Unless specified otherwise, all eligibility criteria time-intervals are assessed with respect to the screening visit.

• Age 18 to 70 years.
• Living donor / deceased donor kidney transplant recipients ≥ 6 months from time of transplant.
• Diagnosis of CABMR determined by kidney biopsy and the presence of human leukocyte antigen (HLA) donor specific antibodies (DSA) using single-antigen bead-based assays.
  • NOTE: If conducted within 6 months (+ 3 weeks) of the start of the Screening Period, the biopsy and DSA analysis do not need to be repeated at Screening. To be considered for determination of study eligibility, the biopsy and DSA analysis must be performed and should occur at least 2 months ± 2 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR and presence of HLA DSA. In addition, treatments for ABMR or TCMR are not allowed within 3 months of the start of Screening. The following histopathologic and serologic diagnostic criteria (based on Banff 2015 criteria [Loupy et al, 2017]) must be met for inclusion:
    • Morphologic evidence of chronic tissue injury, as demonstrated by transplant glomerulopathy (TG) (cg > 0). Biopsies without evidence of chronic tissue injury on light microscopy, but with glomerular basement membrane double contours on electron microscopy (cg1a) are eligible;
    • Evidence of current/recent antibody interaction with vascular endothelium, including 1 or more of the following.
    • Linear complement component 4d (C4d) staining in peritubular capillaries or medullary vasa recta (C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 by immunohistochemistry on paraffin sections);
    • At least moderate microvascular inflammation ([g + ptc] ≥ 2) in the absence of recurrent or de novo glomerulonephritis, although in the presence of acute TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not sufficient; and must be ≥ 1.
  • NOTE: The local pathologist’s diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. Biopsies with other histopathologic changes (e.g., BKV nephropathy or recurrent glomerulonephritis) may be eligible if concurrent CABMR changes (as detailed above) are present and determined to be the predominant cause of renal dysfunction.
  • Serologic evidence of circulating HLA DSA. NOTE: The local laboratory DSA results must be reviewed and confirmed by the central HLA reviewer during the Screening Period.
• Written informed consent obtained from subject (or legally acceptable representative) before any trial-related procedures.

• Participant is unable or unwilling to comply with study procedures in the opinion of the investigator.
• Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient.
• Treatment for ABMR (including CABMR) or TCMR within 3 months of the start of Screening.
• Received T cell depleting agents (e.g., alemtuzumab, anti-thymocyte globulin) within 3 months of the start of Screening.
• Treatment with mTOR inhibitors within 4 weeks of the start of Screening.
• Biopsy indicating predominant cause of renal dysfunction caused by pathology other than CABMR.
• Impaired renal function due to disorders in the transplanted allograft (eg, renal artery stenosis, hydronephrosis).
• eGFR < 25 mL/min/1.73 m^2 or > 65 mL/min/1.73 m^2 (MDRD4).
• Nephrotic range proteinuria defined as spot urine albumin creatinine ratio (UACR) ≥ 2200 mg/g (≥ 220 mg/mmol). If spot UACR is above defined limits, a single repeat test can be performed on a separate day to confirm ineligibility.
• Pregnant, breastfeeding, or unwillingness to practice adequate contraception (eg, a highly effective or acceptable method of contraception) during the study and for 5 months after last dose of IP.
• History of anaphylaxis or known hypersensitivity to clazakizumab or to any constituent of the drug product.
• Abnormal liver function tests (LFTs [alanine aminotransferase (ALT) / aspartate aminotransferase (AST) / bilirubin > 1.5 x upper limit of normal]) or other significant liver disease.
• History of active tuberculosis (TB).
• History of latent TB (eg, positive QuantiFERON-TB test) without history of active TB unless subject has completed a full course of prophylactic treatment.
• History of human immunodeficiency virus (HIV) infection or positive for HIV.
• Seropositive for hepatitis B surface antigen (HBsAg).
• Hepatitis C virus (HCV) RNA positive.
• Known EBV mismatch (at time of transplant): donor seropositive, recipient seronegative.
• History of gastrointestinal (GI) perforation; diverticular disease defined as clinically significant diverticulosis (except if disease has been fully excised) or diverticulitis (except if disease has been fully excised); or inflammatory bowel disease (except fully excised ulcerative colitis).
• Neutropenia (< 1000/mm^3 ) or thrombocytopenia (< 50,000/mm^3 ).
• Active infections requiring systemic antimicrobial agents and unresolved prior to Screening.
• History of or current invasive fungal infection or other opportunistic infection, including (but not limited to) the following: a nontuberculous mycobacterial infection, aspergillosis, pneumocystosis, and toxoplasmosis.
• Active viral infections such as BKV, CMV, or EBV based on polymerase chain reaction (PCR) testing. Active infection is defined as a test result ≥ lower limit of quantification (LLOQ).
• Current or recent (within 3 months) participation in an interventional trial.
• Administration of a live vaccine within 6 weeks of the start of screening, including but not limited to the following:
  • Adenovirus;
  • Measles, mumps, and rubella;
  • Oral polio;
  • Oral typhoid;
  • Rotavirus;
  • Varicella zoster;
  • Yellow fever.
• History of alcohol or illicit substance (including marijuana) abuse.
• Present or previous (within 3 years) malignancy except for basal cell carcinoma, fully excised squamous cell carcinoma of the skin, or nonrecurrent (within 5 years) cervical carcinoma in-situ.
• Presence of a condition or abnormality (i.e., clinically significant endocrine, autoimmune, metabolic, neurological, psychiatric / psychological, renal, GI, hepatic, and hematological or any other system abnormalities that are uncontrolled with standard treatment) that in the opinion of the investigator would compromise the safety or life expectancy of the patient or the quality of the data.
• History of intolerance to trimethoprim and / or sulfamethoxazole. This criterion does not apply if subject is already taking another suitable investigator-approved alternative for PJP prophylaxis, or if subject is willing to begin taking an investigator-approved alternative prophylactic therapy at least 1 week prior to the Day 1 Baseline Visit (Visit 2).
• Prior exposure to clazakizumab, TCZ, or other IL-6 / IL-6R blockers.
• ABO-incompatible transplant recipient.
• Severe hypogammaglobulinemia (defined as immunoglobulin G (IgG) < 400 mg/dL).
• Prior (within 2 years of the start of Screening) exposure to proteasome inhibitors (e.g., bortezomib).
• Active infection with coronavirus disease 2019 (COVID-19):
  • Subject not known to have been previously infected with COVID-19 must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible. If subject is unwell with symptoms suggestive of COVID 19 disease but PCR test is negative, other causes for symptoms must be ruled out to determine subject eligibility;
  • Subject known to have been previously infected with COVID-19 must meet all the following conditions:
  • Must be without symptoms attributable to COVID-19 for at least 1 month before the start of screening and have had 2 consecutive negative PCR tests at least 24 hours apart (either prior to or during screening) to confirm recovery. If the subject has tested negative > 3 months before start of screening, the subject must have a negative PCR test during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible;
  • Must be re-established on background immunosuppressants for at least 2 weeks prior to the start of Screening.

• Subjects scheduled to elective and/or urgent median sternotomy for cardiac surgery, who are preoperative hemodynamically stable. 
• Males and females. 
• Subjects of age 18 years and older. 
• Subjects with both Diabetes Mellitus AND BMI ≥ 30 OR Diabetes Mellitus/BMI ≥ 30 AND at least one of the following: 
  • Current/Previous smoking history ≥ 30 pack year;
  • Chronic Obstructive Pulmonary Disease (COPD).
• Female of childbearing potential should have a negative serum pregnancy test prior to index procedure.
  • Note: All female of childbearing potential must agree to use a highly effective method of contraception (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide) consistently and correctly for the duration of the study. 
• Subject is willing and able to provide a signed Informed Consent Form and is willing and able to comply with study's procedures including follow-up visits.

• Subjects undergoing partial sternotomy. 
• Subjects with any preoperative active significant infection. 
• Subjects that received oral or IV doxycycline during the last 4 weeks prior to screening. 
• Subjects with sensitivity to doxycycline and/or to tetracycline family of drugs and/or other study drug ingredients. 
• Subjects with known allergies to more than 3 substances (an allergy questionnaire will be filled during the screening process). 
• Subjects with history of allergic/hypersensitivity reaction to any substance having required hospitalization and/or treatment with intra-venous steroids/epinephrine or in the opinion of the investigator the patient is at high risk of developing severe allergic/hypersensitivity reactions. 
• Subjects with uncontrolled Asthma (GINA III-IV). 
• Subjects with chronic urticaria. 
• Immunocompromised subjects from any reason, at screening. 
• Subjects with renal failure requiring dialysis. 
• Subjects scheduled to major organ transplantation and/or to other significant concomitant surgical procedure. 
• Subjects scheduled for mechanical assist device. 
• Subjects scheduled to be treated with preventive negative pressure devices.
• Subjects undergone Cerebro-Vascular Accident (CVA)/Transient Ischemic Attack (TIA) within the past 3 months prior to randomization. 
• Subjects that have undergone previously, any cardiac surgery through sternotomy. 
• Subjects with active or previous malignancy in the chest area. 
• Any subject with active malignancy or with malignancy that has not been in complete remission for at least 5 years. Subjects who have had carcinoma in situ of the cervix, squamous cell carcinoma of the skin and basal cell carcinoma of the skin, are eligible. 
• Pregnant or breast-feeding women or women of childbearing age not protected by an effective contraceptive method of birth control (such as double barrier, oral or parenteral hormonal, intrauterine device and spermicide). 
• Subjects enrolled in any intervention study with an investigational medicinal product and/or received any investigational medicinal product within 30 days or 5½ half-lives of the product prior to enrollment (whichever is longer). 
• In the opinion of investigator, subject is not eligible to participate in the study and/or to comply with protocol requirements (e.g., due to a cognitive, medical condition or residency distanced from site that may jeopardize Follow-Up visits attendance etc.).

All Subjects

• Presence of thoracic aortic pathology deemed to warrant surgical repair which requires proximal graft placement in Zone 0-2:
  • Aneurysms:
    • Fusiform aneurysm (≥ 55 mm); or
    • Fusiform aneurysm (> 2 times native aortic diameter); or
    • Saccular aneurysm (no diameter criteria).
  • Non-aneurysms
    • Intramural hematoma (no diameter criteria); or
    • Penetrating aortic ulcer (no diameter criteria); or
    • Traumatic aortic transection (no diameter criteria); or
    • Other isolated lesion with non-diseased proximal and distal landing zone, or Type B aortic dissection requiring treatment for rupture or impending rupture, malperfusion syndrome, rapid expansion, uncontrollable pain, aneurysmal dilatation or prophylactic reasons; or
    • Residual aortic dissection following surgical repair of Type A aortic dissection requiring treatment. TBE implant must be at least 14 days after the surgical repair procedure.
• Age ≥ 18 years at time of informed consent signature.
• Subject is capable of complying with protocol requirements, including follow-up.
• Informed Consent Form (ICF) is signed by Subject or legal representative.
• Must have appropriate proximal aortic landing zone, defined as:
  • Requires placement of the proximal extent of the Aortic Component in Zone 0-2 for exclusion of the lesion.
  • Acceptable proximal landing zone outer curvature length for the required device.
  • Landing zone inner diameters between 16-48 mm in Zone 1-2 Subjects and 24-48 mm in Zone 0 Subjects.
  • Landing zone includes either the brachiocephalic, left common carotid or left subclavian native ostium.
    • If the landing zone includes brachiocephalic it cannot be heavily calcified or heavily thrombosed;
    • If the landing zone includes either the left common carotid or left subclavian it cannot be heavily calcified, heavily thrombosed or aneurysmal.
  • Dissection Patients: Primary entry tear must be distal to the target branch vessel and proximal extent of the proximal landing zone must not be dissected.
  • For patients with prior replacement of the ascending aorta and/or aortic arch by a surgical graft, there must be at least 2 cm of landing zone proximal to the most distal anastomosis site.
• Must have appropriate target branch vessel landing zone, defined as:
  • Length of ≥ 3 cm proximal to first major branch vessel if using Aortic Component with 8 mm portal diameter; or
  • Length of ≥ 2.5 cm proximal to first major branch vessel if using Aortic Component with 12 mm portal diameter (required for Zone 0 Subjects);
  • Target branch vessel inner diameters of 6-15 mm if using Aortic Component with 8 mm portal diameter; or
  • Inner diameters of 11-18 mm if using Aortic Component with 12 mm portal diameter (required for Zone 0 Subjects);
  • Target branch vessel landing zone must be in native aorta that cannot be severely tortuous (i.e., vessel tortuosity that results in a 180 degree turn within the treated target branch vessel length), aneurysmal, dissected, heavily calcified, or heavily thrombosed.
• For patients with aneurysm/isolated lesion, must have appropriate distal aortic landing zone, defined as:
  • Outer curvature length must be ≥ 2 cm proximal to the celiac artery;
  • Aortic inner diameters between 16-48 mm (diameter should be between 16-42 mm if using distal CTAG Device extension);
  • Landing zone cannot be aneurysmal, heavily calcified, or heavily thrombosed;
  • Landing zone in native aorta or previously implanted Conformable GORE® TAG® Device.

Zone 0/1 Subjects Only

• Subject does not have a mechanical aortic valve.
• Subject is considered a high risk candidate for conventional open surgical repair at the discretion of the Investigator.

All Subjects

• Concomitant disease of the ascending aorta or  aneurysm of the abdominal aorta requiring repair.
• Previous endovascular repair of the ascending aorta.
• Previous endovascular repair of the DTA with a non-Gore device.
• Surgery within 30 days prior to enrollment with the exception of:
  • Surgery for Ascending Aortic Dissection and/or placement of vascular conduit for access;
  • Surgery to treat any other presenting injuries in Traumatic Transection subjects only.
• Infected aorta.
• Life expectancy < 2 years.
• Myocardial infarction within 6 weeks prior to treatment.
• Stroke within 6 weeks prior to treatment, stroke defined as rapidly developing clinical signs of focal (or global) disturbance of cerebral function, lasting more than 24 hours or leading to death, with no apparent cause other than that of vascular origin.
• Patient has an active systemic infection (e.g. infection requiring treatment with parenteral anti-infective medication) that may place the patient at increased risk of endovascular infection. Patients with a chronic infection (such as HIV, Hepatitis C, etc.) that is well controlled under their current treatment regimen may be eligible.
• Pregnant female at time of informed consent signature.
• Degenerative connective tissue disease; e.g., Marfan’s or Ehler-Danlos Syndrome.
• Participation in another drug or medical device study within one year of study enrollment.
• Known history of drug abuse within one year of treatment.
• Presence of protruding and/or irregular thrombus and/or atheroma in the aortic arch or ascending aorta.
• Tortuous or stenotic iliac and/or femoral arteries preventing introducer sheath insertion and the inability to use a conduit for vascular access.
• Planned coverage of celiac artery.
• Patient has known sensitivities or allergies to the device materials.
• Patient has known hypersensitivity or contraindication to anticoagulants or contrast media, which is not amenable to pre-treatment.
• Previous instance of Heparin Induced Thrombocytopenia type 2 (HIT-2) or known hypersensitivity to heparin.
• Patient with a history of a hypercoagulability disorder and/or hypercoagulability state.
• Diameter taper outside of the device sizing range between proximal and distal landing zones of aorta and the inability to use additional devices of different diameters to compensate for the taper.
• Mycotic aneurysm.
• Persistent refractory shock (systolic blood pressure < 90 mm Hg).
• Patient has body habitus or other medical condition which prevents adequate visualization of the aorta.
• Renal failure defined as patients with an estimated Glomerular Filtration Rate (eGFR) < 30 (ml/min/1.73 m2) or currently requiring dialysis.

Zone 0/1 Subjects Only

• Patient at high risk for a neurological event; e.g., stroke.

Zone 0/1 Subjects Only:  

• Treatment-naïve or relapsed/refractory CLL patients undergoing CLL antineoplastic treatment. Diagnosis of B-cell CLL established according to International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria and documented within medical records.
• Hypogammaglobulinemia (IgG levels < 5 g/L) as confirmed by the Central Laboratory.
• ≥ 18 years of age.
• Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted.

• IgG treatment within 3 months prior to Screening.
• Antibiotic prophylaxis and/or treatment within 7 days prior to Baseline (with the exception of trimethoprim-sulfamethoxazole [TMP/SMX], diaminodiphenyl sulfone [dapsone] and pentamidine inhalation).
• Current major infection or > 1 major infection in the previous 6 months before Baseline.
• History of anaphylaxis or severe systemic response to immunoglobulin, blood or plasma-derived products or any Panzyga component.
• History of a non-CLL malignancy or other medical condition with life-expectancy of less than two years.
• Severe liver disease, with signs of ascites and/or hepatic encephalopathy.
• Severe kidney disease (as defined by estimated glomerular filtration rate [eGFR] 140 kg.
• Eastern Cooperative Oncology Group (ECOG) performance score of > 2.
• Female patients of childbearing potential unwilling to use a protocol-required method of contraception from the Screening Visit throughout the study treatment period and for 30 days following the last dose of study drug.
• Human immunodeficiency virus (HIV) infection at Screening (defined for the study as positive HIV antibody test).
• Patients found to be chronic carriers of hepatitis B virus (HBV), defined by positive surface antigen (HBsAg), positive Hepatitis B core antibodies (HBcAb) and/or low HBV titers, who will not receive targeted antiviral therapy while undergoing CLL therapy, and patients with active HBV, defined as high HBV titers.
• Uncontrolled hepatitis C infection at Screening (defined for the study as positive hepatitis virus C [HCV] polymerase chain reaction [PCR]).
• Pregnant and lactating women.
• Subjects with a history of thromboembolic events (TEE) such as deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, transient ischemic attack, peripheral artery disease (Fontaine IV) within 6 months before Baseline.
• Planned or ongoing immunosuppressive treatment (other than for CLL or corticosteroids) or other forbidden medication during the entire study duration after study enrollment.
• Participation in another interventional clinical trial that is either blinded or involves an investigational (not approved) product within 3 months before Baseline or during the course of the clinical study. Participation in observational clinical trials or open-label trials involving an approved product may be permitted after consultation with the medical monitor.

Eligibility last updated 3/18/22. Questions regarding updates should be directed to the study team contact.

• Documented diagnosis of relapsed/refractory multiple myeloma (MM) with measurable disease (serum, urine, or free light chain [FLC]) per International Myeloma Working Group (IMWG) criteria.
• At least 3 prior lines of MM therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody (unless contraindicated), and refractory to the last treatment line.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1.
• Absence of donor (product)-specific anti-HLA antibodies.
• Adequate hematologic, renal, hepatic, pulmonary, and cardiac function.

• Current or history of Central Nervous System (CNS) involvement of myeloma or plasma cell leukemia.
• Clinically significant CNS disorder.
• Current or history of thyroid disorder.
• Autologous stem cell transplant within the last 6 weeks, or any allogeneic stem cell transplant.
• Prior treatment with anti-BCMA therapy, any gene therapy, any genetically modified cell therapy, or adoptive T cell therapy.
• History of HIV infection or acute or chronic active hepatitis B or C infection.
• Patients unwilling to participate in an extended safety monitoring period.

Additional Exclusion Criteria for Nirogacestat plus ALLO-715 Cohorts:

• Inability to swallow tablets.
• Subject has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat.
• Use of strong/moderate CYP3A4 inhibitors, and strong CYP3A4 inducers within 14 days before starting nirogacestat.
• Use of concomitant medications that are known to prolong the QT/QTcF interval.

Eligibility last updated 3/24/22. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.

• Age ≥ 18 years.
• Women with an initial pathologically confirmed diagnosis of stage I-III, hormone receptor positive, HER2-neu negative, invasive breast cancer within 18 months prior to enrollment.
• Women who have undergone neo-adjuvant chemotherapy who have no residual invasive disease post-surgery are eligible based on an initial pathologically confirmed diagnosis.
• Hormone receptor positive is defined as estrogen receptor (ER) and/or progesterone receptor (PR) of > 1%.
• HER2-neu negative is defined as 0-1+ by immunohistochemical (IHC) analysis, or non-amplified by fluorescence in situ hybridization (FISH) analysis.
• Patients must have received cancer-directed surgery, and/or completed all other adjuvant therapy, except reconstruction.
• Patients must have initiated an endocrine therapy drug within the 6 months prior to registration, OR have received a prescription with stated intent to initiate within 6 weeks after registration.
• No history of previous cancer as follows:
  • Invasive or non-invasive breast cancer at any time.
  • Non-breast cancer, within the past 5 years, excluding non-melanoma skin cancer.
• Patients must be willing to use a smart phone for study activities.
• Patient is NOT to be deemed ineligible during the recruitment process if they do not have a smart phone.
• If a participant does not own a smart phone or has limited data or texting capabilities or their smart phone cannot support the Alliance electronic patient reported outcomes (ePRO) survey application (app), a smart phone and service can be provided to the participant at no cost through the Ohio State University (OSU) partnership with Verizon Wireless for the duration of the study activities.
• The CRP is ONLY to discuss this option with those patients who self-identify a phone-related barrier to participation, including: lack of a smart phone, insufficient phone plan (minutes/text/data), or a smart phone incompatible with the Alliance ePRO app.
• For OSU provided phones, charges will be paid by the grant through the intervention period. At the end of the 12-month intervention period, patients will be responsible for paying monthly fees, if continued service is desired. The physical phones will belong to the patients at the end of their study activities.
• Patients must be willing to use a Pillsy medication event monitoring system for the duration of study participation.
• In order to complete the mandatory patient-completed measures, participants must be able to speak and read English.

• Adult females enrolled in the Mayo Clinic Biospecimen Resource for Breast Disease (IRB # 1815-04).
• Current ages 18-75 years.
• Have a prior diagnosis of stage 0-3 (in situ or invasive) breast cancer (BCS).
• Have completed active therapy (surgery, radiation, and/or chemotherapy) (8-30  months approximately) prior to provision of the samples).
• Age-matched females with no history of cancer (other than non-melanoma skin cancer) may be selected from the PRISM Study (IRB #18-002366 The Predicting Risk after Screening Mammogram (PRISM) Study) or the Mayo Clinic Breast Mammography practice.

• Male biological sex or gender.
• Pregnant females (insufficient #s, skewed estrogen levels).
• Unwilling to travel to Mayo Clinic Rochester to provide the blood and urine samples.

• Confirmed diagnosis of CD for at least 3 months prior to Baseline. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the investigator, must be available.
• SES-CD (excluding the presence of narrowing component) ≥ 6 (or ≥ 4 for subjects with isolated ileal disease), as confirmed by a central reader.
• Average daily liquid/very soft SF ≥ 4.0 AND/OR average daily AP score ≥ 2.0 at Baseline.
• Demonstrated an inadequate response or intolerance to one or more conventional and/or biologic therapies, in the opinion of the investigator, as defined below:
  • Oral locally acting steroids
  • Signs and symptoms of persistently active disease during or after a course of at least 4 weeks of treatment with 9 mg/day budesonide or 5 mg/day beclomethasone; OR
  • Inability to taper oral budesonide at or below 6 mg/day without recurrent active disease; OR
  • Intravenous or oral corticosteroids
  • Signs and symptoms of persistently active disease despite a history of at least one induction regimen consisting of a dose equivalent to prednisone (or equivalent) ≥ 40 mg/day orally for at least 3 weeks or intravenously for 1 week; OR
  • Inability to taper corticosteroids at or below a dose equivalent to prednisone 10 mg/day without recurrent active disease; OR
  • Immunosuppressants
  • Signs and symptoms of persistently active disease despite a history of at least one 12 weeks regimen of the following:
    • AZA: ≥ 2.0 mg/kg/day (≥ 1 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, OR a documented 6-thioguanine nucleotide (6-TGN) level of > 235 pmol/8 × 108 RBC at a dose < 2 mg/kg/day OR documentation that a dose reduction was required due to elevated 6-MP levels (> 5700 pmol/8 ×108  erythrocytes); OR
    • 6-MP: ≥ 1 mg/kg/day (≥ 0.6 mg/kg/day for subjects in Japan, Korea, Taiwan, Singapore, Hong Kong, or China), rounded to the nearest available tablet or half tablet formulation, (or a 6-TGN level of > 235 pmol/8 ×  108 RBC); OR
    • MTX (≥25 mg/week subcutaneous [SC] or intramuscular); OR
    • Tacrolimus (for subjects in Australia, Japan or Taiwan only): documented trough level of ≥5 ng/mL.
    • Note: Oral MTX use is allowed during the study, however prior or current use of oral MTX is not sufficient for inclusion into the study.
  • Biologic therapies for CD
    • At least one 6-week induction regimen of infliximab (≥5 mg/kg intravenous [IV] at Baseline and Weeks 2, and 6); OR
    • At least one 4-week induction regimen of adalimumab (one 160 mg subcutaneous [SC] dose at Baseline, followed by one 80 mg SC dose at Week 2 [or one 80 mg SC dose at Baseline, followed by one 40 mg SC dose at Week 2, in countries where this dosing regimen is approved]); OR
    • At least one 4-week induction regimen of certolizumab pegol (400 mg SC at Baseline and Weeks 2, and 4); OR
    • At least one 6-week induction regimen of vedolizumab (300 mg IV at Baseline and Weeks 2, and 6); OR
    • At least one 8-week induction regimen of ustekinumab [260 mg (≤55 kg) or 390 mg (> 55 to ≤85 kg) or 520 mg (> 85 kg) IV, followed by 90 mg SC at Week 8]; OR
    • Recurrence of symptoms during scheduled maintenance dosing following prior clinical benefit of the above biologics.
    • Intolerance to corticosteroids may include depression, severe insomnia, osteopenia, cushingoid features, etc. Intolerance to AZA/6-MP should include elevations of liver enzymes, pancreatitis, etc., and may include subjects with known thiopurine methyltransferase (TPMT) genetic mutation or low activity. Intolerance to a biologic may include, but not be limited to infusion-related reaction, rash, serum sickness, anaphylaxis,  elevated liver enzymes, demyelination, congestive heart failure, infection, etc. Demonstration of intolerance requires no minimum dose or duration of use.
    • Note: Non-bio-IR subjects who have received prior biologic for up to 1 year but have not failed may be enrolled; however, subjects must have discontinued the biologic for reasons other than  inadequate response or intolerance (e.g., change of insurance, well controlled disease), and must meet the criteria for intolerance or inadequate response to oral locally acting steroids, systemic steroids (prednisone or equivalent), and/or immunosuppressants as defined above.

• Subject on CD-related antibiotics who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on oral aminosalicylates who:
  • has not been on stable doses of these medications for at least 14 days prior to Baseline, or
  • has discontinued these medications within 14 days of Baseline.
• Subject on corticosteroids who meets the following:
  • prednisone or equivalent dose > 30 mg/day; or
  • budesonide > 9 mg/day; or
  • has not been on the current course for at least 14 days prior to Baseline and on a stable dose for at least 7 days prior to Baseline.
• Subject on MTX who:
  • has not been on the current course for ≥ 42 days prior to Baseline, and
  • has not been on a stable dose for ≥ 28 days prior to Baseline;
• Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral/intramuscular (IM) anti-infectives within 14 days prior to the Baseline Visit
• Subject requiring or receiving any parenteral nutrition and/or exclusive enteral nutrition.
• Subject who received oral or parenteral traditional Chinese medicines within 30 days prior to Baseline.
• Subject who received any live vaccination within 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) prior to Baseline, or who is expected to need live vaccination during study participation including at least 30 days (or longer, if required locally [e.g., 8 weeks for Japan]) after the last dose of study drug. 
• Subject who received cyclosporine, tacrolimus, mycophenolate mofetil, or thalidomide within 30 days prior to Baseline.
• Subject who received azathioprine (AZA) or 6-mercaptopurine (6-MP) within 10 days of Baseline.
• Subject who received fecal microbial transplantation within 30 days prior to Baseline.
• Subject who received nonsteroidal anti-inflammatory drugs (NSAIDs) within 7 days prior to Baseline, except topical NSAIDs and low dose aspirin for cardiovascular protection. 
• Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong CYP3A inducers from Screening through the end of the study (refer to Table 1 for examples of commonly used strong CYP3A inhibitors and inducers).
• Subject who received any of the following agents:
  • adalimumab, certolizumab, golimumab, infliximab, natalizumab, vedolizumab, within 8 weeks prior to Baseline; or 
  • ustekinumab within 12 weeks prior to Baseline;
  • Note: If there is proper documentation of an undetectable drug level measured by a commercially available assay for any of the approved biologics above, there is no minimum washout prior to Baseline.
• Any investigational agent within 30 days or 5 half-lives prior to Baseline, whichever is longer, or is currently enrolled in another interventional study.
• Subject with previous exposure to a JAK inhibitor (e.g., tofacitinib, baricitinib, filgotinib) within 30 days from Baseline.
  • Note: Subjects who received a JAK inhibitor prior to study entry may be enrolled if they have not had inadequate response or loss of response.
•  Subject has been taking both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent) simultaneously, with the exception of topical or inhalers within 14 days prior to Screening or during the Screening Period.
• Subject received IV corticosteroids within 14 days prior to Screening or during the Screening Period.
• Subject has received therapeutic enema or suppository (i.e., rectal aminosalicylates/corticosteroids), other than required for endoscopy, within 14 days prior to endoscopy used for Screening or during the Screening period.
• Subject who received apheresis (e.g., Adacolumn apheresis) within 60 days prior to Screening or during the Screening Period. 
• Subject has cannabis use either recreational or for medical reasons within 14 days prior to Baseline or any history of clinically significant (per investigator's judgment) drug or alcohol abuse in the last 6 months.
• Subject who previously received stem cell transplantation except for local stem cell therapy for complex perianal fistula.
• Subject has been a previous recipient of an organ transplant which requires continued immunosuppression.
• Subject with the following ongoing known complications of CD:
  • abscess (abdominal or peri-anal);
  • symptomatic bowel strictures;
  • > 2 entire missing segments of the following 5 segments: terminal ileum, right colon, transverse colon, sigmoid and left colon, and rectum;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure;
  • fulminant colitis,
  • toxic megacolon;
  • or any other manifestation that might require surgery while enrolled in the study;
  • Subject with ostomy or ileoanal pouch;
  • Subject diagnosed with conditions that could interfere with drug absorption including but not limited to short gut or short bowel syndrome; 
  • Subject with surgical bowel resection within the past 3 months prior to Baseline, or a history of > 3 bowel resections.
  • Subject with positive Clostridium difficile (C. difficile) toxin stool assay during Screening. 
• Any active, chronic or recurrent infection that, based on the investigator's clinical assessment, makes the subject an unsuitable candidate for the study, including hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated (even a single episode) herpes zoster, disseminated (even a single episode) herpes simplex, or HIV infection. Active HBV, HCV and HIV are defined as:
  • HBV: hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) qualitative test for hepatitis B core antibody (HBc Ab) positive (+) subjects;
• HCV: HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV antibody (HCV Ab); 
  • HIV: confirmed positive anti-HIV antibody (HIV Ab) test;
  • Confirmed COVID-19: the Baseline visit must be at least 14 days from onset of signs/symptoms or positive SARS-CoV-2 test, symptomatic subjects must have recovered, defined as resolution of fever without use of anti-pyretics and improvement in symptoms;
  • Suspected COVID-19: subjects with signs/symptoms suggestive of COVID-19, known exposure, or high risk behavior should undergo molecular (e.g., PCR) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a potential exposure.
  • Subject has active TB or meets TB exclusionary parameters. 
  • History of any malignancy except for successfully treated nonmelanoma skin cancer (NMSC) or localized carcinoma in situ of the cervix.
  • Prior or current gastrointestinal dysplasia, other than completely removed low-grade dysplastic lesions in any biopsy performed during or before the Screening endoscopy.
  • History of gastrointestinal perforation (other than appendicitis or mechanical injury), diverticulitis or significantly increased risk for gastrointestinal perforation per investigator judgment.
  • Female who is pregnant, breastfeeding, or is considering becoming pregnant during the study or within 30 days after the last dose of study drug.
  • History of an allergic reaction or significant sensitivity to constituents of the study drug (and its excipients) and/or other products in the same.
  • Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug:
    • Serum AST or ALT > 2.0 × upper limit of normal (ULN); 
    • Total WBC count < 2500/µL;
    • Estimated glomerular filtration rate (eGFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 30 mL/min/1.73 m^2;
    • Hemoglobin < 9 g/dL;
    • Platelet count < 100,000/µL; 
    • Absolute neutrophil count (ANC) < 1200/µL;
    •  Absolute lymphocyte count (ALC) < 750/µL. 37. Any of the following cardiovascular conditions or thrombotic conditions:
    • recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary stenting;
    • current uncontrolled hypertension as defined by a confirmed systolic blood pressure (BP) > 160 mmHg or diastolic BP > 100 mmHg;
    • prior history of thrombotic events including deep venous thrombosis and pulmonary embolism;
    • known inherited conditions that predispose to hypercoagulability. 
• History of clinically significant medical conditions or any other reason that in the opinion of the investigator would interfere with the subject's participation in this study or would make the subject an unsuitable candidate to receive study drug or would put the subject at risk by participating in the study.
• For Japan subjects only: positive result of beta-D-glucan or 2 consecutive indeterminate results of beta-D-glucan during the Screening Period.

• Men or women between 18 and 65 years of age at the time of informed consent (IC).
• Have an EoE diagnosis prior to screening and histologically active disease with an esophageal peak eosinophil count (PEC) of ≥ 15 eosinophils (eos)/high power field (hpf) (~ 60 eos/mm^2 ) from any level (proximal, mid, or distal) of the esophagus at the Screening esophagogastroduodenoscopy (EGD).
• Have dysphagia, defined as solid food going down slowly or getting stuck in the throat with an average frequency of ≥ 2 episodes per week over 2 weeks (as documented using the Dysphagia Symptom Questionnaire (DSQ) during the Screening period).

• History of any of the following non-EoE conditions or procedures that may interfere with the evaluation of or affect the histologic, endoscopic, or symptom endpoints of the study:
  • Conditions that cause or potentially contribute to esophageal eosinophilia (eg, eosinophilic gastritis [EG], gastroenteritis, or colitis with esophageal involvement, severe gastroesophageal reflux disease [GERD], achalasia and other disorders of esophageal dysmotility, hypereosinophilic syndrome, Crohn’s disease [CD] with esophageal involvement, esophageal infection [fungal, viral], connective tissue diseases, hypermobility syndromes, autoimmune disorders and vasculitides, dermatologic conditions with esophageal involvement [ie, pemphigus], drug hypersensitivity reactions, pill esophagitis, graft versus host disease, Mendelian disorders [e.g., Marfan syndrome Type II, hyper-immunoglobulin E (IgE) syndrome, phosphatase and tensin homolog hamartoma tumor syndrome, Netherton syndrome, severe atopy metabolic wasting syndrome]);
  • Conditions that interfere with the evaluation of the esophagus (e.g., esophageal varices with risk of spontaneous bleed, high-grade esophageal stenosis where an 8- to 10-mm endoscope could not pass through the stricture without dilation at the time of Screening EGD);
  • Conditions or procedures that cause or potentially contribute to dysphagia (e.g., Barrett’s esophagus, erosive esophagitis Los Angeles Grade B or above, significant hiatal hernia [≥ 4 cm], esophageal resection, fundoplication, gastric sleeve surgery).
• Undergone dilation of an esophageal stricture within 12 weeks prior to Screening EGD.
• Use of corticosteroids for the treatment of EoE within 8 weeks prior to Screening EGD.
• Discontinue, initiate, or change dosing (dosage/frequency) of the following therapies for EoE within 8 weeks prior to Screening EGD. Subjects on any of the following therapy need to stay on a stable regimen during study participation:
  • Elemental diet;
  • EoE food trigger elimination diet;
  • PPI therapy.
• Used any immunotherapy/desensitization including oral immunotherapy (OIT) or sublingual immunotherapy (SLIT) within 12 months prior to the Screening EGD Note: Stable (i.e., ≥ 6 months prior to the Screening EGD) subcutaneous immunotherapy (SCIT) is permitted. Subjects on SCIT need to stay on a stable treatment during study participation.
• Used any of the following immunomodulatory therapies within the timeframes prior to Baseline as indicated below. The Medical Monitor should be consulted with any questions related to prior use of unlisted immunomodulatory therapies.

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

• Urine protein to creatinine ratio of ≥ 3.0 g/g (as measured from a 24 hour urine collection).
• Active anti-PLA2R antibody positive MN in need for immunosuppressive therapy (IST) according to investigator judgement and diagnosed on the basis of a biopsy, archival biopsy acquired within 5 years prior to screening is acceptable.
• Estimated glomerular filtration rate ≥ 50 ml/min/1.73m² or >30 and < 50 ml/min/1.73m², and interstitial fibrosis and tubular atrophy score of less than 25% on a renal biopsy obtained within the last 6 months prior to start of screening.
• on supportive treatment with an Angiotensin Converting Enzyme Inhibitor or an Angiotensin II Receptor Blocker for at least 4 weeks prior to Screening, having reached a stable dose.
• Systolic BP ≤ 150 mmHg and diastolic BP ≤ 100 mmHg -Vaccinated against Pneumococcus within the last 3 years prior to date of signing informed consent (subjects may be vaccinated during screening to meet this criterion; interval to first dose of MOR202 must be at least 14 days).
• Cohort 1a (newly diagnosed patients):
  • Serum anti-PLA2R antibodies ≥ 150.0 Response Units(RU)/mL determined at screening by Euroimmun ELISA.
• Cohort 1b, relapse subjects:
  • Must have had complete immunological and/or clinical remission according to judgement of the investigator and serum anti-PLA2R antibodies ≥ 50.0 RU/mL determined at screening by Euroimmun ELISA.
• Cohort 2:
  • Failure of previous therapy; i.e., subject never achieved a complete immunological and/or clinical remission according to judgement of the investigator. during or after completion of a recognized IST containing cyclosporine A, tacrolimus, mycophenolate-mofetil, ACTH or alkylating agents (e.g., cyclophosphamide), or rituximab. Serum anti-PLA2R antibodies ≥ 20.0 RU/mL determined at screening by the Euroimmun ELISA.

• Hemoglobin < 90 g/L.
• Thrombocytopenia: Platelets < 100.0x10^9/L.
• Neutropenia: Neutrophils < 1.5x10^9/L.
• Leukopenia: Leukocytes < 3.0x10^9/L.
• Hypogammaglobulinemia: Serum immunoglobulins ≤ 5.0 g/L.
• Secondary cause of MN (e.g., Systemic lupus erythematosus, medications, malignancies). 
• Concomitant renal disease other than MN (e.g., diabetic renal disease, lupus nephritis, IgA nephropathy).

• Age 18 years or older.
• Dysplastic BE (either low or high grade) or BE-related intramucosal EAC on initial diagnosis successfully treated with endoscopic therapy with negative surveillance endoscopy for at least one year from endoscopic therapy.
• Dysplastic BE (either low or high grade) or BE-related intramucosal EAC on initial diagnosis successfully treated with initial endoscopic therapy with remission across two subsequent surveillance endoscopies but evidence of recurrence of intestinal metaplasia, dysplasia, or EAC by the third surveillance endoscopy.
• Tolerance of endoscopy.
• Ability to give informed consent.

• Age < 18 years old.
• Pregnancy.
• Prior gastric surgery.
• Use of any bile acid sequestrants (cholestyramine, colestipol, and colesevelam) at the time of enrollment.
• Evidence of biliary obstruction or cholestasis due to any reason, defined as total bilirubin above the upper limit of normal, alkaline phosphatase above the upper limit of normal, and/or clinical evidence of jaundice.
• Active esophagitis or stricture precluding passage of endoscope and completion of endoscopic procedure.
• Coagulopathy, defined as INR > 1.5 or platelet level 50,000 precluding completion of endoscopic procedure.

• Seizure refractory to at least three standard antiepileptic medications at adequate doses, failed for lack of effectiveness. This may include a rescue medication designated use as PRN.
• A minimum of 3 seizures per month for 2 months by patient diary started at intake interview.
• Subjects should have partial-onset seizures with or without secondary generalization.
• Subjects should have evidence suggesting the target lesion is the source of seizures by standard clinical criteria including at least the description of seizures, physical examination, neuroimaging, and video EEG monitoring capturing at least one seizure.
• Subjects must be taking 2 medications during the Baseline period and the dosage must be stable.
• A diagnosis of intractable epilepsy secondary to a dysplastic subcortical lesion which would include: Hypothalamic hamartoma, Periventricular nodular hetereotopia, Dysembryoplastic neuroepithelial tumor (DNET), Cortical dysplasia, or Tuberous sclerosis.

• Patients with standard contraindications for MR imaging such as non-MRI compatible implanted metallic devices including cardiac pacemakers, size limitations, etc.
• Individuals who are not able or willing to tolerate the required prolonged stationary supine position during treatment (can be up to 4 hrs of total table time.).
• Patients with malignant brain tumors.
• Patients with a known history of psychogenic non-epileptic spells in the last three years.
• Patients with a vagal nerve stimulator, deep brain stimulator, other implanted electronic device, or prior radiofrequency lesion techniques.
• Lesions in the brainstem or cerebellum.
• Subjects with symptomatic generalized epilepsy.
• Subjects with only simple partial seizures.
• Subjects who have had convulsive status epilepticus within 12 months prior to baseline.
• Subjects with a prior diagnosis of psychogenic/non-epileptic seizures within the last 5 years.
• Subjects who are candidates for traditional open surgery or elect to receive traditional open surgery are excluded.

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

Eligibility last updated 9/15/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•Screening Visit:

• Men and women between 18 and 65 years of age at time of treatmentscreening with symptomatic knee pain indicative of articular cartilage defects of the knee with inadequate response to conservative treatment (e.g., analgesics, rest and physical therapy).
• Intact ligaments or sufficiently repaired ligaments such that the target knee is stable at time of procedure.
• Full range of motion of the affected joint (relative to normal knee) defined as : No loss of range of motion of affected limb >5° on extension and >15 ° flexion compared to contralateral knee
• Normally functioning contralateral knee.
• Maximum calculated score of 50 out of possible 100 on the KOOS subdomain of pain scale. (mMinimum rRaw score of 18 out of 36).
• Maximum calculated score of 63 out of possible 100 on the KOOS subdomain of Activities of Daily Living scale. (mMinimum Rraw score of 25 out of 68).
• Subjects who are willing to give voluntary consent to participate in the study, following a full explanation of the nature and purpose of the study, by signing the informed consent form approved by the Institutional Review Board (IRB) prior to all evaluations.
• Life expectancy greater than 5 years.
• Willing and able to perform the study treatments and procedures, able to comply with post-op rehabilitation and sign an Informed Consent and HIPAA authorization.

During Surgery:

At surgery, the screening visit inclusion criteria must again be reviewed and met, along with the following:

• Articular cartilage defect of the medial, lateral or trochlear femoral condyle with a total area of 2.0
  •6.0 cm2 as measured with a graduated probe across the widest portions of the lesion and treatable with one implant
• Defect-grade III or IV according to the ICRS-classification.

Subjects will not be considered for participation in the study if any of the following criteria listed below apply or are discovered prior to randomization:

• Severe obesity (BMI > 40).
• Surgery on the contralateral knee within the 6 months prior to the scheduled arthroscopy.
• Intra-articular injections within 1 month of surgery.
• Prior release and excision of scar tissue except isolated lateral release on target knee.
• Prior surgical treatment using mosaicplasty, autologous chondrocyte implantation and/or microfracture on the target knee.
  • Note: prior debridement and lavage are acceptable if more than three months have passed
• Clinically significant low back and/or lower extremity pain not due to the articular cartilage defect.
• Women of child bearing potential must test negative on standard urine pregnancy test and must agree to practice appropriate contraceptive methods for the first 24 months of the study (e. g. oral contraceptive, double barrier method, IUD, intra-muscular contraceptive).
• Clinically significant rheumatological disease (including Lyme, Fibromyalgia) .
• Clinically significant arthritis.
• Radiologically apparent degenerative joint disease as assessed by X-ray within 3 months of screening including joint space narrowing greater than one third when compared to the normal knee or less than 3 mm joint space measured on x-ray (including, but not limited to, weight bearing AP, PA flexed and lateral with magnification spheres; merchant view; hip to ankle alignment images) (in standing views).
• Documented abnormalities of clinically relevant bone integrity or bone healing (including hyperparathyroid and osteoporosis or osteopenia, chronic renal failure or have had previous fragility fractures unless there is a documented Dexa T-score of >-1 within the past 3 months).
• Bone diseases including but not limited to Paget’s Disease.
• Immune suppression (including CD4 values under 200; and/or chemotherapy).
• Immune modulating drugs such as immunosuppressants (ex. Imuran;) phosphonates; antimetabolites (ex. methotrexate), Gabapentin (neurontin) and Pregabaline (ex Lyrica).
• Current steroid (anabolic or corticosteroid) use or steroid use within the last 3 months prior to screening.
• Autoimmune disease (including Lupus, ankylosing spondylitis or sero negative arthropathy).
• Connective tissue or collagen disease including but not limited to Ehler-Danlos.
• Any degenerative muscular, connective tissue or neurological condition or other disease process that would interfere healing or the evaluation of outcome measures including but not limited to Parkinson’s disease, acute lateral sclerosis, multiple sclerosis.
• Current diagnosis or treatment for any infectious diseases at time of surgery.
• Clinically relevant vascular disorders including but not limited to peripheral vascular disease or peripheral artery disease.
• Subjects currently taking anti-coagulants (i.e., Plavix).
• Current uncontrolled diabetes.
• History of deep vein thrombosis and pulmonary embolism.
• Documented coagulation disorders or thromboembolic disease.
• Any currently active diagnosis of endocrine disorder without satisfactory treatment (ie hyperthyroidism without stable treatment).
• Human growth hormone medications.
• Primary synovial neoplasm.
• Previous malignancy in the bones, cartilage, fat or muscle of the treated limb; or any other location within the past 3 years (except non-melanoma skin cancer) .
• Currently participating, or have participated in any other clinical trial within 3 months prior to the Screening Visit.
• Psychiatric or cognitive impairment, that in the opinion of the investigator, would interfere with the subject’s ability to comply with the study requirements or measurements( e.g., Alzheimer’s Disease).
• Known current or recent history of illicit drug or alcohol abuse (including steroid use), or dependence defined as the continued use of alcohol/drugs despite the development of social, legal or health problems.
• Unable to undergo magnetic resonance imaging (MRI).
• Sensitivity to bovine materials; or history of host reaction/rejection.
• Subjects receiving ongoing Workman’s Compensation or other liability injury claim.

• Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
• Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
• Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
• Subject is willing to undergo core needle or incisional/ excisional biopsy unless sufficient tissue is available from diagnostic tumor/ lymph node biopsy (from within 6 months prior to ICF signature) for translational research purposes.
• Subject has histologically confirmed (per local evaluation) diagnosis of de novo, previously untreated, a-BCL according to 2016 WHO classification including:
  • DLBCL, NOS (including GCB and ABC types);
  • High-grade B-cell lymphoma, with MYC and BCL2 and/or BCL6 rearrangements;
  • Primary mediastinal (thymic) large B-cell lymphoma (PMBCL);
  • Primary cutaneous DLBCL-leg type;
  • EBV+ DLBCL, NOS;
  • Grade 3b FL.
• Chemo- and immunotherapy-naïve FL transformed to a-BCL. Patient must not have received any previous therapy for the FL component.
• Subject is considered an appropriate candidate (per investigator assessment) for induction therapy with 6 cycles of R-CHOP-21 or polatuzumab-R-CHP immunochemotherapy.
• Subject has IPI score 0 to 5 in Part 1 and IPI 2 to 5 in Part 2. For the CELMoD and polatuzumab-R-CHP cohort, the subject must also have IPI score 0 to 5 in Part 2A and IPI 2 to 5 in Part 2B.
• Subjects must have measurable disease defined by at least one FDG-avid lesion for FDG-avid subtype and one bi-dimensionally measurable (> 1.5 cm in longest diameter) disease by computed tomography (CT) or magnetic resonance imaging (MRI), as defined by the Lugano classification (Cheson, 2014).
• Subject has an ECOG performance status of 0, 1, or 2.
• Subjects must have the following laboratory values:
  • ANC ≥ 1.5 × 10^9 /L or ≥ 1.0 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without growth factor support for 7 days (14 days if peg-G-CSF);
  • Hemoglobin (Hb) ≥ 8 g/dL;
  • Platelets (PLT) ≥ 75 × 10^9 /L or ≥ 50 × 10^9 /L in case of documented bone marrow involvement (> 50% or tumor cells), without transfusion for 7 days;
  • AST/SGOT and alanine aminotransferase )ALT)/ serum glutamate pyruvic transaminase (SGPT) ≤ 2.5 × ULN. In the case of documented liver involvement by lymphoma, ALT/SGPT and AST/SGOT must be ≤ 5.0 × ULN;
  • Serum total bilirubin ≤ 2.0 mg/dL (34 μmol/L) except in cases of Gilbert’s syndrome, then ≤ 5.0 mg/dL (86 μmol/L);
  • Subjects receiving polatuzumab vedotin must have serum total bilirubin ≤ 1.5 × ULN (26 μmol/L) (corresponding to mild degree as per National Cancer Institute Organ Dysfunction Working Group [NCI ODWG] criteria) except in cases of Gilbert’s syndrome, then ≤ 3.0 mg/dL (51 μmol/L);
  • Estimated serum creatinine clearance (CrCl) of ≥ 50 mL/min using the modification of diet in renal disease (MDRD) formula.
• All subjects must:
  • Have an understanding that the study drug could have a potential teratogenic risk.
  • Agree to refrain from donating blood while on study treatment, during dose interruptions and for at least 28 days following the last dose of study treatment;
  • Agree not to share study medication with another person;
  • Agree to follow all requirements defined in the Pregnancy Prevention Program (see APPENDIX D) for CC-220 or CC-99282 Pregnancy Prevention Plan for Subjects in Clinical trials.
• Females must agree to abstain from breastfeeding during study participation and for at least 28 days after last dose of CC-220 or CC-99282 discontinuation and according to the approved rituximab product/prescribing information.
• Females of childbearing potential (FCBP^)* must:
  • Have two negative pregnancy tests as verified by the investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. This applies even if the subject practices true abstinence* from heterosexual contact;
  • Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with two forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting IP, during the study treatment (including dose interruptions), and for at least 28 days after the last dose of CC-220 or CC-99282 and for 12 months after the last dose of rituximab or polatuzumab vedotin, whichever is longer. Contraception requirements are detailed in APPENDIX D.
• Male subjects must:
  • Practice true abstinence* (which must be reviewed on a monthly basis and source documented) or agree to use a condom (APPENDIX D) during sexual contact with a pregnant female or an FCBP while participating in the study, during dose interruptions and for at least 28 days after the last dose of CC-220, or CC-99282, 6 months after the last dose of polatuzumab vedotin, or 90 days for rituximab, whichever is longer, even if he has undergone a successful vasectomy.
  • Must agree to refrain from donating sperm while on study treatment, during dose interruptions, and for at least 28 days following last dose of CC-220, CC-99282 6 months after the last dose of polatuzumab vedotin, or 90 days following last dose for rituximab, whichever is longer.
  • ^A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months).
  • *True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria:

• Subject has any significant medical condition, active infection (including SARS-CoV-2 suspected or confirmed), laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study
  • A patient who is excluded for SARS-CoV-2 infection could be rescreened;
  • In the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on investigator assessment in consultation with the clinical trial physician, there are no sequelae that would place the participant at a higher risk receiving investigational treatment;
  • Additionally, a patient who is currently in another interventional trial for COVID-19 may not participate in the clinical trial until the protocol-specific washout period is achieved;
  • Testing to exclude asymptomatic SARS-CoV-2 prior to enrollment should follow local standard practice.
• Subject has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study.
• Subject has any condition that confounds the ability to interpret data from the study.
• Subject has any other subtype of lymphoma.
• Subject has documented or suspected CNS involvement by lymphoma.
• Subject has persistent diarrhea or malabsorption ≥ Grade 2 (NCI CTCAE v5.0), despite medical management.
• Subject has peripheral neuropathy ≥ Grade 2 (NCI CTCAE v5.0).
• Subjects with a history of progressive multifocal leukoencephalopathy.
• Subject is on chronic systemic immunosuppressive therapy or corticosteroids (e.g., prednisone or equivalent not to exceed 10 mg per day within the last 14 days); stable use of inhaled or topical corticosteroids is allowed.
• Subject has impaired cardiac function or clinically significant cardiac disease, including any of the following:
  • Left ventricular ejection fraction (LVEF) < 45% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO);
  • Heart failure (New York Heart Association Class III or IV);
  • Clinically significant abnormal electrocardiogram (ECG) finding at screening;
  • Unstable angina or myocardial infarction ≤ 6 months prior to starting;
  • Persistent or uncontrolled ventricular arrhythmias or atrial fibrillation or cardiac conduction abnormalities not mitigated by a pacemaker.
• Subject had major surgery ≤ 2 weeks prior to starting CC-220 or CC-99282; subject must have recovered from any clinically significant effects of recent surgery.
• Subject has any condition causing inability to swallow tablets.
• Subject has known seropositivity for or active viral infection with human immunodeficiency virus (HIV).
• Subject has known chronic active hepatitis B (hepatitis B virus surface antigen [HBsAg] positive and/or hepatitis B core antibody [anti-HBc] positive with viral DNA positive) or C (positive serology requiring treatment and/or with evidence of liver damage) infection.
• Subject has history of other malignancy, unless being free of the disease for ≥ 3 years; exceptions to the ≥ 3-year time limit include history of the following:
  • Localized nonmelanoma skin cancer;
  • Carcinoma in situ of the cervix;
  • Carcinoma in situ of the breast;
  • Incidental histologic finding of prostate cancer (T1a or T1b as per Tumor Node Metastasis [TNM] staging system) or prostate cancer that has been treated with curative intent.
•  Subject has current treatment with strong CYP3A4/5 modulators.
• Subject has hypersensitivity to the active substance or to murine proteins, or to any of the other excipients of rituximab or polatuzumab vedotin.
• Subject has known hypersensitivity to any component of CHOP/CHP regimen.
• Subject has known allergy to thalidomide, pomalidomide, or lenalidomide.
• Subject received live attenuated vaccines or live COVID-19 vaccines within 30 days prior to initiation of study treatment.

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

Eligibility last updated 12/13/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 3/21/23. Questions regarding updates should be directed to the study team contact.

• Patient 18 years or older with breast cancer and biopsy-proven malignant involvement of an axillary lymph node.
• Surgical management will be determined by Dr. Mara Piltin, who will decide if preoperative I-125 seed localization of the positive node is necessary or if she will retrieve the positive node with intraoperative ultrasound guidance. During surgery, the targeted node, its associated biopsy markers, I-125 seed if placed, and twinkling marker will be resected. The position of the marker in the lymph node or proximity to the node will be noted from the surgical and pathology documentation.
• Surgery will be performed by Dr. Mara Piltin.
• Patients must be able to understand the study procedures and comply with them for the entire length of the study.
• No contraception is necessary or required.

• Current drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention.

• Male or female.
• Between > 18-80 years of age.
• Able and willing to give informed consent 
• Subjects with a suspected glioblastoma tumor on pre-operative brain imaging scans.
• Subjects that are scheduled, or will be scheduled within 4 weeks, for surgical resection or biopsy per standard clinical tumor care.
• Karnofsky Performance Score > 70.
• Able to communicate sensations during the Exablate BBBD procedure.

• Tumor originating from the deep midline, thalamus, midbrain, cerebellum or brainstem.
• Multifocal tumors.
• MRI or clinical findings of:
  • Active or chronic infection(s) or inflammatory processes;
  • Acute or chronic hemorrhages, specifically any lobar microbleeds, and no siderosis, amyloid angiopathy, or macro-hemorrhages;
  • Intracranial thrombosis, vascular malformation, cerebral aneurysm or vasculitis.
• MR non-compatible metallic implants in the skull or the brain or the presence of unknown MR unsafe devices.
• Significant cardiac disease or unstable hemodynamic status:
  • Documented myocardial infarction within six months of enrollment;
  • Unstable angina on medication;
  • Unstable or worsening congestive heart failure;
  • Left ventricular ejection fraction below the lower limit of normal;
  • History of a hemodynamically unstable cardiac arrhythmia;
  • Cardiac pacemaker;
  • History of hypersensitivity to Perflutren lipid microsphere or its components; e.g., polyethylene glycol.
• Uncontrolled hypertension (systolic > 180 and diastolic BP > 120 on medication).
• Unable to discontinue use of anti-coagulant/antiplatelet therapy as per local standard.
• History of a liver disease, bleeding disorder, coagulopathy or a history of spontaneous hemorrhage or evidence of increased risk of bleeding.
• Abnormal coagulation profile (Platelets < 80,000), PT (> 14) or PTT (> 36), and INR > 1.3.
• Known cerebral or systemic vasculopathy.
• Significant depression and at potential risk of suicide.
• Known sensitivity/allergy to gadolinium or DEFINITY®.
•  Active seizures despite medication treatment (defined as > 1 seizure per week) which could be worsened by disruption of the blood brain barrier.
• Active drug or alcohol disorder which have a higher risk for seizures, infection and/or poor executive functioning.
• Positive HIV status, which can lead to increased entry of HIV into the brain parenchyma leading to HIV encephalitis.
• Potential blood-borne infections which can lead to increased entry to brain parenchyma leading to meningitis or brain abscess.
• Any contraindications to MRI scanning, including:
  • Large subjects not fitting comfortably into the scanner;
  • Difficulty lying supine and still for up to 3 hours in the MRI unit or claustrophobia.
• Impaired renal function with estimated glomerular filtration rate < 30 mL/min/1.73m^2.
• Severe Respiratory Illness: chronic pulmonary disorders; e.g.,severe emphysema, pulmonary vasculitis, or other causes of reduced pulmonary vascular cross-sectional area, subjects with a history of severe drug allergies, asthma or hay fever, and multiple allergies where the benefit/risk of administering Definity® is considered unfavorable by the study physicians in relation to the product labeling for Definity®.
• Currently in a clinical trial involving an investigational product or non-approved use of a drug or device.
• Pregnancy or lactation.

• Women of childbearing potential must have a negative serum pregnancy test within 2 weeks prior to registration; patients that are pregnant or breast feeding are excluded; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria:
  • Has not undergone a hysterectomy or bilateral oophorectomy; or
  • Has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
• Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 4 months after completion of study; should a woman become pregnant or suspect while she or her partner is participating in this study, she should inform her treating physician immediately
• Patients must have histologically documented solid tumors or histologically confirmed diagnosis of lymphoma or multiple myeloma requiring therapy and meet one of the following criteria:
  • Patients must have progressed following at least one line of standard systemic therapy and there must not be other approval/standard therapy available that has been shown to prolong overall survival (i.e. in a randomized trial against another standard treatment or by comparison to historical controls); patients who cannot receive other standard therapy that has been shown to prolong overall survival due to medical issues will be eligible, if other eligibility criteria are met; if the patient is currently receiving therapy, the clinician must have assessed that the current therapy is no longer benefitting the patient prior to enrolling on MATCH, regardless of whether it is considered standard OR
  • Patients for whose disease no standard treatment exists that has been shown to prolong overall survival
  • NOTE: No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer; in situ cervical cancer; adequately treated stage I or II cancer from which the patient is currently in complete remission; any other cancer from which the patient has been disease-free for 5 years
• Patients must have measurable disease
• Patients must meet one of the following criteria:
  • Patients must have tumor amenable to image guided or direct vision biopsy and be willing and able to undergo a tumor biopsy for molecular profiling; patients with multiple myeloma other than plasmacytomas are to have a bone marrow aspirate to obtain tumor cells; biopsy must not be considered to be more than minimal risk to the patient
    • NOTE: Registration to screening steps (Step 0, 2, 4, 6) must occur after stopping prior therapy; there is no specific duration for which patients must be off treatment prior to registration to the relevant screening step (and subsequently, the biopsy), as long as all other eligibility criteria are met OR
  • Patient will be undergoing a procedure due to medical necessity during which the tissue may be collected
    • NOTE: Registration to screening steps (Step 0, 2, 4, 6) must occur after stopping prior therapy; there is no specific duration for which patients must be off treatment prior to registration to the relevant screening step (and subsequently, the biopsy), as long as all other eligibility criteria are met OR
  • Formalin-fixed paraffin-embedded tumor tissue block(s) are available for submission following pre-registration (not applicable for bone marrow aspirate specimens); criteria for the submission of formalin-fixed paraffin-embedded (FFPE) tissue are:
    • Tissue must have been collected within 6 months prior to pre-registration to Step 0
      • Patient may receive treatment after tissue collection; however, lack of response must be documented prior to Step 1; the following restrictions apply:
        • Enrollment onto another investigational study is not permitted
        • Intervening therapy that constitutes a new, molecularly targeted therapy is not permitted; please note, immunotherapy is not considered molecularly targeted
          • Continuation of an agent/regimen for which disease progression has been observed prior to biopsy is permitted, including targeted therapy
        • A new immunotherapy regimen is permitted; but, lack of response must also be documented prior to registration to Step 0
    • Formalin-fixed paraffin-embedded tumor tissue block(s) must meet the minimum requirements OR
  • Results from one of the designated outside laboratories indicate a "rare variant" that is an actionable mutation of interest (aMOI) for specific designated rare variant subprotocols; the following requirements apply:
    • The outside laboratory notified the site that patient may be a potential candidate for MATCH due to a detected "rare variant"
    • Patients with an applicable "rare variant" must be able to meet the eligibility criteria for the appropriate subprotocols within 4 weeks following entry on the EAY131 Step 0 screening step
    • Registration to Step 0 must occur after stopping prior systemic anti-cancer therapy; there is no specific duration for which patients must be off treatment prior to registration to Step 0, as long as all eligibility criteria are met
      • NOTE: Other potential aMOIs that would be eligibility criteria for NON RARE arms, as determined by the above laboratories, are not applicable for direct treatment assignment on MATCH
      • NOTE: Tumor tissue for the confirmation of "rare variant" by the MATCH assay is to be submitted, preferably from the same time of collection as that evaluated by the designated outside laboratory
• Patient must not require the use of full dose coumarin-derivative anticoagulants such as warfarin; low molecular weight heparin is permitted for prophylactic or therapeutic use; factor X inhibitors are permitted
  • NOTE: Warfarin may not be started while enrolled in the EAY131 study
  • Stopping the anticoagulation for biopsy should be per site standard operating procedure (SOP)
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 and a life expectancy of at least 3 months
• Patients must not currently be receiving any other investigational agents
• Patients must not have any uncontrolled intercurrent illness including, but not limited to:
  • Symptomatic congestive heart failure (New York Heart Association [NYHA] classification of III/IV)
  • Unstable angina pectoris or coronary angioplasty, or stenting within 6 months prior to registration to Step 0, 2, 4, 6
  • Cardiac arrhythmia (ongoing cardiac dysrhythmias of National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version [v]4 grade ≥ 2)
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • Intra-cardiac defibrillators
  • Known cardiac metastases
  • Abnormal cardiac valve morphology (≥ grade 2) documented by echocardiogram (ECHO) (as clinically indicated); (subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on study); subjects with moderate valvular thickening should not be entered on study
  • NOTE: To receive an agent, patient must not have any uncontrolled intercurrent illness such as ongoing or active infection; patients with infections unlikely to be resolved within 2 weeks following screening should not be considered for the trial
• Patients must be able to swallow tablets or capsules; a patient with any gastrointestinal disease that would impair ability to swallow, retain, or absorb drug is not eligible
• Patients who are human immunodeficiency virus (HIV)-positive are eligible if:
  • CD4+ cell count greater or equal to 250 cells/mm^3
  • If patient is on antiretroviral therapy, there must be minimal interactions or overlapping toxicity of the antiretroviral therapy with the experimental cancer treatment; for experimental cancer therapeutics with CYP3A/4 interactions, protease inhibitor therapy is disallowed; suggested regimens to replace protease inhibitor therapy include dolutegravir given with tenofovir/emtricitabine; raltegravir given with tenofovir and emtricitabine; once daily combinations that use pharmacologic boosters may not be used
  • No history of non-malignancy acquired immune deficiency syndrome (AIDS)-defining conditions other than historical low CD4+ cell counts
  • Probable long-term survival with HIV if cancer were not present
• Any prior therapy, radiotherapy (except palliative radiation therapy of 30 gray [Gy] or less), or major surgery must have been completed ≥4 weeks prior to start of treatment; all adverse events due to prior therapy have resolved to a grade 1 or better (except alopecia and lymphopenia) by start of treatment; palliative radiation therapy must have been completed at least 2 weeks prior to start of treatment; the radiotherapy must not be to a lesion that is included as measurable disease
  • NOTE: Prostate cancer patients may continue their luteinizing hormone-releasing hormone (LHRH) agonist
  • NOTE: Patients may receive non-protocol treatment after biopsy (if clinically indicated) until they receive notification of results; however, lack of response must be documented prior to registration to Step 1; new non-protocol treatment will NOT be permitted as intervening therapy after registration to Step 0; the decision to stop the intervening non-protocol treatment will be left up to the treating physician if patient has an aMOI; however, patients will need to be off such therapy for at least 4 weeks before receiving any MATCH protocol treatment
  • NOTE: For patients entering the study via a designated outside laboratory, no intervening systemic non-protocol treatment is permitted after Step 0 registration; all other eligibility requirements still apply to these patients, including the washouts for prior therapy noted above in this section, the time restrictions outlined, and the eligibility criteria for the intended subprotocol
• Patients with brain metastases or primary brain tumors must have completed treatment, surgery or radiation therapy ≥ 4 weeks prior to start of treatment
• Patients must have discontinued steroids ≥ 1 week prior to registration to Step 0 and remain off steroids thereafter, except as permitted (see below); patients with glioblastoma (GBM) must have been on stable dose of steroids, or be off steroids, for one week prior to registration to treatment (Step 1, 3, 5, 7)
  • NOTE: The following steroids are permitted (low dose steroid use is defined as prednisone 10 mg daily or less, or bioequivalent dose of other corticosteroid):
    • Temporary steroid use for computed tomography (CT) imaging in setting of contrast allergy
    • Low dose steroid use for appetite
    • Chronic inhaled steroid use
    • Steroid injections for joint disease
    • Stable dose of replacement steroid for adrenal insufficiency or low doses for non-malignant disease
    • Topical steroid
    • Steroids required to manage toxicity related to study treatment, as described in the subprotocols
    • Steroids required as pre- or post-chemotherapy medication for acceptable intervening chemotherapy
      • NOTE: Steroids must be completed alongside last dose of chemotherapy
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Leukocytes ≥3,000/mcL
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Absolute neutrophil count ≥ 1,500/mcL
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Platelets ≥ 100,000/mcL
• NOTE: Patients with documented bone marrow involvement by lymphoma are not required to meet the above hematologic parameters, but must have a platelet count of at least 75,000/mcL and neutrophil count of at least 1,000/mcL
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Total bilirubin ≤ 1.5 X institutional upper limit of normal (ULN) (unless documented Gilbert's syndrome, for which bilirubin ≤ 3 x institutional ULN is permitted)
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 X institutional ULN (up to 5 times ULN in presence of liver metastases)
• Within 2 weeks prior to screening step registration and within 4 weeks prior to treatment step registration: Creatinine clearance ≥ 45 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
• Patients must have an electrocardiogram (ECG) within 8 weeks prior to registration to screening step and must meet the following cardiac criteria:
  • Resting corrected QT interval (QTc)&le:480 msec
    • NOTE: If the first recorded QTc exceeds 480 msec, two additional, consecutive ECGs are required and must result in a mean resting QTc ≤ 480 msec; it is recommended that there are 10-minute (+/- 5 minutes) breaks between the ECGs
  • The following only need to be assessed if the mean QTc > 480 msec
    • Check potassium and magnesium serum levels
    • Correct any identified hypokalemia and/or hypomagnesemia and may repeat ECG to confirm exclusion of patient due to QTc
    • For patients with heart rate (HR) 60-100 beats per minute (bpm), no manual read of QTc is required
    • For patients with baseline HR < 60 or > 100 bpm, manual read of QT by trained personnel is required, with Fridericia correction applied to determine QTc
    • Patient must not have hypokalemia (value < institutional lower limit of normal)
  • No factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age or any concomitant medication known to prolong the QT interval
    • NOTE: Patient must be taken off prohibited medication prior to registration to the screening step (Step 0, 2, 4, 6) and remain off these medications thereafter, unless permitted on a subprotocol for the management of treatment related toxicity; patient must be off the drug for at least 5 half-lives prior to registration to the treatment step (Step 1, 3, 5, 7); the medication half-life can be found in the package insert for Food and Drug Administration (FDA) approved drugs

• Symptoms of chronic nausea or vomiting compatible with gastroparesis (idiopathic or diabetic) must be present for at least one year (does not have to be contiguous) prior to registration.
• Must have a mean total Gastroparesis Cardinal Symptom Index (GCSI) score of ≥ 3 at screening visit.
• Refractory gastroparesis, defined using our previously published data, as a failure to improve over the last 6 months, despite an adequate trial of one or more standard prokinetics (metoclopramide, erythromycin, prucalopride), antinauseants (5-HT3  antagonists, promethazine, prochlorperazine, dronabinol), or neuromodulators (mirtazapine, buspirone).
• Moderate to severe delay in gastric emptying, defined as > 25% solid retained at 4 hours or > 75% retained at 2 hours hours or gastric emptying T half greater than 174 minutes. For inclusion, the qualifying gastric emptying scintigraphy will be the baseline gastric emptying test.
• No evidence of mechanical obstruction based on upper GI endoscopy or upper GI series in their medical history.

• Another active disorder which could explain symptoms in the opinion of the investigator
• Gastric retention of solids at 4 hours < 25% or < 75% at 2 hours.
• Ongoing use of prokinetic agents (e.g., metoclopramide, erythromycin, prucalopride) GLP -1 analog or agonists, or drugs that slow down gastric emptying (narcotics). Neuromodulators such as tricyclic antidepressants (amitriptyline or nortriptyline) or others that are being used at stable doses for a month prior to randomization may continue at the discretion of the care provider.
• Significant systemic illness such as chronic renal failure (adjusted for age) or liver disease as defined by Child-Pugh score of 10 or greater.
• Poorly controlled diabetes with HbA1c of greater than 10% at time of screening.
• New medications for gastroparesis-related symptoms started within 1 month prior to registration.
• Pregnancy or nursing.
• Failure to give informed consent.
• Any other condition, which in the opinion of the investigator would impede compliance or hinder completion of the study.
• Botox injection into the pylorus within 3 months prior to registration.
• Allergy to eggs or Egg Beaters and Ensure.

Eligibility last updated 12/5/23. Questions regarding updates should be directed to the study team contact.

• Volar reconstruction of the scapholunate ligament

• Institutional follow-up <12 months

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

Eligibility last updated 5/4/23. Questions regarding updates should be directed to the study team contact.

• Patients must be ≥ 18 years of age at the time of signing the informed consent form (ICF)
• The Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2
• Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions guidelines and must be willing to undergo a bone marrow aspirate.
• Patients must have one of the following for eligibility into the study:
  • In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Myelodysplastic Syndrome (LR MDS) who failed to respond to or did not tolerate ESAs or luspatercept or HMAs and patients with del 5q who failed to respond to or did not tolerate lenalidomide; or
  • In dose optimization and expansion: IPSS-R defined very low, low or intermediate risk Chronic Myelomonocytic Leukemia (LR CMML) who failed to respond to or did not tolerate hydroxyurea or HMAs.

• Systemic antineoplastic therapy (including cytotoxic chemotherapy, alpha-interferon, kinase inhibitors or other targeted small molecules, and toxin-immunoconjugates) or any experimental therapy within 28 days or 5 half-lives, whichever is longer, and recovered from the toxicities before the first dose of study treatment. For patients that received antibodies the washout period is 4 weeks prior to study treatment.
• History of hypersensitivity to the study treatment or its excipients or to drugs of similar chemical classes.
• Patients who have previously been treated with agents that have the same mechanism of action as DFV890 as defined in Table 6-8, list of prohibited medications (e.g., drugs targeting the NLRP3 inflammasome pathway and the IL-1 pathway (canakinumab and anakinra)).
• Use of hematopoietic colony-stimulating growth factors (e.g., G-CSF, GM-CSF, M-CSF), thrombopoietin mimetics or erythroid stimulating agents anytime ≤ 1 week (or 5 half lives, whichever is longer) prior to start of study treatment.
• Patients receiving:
  • concomitant medications that are known to be modulators of cytochrome P450 enzymes CYP2C9 and/or CYP3A (specifically strong or moderate inducers of CYP2C9, strong inducers of CYP3A enzymes, strong inhibitors of CYP2C9 and/or strong or moderate dual inhibitors of CYP2C9/CYP3A); and
  • patients, who are poor CYP2C9 metabolizers receiving concomitant medications known to be strong or moderate inhibitors of CYP3A, whose concomitant medications cannot be discontinued or switched to a different medication within 5 half-lives or 1 week (whichever is longer) prior to start of study treatment and for duration of the study.
• Known malignancy, unless the diagnosis unde the study, which is progressing or has active treatment within the lat 12 months.  Exceptions to this exclusion include the following:
  • completely resectd basal cell and squamous cell skin cancers; and
  • completely resected carcinoma in situ of any type. 
• Patients with secondary MDS or therapy-related myeloid neoplasms.

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

Eligibility last updated 11/29/23. Questions regarding updates should be directed to the study team contact.

• Are able and willing to give informed consent, following a detailed explanation of participation in the protocol and signed consent obtained.
• Are aged 18 years or older of either gender.
• Have been diagnosed with NCFB by CT (or high-resolution CT) as recorded in the subject’s notes.
• Have had at least 2 pulmonary exacerbations requiring oral antibiotics or 1 pulmonary exacerbation requiring intravenous antibiotics in the 12 months preceding the Screening Visit (Visit 1) and had no pulmonary exacerbation with or without treatment during the period between Visit 1 and Visit 2.
• Have a documented history of P. aeruginosa infection.
• Are clinically stable and have not required a change in pulmonary treatment for at least 30 days before the Screening Visit (Visit 1).
• Have pre-bronchodilator FEV1 ≥ 30% of predicted.
• Have had a positive sputum culture for P. aeruginosa from an adequate sample taken at the Screening Visit (Visit 1).

• Known bronchiectasis as a consequence of cystic fibrosis (CF).
• Known history of hypogammaglobulinaemia requiring treatment with immunoglobulin, unless fully replaced and considered immuno-competent by the Investigator.
• Myasthenia gravis or porphyria.
• Severe cardiovascular disease such as severe uncontrolled hypertension, ischaemic heart disease or cardiac arrhythmia and any other conditions that would confound the evaluation of safety, in the opinion of the Investigator.
• Have had major surgery in the 3 months prior to the Screening Visit (Visit 1) or planned inpatient major surgery during the study period.
• Are receiving treatment for ABPA.
• Have had massive haemoptysis (greater than or equal to 300 mL or requiring blood transfusion) in the preceding 4 weeks before the Screening Visit (Visit 1) or between Visit 1 and Visit 2.
• Having respiratory failure that would compromise patient safety or confound the evaluation of safety or efficacy of the study in the opinion of the Investigator.
• Current active malignancy, except for basal cell carcinoma of the skin without metastases.
• Taking immunosuppressive medications (such as azathioprine, methotrexate, cyclosporin, tacrolimus, sirolimus, mycophenolate, anti-cytokine medications, rituximab, anti-IL-6 and anti-tumour alpha necrosis factor products) in the preceding year before the Screening Visit (Visit 1).
• Known history of human immunodeficiency virus (HIV).
• Current treatment for non-tuberculous mycobacterial (NTM) lung disease or tuberculosis.
• Known or suspected to be allergic or unable to tolerate colistimethate sodium (intravenous or inhaled) or other polymixins, including evidence of bronchial hyper-reactivity following inhaled colistimethate sodium.
• Treatment with long term (≥ 30 days) prednisone at a dose of greater than 15 mg a day (or equivalent dose of any other corticosteroid) (e.g.,  azithromycin/ erythromycin/clarithromycin) started within six months of the Screening Visit (Visit 1).
• New maintenance treatment with any oral macrolides within 30 days of the Screening Visit (Visit 1) or started between Visit 1 and Visit 2.
• Use of any intravenous or intramuscular or oral or inhaled anti-pseudomonal antibiotic (except chronic macrolides with a stable dose) within 30 days prior to the Screening Visit (Visit 1) and between Visit 1 and Visit 2.
• Pregnant or breast-feeding or plan to become pregnant over the next two years or of child-bearing potential and unwilling to use a reliable method of contraception for at least one month before randomisation and throughout their involvement in the trial.
• Significant abnormality in clinical evaluations and/or laboratory tests (physical examination, vital signs, haematology, clinical chemistry, clinically relevant impaired renal function, defined as serum creatinine levels ≥ 2.0x upper limit of normal, ECG) endangering the safe participation of the patient in the study at the Screening Visit (Visit 1) and during the study.
• Participated in another investigational, interventional trial within 30 days prior to the Screening Visit (Visit 1).
• In the opinion of the Investigator, not suitable for inclusion for whatever reason.

Eligibility last updated 12/7/21. Questions regarding updates should be directed to the study team contact.

• Current and former adult collegiate male and female athletes.
• Aged 18 years and older.
• Participants in football, rugby, soccer, hockey, lacrosse, and/or volleyball. 
  • Note:  “Former collegiate athletes” is defined as having competed in the applicable sports within the previous two years.
• Body mass index (estimated based on height and weight) from 20 to 37.
• Agree to maintain current level of physical activity throughout the study
• Willing and able to provide written informed consent.
• Willing and able to ingest the test substance.
• Willing and able to comply with study instructions.
• Not pregnant or breast feeding

• Presence of prolonged (more than 5 minutes) loss of consciousness.
• Normal contraindications to MRI procedures, including but not limited to implanted medical (metal, magnetic, or electronic) devices or having metal objects or pacemakers.
• History of epilepsy.
• History of more than 3 concussions.
• History of headache preceding concussions.
• History of complex spine and/or skull traumas.
• History of depression preceding concussions.
• History of intracranial bleeding or strokes.
• History of post-traumatic seizures.
• History of developmental delay.
• History of ADHD.

• Current and former adult collegiate male and female athletes.
• Aged 18 years and older.
• Participants in football, rugby, soccer, hockey, lacrosse, and/or volleyball. 
  • Note:  “Former collegiate athletes” is defined as having competed in the applicable sports within the previous two years.
• Body mass index (estimated based on height and weight) from 20 to 37.
• Agree to maintain current level of physical activity throughout the study
• Willing and able to provide written informed consent.
• Willing and able to ingest the test substance.
• Willing and able to comply with study instructions.
• Not pregnant or breast feeding

• Presence of prolonged (more than 5 minutes) loss of consciousness.
• Normal contraindications to MRI procedures, including but not limited to implanted medical (metal, magnetic, or electronic) devices or having metal objects or pacemakers.
• History of epilepsy.
• History of more than 3 concussions.
• History of headache preceding concussions.
• History of complex spine and/or skull traumas.
• History of depression preceding concussions.
• History of intracranial bleeding or strokes.
• History of post-traumatic seizures.
• History of developmental delay.
• History of ADHD.

Patients'

• 21 years of age or older.
• English language proficiency.
• Diagnosed with 2 or more conditions from a pre-specified list of 20 chronic conditions (e.g., selected cancer types, arthritis, COPD, hypertension).
• Screened positive for high likelihood of treatment burden.

Patients'

• Diagnosis of dementia, psychoses, or other conditions that might involve severe physical or cognitive impairment that would make completing surveys or using the PETS-Now tool difficult.
• Prior participation in the qualitative research on the design of the PETS-Now tool (IRB #16-010356, Patient Experience with Treatment and Self-care Clinical Tool: Patient and Healthcare Provider Discussion Groups).

Clinicians'

• MD, RN, PA, NP, LSW, Community health worker.
• Practicing in Family Medicine or Primary Care Internal Medicine.

Clinicians'

• Prior participation in the qualitative research on the design of the PETS-Now tool (IRB #16-010356, Patient Experience with Treatment and Self-care Clinical Tool: Patient and Healthcare Provider Discussion Groups).