or active infection;
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Cardiac arrhythmia;
  • Psychiatric illness/social situations that would limit compliance with study requirements;
  • Autoimmune disease.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Active second malignancy currently receiving systemic treatment ≤ 6 months prior to pre-registration.
• History of myocardial infarction ≤ 6 months prior to pre-registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.

Exclusion Criteria
•Registration:

• Identification of non-peritoneal metastasis during laparoscopy.
• Any of the following because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects:
• • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential and persons able to father a child who are unwilling to employ adequate contraception.
• Any of the following therapies: prior immune checkpoint inhibitors, prior IL-2, or chronic corticosteroids or immunosuppressive agents:
  • NOTE: Inhaled corticosteroids are allowed. One-time antiemetic dose is allowed.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Immunocompromised patients and patients known to be HIV positive and currently receiving antiretroviral therapy.
• Uncontrolled intercurrent illness including, but not limited to:
• • Ongoing or active infection;
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Cardiac arrhythmia;
  • Psychiatric illness/social situations (e.g., substance abuse) that would limit compliance with study requirements;
  • Autoimmune disease requiring systemic treatment;
  • Small bowel obstruction.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Active malignancy currently receiving systemic treatment ≤ 6 months prior to registration.
• History of myocardial infarction ≤ 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Small bowel obstruction < 15 days prior to registration.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 1/31/23. Questions regarding updates should be directed to the study team contact.

• Diagnosis of large duct PSC.
• Liver biopsy at screening that is deemed acceptable for interpretation and demonstrates stage F0. 
• F3 fibrosis in the opinion of the central reader. 
• Individual has the following laboratory parameters at the screening visit, as determined by the central laboratory: 
  • Platelet count ≥ 150,000/mm^3; 
  • Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation;
  • ALT ≤ 8 x upper limit of the normal range (ULN);
  • Total bilirubin < 2 mg/dL, unless the individual is known to have Gilbert's syndrome or hemolytic anemia; 
  • International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation;
  • Negative anti-mitochondrial antibody.

Current or prior history of any of the following:

• Cirrhosis; 
• Liver transplantation; 
• Cholangiocarcinoma or hepatocellular carcinoma (HCC); 
• Ascending cholangitis within 30 days of screening; 
• Presence of a percutaneous drain or biliary stent;
• Other causes of liver disease; 
• Current or prior history of unstable cardiovascular disease;
• Current moderate to severely active inflammatory bowel disease (IBD).

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 6/19/23. Questions regarding updates should be directed to the study team contact.

• Diagnosis of one of the syndromes of interest using established criteria
• Age 40-90 inclusive
• MMSE score above 10
• No active medical disorder that could preclude participation
• Stable medication regimen over previous four weeks
• Absence of certain medications that could significantly impact the DaTscan findings
• For those with dementia, caregiver that is with the patient at least 4 hours/day for at least 5 days per week
• For those with dementia, or severe parkinsonism, patient and caregiver willing and able to participate in all study-related procedures
• Patient is capable of giving informed consent, or if appropriate, has caregiver capable of giving consent on the subject's behalf.

• Does not fulfill criteria for any of the desired diagnoses
• Age <40 or >90
• Women with intact uterus and not post-menopausal unless pregnancy test performed at screening is negative
• Women who are pregnant or are breast-feeding an infant
• MMSE score <10
• Active medical disorder that could preclude participation in this protocol
  • Hypersensitivity to the radioligand, cocaine, or iodine (including seafood allergy)
  • Myocardial infarction or cerebral infarct over preceding year, stable or unstable angina, known symptomatic coronary artery disease
  • Renal or liver disease viewed by the physician to be too severe to warrant DaTscan infusion/imaging
  • History of significant alcohol or drug abuse
  • Any other medical disorder considered by the study physicians as inappropriate for this protocol
• Patient or caregiver unwilling or unable to participate in all study-related procedures
• Caregiver is not with a patient with dementia or severe parkinsonism at least 4 hours/day for at least 5 days/week
• Patient or caregiver unwilling or unable to provide informed consent

• Non-Infectious Active Uveitis of the posterior segment of the eye.

• Females who are pregnant, nursing, or planning a pregnancy.
• Confirmed or suspected infectious uveitis.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/1/23. Questions regarding updates should be directed to the study team contact.

• Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C)
• Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status
• Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
• Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
• Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented; positive radial margins are not excluded as long as en bloc resection was performed; proximal or distal margin positivity is excluded
• Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary
• Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (distal includes), and further categorization will be as follows: cecum/ascending, descending, sigmoid colon, or rectosigmoid colon
• No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible
• No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for colon cancer except for one cycle of mFOLFOX6
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• For women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
• Absolute neutrophil count (ANC) >= 1500 mm^3
• Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration
• Creatinine =< 1.5 x upper limit of normal (ULN) or
• Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
• No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
• No known active hepatitis B or C
  • Active hepatitis B can be defined as:
    • Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;
    • Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
    • Persistent or intermittent elevation in ALT/AST levels
    • Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
  • Active hepatitis C can be defined as:
    • Hepatitis C antibody (AB) positive AND
    • Presence of hepatitis C virus (HCV) RNA
• Excluded if known active pulmonary disease with hypoxia defined as:
  • Oxygen saturation < 85% on room air, or
  • Oxygen saturation < 88% despite supplemental oxygen
• No grade >= 2 peripheral motor or sensory neuropathy
• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:
  • A stable regimen of highly active anti-retroviral therapy (HAART)
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests
• No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
• No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
• No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
• No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
• No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin

• Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C)
• Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status
• Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
• Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
• Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented; positive radial margins are not excluded as long as en bloc resection was performed; proximal or distal margin positivity is excluded
• Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary
• Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (distal includes), and further categorization will be as follows: cecum/ascending, descending, sigmoid colon, or rectosigmoid colon
• No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible
• No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for colon cancer except for one cycle of mFOLFOX6
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• For women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
• Absolute neutrophil count (ANC) >= 1500 mm^3
• Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration
• Creatinine =< 1.5 x upper limit of normal (ULN) or
• Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
• No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
• No known active hepatitis B or C
  • Active hepatitis B can be defined as:
    • Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;
    • Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
    • Persistent or intermittent elevation in ALT/AST levels
    • Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
  • Active hepatitis C can be defined as:
    • Hepatitis C antibody (AB) positive AND
    • Presence of hepatitis C virus (HCV) RNA
• Excluded if known active pulmonary disease with hypoxia defined as:
  • Oxygen saturation < 85% on room air, or
  • Oxygen saturation < 88% despite supplemental oxygen
• No grade >= 2 peripheral motor or sensory neuropathy
• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:
  • A stable regimen of highly active anti-retroviral therapy (HAART)
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests
• No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
• No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
• No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
• No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
• No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin

• Histologically proven stage III colon adenocarcinoma (any T [Tx, T1, T2, T3, or T4], N1-2M0; includes N1C)
• Presence of deficient (d) DNA mismatch repair (dMMR); MMR status must be assessed by immunohistochemistry (IHC) for MMR protein expression (MLH1, MSH2, MSH6, PMS2) where loss of one or more proteins indicates dMMR; dMMR may be determined either locally or by site-selected reference lab; Note: loss of MLH1 and PMS2 commonly occur together; formalin-fixed paraffin-embedded (FFPE) tumor tissue is required for subsequent retrospective central confirmation of dMMR status
• Patients with testing that did not show dMMR (loss of MMR protein) are not eligible to participate; patients whose tumors show MSI-H by polymerase chain reaction (PCR)-based assay are not eligible to participate unless they also have MMR testing by IHC and are found to have dMMR (i.e. loss of one or more MMR proteins)
• Patients who are known to have Lynch syndrome and have been found to carry a specific germline mutation in an MMR gene (MLH1, MSH2, MSH6, PMS2) are eligible to participate
• Tumors must have been completely resected; in patients with tumor adherent to adjacent structures, en bloc R0 resection must be documented; positive radial margins are not excluded as long as en bloc resection was performed; proximal or distal margin positivity is excluded
• Entire tumor must be in the colon (rectal involvement is an exclusion); surgeon confirmation that entire tumor was located in the colon is required only in cases where it is important to establish if the tumor is a colon versus (vs.) rectal primary
• Based upon the operative report and other source documentation, the location of the primary tumor will be categorized as proximal or distal to the splenic flexure (distal includes), and further categorization will be as follows: cecum/ascending, descending, sigmoid colon, or rectosigmoid colon
• No evidence of residual involved lymph node disease or metastatic disease at the time of registration based on clinician assessment of imaging; the treating physician will determine if incidental lesions on imaging require workup to exclude metastatic disease; if based on review of images, the treating physician determines the patient to be stage III, then the patient is eligible
• No prior medical therapy (chemotherapy, immunotherapy, biologic or targeted therapy) or radiation therapy for colon cancer except for one cycle of mFOLFOX6
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• For women of childbearing potential only, a negative pregnancy test done =< 7 days prior to registration is required; a female of childbearing potential is a sexually mature female who:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 12 consecutive months (i.e. has had menses at any time in the preceding 12 consecutive months)
• Absolute neutrophil count (ANC) >= 1500 mm^3
• Platelet count >= 100,000 mm^3; platelets >= 75,000 required for patients who received cycle 1 of mFOLFOX6 prior to registration
• Creatinine =< 1.5 x upper limit of normal (ULN) or
• Calculated creatinine clearance >= 45 mL/min by Cockcroft-Gault equation
• Total bilirubin =< 1.5 x upper limit of normal (ULN) except in the case of Gilbert disease
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
• Thyroid-stimulating hormone (TSH) within normal limits (WNL); supplementation is acceptable to achieve a TSH WNL; in patients with abnormal TSH, if free T4 is normal and patient is clinically euthyroid, patient is eligible
• No active known autoimmune disease, including colitis, inflammatory bowel disease (i.e. ulcerative colitis or Crohn's disease), rheumatoid arthritis, panhypopituitarism, adrenal insufficiency
• No known active hepatitis B or C
  • Active hepatitis B can be defined as:
    • Hepatitis B virus surface antigen (HBsAg) detectable for > 6 months;
    • Serum hepatitis B virus (HBV) DNA 20,000 IU/ml (105 copies/ml); lower values 2,000-20,000 IU/ml (104-105 copies/ml) are often seen in hepatitis B virus e antigen (HBeAg)-negative chronic hepatitis B
    • Persistent or intermittent elevation in ALT/AST levels
    • Liver biopsy showing chronic hepatitis with moderate or severe necroinflammation
  • Active hepatitis C can be defined as:
    • Hepatitis C antibody (AB) positive AND
    • Presence of hepatitis C virus (HCV) RNA
• Excluded if known active pulmonary disease with hypoxia defined as:
  • Oxygen saturation < 85% on room air, or
  • Oxygen saturation < 88% despite supplemental oxygen
• No grade >= 2 peripheral motor or sensory neuropathy
• Patients positive for human immunodeficiency virus (HIV) are eligible only if they meet all of the following:
  • A stable regimen of highly active anti-retroviral therapy (HAART)
  • No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • A CD4 count above 250 cells/mcL, and an undetectable HIV viral load on standard PCR-based tests
• No other planned concurrent investigational agents or other tumor directed therapy (chemotherapy, radiation) while on study
• No systemic daily treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 7 days of registration
• No known history of severe allergic anaphylactic reactions to chimeric, human or humanized antibodies, or fusion proteins
• No known hypersensitivity to Chinese hamster ovary (CHO) cell products or any component of the atezolizumab formulation
• No known allergy to 5-fluorouracil, oxaliplatin, or leucovorin

Eligibility last updated 7/1/22]. Questions regarding updates should be directed to the study team contact.

• Willing and able to provide signed informed consent at the screening visit as well as comply with all study visits and requirements through the end of the study.
• Male or female, age ≥ 18 years at the screening visit.
• Have a diagnosis of PBC in line with the AASLD guidelines as demonstrated by having at least 2 of the following (Lindor et al. 2019):
  • History of sustained increased ALP levels > ULN first recognized at least 6 months prior to the screening visit (sustained ALP elevations at the time of screening is not required, recognizing that the ALP may have decreased on UDCA therapy);
  • Documented positive AMA titer (> 1:40 titer on immunofluorescence or M2 positive by enzyme-linked immunosorbent assay) or PBC-specific ANA immuno-fluorescence patterns (multiple nuclear dots and/or punctuate nuclear rim);
  • Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts. Liver biopsy could have been done at any time in the past.
• Those treated with UDCA will be allowed to enroll if they meet one of the following criteria at Visit 1:
  • A minimum of 8 weeks of stable treatment at a dose of ≤ 20 mg/kg/day; OR
  • A minimum of 8 weeks off treatment and consequently determined by the investigator to be clinically stable
• Systemic therapies intended to address cholestatic pruritus, specifically fibrates, SSRIs, rifampin/rifampicin, gabapentin, cholestyramine, and opioid-receptor antagonists are allowed if one of the following criteria is met at the screening visit:
  • A minimum of 8 weeks of stable treatment (12 weeks of stable treatment for cholestyramine) OR b. A minimum of 4 weeks off treatment.
• Average daily Adult ItchRO score ≥ 4 during screening to be enrolled in the study at Visit 2.
• Overall compliance of ≥ 80% in daily completion of the Adult ItchRO assessments during the screening period.
• To be eligible for randomization, participants must meet the following additional criteria specific to the 4-week, single-blind, placebo run-in period:
• Completion of ≥ 80% of Adult ItchRO assessments during the single-blind, placebo run‑in period.
• Study drug compliance of ≥ 80% during the single-blind, placebo run-in period

• Pruritus associated with an etiology other than PBC.
• Evidence or clinical suspicion of decompensated cirrhosis or a history of decompensation events (e.g., variceal bleeding, ascites, hepatic encephalopathy, hepatorenal syndrome).
• Current symptomatic cholelithiasis or inflammatory gallbladder disease. Those with history of cholecystectomy ≥ 3 months before the screening visit may be eligible for enrollment.
• History of small bowel surgery/resection impacting the terminal ileum (e.g., ileostomy, ileo-anal pouch, or other surgeries/conditions) that may disrupt the enterohepatic circulation.
• Evidence, history, or suspicion of other liver diseases, including but not limited to:
  • Active hepatitis A or E infection;
  • Active hepatitis B infection as defined by the presence of hepatitis B surface antigen (HBsAg) or presence of hepatitis B virus DNA;
  • c. Hepatitis C as defined by the presence of hepatitis C virus (HCV) antibody and positive HCV RNA. Infection documented to have been cured for >1 year prior to the screening visit may be eligible;
  • Secondary sclerosing cholangitis, autoimmune hepatitis, PSC, immunoglobulin G4-related cholangitis, Wilson disease, alpha-1-antitrypsin deficiency, or hemochromatosis;
  • Suspected or proven cholangiocarcinoma or hepatocellular carcinoma;
  • History of liver transplantation;
  • Histologically confirmed diagnosis of NASH;
  • Alcohol-related liver disease.
• Unstable and/or serious medical disease that is likely to impair the participant’s ability to participate in all aspects of the study, confound efficacy and/or safety assessments, or result in substantially shortened life expectancy (e.g., any active malignancy including hematological malignancy, end-stage heart failure, active infection, acute and chronic diarrhea):
  • Previous history of malignancy, adequately treated/in remission, that in opinion of investigator and medical monitor does not impact participant safety and participation in the study, may be allowed. The investigator should contact the sponsor medical monitor to discuss these cases and seek approval before the screening period.
• Moderate alcohol consumption as defined for this study by > 1 and > 2 standard drinks on average per day for women and men, respectively, within 24 weeks of screening visit. A standard drink is defined as 1.5 oz (one shot) of liquor, 5 oz of nonfortified wine, or 12 oz of beer (1 oz=29.57 mL; NIAAA).
• Drug abuse within the 24 weeks prior to, or a positive drug screening result, at the screening visit unless it can be explained by a drug prescription:
  • Use of cannabinoids (legal, prescribed, or otherwise) is allowed, provided use is stable for at least 12 weeks prior to screening and throughout the entire study.
• Women who are pregnant or nursing. Specific criteria for defining childbearing potential and acceptable methods of birth control are outlined in the protocol.
• Known intolerance/hypersensitivity to volixibat or its excipients.
• History of nonadherence to medical regimens, unreliability, medical condition, mental instability, or cognitive impairment that, in the opinion of the investigator, could compromise the validity of informed consent, compromise the safety of the participant, or lead to nonadherence with the study protocol or inability to conduct the study procedures.
• Participation in an interventional clinical study within 4 weeks OR, if applicable, 5 times the half-life, whichever is greater, prior to the screening visit. Always adhere to other eligibility criteria that apply to specified concomitant medication.

Eligibility Criteria
•Open-Label Extension:

To maintain eligibility for the OLE, participants must:

• Have successfully completed the 24-week double-blind study drug treatment period.
• Have not experienced an AE(s) or SAE(s) related to volixibat during the double-blind study treatment period that led to permanent discontinuation.
• Have no changes in their medical condition or treatment that would preclude their participation in the LTE period at the discretion of the investigator or medical monitor.
• Complete ≥ 80% of Adult ItchRO assessments during the double-blind study treatment period.

Eligibility last updated 12/20/23. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

Eligibility Criteria
•Pre-Registration:

• Patients ≥ 18 years of age.
• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition.
• No inflammatory breast cancer.
• No other malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• All patients must have had an axillary ultrasound with fine needle aspiration (FNA) or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
  • Note: Biopsy of intramammary nodes does not fulfill eligibility criteria.
• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery. Planned sandwich chemotherapy is not allowed (i.e., anthracycline/Cytoxan or taxane chemotherapy planned to be given after surgery). Patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes.
  • Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered. More than 4 cycles of NAC may be administered at the discretion of the treating medical oncologist.
• Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab or trastuzumab + pertuzumab or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial.  Completion of a course of trastuzumab, pertuzumab, TD-M1 and/or other anti-Her2 neu therapy after surgery is allowed.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • NOTE: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy.
  • Note: An ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy. If performed, its findings do NOT impact eligibility.
• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy.
• No neoadjuvant radiation therapy.
• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
• No prior history of ipsilateral breast cancer (invasive disease or DCIS). LCIS and benign breast disease is allowed.
• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
• No history of prior or concurrent contralateral invasive breast cancer. Benign breast disease, LCIS or DCIS of contralateral breast is allowed. Ipsilateral multifocal or multicentric disease is allowed.
• Patients must not be pregnant or nursing. A negative pregnancy test is required prior to registration for women of childbearing potential.
  • NOTE: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential.
• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1.

Eligibility Criteria
•Intra-Operative Registration/ Randomization:

• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised during the sentinel lymph node surgery. More than 8 nodes identified by either surgeon or pathologist is NOT allowed. Note: Patients who do not have an identifiable sentinel lymph node will not proceed to Registration/Randomization.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
  • NOTE: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study.
• ALND is not to be performed prior to Registration/Randomization.
  • NOTE: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/ randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study “A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy.”

Eligibility Criteria
•Post-Operative Registration/ Randomization:

• For cases where ALND has not been performed and one of the following is true:
  • intraoperative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm; OR
  • lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm).
• Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 112 days of the completion of the last dose of neoadjuvant chemotherapy. No additional chemotherapy and no radiation therapy are allowed in the intervening 112 days. Endocrine therapy or HER2-targeted therapy as a bridge between cytotoxic and surgical treatments are allowed. No experimental agents are allowed during this time.
• Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink. Patients may be registered and randomized with positive margins if there are plans to clear the margins prior to radiation therapy. Negative margins are required prior to initiation of radiation therapy, and if not achieved, the patient should discontinue participation in the study.
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed).
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure.
  • NOTE: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization.

Eligibility last updated 11/12/21. Questions regarding updates should be directed to the study team contact.

• Patients must have histologically confirmed recurrent platinum-resistant epithelial ovarian carcinoma (EOC) of any histology, as defined by progression within 6 months of the last dose of platinum-based chemotherapy. Both primary platinum resistant and acquired platinum resistant patients are allowed.
• High-grade serous histology is required (for the dose expansion cohort only).
• Patients must have received 1-3 prior systemic therapies.
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%).
• Hemoglobin ≥ 10 g/dL (within 28 days prior to administration of study treatment).
• Patients may receive erythrocyte transfusions to achieve this hemoglobin level at the discretion of the investigator. Initial treatment must not begin earlier than the day after the erythrocyte transfusion.
• Absolute neutrophil count ≥ 1,500/mcL (within 28 days prior to administration of study treatment).
• Platelets ≥ 100,000/mcL (within 28 days prior to administration of study treatment).
• Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) (within 28 days prior to administration of study treatment).
• Patients with Gilbert's syndrome with a total bilirubin ≤ 2.0 times ULN and direct bilirubin within normal limits are permitted.
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN (within 28 days prior to administration of study treatment).
• Patients must have creatinine clearance estimated of ≥ 51 mL/min using the Cockcroft-Gault equation or based on a 24-hour urine test (within 28 days prior to administration of study treatment).
• Glomerular filtration rate (GFR) ≥ 60 mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (within 28 days prior to administration of study treatment). Estimated GFR calculated using Cockcroft-Gault equation.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Active hepatitis B virus (HBV) is defined by a known positive HBV surface antigen (HBsAg) result. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody and absence of HBsAg) are eligible.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
• Patients with treated brain metastases are eligible if patient is stable for at least 4 weeks status post (s/p) radiation therapy and off corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging [MRI] or computed tomography [CT] scan) during the screening period.
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better.
• Postmenopausal or evidence of non-childbearing status, a negative urine or serum pregnancy test within 28 days of study treatment and confirmed prior to treatment on day 1. Postmenopausal is defined as:
  • Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments;
  • Luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in the postmenopausal range for women under 50;
  • Radiation-induced oophorectomy with last menses > 1 year ago;
  • Chemotherapy-induced menopause with > 1 year interval since last menses;
  • Surgical sterilization (bilateral oophorectomy or hysterectomy).
• The effects of abemaciclib and olaparib on the developing human fetus are unknown. For this reason and because CDK-and PARP-inhibiting agents are known to be teratogenic, women of child-bearing potential and their partners, who are sexually active, must agree to the use of one highly effective form of contraception and their partner must use a male condom prior to study entry, for the duration of study participation, and for 1 month after the last dose of study treatment. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• For the dose expansion cohort, patients must have disease amenable to biopsy for correlative studies, specifically at least 1 tumor accessible and safe for biopsy on office exam or tumor that a radiologist deems is safe for biopsy in interventional radiology department based on imaging (dose expansion cohort only). For the dose escalation cohort, patients with evaluable disease are acceptable.

For inclusion in i) the optional genetic research and ii) the optional biomarker research, patients must fulfill the following criteria:

• Provision of informed consent for genetic research prior to collection of sample.
• Provision of informed consent for biomarker research prior to collection of sample.
• If a patient declines to participate in the optional exploratory genetic research or the optional biomarker research, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study.
• Patients may not have received prior CDK 4/6 inhibitors. Previous PARP inhibitor use is allowed in front-line treatment but not for recurrent disease.
• Patients who received chemotherapy must have recovered (Common Terminology Criteria for Adverse Events [CTCAE] grade ≤ 1) from the acute effects of chemotherapy except for residual alopecia or grade 2 peripheral neuropathy prior to randomization. A washout period of at least 21 days is required between last chemotherapy dose and randomization (provided the patient did not receive radiotherapy).
• Patients who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 28 days is required between end of radiotherapy and randomization.
• For agents other than chemotherapy, a 4 week washout period is required. Previous bevacizumab use is allowed.
• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

• Patients who are receiving any other investigational agents.
• History of allergic reaction or hypersensitivity attributed to compounds of similar chemical or biologic composition to abemaciclib, olaparib or any of the excipients of these products.
• Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting study treatment is 2 weeks. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
• Patients with psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study because abemaciclib is a CDK-inhibiting agent and olaparib is a PARP inhibiting agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with abemaciclib and olaparib, breastfeeding should be discontinued if the mother is treated with abemaciclib and olaparib.
• Other malignancy unless curatively treated with no evidence of disease for ≥ 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS), stage 1, grade 1 endometrial carcinoma.
• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT [QTcF] prolongation > 500 ms, electrolyte disturbances, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest, etc.), or patients with congenital long QT syndrome.
• Patients with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome/acute myeloid leukemia (MDS/AML).
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection that, in the judgment of the investigator, would preclude participation in this study. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan, severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g., estimated creatinine clearance < 30 ml/min], history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline grade 2 or higher diarrhea).
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.
• Major surgery within 2 weeks of starting study treatment and patients must have recovered from any effects of any major surgery.
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Patients with an active systemic fungal infection.

Eligibility last updated 2/22/23 to match clinicaltrials.gov. Questions regarding updates should be directed to the study team contact.

Key

Note: Other protocol defined Inclusion/Exclusion Criteria may apply.

Eligibility last updated 11/29/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Body weight > 30 kg.
• Primary non small cell lung cancer treated previously on PACIFIC regimen (concurrent chemoradiation followed by durvalumab for stage III lung cancer).
• Progression during duvalumab administration or within 6 months after completion of final durvalumab infusion.
• Extracranial lesion > 4 cm amenable to grid therapy.
• Patients with brain metastases are permitted to enroll.
• Patients with polymetastatic disease are permitted to enroll.
• Patients with local recurrence are permitted to enroll.
• Patients who do not have rapid polymetastatic progression (at the discretion of the enrolling physician).
• Patients who have not had SBRT within 1 month of enrolment.
• Patients may receive conventional palliative radiation to other symptomatic metastatic disease.
• ECOG Performance Status (Dronca, Liu, et al.) 0-2.
• The following laboratory values obtained ≤15 days prior to registration:
  • Hemoglobin ≥ 9.0 g/dL;H
  • Absolute neutrophil count (ANC) ≥ 1500/mm^3;
  • Platelet count ≥ 100,000/mm^3;
  • Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ULN if total bilirubin is > 1.5 x ULN;
  • Alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement);
  • Creatinine OR glomerular filtration rate (GFR) ≤ 1.5 x ULN; OR
  • GFR > 60 mL/min for patients with creatinine > 1.5 x ULN.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Persons able to become pregnant OR able to father a child must be willing to use an adequate method of contraception while on treatment and for 120 days after last treatment.
• Life expectancy ≥ 12 weeks.
• Provide written informed consent..
• Willingness to provide mandatory blood specimens for correlative research.
• Willing to return to Mayo Clinic for follow-up (during the Active Monitoring Phase of the study).

• < 18 years of age.
• Any of the following because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:
  • Pregnant persons;
  • Nursing persons;
  • Persons of childbearing potential OR able to father a child who are unwilling to employ adequate contraception.
• Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Active autoimmune disease requiring systemic treatment, documented history of severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
• NOTE: Exceptions are allowed for:
  • Vitiligo;
  • Resolved childhood asthma/atopy;
  • Intermittent use of bronchodilators or inhaled steroids;
  • Daily steroids at dose of ≤10mg of prednisone (or equivalent);
  • Local steroid injections;
  • Stable hypothyroidism on replacement therapy;
  • Stable diabetes mellitus on non-insulin therapy;
  • Sjögren’s syndrome.
• Uncontrolled intercurrent illness including, but not limited to:
  • Ongoing or active infection requiring systemic therapy;
  • Interstitial lung disease;
  • Serious, chronic gastrointestinal conditions associated with diarrhea (e.g., Crohn’s disease or others);
  • Known active hepatitis B (i.e., known positive HBV surface antigen (HBsAg) reactive);
  • Known active hepatitis C (i.e., positive for HCV RNA detected by PCR);
  • Known active tuberculosis (TB);
  • Symptomatic congestive heart failure;
  • Unstable angina pectoris;
  • Unstable cardiac arrhythmia; or
  • Psychiatric illness/social situations that would limit compliance with study requirements (e.g., substance abuse).
• History of myocardial infarction ≤ 6 months, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening ventricular arrhythmias.
• Receiving any other investigational agent which would be considered as a treatment for the primary neoplasm.
• Hypersensitivity to durvalumab or any of its excipients.
• Previous adverse event attributed to durvalumab or other PD-1 or PD-L1 directed therapy that led to drug discontinuation.
• History of Grade ≥ 3 immune-related adverse event or any grade of immune-related neurologic or ocular adverse event while receiving immunotherapy.
  • Note: Patients who had endrocrine adverse events ≤ Grade 2 are allowed to enroll if they are stable on appropriate replacement therapy and asymptomatic.
• Other active malignancy < 6 months prior to registration.
  • EXCEPTIONS: Non-melanotic skin cancer, papillary thyroid cancer, prostate cancer, or carcinoma-in-situ of the cervix, or others curatively treated and now considered to be at less than 30% risk of relapse.

• Patients who are ≥ 18 years of age.
• Patient must have SM, confirmed by Central Pathology Review of BM biopsy, and ISM or SSM subtype, as confirmed by WHO diagnostic criteria. In Part 1 of the study, only patients with a diagnosis of ISM are eligible.
• Patient must have moderate-to-severe symptoms based on minimum mean TSS over the 14-day eligibility screening period for assessment of TSS and ≥ 1 symptom in skin or GI domains of the ISM-SAF at Baseline. Minimum TSS for eligibility is ≥ 28.
• Patient must have failed to achieve symptom control for 1 or more Baseline symptoms, as determined by the Investigator, with at least 2 of the following symptomatic therapies administered at optimal (approved) dose and for a minimum of 4 weeks (28 days) before starting the ISM-SAF for determination of eligibility: H1 blockers, H2 blockers, proton-pump inhibitors, leukotriene inhibitors, cromolyn sodium, corticosteroids, or omalizumab.
• The patient’s SM symptomatic therapies (e.g., H1 and H2 blockers) must be stable (same dose, no new medications for SM) for ≥ 14 days before starting the ISM-SAF for determination of eligibility.
• If the patient is receiving corticosteroids, the dose must be ≤ 20 mg/d prednisone or equivalent, and the dose must be stable for ≥ 14 days before starting the ISM-SAF for determination of eligibility.
• Patient must have an Eastern Cooperative Oncology Group Performance Status of 0 to 2.
• Patient must be able to give written informed consent.

• Patient must not have received prior treatment with avapritinib.
• Patient must not have had any cytoreductive therapy including but not limited to masitinib and midostaurin, or investigational agent for < 14 days or 5 half-lives of the drug (whichever is longer), and for cladribine, interferon alpha, pegylated interferon, or antibody therapy < 28 days or 5 half-lives of the drug (whichever is longer), before starting the ISM-SAF for determination of eligibility.
• Patient must not have received radiotherapy or psoralen and ultraviolet A (PUVA) therapy < 14 days before starting the ISM-SAF for determination of eligibility.
• Patient must not have received any hematopoietic growth factor < 14 days before starting the ISM-SAF for determination of eligibility.
• Patient must not require therapy with a concomitant medication that is a strong inhibitor, strong inducer, or moderate inducer of cytochrome P450 3A4 (CYP3A4).
• Patient must not have a QT interval corrected using Fridericia’s formula (QTcF) of > 480 msec.
• Patient must not have a history of a seizure disorder (e.g., epilepsy) or requires antiseizure medication.
• Patient must not have a history of a cerebrovascular accident or transient ischemic attacks within 12 months before the first dose of study drug.
• Patient must not have a known risk or recent history (12 months before the first dose of study drug) of intracranial bleeding (e.g., brain aneurysm).

• Adults and adolescents (aged ≥ 12 years.
• Children 6 to 11 years of age.
• Children 2 to 5 years of age.
• Infants and newborns from birth to < 2 years of age.
• Documented diagnosis of PH1 or PH2, confirmed by genotyping (historically available genotype information is acceptable for study eligibility).
• Estimated GFR at Screening < 30 mL/min normalized to 1.73 m^2 BSA.  For infants aged less than 12 months, serum creatinine above the 97th percentile of a healthy population (Boer et al., 2010).
• Median of 3 plasma oxalate values > 30 µmol/L during Screening.
• Less than 20% variation from the median Screening period Pox value.
• For participants receiving hemodialysis or peritoneal dialysis, total duration of hemodialysis or peritoneal dialysis must be less than or equal to 18 months and hemodialysis or peritoneal dialysis regimen must have been stable for at least 3 months prior to Screening.
• Body weight of:
  • Adults and adolescents aged ≥ 12 years: ≥ 31.0 kg;
  • Children 6 to 11 years of age: to be determined;
  • Children 2 to 5 years of age: to be determined;
  • Infants and newborns from birth to < 2 years of age: to be determined.
• Male participants: A male participant with a female partner of childbearing potential must agree to use contraception during the treatment period and for at least 12 weeks after the last dose of study intervention and refrain from donating sperm during this period.
• Female participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP);OR
  • A WOCBP who agrees to follow the contraceptive guidance for the 4 weeks prior to randomization, during the treatment period, and for at least 12 weeks after the last dose of study intervention and agrees to refrain from harvesting/freezing eggs during this period. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Participant (and/or participant’s parent or legal guardian if participant is a minor [defined as patient < 18 years of age, or younger than the age of majority according to local regulations]) is capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
  • Adolescents (12 to < 18 years of age, or older than 12 years but younger than the age of majority according to local regulations) must be able to provide written assent for participation;
  • For children younger than 12 years of age, assent will be based on local regulations.
• Affiliated with or is a beneficiary of a health insurance system (if applicable per national regulations).

• Prior hepatic transplantation; or scheduled transplantation within 6 months of Day 1. Renal transplantation planned in the 6 months from Day 1. Prior renal transplantation is allowed.
• Known history of severe systemic oxalosis.
• Presence of any condition or comorbidities that would interfere with study compliance or data interpretation or potentially impact patient safety including, but not restricted to:
  • Severe intercurrent illness;
  • Known causes of active liver disease/injury (e.g., alcoholic liver disease, nonalcoholic fatty liver disease/steatohepatitis);
  • Non-PH related conditions contributing to renal insufficiency;
  • Physician concerns about intake of drugs of abuse or excessive alcohol intake, or history of excessive alcohol intake in the 2 years prior to enrollment (defined as ≥ 21 units of alcohol per week in men and ≥ 14 units of alcohol per week in women; where a “unit” of alcohol is equivalent to a 12-ounce beer, 4-ounce glass of wine, or 1-ounce shot of hard liquor).
• Use of an RNAi drug, other than DCR-PHXC, within the last 6 months.
• History of one or more of the following reactions to an oligonucleotide-based therapy:
  • Severe thrombocytopenia (platelet count ≤ 100,000/µL);
  • Hepatotoxicity, defined as alanine transaminase (ALT) or aspartate transaminase (AST) > 3 times the upper limit of normal (ULN) and total bilirubin > 2 × ULN or international normalized ratio (INR) >1.5;
  • Severe flu-like symptoms leading to discontinuation of therapy;
  • Localized skin reaction from the injection (graded severe) leading to discontinuation of therapy;
  • Coagulopathy/clinically significant prolongation of clotting time.
• Participation in any clinical study in which they received an investigational medicinal product (IMP) other than DCR-PHXC within 4 months or 5 times the half-life of the drug (whichever is longer) before Screening.
• Liver function test abnormalities: ALT and/or AST >1.5 × ULN for age and gender.
• Positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibody test at Screening.
• Known hypersensitivity to DCR-PHXC or any of its ingredients.
• Inability or unwillingness to comply with the specified study procedures, including lifestyle considerations.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 9/19/22. Questions regarding updates should be directed to the study team contact.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 7/18/23. Questions regarding updates should be directed to the study team contact.

• Male or female, between 18 and 65 years of age (inclusive) at the time of Screening.
• Female subjects must:
  • not be pregnant, lactating, or breastfeeding;
  • be either postmenopausal (defined as amenorrhea for ≥ 12 months), surgically sterile (defined as having undergone hysterectomy and/or bilateral oophorectomy), or if of child-bearing potential (WOCBP) must agree to practice appropriate methods of birth control or remain abstinent during the study and for 30 days after the last dose of study drug;
  • Acceptable forms of contraception include any of the following:
  • oral contraceptives;
  • double barrier methods of non-hormonal contraception are permitted in this study:
  • female condom with spermicide (cream, spray, gel, suppository, contraceptive sponge, or polymer film)
  • diaphragm with spermicide (with or without a condom)
  • cervical cap with spermicide (with or without a condom)
  • male sexual partner who agrees to use a male condom in addition to female subject’s use of spermicide (cream, spray, gel, suppository, contraceptive
  • other explanation for the ALT elevations and the agreement of the medical monitor and sponsor.
  • Permanent discontinuation of prior tolvaptan treatment because of the abnormal liver chemistry test results.
  • If re-challenge with tolvaptan was performed, the ALT level should have increased to >2 x ULN upon re-challenge or the ALT level was increasing but tolvaptan was stopped for patient safety reasons before it reached > 2 x ULN after having previously normalized.
  • Appropriate control of hypertension including an angiotensin converting enzyme inhibitor or angiotensin receptor blocker (unless not considered appropriate for the subject) without the use of a diuretic in concert with KDIGO “Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease”.
  • Have read, understood, and provided written informed consent after the nature of the study has been fully explained and must be willing to comply with protocol requirements and study- related procedures.

• Known sensitivity or idiosyncratic reaction to any compound present in lixivaptan and related compounds.
• Hypovolemia or inability to perceive thirst.
• Subjects who are taking, have taken within the past 2 weeks, or are expected to be taking, strong or moderate CYP3A4 or CYP2C8 inhibitors or inducers including regular use of grapefruit juice, Seville oranges, or St. John's wort.
• Prior use of tolvaptan within the past 3 months or until a previously elevated ALT level has returned to ≤ 1 x ULN.
• Prior use of conivaptan, somatostatin analogs (e.g., lanreotide, pasireotide, octreotide, etc.), metformin, nicotinamide, bardoxolone, venglustat, demeclocycline, or mammalian Target of Rapamycin (mTOR) kinase inhibitors (e.g., everolimus, sirolimus, etc.) to treat ADPKD within the past 3 months.
• Requirement for chronic diuretic use.
• Advanced diabetes (e.g., glycosylated hemoglobin [HgbA1c] > 7.5%, and/or glycosuria by dipstick, significant proteinuria [>300 mcg albumin/mg creatinine]), other significant renal disease, transplanted kidney, recent kidney surgery within the past 6 months (including cyst drainage or fenestration) or acute kidney injury within past 6 months.
• Clinically significant incontinence, overactive bladder, or urinary retention (e.g., benign prostatic hyperplasia).
• New York Heart Association Functional Class 3 or 4 heart failure or other significant cardiac or electrocardiogram (ECG) findings that could pose a safety risk to the subject.
• Clinically significant liver disease or impairment or active chronic hepatitis at Screening.
• Elevated baseline levels of serum ALT or total bilirubin.
• History of drug or alcohol abuse in the past 2 years.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 6/6/23. Questions regarding updates should be directed to the study team contact.

- Patients with atopic asthma (n= 20), based upon historic record of positive test for atopy (if available), or confirmed at screening by any positive test result from a panel of standard allergens including cat dander, dog dander, cockroach, dust mite, mold, and relevant local allergens, as determined through use of ImmunoCAP Specific IgE test, skin prick test, or radioallergosorbent test (RAST)

- Patients with non-atopic asthma (n=20), based upon historic record of negative test for atopy (if available), or confirmed at screening by negative test result across chosen atopy testing panel and no history or symptoms suggesting atopy

- No history of smoking or former smoker with smoking history of < 20 pack-years or equivalent history Smoking is defined as use of inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes). A former smoker is defined as someone with smoking history who has not used inhaled tobacco or cannabis products within 6 months prior to screening.

Inclusion Criteria for Patients with UCC (Part A):

- Patients with UCC must meet the following criteria for study entry:

- Diagnosis of UCC 

- No history of smoking or former smoker with smoking history of < 20 pack-years or equivalent history

- Smoking is defined as use of inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes).

- A former smoker is defined as someone with smoking history who has not used inhaled tobacco or cannabis products within 6 months prior to screening.

Inclusion Criteria for Patients with CRC COPD-CB or Patients with CRC COPD (Part B):

- Diagnosis of COPD GOLD I-II ± CB.

- Stable background treatment consisting of a bronchodilator medication and or stable
ICS therapy for ≥ 12 weeks prior to screening visit.

- Former smoker with ≥10 pack-years or equivalent history who has not used inhaled tobacco or cannabis products (e.g., cigarettes, cigars, electronic cigarettes, vaporizing devices, or pipes) within 6 months prior to screening

- Post-bronchodilator FEV1/ forced vital capacity (FVC) ratio ≤ 0.70 at screening.

- Chest X-ray or CT scan within 6 months prior to screening visit or during the screening period (prior to randomization [Study Visit 2]), that confirms the absence of clinically significant lung disease besides COPD.

Patients who meet any of the following criteria will be excluded from study entry:

-  Pregnant or breastfeeding, or intention of becoming pregnant during the study or within 28 days after the final dose of GDC-6599 Women of childbearing potential must have a negative serum pregnancy test result at screening and a negative urine pregnancy test within 1 day prior to initiation of study drug.

- History of diagnosed bleeding diathesis or easy bruising or bleeding (i.e., bruising or bleeding out of proportion to the degree of trauma).

- Post-bronchodilator FEV1/FVC ratio< 0.60 at screening (patients with CRC asthma and UCC only: Part A)

- Acute exacerbations of asthma or COPD within 8 weeks prior to screening

- Use of oral or systemic corticosteroids for the treatment of respiratory diseases, including cough, within 8 weeks prior to screening

- Continued, chronic use of oral or systemic corticosteroids for non-respiratory conditions is permitted, provided patient has been receiving a stable treatment regimen for at least 8 weeks prior to screening and, in the opinion of the investigator, is likely to remain on the stable treatment regimen through completion of the study.

- Use of anticoagulant or anti-platelet therapies within 2 weeks prior to screening

- Initiation of proton-pump inhibitor (PPI) therapy within 8 weeks prior to screening

- History of significant hepatic impairment, defined as Child-Pugh Class B or C, corresponding to a Child-Turcotte-Pugh Score ≥ 7

- History of aspiration pneumonia

- Respiratory infection (including upper respiratory infection), known COVID-19 infection, persistent symptoms of known prior COVID-19 infection, and/or known positive COVID-19 test within 8 weeks prior to screening and randomization COVID-19 testing is not required for participation in the study unless required by local regulations or institutional policies.

- Positive HIV antibody test at screening

- Positive hepatitis B surface antigen (HBsAg) at screening

- Positive hepatitis C virus (HCV) antibody test followed by a positive HCV RNA test at screening

- The HCV RNA test must be performed if a patient has a positive HCV antibody test at screening to determine if the patient has an HCV infection.

- Treatment with investigational therapy within 28 days or 5 drug-elimination half-lives (if known), whichever is longer, prior to initiation of study drug

- Treatment with any strong inhibitor or inducer of CYP3A within 28 days or 5 drug-elimination half-lives, whichever is longer, prior to initiation of study drug

- Need for ongoing treatment with strong CYP3A inhibitor or inducer during the study

- Treatment with any vaccine within 7 days prior to initiation of study drug or a scheduled vaccination during study period (through follow-up/early termination visit)

- Treatment with angiotensin-converting enzyme (ACE) inhibitor within 8 weeks prior to screening

- Treatment with opioids (including codeine), pregabalin, gabapentin, amitriptyline, or nortriptyline for the treatment of cough within 2 weeks prior to screening

- Treatment with any of these medications for indications other than chronic cough is permitted, provided the patient is receiving a stable treatment regimen for at least 2 weeks prior to screening and, in the opinion of the investigator, is likely to remain on the stable treatment regimen through completion of the study.

- Treatment with dextromethorphan, guaifenesin, benzonatate, and any other overthe-counter or prescription medication containing an anti-tussive or expectorant for the treatment of cough within 2 weeks prior to screening

- History of serious adverse reaction or serious hypersensitivity to any drug or the study drug formulation excipients

- Malabsorption syndrome or other condition that would interfere with enteral absorption

- Planned major surgical intervention that may require general anesthetic and/or hospital stay during the study

- Serious infection requiring oral or IV antibiotics within 14 days prior to screening or randomization

- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study

- History of malignancy within 5 years prior to screening, except for appropriately treated carcinoma in situ of the cervix or non-melanoma skin carcinoma

- Clinical laboratory value outside the reference range for the test laboratory at screening unless the value is deemed not clinically significant by the investigator. The Medical Monitor should be informed of the test result and the decision to include the patient in the study by investigator

- Any of the following clinical laboratory values at screening (even if not considered clinically significant):

– PT (INR) > upper limit of normal (ULN), PTT > ULN or platelet < lower limit of normal (LLN) – ALT or AST >ULN – Total bilirubin > ULN; patients with Gilbert syndrome may enroll provided total bilirubin ≤ 1.5× ULN and direct (conjugated) bilirubin is ≤ ULN

Eligibility last updated 12/29/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years old.
• ***Histologically documented Squamous Cell Carcinoma of the oropharynx (AJCC v7** Stage III-IV A,B).
• *Tumor tissue (primary or cervical metastasis) available for human papilloma virus (HPV) and/or p16 (in situ hybridization (ISH), immunohistochemistry (IHC) or genotyping testing).
• If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
• Eastern Cooperative Oncology Group (ECOG) performance status= 0, 1, or 2.
• Negative pregnancy test for women of child bearing potential.
• Concurrent chemotherapy.
• Bilateral neck radiation.

• Previous radiation treatment for head and neck mucosal primary cancers within the past 5 years (i.e., oropharynx, nasopharynx, hypopharynx, larynx, and oral cavity).
• Pregnant or breast-feeding females.
• Clinically significant uncontrolled major cardiac, respiratory, renal, hepatic, gastrointestinal or hematologic disease but not limited to:
  • Symptomatic congestive heart failure, unstable angina, or cardiac dysrrhythmia not controlled by pacer device;
  • No myocardial infarction within 3 months of registration.
• Distant metastases (AJCC v7** Stage IV C, any T, any N and M1).
• Previous surgical resection or neck dissection for oropharyngeal cancer, administered with therapeutic intent.

*    If you do not have enough leftover tumor tissue available, you will have a tumor biopsy for tumor marker testing.
**  American Joint Committee on Cancer (AJCC) 7th edition.
*** For clinically visible or radiographically diagnosed oropharynx cancer, neck mass biospy/US FNA is acceptable.