• Male or female patients aged 18 years or older.
• Be willing and able to provide written informed consent for the study.
• For patients with MM (for Phase 1b and Phase 2):
  • A prior diagnosis of MM as defined by the IMWG criteria with documented disease progression;
  • Has measurable disease defined as one of the following:
  • Serum M-protein ≥ 0.5 g/dL (≥ 5 g/L);
  • Urine M-protein ≥ 200 mg/24 hours;
  • In patients without measurable M-protein in serum protein electrophoresis (SPEP) or urine protein electrophoresis (UPEP), a serum free light chain (FLC) assay result with involved FLC level ≥ 10 mg/dL (≥ 100 mg/L), provided serum FLC ratio is abnormal.
  • Has undergone stem cell transplant or is considered transplant ineligible; and
  • Patients with a history of autologous stem cell transplant are eligible if the transplant was > 100 days prior to study consent;
  • Has failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (eg, daratumumab, daratumumab and hyaluronidase-fihj, isatuximab) alone or in combination; and
  • Is either refractory, or intolerant to at least 1 IMiD (ie, lenalidomide or pomalidomide [thalidomide excluded]), at least 1 proteasome inhibitor (i.e., bortezomib, ixazomib or carfilzomib), and refractory to at least 1 anti-CD38 antibody and who have demonstrated disease progression with the last therapy;
  • Refractory myeloma is defined as disease that is nonresponsive while on therapy or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve at least minimal response or development of PD while on therapy;
  • A line of therapy consists of ≥ 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens (e.g., 3-6 cycles of initial therapy with bortezomib-dexamethasone followed by a stem cell transplantation, consolidation, and maintenance is considered 1 line).
• Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
• Have suitable venous access for safe drug administration and the study-required blood sampling, including PK and pharmacodynamic sampling.
• Have adequate organ function as specified below at screening:
  • Platelet count ≥ 75, 000 mm^3 (≥ 75 × 10^9 /L); value of ≥ 50,000 mm^3 (≥ 50 × 10^9 /L) may be acceptable for patients with ≥ 50% bone marrow burden following discussion with the sponsor (platelet transfusion will be allowed > 3 days before assessment);
  • Hemoglobin must be ≥ 8 g/dL. (RBC transfusion allowed ≥14 days before assessment);
  • Absolute neutrophil count (ANC) ≥ 1000 mm^3 (≥ 1.0 × 10^9 /L); value of ≥ 750 mm^3 (≥ 0.75 × 10^9 /L) may be acceptable for patients with ≥ 50% bone marrow burden following discussion with the sponsor;
  • Estimated creatinine clearance using the Cockcroft-Gault formula ≥ 30 mL/minute for patients with serum creatinine concentrations above the upper limit of normal range (ULN).
• AST (glutamic oxaloacetic transaminase [GOT]) and ALT (GPT) ≤ 3.0 × ULN; bilirubin ≤ 1.5 × ULN. Patients with Gilbert’s syndrome may have a bilirubin level > 1.5 × ULN, per discussion between the investigator and the medical monitor.
• Have recovered to Grade 1 or baseline from all toxicity associated with previous therapy or have the toxicity established as sequela.
  • Note: except Neuropathy Grade ≤ 2, any grade alopecia, or bone marrow parameters [any of Grade 1 or 2 permitted if directly related to bone marrow involvement].
• Female patients who:
  • Are postmenopausal for at least 1 year before the screening visit; OR
  • Are surgically sterile; OR
  • If they are of childbearing potential, agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 6 months after the last dose of drug in the combination; OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.)
• Male patients, even if surgically sterilized (ie, status postvasectomy), who:
  • Agree to practice effective barrier contraception during the entire study treatment period and through 6 months after the last dose of drug in the combination; OR
  • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together).
• Must be willing and able to comply with clinic visits and procedures outlined in the study protocol.

• Received treatment with systemic anticancer treatments within 14 days before the first dose of study drug or any investigational products (IPs) within 5 half-lives of the first dose of study drug, whichever is appropriate to last therapy received. (e.g., non-IP IMiD, proteasome inhibitor, anti-CD38 mAb could be considered to be eligible if there is at least 14 days after last dose before first dose of study drug).
  • Note: Treatment with a single course of glucocorticoids (maximum dose of corticosteroids should not exceed the equivalent of 160 mg [for example, 40 mg/d for 4 days] of dexamethasone), hormonal therapy for prostate cancer or breast cancer (as adjuvant treatment), and treatment with bisphosphonates and receptor activator of nuclear factor kappa-Β ligand (RANKL) inhibitors are allowed.
• Current participation in another interventional study, including other clinical trials with investigational agents (including investigational vaccines or investigational medical device for disease under study) within 4 weeks of the first dose of TAK-981 and throughout the duration of this trial.
• Prior radiation therapy within 14 days of the first dose of TAK-981.
  • Note: Prophylactic localized (“spot”) radiation for areas of pain is allowed.
• Major surgery within 4 weeks before C1D1. Patients should be fully recovered from any surgically related complications.
  • Note: Kyphoplasty is not considered major surgery.
• Plasmapheresis within 28 days of randomization.
• Diagnosis of primary amyloidosis, Waldenström’s disease, monoclonal gammopathy of undetermined significance or smoldering multiple myeloma (SMM) per IMWG criteria or standard diagnostic criteria, plasma cell leukemia (according to the World Health Organization [WHO] criterion: ≥ 20% of cells in the peripheral blood with an absolute plasma cell count of more than 2 × 10^9 /L), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes), myelodysplastic syndrome, or myeloproliferative syndrome.
• With disease where the only measurable parameter is plasmacytoma.
• Second malignancy within the previous 3 years, except treated basal cell or localized squamous skin carcinomas, localized prostate cancer, cervical carcinoma in situ, resected colorectal adenomatous polyps, breast cancer in situ, or other malignancy for which the patient is not on active anticancer therapy.
• Evidence of central nervous system involvement and/or meningeal involvement of MM exhibited during screening.
• Known severe allergic or anaphylactic reactions to human recombinant proteins or excipients used in the TAK-981 formulation or the mAbs (such as daratumumab or daratumumab and hyaluronidase-fihj as per the prescribing information and for mezagitamab as outlined in the Mezagitamab IB).
• History of treatment discontinuation due to treatment-related toxicity to the combination partner (daratumumab or daratumumab and hyaluronidase-fihj).
• Prior treatment with more than 1 anti-CD38 antibody.
• Chronic obstructive pulmonary disease (COPD) with forced expiratory volume in 1 second (FEV1) 10 mg/day or equivalent doses, or any other form of immunosuppressive therapy. Hormone therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered an excluded form of systemic treatment of an autoimmune disease.
• Active or history of noninfectious pneumonitis that required steroids or a history of interstitial lung disease.
• History of allogeneic tissue or solid organ transplant.
• Receipt of any live vaccine (e.g., varicella, pneumococcus) within 4 weeks of initiation of study treatment.
• Receiving or requiring the continued use of medications that are known to be strong or moderate inhibitors and inducers of cytochrome P450 (CYP) 3A4/5 or are strong P-glycoprotein (Pgp) inhibitors at screening. To participate in this study, such patients should discontinue use of such agents for at least 2 weeks or 5 times the half-life (whichever is shorter) before receiving a dose of TAK-981.
• Requires the use of drugs known to prolong the corrected QT interval (QTc) (during Phase 1b only).
• History of any of the following ≤ 6 months before first dose: congestive heart failure New York Heart Association Grade III or IV, unstable angina, myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, ongoing symptomatic cardiac arrhythmias > Grade 2, pulmonary embolism or symptomatic cerebrovascular events, or any other serious cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy). Chronic atrial fibrillation on stable anticoagulant therapy is allowed.
• Baseline prolongation of the QT interval with Fridericia’s correction method (QTcF) (e.g., repeated demonstration of QTcF interval > 480 ms, history of congenital long QT syndrome, or torsades de pointes). If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
• Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or has compromised ability to provide written informed consent.
• Admission or evidence of illicit drug use, drug abuse, or alcohol abuse.
• Female patients who are lactating and breastfeeding or have a positive serum pregnancy test during the screening period or a on Day 1 before first dose of TAK-981 study drug.

Eligibility last updated 12/10/21. Questions regarding updates should be directed to the study team contact.

• Adults, ≥ 18 years of age.
• Waitlist active, temporarily inactive, and deferred adult lung transplant candidates from Mayo Clinic Florida; Mayo Clinic Rochester; or UW Medicine.

• Children < 18 years old.
• Patients who are non-verbal, non-English speakers, or extremely hard-of-hearing.

• Pediatric patients age to 17 years old, inclusive.
• Parental or LAR informed consent for patients ages 6 years and younger.
• Parental or LAR informed consent and subject assent for subjects ages to 17.

• Any condition that, in the opinion of the Investigator, would make the subject inappropriate for the evaluation.

• Adult women, ≥ 18 years of age.
• Breast lesion and are scheduled for clinically-indicated biopsy.

• < 18 years of age.
• Previous breast surgery or breast implant.
• Lacking capacity to consent.
• Pregnant or lactating.
• Receiving cancer therapy such as chemotherapy or radiation therapy.

• Patients with newly diagnosed stages 2
  •4 diffuse anaplastic Wilms tumor must be enrolled on AREN03B2 and have risk assignment or final pathology classification (if at delayed nephrectomy) results available prior to enrollment on AREN1921. Enrollment on AREN03B2 is not applicable for patients with relapsed favorable histology Wilms tumor.
• Patients must be ≤ 30 years old at study enrollment.
• Patients with the following diagnoses are eligible for this study:
  • Newly diagnosed stages 2
    •4 diffuse anaplastic Wilms tumor as confirmed by central review;
  • Favorable histology Wilms tumor at first relapse. Relapsed FHWT patients must have previously achieved remission for their initial FHWT diagnosis to be eligible for this study. The relapse risk groups are defined as follows, regardless of radiation therapy:
  • Standard-Risk relapse: Patients who received two chemotherapy agents for frontline therapy; primarily actinomycin D and vincristine;
  • High-Risk relapse: Patients who received three chemotherapy agents for frontline therapy; primarily vincristine, actinomycin D and doxorubicin or vincristine, actinomycin D and irinotecan;
  • Very High-Risk relapse: Patients who received four or more chemotherapy agents as part of initial therapy; primarily Regimen M or its variations.
• Patients with newly diagnosed DAWT must have had histologic verification of the malignancy. For relapsed FHWT patients, biopsy to prove recurrence is encouraged, but not required.
  • Note: for relapsed FHWT patients, an institutional pathology report confirming favorable histology Wilms tumor (from relapse, if available, or from original diagnosis) must be available for upload prior to initiation of protocol therapy
• Patients with newly diagnosed stages 2
  •4 diffuse anaplastic Wilms tumor must be enrolled on AREN1921 within 2 weeks of the first tumor-directed surgery or biopsy procedure (surgery/biopsy is day 0), except for patients who received prior therapy for presumed favorable histology Wilms tumor, later confirmed to have diffuse anaplastic Wilms tumor at subsequent review
• Patients with newly diagnosed DAWT who undergo upfront nephrectomy must have at least 1 lymph node sampled prior to study enrollment
• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients ≤ 16 years of age
• Patients must have a life expectancy of ≥ 8 weeks
• Histology must have had no prior systemic therapy, except in the following situations:
  • Patients with diffuse anaplastic Wilms tumor who received no more than 12 weeks of pre nephrectomy chemotherapy for what was originally presumed to be favorable histology Wilms tumor, subsequently confirmed to be diffuse anaplastic Wilms tumor at delayed nephrectomy;
  • Patients with diffuse anaplastic Wilms tumor who received no more than 6 weeks of chemotherapy following upfront nephrectomy or biopsy for presumed favorable histology Wilms tumor based on institutional review, but subsequently corrected to diffuse anaplastic Wilms tumor based on the AREN03B2 initial risk assignment results;
  • Treatment consisting of vincristine/doxorubicin/ cyclophosphamide initiated on an emergent basis and within allowed timing as described.
• Patients who received prior therapy for presumed favorable histology Wilms tumor, later identified to have diffuse anaplastic Wilms tumor as per above, must begin study treatment starting at cycle 3 (week 7) of regimen UH 3. For treatment details specific to this group of patients.
• Patients who received emergency radiation to preserve organ function are eligible as noted.
• Relapsed Favorable Histology Wilms Tumor:
  • Patients must not have received prior chemotherapy for their relapsed favorable histology Wilms tumor diagnosis. In addition, patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
  • Myelosuppressive chemotherapy;
  • Must not have received within 2 weeks of entry onto this study.
  • Radiation therapy (RT):  2 weeks (wks) must have elapsed for local palliative RT (small port); ≥ 6 months must have elapsed if prior craniospinal RT or if ≥ 50% radiation of pelvis; ≥ 6 wks must have elapsed if other substantial BM radiation. Patients with relapsed favorable histology Wilms tumor who received emergency radiation to preserve organ function are eligible and do not need to washout with the above criteria.
• Patients may not be receiving any other investigational agents (within 4 weeks prior to study enrollment).
• Peripheral absolute neutrophil count (ANC) ≥ 750/uL (performed within 7 days prior to enrollment).
• Platelet count ≥ 75,000/uL (transfusion independent) (performed within 7 days prior to enrollment).
• Hemoglobin ≥ 8.0 g/dL (may receive red blood cell [RBC] transfusions) (performed within 7 days prior to enrollment).
• Patients with high-risk or very high-risk relapsed FHWT who will be treated with Regimen ICE/Cyclo/Topo, must have renal function assessed by creatinine clearance or radioisotope glomerular filtration rate (GFR) and meet the following requirement:
  • Creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73 m^2 (performed within 7 days prior to enrollment).
• Patients diagnosed with stage 2-4 DAWT or standard risk relapsed FHWT, who will be treated with Regimen UH 3, may either obtain a creatinine clearance, radioisotope GFR (meeting the above criteria of GFR ≥ 60 mL/min/1.73 m^2), or an adequate serum creatinine as per the following table:
  • Age: Maximum Serum Creatinine (mg/dL);
  • 1 month to < 6 months: 0.4 (male and female);
  • 6 months to < 1 year: 0.5 (male and female);
  • 1 to < 2 years: 0.6 (male and female);
  • 2 to < 6 years: 0.8 (male and female);
  • 6 to < 10 years: 1 (male and female);
  • 10 to < 13 years: 1.2 (male and female);
  • 13 to < 16 years: 1.5 (male), 1.4 (female);
  • ≥ 16 years: 1.7 (male), 1.4 (female).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age or direct bilirubin ≤ ULN for patients whose total bilirubin > 1.5 x ULN (performed within 7 days prior to enrollment).
• Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) or serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 2.5 x upper limit of normal (ULN) for age or ≤ 5 x ULN for patients with liver metastases (performed within 7 days prior to enrollment);
• Shortening fraction of ≥ 27% by echocardiogram, or ejection fraction of ≥ 50% by radionuclide angiogram (performed within 7 days prior to enrollment).

• Patients with a history of bilateral Wilms tumor (synchronous or metachronous).
• Patients with any uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, or symptomatic congestive heart failure (defined as grade 2 or higher heart failure per Common Terminology Criteria for Adverse Events [CTCAE] version 5.0).
• Relapsed FHWT patients who did not receive frontline chemotherapy (e.g., very low risk FHWT initially observed without chemotherapy) or received only one chemotherapy agent for frontline therapy.
• For patients with high-risk or very high-risk relapsed FHWT:
  • Patients with renal tubular acidosis (RTA) as evidenced by serum bicarbonate < 16 mmol/L and serum phosphate =< 2 mg/dL (or < 0.8 mmol/L) without supplementation.
• For stages 2-4 DAWT and standard-risk relapsed FHWT patients:
  • Chronic inflammatory bowel disease and/or bowel obstruction;
  • Concomitant use of St. John's wort, which cannot be stopped prior to the start of trial treatment.
• Female patients who are pregnant since fetal toxicities and teratogenic effects have been noted for several of the study drugs. A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.

• Admission to PICU or SDU at any point during illness due to severity (not due to bed availability).
• ≤ 21 years old on admission.
• Influenza-associated LRTI:
  • Positive influenza test (rapid antigen, DFA or PCR); and
  • > 1 sign of acute respiratory illness: cough, shortness of breath, tachypnea or retractions, invasive or non-invasive mechanical ventilation, need for FiO2 to maintain SpO2 > 92%, pulmonary infiltrate or hyperinflation on chest imaging.
• At least 1 parent or legal guardian able and willing to provide permission.

• Previous enrollment in this study during the current season.
• Hospital acquired influenza infection as determined by site hospital infection control experts.
• Pre-existing conditions that are known risk factors for severe influenza infection (with the exception of asthma or reactive airways disease (RAD).  Exclusions include:
  • Chronic pulmonary (except asthma/RAD) or upper airway disorders;
  • History of prematurity in patients < 1 year of age;
  • Known immune disorders;
  • Cardiac disease with compromise requiring medications or alterations in activities;
  • Neurologic disorders impairing respiratory muscle strength or secretion management;
  • Sickle cell disease;
  • Complex genetic disorders impairing multiple organ systems; AND
  • Metabolic disorders that may be worsened by infection including diabetes mellitus.

• Age ≥ 18 years.
• Cirrhosis or chronic liver disease (defined as FIB-4 > 1.45 or other non-invasive markers that show > F3 fibrosis on outpatient values).
• Admitted for non-elective reasons.
• Able to consent or have a legal representative who can consent.

• Individuals < 18 years of age.
• Acute liver failure.
• Unable to consent.
• Admitted electively.
• Life expectancy < 48 hours.
• Prisoners.
• HCC without loco-regional control for > 6 months or patients on systemic therapy for Hepatocellular Carcinoma (HCC) currently.
• COVID-19 diagnosis confirmed during the current admission.
• Post-TIPS if TIPS is > 6 months prior.
• Known recent MI (< 6 months) or stroke with residual defects.

• Mayo Clinic patients with a previously confirmed infection with the novel SARS-CoV-2 virus who have been seen in the PCCOC, CARP, Pulmonary for post COVID clinic, Neurology, or approval by MAGPIES research group.
• Aged 5 years and older.
• All racial and ethnic groups are eligible.

• Lacking the capacity to consent.
• Prisoners and institutionalized individuals.

Eligibility last updated 9/8/21. Questions regarding updates should be directed to the study team contact.

.

• Physicians, Nurse Practitioners, and Physician Assistants.
• No prior training in pharmacogenomics.

• Any reported prior training in pharmacogenomics.

• Male or female, ≥  18
  •40 years of age.
• A healthy volunteer will be defined as an otherwise healthy person who does not have a medical condition that affects brain function or have problems with concentration, memory, balance, or coordination.

• Subjects with non-MRI compatible devices, required sedation (claustrophobia or unable to remain still for exam), or women who are pregnant will be excluded.

• Age 18 or over.
• Diagnosis of alcohol-associated liver disease and alcohol use disorder:
  • The diagnosis of ALD will be determined by a hepatologist based on history of regular and excessive alcohol consumption in the absence of other causes of liver cirrhosis or acute hepatitis, compatible clinical, imaging, and laboratory findings and typical histology on liver biopsy, if performed;
  • The diagnosis of AUD will be determined by a hepatologist and/or addiction psychiatrist based on history obtained that is consistent with DSM-5 diagnostic criteria for AUD (all categories of mild, moderate, and severe considered eligible).
• Capacity to provide consent.
• Access to a smartphone, cellular data, and wireless internet connection through the smartphone device.

• Inability to respond to smartphone-delivered questionnaires.
• Inability to send and receive text messages.
• Moderate to severe hepatic encephalopathy, defined by West-Haven score of 3 or higher.
• Severe psychiatric comorbidity, not controlled on pharmacological or non-pharmacological therapy.

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

• Able to read and write English fluently.
• Can sign consent for themselves.
• Age 18 years or older.
• Diagnosis of sporadic Vestibular Schwannoma (VS) (also called acoustic neuroma).

• Age less than 18 years old.
• Diagnosis of VS secondary to neurofibromatosis type 2 (NF2).
• Lack of capacity to consent.
• Unable to read/write English fluently.

Inclusion Criteria
•All Groups:

• All participants must sign an informed consent indicating that they are aware of the investigational nature of this study and willing to undergo study interventions, and authorizing the use of their protected health information for research purposes.
• Meet one set of group-specific inclusion criteria listed below.
• All participants must be ≥ 18 years old and ≤ 75 years at the time of enrollment.

Inclusion Criteria
•No Pancreas Disease Controls:

• No personal history or symptoms of pancreatic disease.
• No upper abdominal symptoms
• *Participant will answer “No” and “None” to below questions to meet this criterion:
  • Have you had a stomach ache or pain more than SIX times in the past year?
  • □ YES            □ NO
• How many times have you had a feeling of WANTING TO THROW UP (nausea) in the last year?
  • □ NONE        □ ANY
• No family history of pancreatic disorders, celiac disease, cystic fibrosis.
• No history of acute infectious or inflammatory conditions requiring medical treatment or evaluation in the preceding 6 months (per provider clinical judgment).
• No history of cancer, except for non-melanoma skin cancers.
• No known pregnancy at the time of enrollment.
• No solid organ transplant or history of HIV/AIDS.
• Able to provide an informed consent.
• Not currently incarcerated.
• ASA 1-2.

Inclusion Criteria - Chronic Upper Abdominal Pain of Suspected Pancreatic Origin:

• Referred to a pancreas or GI clinic or admitted to the hospital for evaluation of unexplained upper abdominal pain of at least 3 months in duration for which a pancreatic origin is clinically considered in the differential diagnosis.*

* Pancreatic type pain is defined as epigastric pain that is often constant, often worsens post-prandially, and may radiate to the back. This can often be associated with lipase/amylase elevations that do not meet the threshold for diagnosis of AP (i.e. <3-fold upper limit of normal).

• No history of AP or CP.
• No prior endoscopic sphincterotomy or pancreatic surgery.
• Normal cross-sectional abdominal imaging (CT and MRI/MRCP).**

** CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment as “Chronic Abdominal Pain – Undifferentiated”. The second imaging study can be performed in this situation after the enrollment and the final assignment into the appropriate subgroup can be done after review of the imaging results.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation and attempts will be made to complete this during follow-up as feasible. If the second study could not be performed, the subject will be assigned to Chronic upper abdominal pain group if the available study was normal or as Indeterminate CP if the available study shows Cambridge 1-2 findings.

Inclusion Criteria - Indeterminate CP with no history of AP:

• Referred to a pancreas or GI clinic or admitted to the hospital for evaluation of unexplained upper abdominal pain of at least 3 months in duration for which a pancreatic origin is clinically considered in the differential diagnosis*

* Pancreatic type pain is defined as epigastric pain that is often constant, often worsens post-prandially, and may radiate to the back. This can often be associated with lipase/amylase elevations that do not meet the threshold for diagnosis of AP (i.e. <3-fold upper limit of normal).

• No history of AP or CP.**

**AP is defined as compatible symptoms (upper abdominal pain) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR).

• Cambridge grade I-II changes of CP# on cross-sectional imaging (CT or MRI/MRCP).***

*** CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment.  CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment as “Chronic Abdominal Pain – Undifferentiated”. The second imaging study can be performed in this situation after the enrollment and the final assignment into the appropriate subgroup can be done after review of the imaging results.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation and attempts will be made to complete this during follow-up as feasible. If the second study could not be performed by month 6 after enrollment, the subject will be assigned to Chronic upper abdominal pain group if the available study was normal or as Indeterminate CP if the available study shows Cambridge 1-2 findings. 
• No prior endoscopic sphincterotomy or pancreatic surgery.

Inclusion Criteria - Acute Pancreatitis (AP):

•  History of one documented attack of AP in the preceding 18 months.*

* AP is defined as compatible symptoms (upper abdominal pain) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR). Patient should not have had an attack of AP in the month prior to enrollment.

• Patients should not have had an ERCP prior to the episode of AP.
• Pancreatitis episode is not attributable to gallstones (i.e., suspected or definite biliary etiology), medications, trauma or autoimmune pancreatitis.
• Pancreatic necrosis, if present, is <50% (to be verified by a CPDPC site radiologist).
• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP).***

*** CT and MRI/MRCP must be performed ≤ 24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study  can be performed in this situation after the enrollment.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation. Final group assignment in this situation will be based on the available study.   
• No prior pancreatic surgery.

Inclusion Criteria - Recurrent Acute Pancreatitis (RAP):

• Two or more documented attacks of AP* separated by at least 1 month, with complete symptom resolution between the attacks.

* AP is defined as compatible symptoms (epigastric pain with nausea or vomiting) together with A) ≥ 3-fold elevation of serum amylase and/or lipase above upper limit of normal, AND/OR B) features of AP on cross-sectional imaging (CT and/or MR).

• Patient should not have had an ERCP prior to having first documented attack of pancreatitis.
• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP)**

**CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study can be performed in this situation after the enrollment.

• Cambridge grade < III changes of CP# on cross-sectional imaging (CT or MRI/MRCP).**

**CT and MRI/MRCP must be performed ≤24 months prior to enrollment OR within 6 months after study enrollment. CT and MRI scans must be intravenous contrast-enhanced and MRCP with secretin (a non-contrast MRI and MRCP without secretin prior to enrollment is acceptable at baseline to be used for enrollment). If the patient has had only one imaging study, the patient is eligible for enrollment. The second study can be performed in this situation after the enrollment.

• If the second study was planned within 6 months after enrollment but could not be completed, it will not be considered as eligibility violation. Final assignment in this situation will be based on the available study.
• In a rare circumstance, the last imaging patient had was >24 months prior to enrollment. In this circumstance, the patient is still eligible for enrollment, and can undergo CT scan first, and if there is no evidence of Cambridge 3-4 findings, undergo an MRI/MRCP to fulfill entry criteria. If the planned studies could not be completed within 6 months after enrollment, the final group assignment will be in this situation will be based on the available study.
• Pancreatitis episodes are not attributable to gallstones, medications, trauma or autoimmune pancreatitis.
• No prior pancreatic surgery.

Inclusion Criteria - Definite Chronic Pancreatitis

• Presence of unequivocal CP (i.e., Cambridge grade ≥ 3) and/or parenchymal and/or ductal calcifications by cross-sectional imaging (IV contrast-enhanced MRI/MRCP or CT) verified by the CPDPC site radiologist.*

* Must exclude the possibility that calcifications are vascular. Calcifications noted by EUS only (and not correlated with CT) are not included as definite CP. A non-contrast CT scan or MRI/MRCP documenting definite CP as per criteria is acceptable for enrollment.

• Pancreatic histology diagnostic of CP (including findings of fibrosis [Ammann’s ≥ 6], chronic inflammation, and acinar loss) as verified by a CPDPC site pathologist, if pathology slides are available for review.

• History of autoimmune or traumatic pancreatitis, or sentinel attack of acute necrotizing pancreatitis which   results in suspected disconnected duct syndrome.
• Primary pancreatic tumors
  •pancreatic ductal adenocarcinoma, suspected cystic neoplasm (> 1 cms in size or main duct involvement), neuroendocrine tumors, and other uncommon tumors. 
• Pancreatic metastasis from other malignancies.
• History of solid organ transplant, HIV/AIDS.
• Known isolated pancreatic exocrine insufficiency (e.g., in the absence of any eligible inclusion criteria).
• Participants must not have medical or psychiatric illnesses or ongoing substance abuse that in the investigator’s opinion would compromise their ability to tolerate study interventions or participate in longitudinal follow up.
• Patients with known abnormal creatinine (GFR < 30) or renal failure (applies to patients with chronic upper abdominal pain of suspected pancreatic origin and suspected CP (yellow) subgroups).
• Failure to agree for longitudinal follow-up.
• Known Pregnancy. All participants of childbearing potential, except if post-menopausal [i.e., no menses for ≥ 2 years] or had a hysterectomy, bilateral tubal ligation/clip (surgical sterilization) or surgical removal of both the ovaries), must have a negative urine or serum B-HCG pregnancy test documented within 2 days prior to any endoscopic or radiologic procedures done for research purposes. Any standard of care tests will follow institutional policies regarding pregnancy test.
• Currently incarcerated.
• Inability to get MRI/MRCP in patients with chronic abdominal pain of suspected pancreatic origin (Green II) or Suspected CP (Yellow groups) at baseline (e.g., metal object in the body which precludes performance of MRI).

• Age greater than 28 days and less than 85 years.
• Planned complex cardiac surgery with planned use of cardiopulmonary bypass.

• Expected order for washed or volume reduced platelets.
• Patient with known anti-platelet antibodies.
• Platelet transfusion refractoriness due to anti-HLA antibodies.
• Known or suspected pregnancy.
• Previously randomized in this study.
• Conscious objection or unwillingness to receive blood products.
• Known IgA deficiency.
• Known congenital platelet disorder.
• Known congenital bleeding disorder.
• Planned post-operative extracorporeal membrane oxygenation (ECMO), ventricular assist device (VAD), and/or continuous renal replacement therapy (CRRT)/ hemodialysis.
• Patients intended to receive whole blood either intra-operative or post-operative for bleeding.
• Platelet transfusion (of any type) within 24 hours prior to receiving study platelets.
• Pre-operative thrombocytopenia.

Eligibility last updated 11/2/21. Questions regarding updates should be directed to the study team contact.

• Resident, fellow or teaching physicians participating and endoscopic sinus surgery for chronic rhinosinusitis.

• Anyone not meeting inclusion criteria or anyone not wishing to participate.

• Written informed consent.
• Age ≥ 18 years.
• Presenting with at least one of the three criteria below as evidence of systemic MCA:
  • Involvement of 2 or more organ systems, characterized by skin (pruritus, urticaria, flushing and angioedema), cardiovascular (tachycardia, syncope, and hypotension), gastrointestinal (diarrhea, nausea, vomiting, and gastrointestinal cramping) or respiratory/naso-ocular (wheezing, conjunctival injection, and nasal stuffiness) AND sBT levels ≥ 8 ng/ml. One of the organ systems must be the cardiovascular system;
  • Involvement of 2 or more organ systems, characterized by skin (pruritus, urticaria, flushing, and angioedema), cardiovascular (tachycardia, syncope, and hypotension), gastrointestinal (diarrhea, nausea, vomiting, and gastrointestinal cramping) or respiratory/naso-ocular (wheezing, conjunctival injection, and nasal stuffiness) AND sBT levels ≥ 8 ng/ml. One of the organ systems must be the cardiovascular system;
  • Severe anaphylaxis (Ring and Messmer grading ≥ II) due to Hymenoptera sting, regardless of sBT levels;
  • Severe anaphylaxis (Ring and Messmer grading ≥ II), with cardiovascular involvement and documented event-related tryptase elevation fitting the formula 20% of baseline plus 2 ng/ml evaluated in at least 1 event.

• Patient diagnosed with any of the following WHO SM sub-classifications:
  • Mastocytosis in the Skin (MIS; Adult CM);
  • Indolent Systemic Mastocytosis (ISM);
  • Smoldering Systemic Mastocytosis (SSM);
  • SM-Associated Hematologic Neoplasm (SM-AHN);
  • Aggressive Systemic Mastocytosis (ASM);
  • MC Leukemia (MCL);
  • MC Sarcoma (MCS).

Eligibility last updated 5/13/22. Questions regarding updates should be directed to the study team contact.

Registration
•

• Age ≥ 18 years.
• Histologically or cytologically-confirmed cancer in an advanced incurable stage.
• ECOG Performance Status (PS) 0, 1 or 2.
• Chronic nausea that has been present for at least one week (daily score > 5, on a 0-10 visual analogue scale).
• Serum creatinine < 2.0 mg/dl and SGOT (AST) or SGPT (ALT) values < 3 times upper limits of normal, ≤ 120 days prior to registration.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Able to provide written informed consent.
• Able to complete questionnaire(s) by themselves or with assistance.

Registration
•

Any of the following because this study involves:

• An agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons.
• Received chemotherapy or radiation within the prior 14 days (advanced cancer patients receiving hormonal therapy or targeted therapy that does not come with a recommendation for prophylactic anti-emetic therapy are eligible).
• Receiving treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone for ≤ 30 days prior to registration or planned during protocol therapy (patients may have received prochloperazine and other phenothiazines as prior anti-emetic therapy).           
• Those with concurrent use of ethyol; severe cognitive compromise; concurrent use of amifostine; concurrent use of quinolone antibiotic therapy; known hypersensitivity to olanzapine; or have planned chemotherapy or radiation during the 7 days following study initiation.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection (including HIV);
  • cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient;
  • psychiatric illness/social situations that would limit compliance with study requirements.
• Inability to swallow oral formulations of the agent(s).
• Tube feeding or nasogastric tube.

Eligibility last updated 10/27/21. Questions regarding updates should be directed to the study team contact.

Registration
•

• Age ≥ 18 years.
• Histologically or cytologically-confirmed cancer in an advanced incurable stage.
• ECOG Performance Status (PS) 0, 1 or 2.
• Chronic nausea that has been present for at least one week (daily score > 5, on a 0-10 visual analogue scale).
• Serum creatinine < 2.0 mg/dl and SGOT (AST) or SGPT (ALT) values < 3 times upper limits of normal, ≤ 120 days prior to registration.
• Negative pregnancy test done ≤ 7 days prior to registration, for persons of childbearing potential only.
• Able to provide written informed consent.
• Able to complete questionnaire(s) by themselves or with assistance.

Registration
•

Any of the following because this study involves:

• An agent that has known genotoxic, mutagenic and teratogenic effects:
  • Pregnant persons;
  • Nursing persons.
• Received chemotherapy or radiation within the prior 14 days (advanced cancer patients receiving hormonal therapy or targeted therapy that does not come with a recommendation for prophylactic anti-emetic therapy are eligible).
• Receiving treatment with another antipsychotic agent such as risperidone, quetiapine, clozapine, phenothiazine or butyrophenone for ≤ 30 days prior to registration or planned during protocol therapy (patients may have received prochloperazine and other phenothiazines as prior anti-emetic therapy).           
• Those with concurrent use of ethyol; severe cognitive compromise; concurrent use of amifostine; concurrent use of quinolone antibiotic therapy; known hypersensitivity to olanzapine; or have planned chemotherapy or radiation during the 7 days following study initiation.
• Uncontrolled intercurrent illness including, but not limited to:
  • ongoing or active infection (including HIV);
  • cardiac disease which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient;
  • psychiatric illness/social situations that would limit compliance with study requirements.
• Inability to swallow oral formulations of the agent(s).
• Tube feeding or nasogastric tube.

Eligibility last updated 10/27/21. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.
• Biopsy proven Focal Segmental Glomerulosclerosis (FSGS) lesion
• Foot process effacement ≥ 80% on electron microscopy.
• Presence of nephrotic syndrome (proteinuria > 3.5g/24hrs and serum albumin < 3.5 g/dl) prior to initiation of immunosuppressive therapy.
• Resistant or dependent on therapy, including corticosteroids or calcineurin inhibitors or who have failed rituximab. Patient who have contraindication to or refuse to take high dose corticosteroids are allowed. 

• Genetic or secondary forms of FSGS.
• Hepatitis B, C or HIV positive.
• Pregnant or breast-feeding.
• Active infection.
• Kidney transplant.
• Anemia with Hgb < 8.0 g/dL.
• Thrombocytopenia with platelet count < 100’000.
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complication.
• Patients who have received cyclophosphamide in the last 6 months.
• Patients who received rituximab previously with CD20 count of < 5 cells/microliter  at the time of enrollment.
• For women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use two adequate methods of contraception, including at least one method with a failure rate of less than (<) 1 percent (%) per year, during the treatment period and for at least 18 months after the last dose of study drug.
• For men: agreement to remain abstinent or use two adequate methods for contraception, including at least one method with failure rate of less than 1% per year during the treatment period and for at least 6 months (180 days) after the last dose of drug.

• Males or females, aged ≥ 50 years and ≤ 89 years.
• An ETDRS BCVA letter score between ≤ 78 and ≥ 40 in the study eye at Screening Visit 1.
• If both eyes are eligible, the study eye must be the participant’s worse-seeing eye, as determined by the investigator prior to randomization.
• Must have a diagnosis of subfoveal CNV secondary to AMD in the study eye, along with fluid within the parafovea (3-mm center of the macula, based on the early treatment diabetic retinopathy grid) at Screening Visit 1.
  • CNV lesion characteristics as assessed by the CRC: lesion size needs to be less than 10-disc areas (typical disc area = 2.54 mm^2).
• Must be pseudophakic (at least 12 weeks postcataract surgery) in the study eye.
• Must be willing and able to comply with all study procedures and be available for the duration of the study.
• Women must be postmenopausal (defined as being at least 12 consecutive months without menses) or surgically sterilized (ie, having a bilateral tubal ligation/bilateral salpingectomy, bilateral tubal occlusive procedure, hysterectomy, or bilateral oophorectomy).
• Male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms (and their partners to use a medically accepted method of contraception) from the day of RGX-314 administration until 4 weeks after RGX-314 administration.
• Must be willing and able to provide written, signed informed consent.
• Response criteria: Based on the Screening Visit 2 SD-OCT, participants must have improvement in fluid of > 50 μm or, if the participant has < 50 μm of fluid, then any improvement in fluid and have a CRT < 400 μm at the screening visit, as determined by the CRC. Note that, if the participant has disease other than fluid contributing to an increase (i.e., pigment epithelial detachment [PED] or subretinal hyper-reflective material [SHRM]) in CRT, they will be enrolled if they have < 50 μm of fluid (intraretinal or subretinal), as determined by the CRC.
• Additionally, participants who received 10 to 12 anti-VEGF injections in the study eye in the 12 months prior to Screening Visit 1 must demonstrate a complete fluid response as determined by CRC review of the Screening Visit 2 SD-OCT, defined as complete resolution of fluid.

• CNV or macular edema in the study eye secondary to any causes other than AMD.
• Subfoveal fibrosis or atrophy as determined by the CRC.
• Study eye that required > 12 anti-VEGF injections in the 12 months prior to the Screening Visit
• Any condition in the investigator’s opinion that could limit VA improvement in the study eye.
• Active or history of retinal detachment in the study eye.
• Advanced glaucoma in the study eye defined as IOP of > 23 mmHg not controlled by 2 IOP-lowering medications or any invasive procedure to treat glaucoma (e.g., shunt, tube, or minimally invasive glaucoma surgery [MIGS] devices; selective laser trabeculectomy, and argon laser trabeculoplasty are permitted).
• Study eye with nAMD diagnosed > 4 years from Screening Visit 1.
• Any condition in the study eye that, in the opinion of the investigator, may increase the risk to the participant, require either medical or surgical intervention during the course of the study to prevent or treat vision loss, or interfere with study procedures or assessments.
• History of intraocular surgery in the study eye within 12 weeks prior to Screening Visit 1. Yttrium aluminum garnet capsulotomy is permitted if performed > 10 weeks prior to the Screening Visit 1.
• History of intravitreal therapy in the study eye, such as intravitreal steroid injection or investigational product, other than anti-VEGF therapy, in the 6 months prior to Screening Visit 1.
• Presence of any implant in the study eye at Screening Visit 1 (excluding intraocular lens or MIGS).
• History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation in the 5 years prior to Screening Visit 1. Localized basal cell carcinoma will be permitted.
• Receipt of any investigational product within the 30 days of enrollment or 5 half-lives of the investigational product, whichever is longer.
• Received gene therapy.
• History of retinal toxicity caused by a therapy that may affect VA, eg, chloroquine or hydroxychloroquine.
• Ocular or periocular infection in the study eye that may interfere with the surgical procedure.
• Myocardial infarction, cerebrovascular accident, or transient ischemic attack within the past 6 months.
• Uncontrolled hypertension (systolic blood pressure [BP] > 180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
• Any participant with the following laboratory values at Screening Visit 1 will be withdrawn from study:
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 × upper limit of normal (ULN);
  • Total bilirubin > 1.5 × ULN, unless the participant has a previously known history of Gilbert’s syndrome and a fractionated bilirubin that shows conjugated bilirubin < 35% of total bilirubin;
  • Prothrombin time > 1.5 × ULN, unless the participant is anticoagulated:
    • Participants who are anticoagulated will be monitored by local labs and managed per local practice to hold or bridge anticoagulant therapy for the study procedure; consultation with the Medical Monitor is also required;
  • Hemoglobin < 10 g/dL for male participants and < 9 g/dL for female participants;
  • Platelets < 100 × 10^3/μL;
  • Estimated glomerular filtration rate < 30 mL/min/1.73 m^2.
• Currently taking anticoagulation therapy for which holding anticoagulation therapy for RGX-314 administration is not indicated or considered to be unsafe in the opinion of the treating investigator (i.e., retinal surgeon), as well as the physician prescribing anticoagulation for the participant.
• Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.
• Known hypersensitivity to ranibizumab or any of its components.
• Has a serious, chronic, or unstable medical or psychological condition that, in the opinion of the investigator or Sponsor, may compromise the participant’s safety or ability to complete all assessments and follow-up in the study.
• Prior corneal transplant in the study eye.
• Pigmentary glaucoma in the study eye.

Inclusion Criteria for Participants in the Control Arm Who Cross Over to RGX-314 Treatment After Week 54:

• Study eye will be the eye that qualified at randomization.
• Study eye has a CRT < 400 μm of fluid or (in cases where a participant may have nonfluid elevation in the CRT, eg, pigment epithelial defect) < 50 μm of excess fluid, as confirmed by the masked CRC.
• Male participants engaged in a sexual relationship with a woman of childbearing potential must be willing to use condoms (and their partners to use a medically accepted method of contraception) from the day of RGX-314 administration until 4 weeks after RGX-314 administration.

• CNV or macular edema in the study eye secondary to any causes other than AMD.
• New subfoveal fibrosis or atrophy since randomization, as determined by the CRC, or any condition preventing VA improvement in the study eye.
• Ocular or periocular infection in the study eye that may interfere with the surgical procedure.
• Myocardial infarction, cerebrovascular accident, or transient ischemic attacks since randomization.
• Uncontrolled hypertension (systolic BP > 180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
• Any concomitant treatment that, in the opinion of the investigator, may interfere with ocular surgical procedure or healing process.
• History of malignancy or hematologic malignancy that may compromise the immune system requiring chemotherapy and/or radiation since randomization. Localized basal cell carcinoma will be permitted.
• Currently taking anticoagulation therapy for which holding anticoagulation therapy for RGX-314 administration is not indicated or considered to be unsafe in the opinion of the treating investigator as well as the physician prescribing anticoagulation for the participant.

Eligibility last updated 10/27/21. Questions regarding updates should be directed to the study team contact.

​​​​​​

• Lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 1 cm with CT or MRI (or ≥ 1.5 cm for lymph nodes). Non-measurable disease includes disease smaller than these dimensions or lesions considered truly nonmeasurable including: leptomeningeal disease, ascites, pleural or pericardial effusion, lymphangitic involvement of skin or lung.
• Prior treatment with other chemotherapy, radiotherapy (including peptide radionuclide receptor therapy [PRRT]), or surgery must be completed ≥ 28 days prior to registration. Patients must have recovered from any effects of any major surgery prior to registration. Prior treatment with radiolabeled MIBG must be completed ≥ 12 weeks prior to registration and lifetime cumulative 131I-MIBG dose must be < 1000 MBq kg-1 (36 mCi kg-1 ). Prior treatment with antibiotics must be completed ≥ 7 days prior to registration. No prior treatment with temozolomide, dacarbazine, or a poly ADP ribose polymerase (PARP) inhibitor. No prior allogeneic bone marrow transplant or double umbilical cord blood transplantation (dUCBT).
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic, and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 7 days prior to registration is required.
• Therapy utilized in this trial is associated with medium/high fetal risk. Women of childbearing potential and their partners, who are sexually active, must agree to use two highly effective forms of contraception in combination. This should be started from the time of registration and continue throughout the period of taking study treatment and for at least 1 month after last dose of study drug(s), or they must totally/truly abstain from any form of sexual intercourse. Male patients must use a condom during treatment and for 3 months after the last dose of study drug(s) when having sexual intercourse with a pregnant woman or with a woman of childbearing potential. Female partners of male patients should also use a highly effective form of contraception if they are of childbearing potential.
• Male patients should not donate sperm throughout the period of taking study drug(s) and for 3 months following the last dose of study drug(s).
• Age ≥ 18 years old.
• ECOG Performance Status: 0-2.
• Required Initial Laboratory Values:
  • Absolute Neutrophil Count ≥ 1,500/mm^3;
  • Platelet Count ≥ 100,000/mm3;
  • Hemoglobin ≥ 10 mg/dL* ;
  • Total Bilirubin ≤ 1.5 x upper limit of normal (ULN)** ;
  • AST/ALT ≤ 3.0 x ULN;
  • Creatinine < 1.5 x ULN OR Calc. Creatinine Clearance > 50 mL/min.***

*.   In the absence of transfusion within the previous 24 hours.
**   Except in the case of Gilbert’s syndrome, then Total Bilirubin must be ≤ 3.0 x ULN.
*** Calculated by Cockcroft-Gault equation.

• No indication of uncontrolled, potentially reversible cardiac condition(s) as determined by investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, QTcF prolongation > 500 msec, electrolyte disturbances, etc.) and no known congenital long QT syndrome.
• No extensive bilateral lung disease or pneumonitis.
• No abnormal organ or bone marrow function ≤ 28 days prior to registration.
• Patients with HIV positivity are allowed if CD4 Count > 250 cells/μL and they have an undetectable HIV viral load within 6 months of registration.
• No active infection.
• No history of myelodysplastic syndrome (MDS) (or any dysplastic leukocyte morphology suggestive of MDS) or acute myeloid leukemia.
• No known gastrointestinal condition(s) that might predispose for drug intolerability or poor drug absorption.
• No known medical condition causing an inability to swallow oral formulations of agents.
• No history of allergic reaction attributed to compounds of similar chemical or biologic composition to PARP inhibitors.
• Concurrent use of combination antiretroviral therapy (ART) is not permitted.
• Chronic concomitant treatment with strong or moderate CYP3A4 inducers or inhibitors is not allowed.
• Patients must discontinue the agent(s) ≥ 21 days prior to registration; enzalutamide and/or phenobarbital must be discontinued ≥ 5 weeks prior to registration. 

• Age 18-75.
• Persistent (at least 12 weeks apart) aPL-positivity within 12 months prior to the screening defined as: o aCL IgG/M/A (> 40U, medium-to-high titer, and/or greater than the 99th percentile) and/or o aβ2GPI IgG/M/A (>40U, medium-to-high titer, and/or greater than the 99th percentile) and/or o Positive LA test based on the International Society of Thrombosis & Haematosis Recommendations.

• Patient refusal.
• Inability to comply with study and follow-up procedures.

• Age 18+.
• English speaking.
• Consented for Outcomes Registry Study (15-000136).
• Undergoing radiotherapy for cancer treatment with curative intent.
• Willing to and able to give consent and participate in study.
• Willing to complete all questionnaires and surveys.
• Able to access a device (computer, smartphone, or tablet) with web access every day to complete study surveys.
• Willing to connect to a device (i.e., a smartphone, Fitbit or tablet) that can regularly link to Hugo for data transfer.
• Willing to use the Hugo health data sharing platform.
• Willing to create a Mayo Clinic Patient Portal (if not already created).

• Unable to give consent and enroll prior to administration of baseline survey.
• Partial breast RT (3 fraction), due to overlap in cadence used for all disease sites.
• SBRT to the lung, due to overlap in cadence used for all disease sites.
• Co-enrollment on another PRO related study (soft rule):
  • Coordinator would need to get source data from Adam via Hugo;
  • Response data will only be accessible by select people.

• Provision of signed and dated informed consent form.
• Adults, males and females, ages 18 -79 who have a bilateral sensorineural hearing loss with postlingual onset.
• Minimum of 30 days experience with appropriately fit binaural amplification (standardized NAL fitting method) verified with real ear measurements within 5 dB SPL of targets.
• Limited benefit from conventional amplification in the best aided condition as defined by test scores of:
  • The ear to implanted: CNC words ≤ 60% or AzBio sentences (+10, +5 dB SNR ≤ 60% correct);
  • Contralateral ear: ≤ 80% on CNC words or AzBio sentences (+10, +5 dB SNR ≤ 80% correct);
  • Low frequency Pure Tone Average (PTA- 125, 250, 500 Hz) ≤ 55 dB HL in the ear to be implanted;
  • Severe to profound mid to high-frequency sensorineural hearing loss (threshold average of 1000, 2000, 3000, and 4000 Hz ≥75 dB HL) in the ear to be implanted;
  • Low frequency PTA ≤ 55 dB HL sloping to moderately severe to profound mid-to high frequency sensorineural hearing loss (threshold average of 1000, 2000, 3000, 4000 Hz ≥ 60 dB) in the contralateral ear.
• Proficient in English.
• Undergoing implantation with a current generation cochlear implant device from either Cochlear Limited or Advanced Bionics AG.
• Cochlear Limited devices include: Nucleus CI612, CI622, CI632, CI624.
• Advanced Bionics AG devices include:  HiFocus SlimJ, Mid-Scala.
• Stated willingness and ability to complete testing and all associated study visits.

• An individual who meets any of the following criteria will be excluded from participation in this study:
  • Previous cochlear implantation;
  • Prelingual onset of hearing loss;
  • Abnormal inner ear anatomy on CT imaging;
  • Auditory neuropathy spectrum disorder;
  • Retrocochlear pathology such as a vestibular schwannoma or stroke.
• Unwillingness or inability to comply with all investigational requirements including the randomization process.
• Additional medical, or social barriers that would prevent completion of all study requirements.
• Medical condition contraindicated for surgery.
• Device selection of Med El cochlear implant (per the patient’s selection).

• Written informed consent.
• Male or female between the ages of 18 and 75 years, inclusive, at Screening.
• Meets the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria for SSc with a total score of ≥ 9 (Van den Hoogen et al., 2013).
• Classified as having skin involvement proximal to the elbow and knee (diffuse cutaneous SSc subset by LeRoy and Medsger, 2001).
• At the time of enrollment, less than 36 months since the onset of the first SSc manifestation, other than Raynaud's phenomenon.
• Based on data available through medical history and/or medical records, the subject should have at least 1 of the following:
  • disease duration ≤ 18 months;
  • increase ≥ 3 in mRSS units compared with the last visit within the previous 1 month to 6 months;
  • involvement of 1 new body area with ≥ 2 mRSS units or 2 new body areas with ≥1 mRSS unit;
  • documentation of worsening skin thickening for subjects who did not have mRSS performed during the previous visit;
  • presence of tendon friction rub at Screening.
• Presence of at least 1 of the following features of elevated acute phase reactants at Screening:
  • high-sensitivity C-reactive protein (hsCRP) ≥0.6 mg/dL (≥ 6 mg/L);
  • erythrocyte sedimentation rate (ESR) ≥ 28 mm/hr;
  • platelet count ≥ 330 × 10^9/L (330,000/μL).
• Skin thickening from SSc in the forearm suitable for repeat biopsy.
• mRSS units ≥ 15 at Screening.
• FVC ≥ 45% predicted at Screening, as determined by spirometry.
• Willing and able to comply with the prescribed treatment protocol and evaluations for the duration of the trial.

• Positive for anti-centromere antibodies.
• Diagnosed with sine scleroderma or limited cutaneous SSc.
• Diagnosed with other autoimmune connective tissue diseases, except for fibromyalgia, scleroderma-associated myopathy and secondary Sjogren's syndrome.
• Scleroderma renal crisis diagnosed within 6 months of the Screening Visit.
• Any of the following cardiovascular diseases:
  • uncontrolled, severe hypertension (≥ 160/100 mmHg) or persistent low blood pressure (systolic blood pressure < 90 mmHg) within 6 months of Screening,
  •  myocardial infarction within 6 months of Screening,
  •  unstable cardiac angina within 6 months of Screening.
• DLCO < 40% predicted (corrected for hemoglobin). If severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure is of clinical concern for any subject, consider using a DLCO up to 6 months before the Screening Visit.
• Pulmonary arterial hypertension (PAH) by right heart catheterization requiring treatment with more than 1 oral PAH-approved therapy or any parenteral therapy. Treatment is allowed for erectile dysfunction and/or Raynaud's phenomenon/digital ulcers.
• Corticosteroid use for conditions other than SSc within 4 weeks prior to Screening (topical steroids for dermatological conditions and inhaled/intranasal/intra-articular steroids are allowed).
• Use of any other non-steroid immunosuppressive agent, small biologic molecule, cytotoxic or anti-fibrotic drug within 4 weeks of Screening, including cyclophosphamide, azathioprine (Imuran®) or other immunosuppressive or cytotoxic medication. Exceptions include mycophenolate mofetil (CellCept®), mycophenolic acid (Myfortic®), methotrexate and low-dose prednisone, as follows: use of CellCept ≤ 3 g/day, Myfortic ≤ 2.14 g/day, methotrexate ≤ 15 mg/week and prednisone ≤ 10 mg/day (or equivalent dosing of glucocorticoids) is allowed. Subjects taking CellCept, Myfortic or methotrexate must have been doing so for ≥ 6 months and the dose must have been stable for ≥ 16 weeks prior to the Day 1 Visit. Prednisone must have been at a stable dose for ≥ 8 weeks prior to the Day 1 Visit. It is acceptable to be on background low-dose prednisone and anti-malarial drug along with CellCept, Myfortic or methotrexate. Rituximab must not have been used within 6 months of the Day 1 Visit.
• Known active bacterial, viral, fungal, mycobacterial or other infection, including tuberculosis or atypical mycobacterial disease (fungal infections of nail beds are allowed).
• Use of a United States Food and Drug Administration-approved agent for SSc or an investigational agent for any condition within 90 days or 5 half-lives, whichever is longer, prior to Screening or anticipated use during the course of the trial. 12. Malignant condition in the past 5 years (except successfully treated basal/squamous cell carcinoma of the skin or cervical cancer in situ).
•  Women of childbearing potential or male subjects not agreeing to use highly effective method(s) of birth control throughout the trial and for 1 month after last dose of trial drug. Male subjects must refrain from sperm donation and females from egg/ova donation for this same time period.
• Pregnant or lactating women.
• Current drug or alcohol abuse or history of either within the previous 2 years, in the opinion of the Investigator or as reported by the subject.
• Previous enrollment in this trial or participation in a prior HZN-825 or SAR100842 clinical trial.
• Known history of positive test for human immunodeficiency virus.
• Active hepatitis (hepatitis B: positive hepatitis B surface antigen and positive anti-hepatitis B core antibody [anti-HBcAb] and negative hepatitis B surface antibody [HBsAb] or positive for HBcAb with a positive test for HBsAb and with presence of hepatitis B virus DNA at Screening; hepatitis C: positive anti-hepatitis C virus [anti-HCV] and positive RNA HCV).
• Current alcoholic liver disease, primary biliary cirrhosis or primary sclerosing cholangitis.
• Previous organ transplant (including allogeneic and autologous marrow transplant).
• International normalized ratio > 2, prolonged prothrombin time > 1.5 × the upper limit of normal (ULN) or partial thromboplastin time > 1.5 × ULN at Screening.
• Alanine aminotransferase or aspartate aminotransferase > 2 × ULN.
• Estimated glomerular filtration rate < 30 mL/min/1.73 m^2 at Screening.
• Total bilirubin > 2 × ULN. Subjects with documented diagnosis of Gilbert's syndrome may be enrolled if their total bilirubin is ≤ 3.0 mg/dL.
• Any other condition that, in the opinion of the Investigator, would preclude enrollment in the trial.

• All patients ≥ 16 years old.
• Scheduled for a primary Hip Arthroscopy at Mayo Clinic (Rochester, MN), and Mayo Clinic Orthopedics and Sports Medicine (Minneapolis, MN). 

• Patients with a medical history of known allergies or intolerance to allergies or intolerance to Motrin, Gabapentin, Tylenol, dexamethasone, tramadol, or Robaxin.
• Substantial alcohol or drug abuse.
• History of narcotics within 6 months of surgery.
• Pregnancy.
• Renal impairment.
• Peptic ulcer disease.
• GI bleeding.

• All patients ≥ 16 years old.
• Scheduled for a primary Hip Arthroscopy at Mayo Clinic (Rochester, MN), and Mayo Clinic Orthopedics and Sports Medicine (Minneapolis, MN). 

• Patients with a medical history of known allergies or intolerance to allergies or intolerance to Motrin, Gabapentin, Tylenol, dexamethasone, tramadol, or Robaxin.
• Substantial alcohol or drug abuse.
• History of narcotics within 6 months of surgery.
• Pregnancy.
• Renal impairment.
• Peptic ulcer disease.
• GI bleeding.

PRIOR TO STEP 1 REGISTRATION

• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration.
• High-risk disease defined as having at least one or more of the following:
  • PSA > 20 ng/mL prior to starting ADT;
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]);
  • Gleason score of 8-10;
  • Node positive by conventional imaging with a short axis of at least 1.0 cm;
  • Appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 120 days prior to registration;
    • Bone imaging within 120 days prior to registration;
      • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative Na F PET/CT or negative axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed).
  • Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or Na F PET will still be eligible.
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only.
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by > 10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e., N1), but whose nodes do not meet traditional size criteria for positivity (i.e., they measure ≤ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration.
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration).
  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility.
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) within 120 days prior to registration.
    • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible.
    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration).
    • Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration).
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (didanosine [DDI] is not permitted) with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to abiraterone acetate and apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with abiraterone acetate and apalutamide.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

PRIOR TO STEP 2 RANDOMIZATION

• Confirmation of Decipher score.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs.
• Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol.

For patients entering the Intensification Cohort ONLY:

• Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization.

For patients entering the Intensification Cohort ONLY:

• Serum potassium ≥ 3.5 mmol/L prior to Step 2 randomization.

PRIOR TO STEP 1 REGISTRATION

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI).
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration.
• Prior radical prostatectomy.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Current use of 5-alpha reductase inhibitor.
  • Note: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible.
• Didanosine (DDI) antiretroviral therapy is not permitted.
• History of any of the following:
  • Seizure disorder;
  • Current severe or unstable angina;
  • New York Heart Association Functional Classification III/IV;
    • Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
  • History of any condition that in the opinion of the investigator, would preclude participation in this study.
• Evidence of any of the following at registration:
  • Active uncontrolled infection requiring IV antibiotics;
  • Baseline moderate and severe hepatic impairment (Child-Pugh class B & C);
  • Inability to swallow oral pills;
  • Any current condition that in the opinion of the investigator, would preclude participation in this study.
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA and testosterone must be obtained prior to the start of any ADT.

PRIOR TO STEP 2 RANDOMIZATION

• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration.

For patients entering the Intensification Cohort ONLY:

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily.

For patients entering the Intensification Cohort ONLY:

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg);
• Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.

PRIOR TO STEP 1 REGISTRATION

• Pathologically proven diagnosis of adenocarcinoma of prostate cancer within 180 days prior to registration.
• High-risk disease defined as having at least one or more of the following:
  • PSA > 20 ng/mL prior to starting ADT;
  • cT3a-T4 by digital exam or imaging (American Joint Committee on Cancer [AJCC] 8th edition [Ed.]);
  • Gleason score of 8-10;
  • Node positive by conventional imaging with a short axis of at least 1.0 cm;
  • Appropriate stage for study entry based on the following diagnostic workup:
    • History/physical examination within 120 days prior to registration;
    • Bone imaging within 120 days prior to registration;
      • Note: To be eligible, patient must have no definitive evidence of bone metastases (M0) on bone scan or sodium fluoride (NaF) PET within 120 days prior to registration (negative Na F PET/CT or negative axumin or choline PET or negative fluciclovine, choline or prostate-specific membrane antigen (PSMA) PET within 120 days prior to registration is an acceptable substitute if they have been performed).
  • Patients who have bone metastases established only fluciclovine, choline, or PSMA PET but not definitive on bone scan or Na F PET will still be eligible.
  • CT or MRI of the pelvis within 120 days prior to registration (negative fluciclovine, choline, or PSMA PET within 120 days prior to registration is an acceptable substitute). As with bone staging, nodal staging for trial purposes will be based off of conventional imaging findings only.
  • Patients with confirmed N1 metastases on conventional imaging (CT/MRI) as defined by > 10 mm on short axis are eligible but will be automatically assigned to the intensification study. Patients who are positive by fluciclovine, choline, or PSMA PET (i.e., N1), but whose nodes do not meet traditional size criteria for positivity (i.e., they measure ≤ 10 mm on either the CT or MRI portion of the PET or on a dedicated CT or MRI) will not be considered N1 for the trial and will not automatically be assigned to the intensification study.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 120 days prior to registration.
  • Hemoglobin ≥ 9.0 g/dL, independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Platelet count ≥ 100,000 x 10^9/uL independent of transfusion and/or growth factors (within 120 days prior to registration).
  • Creatinine clearance (CrCl) ≥ 30 mL/min estimated by Cockcroft-Gault equation (within 120 days prior to registration).
  • For Black patients whose renal function is not considered adequate by Cockcroft-Gault formula, an alternative formula that takes race into account (Chronic Kidney Disease Epidemiology Collaboration CKD-EPI formula) may be used for calculating creatinine clearance for trial eligibility.
  • Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN) within 120 days prior to registration.
    • Note: In subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤ 1.5 x ULN, subject is eligible.
    • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) or alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 2.5 x institutional ULN (within 120 days prior to registration).
    • Serum albumin ≥ 3.0 g/dL (within 120 days prior to registration).
• The patient must agree to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agree to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug.
• Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy (didanosine [DDI] is not permitted) with undetectable viral load within 6 months are eligible for this trial and have a CD4 count ≥ 200 cells/microliter within 60 days prior to registration. Note: HIV testing is not required for eligibility for this protocol. Of note, for patients with HIV in the intensification trial randomized to abiraterone acetate and apalutamide, highly active antiretroviral therapy (HAART) may need to be adjusted to medications that do not interact with abiraterone acetate and apalutamide.
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable after or on suppressive therapy within 60 days prior to registration, if indicated.
  • Note: HBV viral testing is not required for eligibility for this protocol.
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
  • Note: Any patient with a cancer (other than keratinocyte carcinoma or carcinoma in situ or low-grade non-muscle invasive bladder cancer) who has been disease-free for less than 3 years must contact the principal investigator.
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry.

PRIOR TO STEP 2 RANDOMIZATION

• Confirmation of Decipher score.
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 60 days prior. Note: Apalutamide may interfere with HCV drugs.
• Patients on HCV medications should alert their infectious diseases physician if they get randomized to apalutamide due to the possibility that apalutamide can affect the bioavailability of some HCV medications. HCV viral testing is not required for eligibility for this protocol.

For patients entering the Intensification Cohort ONLY:

• Patients must discontinue or substitute concomitant medications known to lower the seizure threshold at least 30 days prior to Step 2 randomization.

For patients entering the Intensification Cohort ONLY:

• Serum potassium ≥ 3.5 mmol/L prior to Step 2 randomization.

PRIOR TO STEP 1 REGISTRATION

• Definitive radiologic evidence of metastatic disease outside of the pelvic nodes (M1a, M1b or M1c) on conventional imaging (i.e., bone scan, CT scan, MRI).
• Prior systemic chemotherapy within ≤ 3 years prior to registration; note that prior chemotherapy for a different cancer is allowed (completed > 3 years prior to registration.
• Prior radical prostatectomy.
• Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Current use of 5-alpha reductase inhibitor.
  • Note: If the alpha reductase inhibitor is stopped prior to randomization the patient is eligible.
• Didanosine (DDI) antiretroviral therapy is not permitted.
• History of any of the following:
  • Seizure disorder;
  • Current severe or unstable angina;
  • New York Heart Association Functional Classification III/IV;
    • Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification.
  • History of any condition that in the opinion of the investigator, would preclude participation in this study.
• Evidence of any of the following at registration:
  • Active uncontrolled infection requiring IV antibiotics;
  • Baseline moderate and severe hepatic impairment (Child-Pugh class B & C);
  • Inability to swallow oral pills;
  • Any current condition that in the opinion of the investigator, would preclude participation in this study.
• Prior pharmacologic androgen ablation for prostate cancer is allowed only if the onset of androgen ablation (both luteinizing hormone-releasing hormone [LHRH] agonist and oral anti-androgen) is ≤ 60 days prior to registration; Please note: baseline PSA and testosterone must be obtained prior to the start of any ADT.

PRIOR TO STEP 2 RANDOMIZATION

• Evidence of known gastrointestinal disorder affecting absorption of oral medications at registration.

For patients entering the Intensification Cohort ONLY:

• Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/prednisolone once daily.

For patients entering the Intensification Cohort ONLY:

• Presence of uncontrolled hypertension (persistent systolic blood pressure [BP] ≥ 160 mmHg or diastolic BP ≥ 100 mmHg);
• Subjects with a history of hypertension are allowed, provided that BP is controlled to within these limits by anti-hypertensive treatment.