• Adult men originally from each of these geographic regions (East, West, Central, and Southern Africa) and have been diagnosed with prostate cancer. 
• Able to provide oral consent and conduct an interview.

• Patients below the age of 18.
• Patients not belonging to any of four regions.

• Renal function at screening:
• Creatinine clearance: < 50 mL/min as determined using the Cockcroft-Gault formula; 
• Albumin: < LLN;
• Hepatic function at screening: AST and/or ALT: > 2.5 x ULN;
• Total Bilirubin (serum): >1.5 x ULN.

4. Subject has received neo-adjuvant therapy, radiation therapy, focal ablation therapy, hormonal therapy, or androgen deprivation therapy within the last 4 months.

5. Subject is currently receiving an investigational therapeutic agent; or has participated in a study of an investigational therapeutic agent within the past 6 months prior to the day of IS-002 infusion; or is involved in a significant risk
investigational device study within the past 6 months prior to the day of IS-002 infusion.

6. Subject has any other condition or personal circumstance that, in the judgment of the site Investigator, might interfere with the collection of complete quality data or represents an unacceptable safety profile.

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

Eligibility last updated 9/28/23. Questions regarding updates should be directed to the study team contact.

• Patient age ≥ 18 years.
• Patient has presented to the Renal Studies Unit for a short renal clearance (iothalamate) study ordered by his/her health care provider.

• History of severe reaction to contrast agents or iodine.
• Patients who are know to be pregnant.

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

Eligibility last updated 7/20/23. Questions regarding updates should be directed to the study team contact.

• Patients presenting for evaluation of an ocular tumor.
• Age ≥18 years.
• Any gender.
• Have capacity to consent.

• Inability to provide informed consent.
• Lack of an ocular tumor.
• Lack of evaluation in the Mayo Clinic Rochester clinical practice.

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

Eligibility last updated 3/24/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 40 years.
• Clinically localized prostate cancer (American Urological Association Grade Groups 1-2; cT1c or cT2a-b; PSA < 10) without clinic or imaging evidence of localized extra-prostatic or metastatic disease (i.e., AUA low and favorable intermediate risk prostate cancer).
• International Index of Erectile Function (IIEF) of ≥ 21 points at baseline (no or mild erectile dysfunction).
• Patient-expressed interest in consultation for sexual function (erectile function) preservation/ optimization.
• Planned bilateral nerves-paring prostatectomy.

• Moderate or severe ED based in IIEF criteria (score < 21).
• History of prior pelvic or penile surgery.
• Current or prior androgen deprivation therapy.
• Planned non-nerve sparing prostatectomy.

Eligibility last updated 4/14/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 60 years.
• Post-menopausal status
  •determined by self-reported last menstrual period ≥ 1 year ago, and/or history of hysterectomy +/- bilateral oophorectomy.
• Diagnosis of Multiple Myeloma (MM) based on IMWG diagnostic criteria, leukemia (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia) myelodysplastic syndrome, lymphoma (non-hodgkins lymphoma, hodgkins lymphoma).
• Planned to start a new treatment within 30 days at Mayo Clinic in Rochester, MN. Patients who are receiving treatment at a location other than Mayo Clinic in Rochester, MN but undergoing evaluation prior to each cycle at Mayo Clinic in Rochester, MN.
• Transplant eligible or ineligible.
• Fluent in English (all assessment tools are in English).
• Able to provide written informed consent.

• Not able to give informed consent.

Eligibility last updated 7/10/23. Questions regarding updates should be directed to the study team contact.

Candidates for this study must meet ALL of the following criteria:

• Patient is 22 years of age or older.
• Patient has suspected or confirmed metastatic cancer within the lungs, or stage IV nonsmall cell lung cancer (NSCLC) requiring biopsy.
• Patient has radiologically documented suspected or confirmed tumor(s) that are ≤ 5 cm in longest diameter and deemed suitable by the investigator per study procedural guidelines for treatment with PEF.
• Patient is deemed eligible to receive 1L SOC therapy for their malignancy.
• In the opinion of the investigator, the patient is not a surgical candidate for curative intent, or the patient has refused surgery.
• Life expectancy ≥ 6 months.
• Patient has provided informed consent.

Candidates will be excluded if ANY of the following apply:

• Patient has received any prior cancer therapy for current tumor(s) to be treated with PEF.
• Patient is scheduled to receive investigational therapies (including device-based therapy) that may interfere with the study endpoints while on this study.
• Patient has clinical evidence of leptomeningeal disease or brain metastases that require SOC treatment within 4 weeks post-PEF treatment.
• Patient with active, known, or suspected autoimmune disease:
  • Patient with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll;
  • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• Patient has received systemic treatment with corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 30 days prior to study enrollment. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone or equivalent are permitted in the absence of active autoimmune disease.
• Patient has any history of primary immunodeficiency.
• Patient has clinical signs or symptoms of active tuberculosis infection.
• Patient has documented evidence of acute hepatitis or has an active or uncontrolled infection.
• Patient has undergone major surgery (excluding placement of vascular access) within 28 days prior to study enrollment or has planned major surgeries while enrolled in the study.
• Patient with ≥ Grade 2 peripheral neuropathy.
• Patient has received any vaccine against infectious diseases (e.g., influenza, COVID-19, varicella, etc.) within 30 days of PEF procedure.
• Patient has electronic implant(s) such as cardiac pacemaker, and the patient is not suitable for PEF treatment in the opinion of the investigator.
• Patient has active alcohol or drug addiction or any other condition that, in the investigator’s opinion, would interfere with their ability to comply with the study requirements or jeopardize the safety of the patient or compliance with the protocol.
• Patient is unable or unwilling to complete all required study activities.
• Patient is pregnant or nursing.
• Patient is involuntarily incarcerated or compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness.

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

Eligibility last updated 5/16/23. Questions regarding updates should be directed to the study team contact.

• For 20 healthy controls, individuals without a history of easy bruising/bleeding who have not consumed aspirin-containing prescription or over-the-counter medications or prescription anti-platelet agents for 10 days prior to study enrollment. 
• For the 20 volunteers in the anti-platelet agent group, 20 patients who have taken both aspirin and clopidogrel [KBMP1] on the day of study enrollment.

• History of easy bruising/bleeding, taking over-the-counter or prescription aspirin or anti-platelet medication (group 1).
• Not taking either aspirin or clopidogrel on the day of the study, abnormal hemoglobin or platelet count, active bleeding (group 2). 

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

  Eligibility last updated 5/1/23. Questions regarding updates should be directed to the study team contact.

• Male with original diagnosis of adenocarcinoma of the prostate following definitive therapy.
• Men with Biochemical Recurrence (defined below) and planned to undergo PSMA PET imaging:
  • After radiotherapy or cryotherapy: 3 consecutive PSA rises and/or PSA rise by 2.0 ng/mL or more above nadir (ASTRO-Phoenix);
  • After prostatectomy, PSA > 0.2 ng/mL on 2 or more determinations (American Urological Association).
• Life expectancy of 6 months or more as judged by the investigator.
• Willing and able to undergo all study procedures.
• Informed consent in writing (dated and signed).

• Age: less than 18 years.
• Variant prostate pathology including but not limited to :
  • Small cell prostate cancer;
  • Ductal prostate cancer;
  • Neuroendocrine prostate cancer.
• Prior focal therapy for prostate cancer.
• Prior neoadjuvant therapy for prosate cancer.
• Contraindications to any of the ingredients of PET.
• Close affiliation with the investigational site; e.g., first-degree relative of the investigator.
• Mental conditions rendering the subject incapable to understand the nature, scope, and consequences of the trial.
• Being clinically unstable or requiring emergency treatment.
• Patients who are unable to undergo a PET/CT scan (e.g., patients who are extremely obese, unable to lie flat or remain still, or have uncontrollable claustrophobia).

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

Eligibility last updated 9/25/23.  Questions regarding updates should be directed to the study team contact.

• Patients must have biopsy-confirmed high grade serous epithelial ovarian cancer.
• Patients must present with stage III or IV disease and be appropriate to receive neoadjuvant chemotherapy.
• Patients must be willing to provide an archival tumor tissue block or slides, or undergo procedure to obtain a new biopsy using a low-risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FR? positivity.
• Patients must have a performance status of 0 or 1.
• Patient's tumor must be positive for FR? expression as defined by a score of PS2+ intensity in > 75% of cells.
• Patients must have adequate hematologic, liver and kidney functions defined as:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1,500/µL);
  • Platelet count ≥ 100 x 10^9/L (100,000/µL) without platelet transfusion in the prior 10 days;
  • Hemoglobin ≥ 9.0 g/dL;
  • Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN;
  • Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin < 3.0 x ULN);
  • Serum albumin ≥ 2 g/dL.
• Patients must be willing and able to sign the informed consent form (ICF) and to adhere to the protocol requirements.
• Women of childbearing potential (WCBP) must agree to use highly effective contraceptive method(s) (while on MIRV and for at least 4 months after the last dose.
• WCBP must have a negative pregnancy test within the 4 days prior to the first dose of MIRV.

• Patients who have previously been treated with a systemic anti-cancer therapy.
• Patients with low-grade serous, endometrioid, clear cell, or mucinous histology.
• Patients with active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and /or monocular vision.
• Patients with serious concurrent illness or clinically relevant active infection, including, but not limited to the following:
  • History of hepatitis B or C infection (whether or not on active antiviral therapy);
  • History of human immunodeficiency virus (HIV) infection;
  • Any other concurrent infectious disease requiring IV antibiotics within 2 weeks prior to the first dose of MIRV.
• Patients with a history of multiple sclerosis (MS) or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome).
• Patients with clinically significant cardiac disease including, but not limited to, any of the following:
  • Myocardial infarction ≤ 6 months prior to first dose;
  • Unstable angina pectoris;
  • Uncontrolled congestive heart failure (New York Heart Association > class II);
  • Uncontrolled ≥ Grade 3 hypertension (per CTCAE);
  • Uncontrolled cardiac arrhythmias;
  • Patients with a history of hemorrhagic or ischemic stroke within 6 months prior to enrollment;
  • Patients with a history of cirrhotic liver disease (Child-Pugh Class B or C);
  • Patients with a previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonitis.
• Patients requiring use of folate-containing supplements (e.g., folate deficiency)
• Patients with prior hypersensitivity to monoclonal antibodies (mAb)
• Women who are pregnant or breastfeeding
• Patients who received prior treatment with MIRV or other FRα-targeting agents
• Patients with untreated or symptomatic central nervous system (CNS) metastases
• Patients with a history of other malignancy within 3 years prior to enrollment.
  • Note:  patients with tumors with a negligible risk for metastasis or death (e.g., adequately controlled basal-cell carcinoma or squamous-cell carcinoma of the skin, or carcinoma in situ of the cervix or breast) are eligible.

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

Eligibility last updated 12/8/22. Questions regarding updates should be directed to the study team contact.

• History of Non-Hodgkin's Lymphoma (NHL) with relapsed or refractory disease.
• Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.

• Life expectancy ≤ 2 months.
• Received prior systemic anti-cancer treatment (approved or investigational) ≤ 5 half-lives or 4 weeks prior to starting CC-99282, whichever is shorter.
• Is on chronic systemic immunosuppressive therapy or corticosteroids or has clinically significant graft-versus-host disease (GVHD).
• Impaired cardiac function or clinically significant cardiac disease.

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

Eligibility last updated 12/29/22. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age
• Completed mammography appointment at Mayo.
• Patients who enrolled in the STRIVE Study IRB#16-008471 previously consented to long-term follow-up. 

• < 18 years of age.

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

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

• Patients with acute hypoxemic and/or hypercapnic respiratory failure.
• Patients requiring intubation and mechanical ventilation for more than 24 hours.
• VentCoach protocol is specific to volume controlled continuous mandatory ventilation (S-CMV).
• Patient who are admitted to RMH 10-3/10-4 and MB 6BGF ICUs.
• Age greater than or equal to 18 years.
• Patient’s legal representative should be able to provide informed consent to the study. Any participant speaking any language will be offered participation.

• Intubation and mechanical ventilation for airway protection in the setting of procedures/surgeries; e.g. interventional radiology, surgery, or endoscopy.
• Intubation and mechanical ventilation due to drug overdose with expected extubation of less than 24 hours.
• Intubation and mechanical ventilation in the setting of cardiac arrest of primary cardiac etiology.
• Intubation and mechanical ventilation for a primary neurological etiology; e.g. increased intracranial pressure, tumor mass effect, ischemic/hemorrhagic stroke, status epilepticus, etc.
• Mechanical ventilation to be guided by esophageal balloon.
• Subject deprived of freedom, minor, subject under a legal protective measure.
• Change in end-of-life decision anticipated after enrollment (or estimated 6-month mortality rate of greater than 50%).

Note: Prone positioning is not a contraindication for participation.

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

Eligibility last updated 5/22/23. Questions regarding updates should be directed to the study team contact.

• Peri- and postmenopausal females (ages 45-60).

• Known adhesive allergies.

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

Eligibility last updated 6/1/23. Questions regarding updates should be directed to the study team contact.

• Confirmed genetic diagnosis of Friedreich’s Ataxia (FA), with onset being before 25 years of age.
• Protocol specified ranges for antibodies.
• Protocol specified measures of FA cardiomyopathy.

• Protocol specified ranges for left ventricular ejection fraction (LVEF) as measured by cardiac ECHO.
• Uncontrolled diabetes.
• Abnormal liver function.
• Active infection of any type, including hepatitis virus (A, B or C) or human immunodeficiency virus (HIV-1 and HIV-2).
• Contraindication to cardiac MRI.
• Contraindications to cardiac biopsies.
• Participants who are receiving systemic corticosteroids or other immunosuppressive medications.
• History of significant coronary artery disease or any structural heart or vascular disease other than FA cardiomyopathy.
• Presence of clinically significant, hemodynamically unstable arrhythmias, requiring physician intervention.
• Presence of clinically significant abnormalities as determined by the investigator, other than ECG abnormalities related to FA.
• Uncontrolled psychiatric disease.

Other Inclusion/Exclusion Criteria to be applied as per protocol.

Eligibility last updated 7/13/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 6/29/23. Questions regarding updates should be directed to the study team contact.

• Patients with adequate clinical residual serum ( ≥ 0.5 mcL) or prospectively drawn blood obtained within 10 days of native renal biopsy, and prior to initiation of immunosuppressive therapy. 
• The glomerular diseass of interest occur in varied patient populations; therefore, both adult and pediatric patients will be enrolled.   

• Does not meet Inclusion Criteria.

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

Eligibility last updated 4/14/23. Questions regarding updates should be directed to the study team contact.

• Female patients aged 18-53.
• Receiving or planning fertility treatment (ovulation induction (OI), intrauterine insemination (IUI), therapeutic donor insemination (TDI), in-vitro fertilization (IVF).

AND

• Reported depression screening scores: PHQ-9 score  >5;  OR
• Reported anxiety screening scores: GAD-7 score > 5;  OR
• Reported increase in infertility related stress: FPI score.

• Not English Speaking.
• Reported or recent psychotic episode within 6 months as documented in medical chart/EPIC.
• Psychiatric hospitalization in the past 6 months as documented in medical chart/EPIC.

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

Eligibility last updated 5/31/23. Questions regarding updates should be directed to the study team contact.

• Males or females, ≥ 18 years of age.
• Recurrent Prosthetic Joint Infection (PJI) of the knee or hip.
• History of one failed previous surgery for PJI.
• Female patients of childbearing potential who agree to use contraception.
• Confirmed phage match.
• No anticipated need for long-term antibiotics.

• Soft tissue defect requiring reconstruction.
• Hardware misalignment.
• Additional orthopedic hardware in connection with the infected prosthesis.
• Active infection (other than PJI) requiring long term antibiotics.
• Unable to tolerate SAT.
• Septic shock or hemodynamic instability.
• Chronic kidney disease.
• Liver disease.
• Decompensated heart failure.
• Positive drug screen.
• Receiving chemotherapy.
• Immunocompromised.
• Treatment with antiviral medication within 2 weeks prior to randomization.
• Currently participating in another clinical trial.
• Known phage allergy.
• Pregnant/ breast feeding.
• Lack of capacity to consent.

Eligibility last updated 4/6/23. Questions regarding updates should be directed to the study team contact.

• Disabling (moderate-to-severe) PTS, defined by a) presence of chronic venous disease > 3 months duration in a leg with history of DVT, as determined by the site principal investigator or a physician co-investigator; and b) substantial limitation of daily activities or work capacity due to venous symptoms or an open venous ulcer, per the same investigator.
• Ipsilateral iliac vein obstruction documented within 3 months prior to screening by either:
  • Occlusion or >50% stenosis of the iliac vein on venogram, CT venogram, MR venogram, or intravascular ultrasound (IVUS); or
  • Air plethysmography showing deep venous obstruction of the ipsilateral leg (reduced venous outflow fraction), and ultrasound showing echogenic material in the ipsilateral iliac vein and non-phasic continuous Doppler flow in the ipsilateral common femoral vein (CFV) in the presence of normal phasic Doppler flow in the contralateral CFV.

• Age less than 18 years.
• Acute ipsilateral proximal DVT episode within the last 3 months, or acute contralateral DVT for which thrombolytic therapy is planned.
• Lack of suitable inflow into the ipsilateral common femoral vein per the treating physician.
• Previous stent placement in the infrarenal IVC or ipsilateral iliac or common femoral vein.
• Absence of PTS of at least moderate severity.
• Chronic arterial limb ischemia (ankle-brachial index < 0.5 within the previous 1 month) in the ipsilateral leg (if peripheral arterial disease is present or suspected, an ankle-brachial index should be obtained and documented).
• Presence of open venous ulcer > 50 cm2 area, suspicion for active ulcer infection, or visualization of bone or tendon within the ulcer in the ipsilateral leg.
• Inability to tolerate endovascular procedure due to acute illness, or general health.
• Severe allergy to iodinated contrast refractory to steroid premedication.
• Known allergy to stent or catheter components.
• Hemoglobin < 8.0 g/dl, uncorrectable INR > 3.05, or platelet count < 75,000/ml.
• Severe renal impairment (on chronic dialysis or estimated GFR < 30 ml/min).
• Disseminated intravascular coagulation or other major bleeding diathesis.
• Pregnancy (positive pregnancy test).
• Life-expectancy < 6 months or chronically non-ambulatory for reasons other than PTS.
• Inability to provide informed consent or to comply with study assessments.
  • Note:  patients who initially meet an exclusion criterion can have eligibility re-evaluated on a subsequent occasion.

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

Eligibility last updated 12/15/22. Questions regarding updates should be directed to the study team contact.

Sequelae Group

• Age ≥18 years at screening, PCR confirmed COVID19 illness (+PCR defines day 0 of illness), hospitalization for COVID-19, absence of pre-existing history of interstitial lung disease, or significant other lung disease.
• Severity of illness will be categorized as moderate disease (supplemental oxygen need 1-8L at any time during hospitalization), severe disease (need for high flow oxygen delivery ≥ 8L at any time during hospitalization) and critical illness (need for ICU admission or mechanical ventilation).

Control Recovery Group

• Age ≥ 18 years at screening.
• PCR confirmed COVID-19 cases who had nonsymptomatic or mild acute infection that do not require hospitalization.
• Absence of pre-existing history of interstitial lung disease, or significant other lung disease, absence of any ongoing respiratory and systemic symptoms.

• Inability to provide informed consent, evidence of pre-existing interstitial lung disease or chronic lung disease.
• Active cigarette smoking, vaping or other inhalation use.
• Immunocompromised host status due to ongoing therapy with methotrexate CellCept, azathioprine, rituximab, cyclophosphamide or other biologic agents.
• > 20 pack year smoking history.
• history of chemotherapy or radiation therapy in the last two years; and pregnancy.

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

Eligibility last updated 2/20/23. Questions regarding updates should be directed to the study team contact.

• Previous experience with treadmill walking and the ability to complete four consecutive 6-minute walks for a total of twenty-four minutes of walking.

• Individuals reporting any abnormalities (e.g., due to orthopedic injury, lower limb pain, or neurological injury) that may impact gait or balance; required use of assistive devices.

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

Eligibility last updated 11/9/22. Questions regarding updates should be directed to the study team contact.

• Males and females aged ≥ 18 years (or ≥ 19 years according to local regulatory guidelines) at the time of screening.
• Has adequate organ and marrow function as defined in protocol.
• Measurable disease as per RECIST v1.1.
• ECOG performance status 0-1.
• Adverse events related to any prior chemotherapy, radiotherapy, immunotherapy, other prior systemic anti-cancer therapy, or surgery must have resolved to Grade ≤1, except alopecia and Grade 2 peripheral neuropathy.
• HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease as defined in protocol.

• Has known active CNS metastases and/or carcinomatous meningitis.
• An active second malignancy.
• Has active or a known history of Hepatitis B or known active Hepatitis C virus infection.
• Has active tuberculosis or has a known history of active tuberculosis.
• Active or uncontrolled infections, or severe infection within 4 weeks before study treatment administration.
• History of chronic liver disease or evidence of hepatic cirrhosis, except patients with liver metastasis.
• Has an active autoimmune disease that has required systemic treatment in past 2 years.
• Previous immunotherapies related to mode of action of GI-102.
• Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive medications within 2 weeks prior to Cycle 1 Day 1.
• Administration of prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to treatment.
• Radiotherapy within the last 2 weeks before start of study treatment administration, with exception of limited field palliative radiotherapy.
• Administration of a live, attenuated vaccine within 4 weeks before Cycle 1 Day 1.
• Known hypersensitivity to any of the components of the drug products and/or excipients of GI-102.

Eligibility last updated 7/6/23. Questions regarding updates should be directed to the study team contact.

• Males and females, 18-80 years of age.
• Patients with cHP for ≥ 12 months at the time of screening.
• Two paired measurements of showing low parathyroid hormone (PTH) and serum calcium either below normal or within normal under standard of care.
• Requirement for therapy with calcitriol ≥0.5 mcg per day or alphacalcidol ≥1 mcg per day, and requirement for supplemental oral calcium treatment ≥ 1000 mg per day over and above patient's dietary calcium intake at Day 1 visit.
• Successful completion of the Optimization period based on two consecutive measurements of albumin-adjusted serum calcium at least 1 week apart within the range of 7.8 to 9.0 mg/dL and with no more than 25% of change in the daily dose of any of active vitamin D and oral calcium supplements between the two measurements.
• Thyroid-stimulating hormone (TSH) within the lower limit of normal and 1.5-fold of the upper limit of normal at screening; if on suppressive therapy for a history of thyroid cancer, TSH level must be ≥ 0.2 mIU/mL and thyroid medication should be stable for at least 6 weeks prior to treatment.
• Prior to start of treatment:
  • Magnesium level within laboratory normal limits;
  • 25(OH) vitamin D levels of 30-70 ng/mL (75-175 nmol/L);
  • eGFR ≥ 30 mL/min/1.73m² during screening.
• Able to perform daily subcutaneous self-injections of study drug (or have a designee to perform injections) via a pre-filled injection pen.
• Female patients of non-childbearing potential or using an effective method of contraception throughout the study. Women of childbearing potential should have a negative pregnancy test.
• Able and willing to provide written and signed informed consent in accordance with GCP.

• Mental incapacity, unwillingness, or language barriers precluding adequate understanding or cooperation.
• Clinically significant abnormal values at screening for hematology, clinical chemistry, coagulation or urinalysis.
• Abnormal arterial pressure at screening, defined as (1) systolic blood pressure < 100 mmHg, or (2) systolic blood pressure > 150 mmHg, and/or diastolic blood pressure > 100 mmHg.
• Heart rate at rest outside the range of 50-100 beats/minute at screening.
• Clinically significant abnormal standard 12-lead electrocardiogram indicative of severe cardiac disease.
• Known history of autosomal-dominant hypocalcemia or known pseudohypoparathyroidism (impaired responsiveness to PTH).
• Any current disease (other than hypoparathyroidism) that might affect calcium metabolism, calcium-phosphate homeostasis or PTH levels.
• Patients with increased risk for osteosarcoma.
• Current uncontrolled active disease processes that may adversely affect gastrointestinal absorption.
• History of cerebrovascular accident within 6 months prior to screening.
• History of active uncontrolled malignancy over the past 2 years at time of screening.
• History of any other cancer other than thyroid cancer (except basal cell skin cancer or squamous cell skin cancer) who have not been disease-free for a period of at least 2 years at the time of screening.
• Acute gout < 2 months prior to screening.
• Dependent on parenteral calcium infusions to maintain calcium homeostasis.
• Use of medications such as loop and thiazide diuretics, raloxifene hydrochloride, lithium, methotrexate, cardiac glycosides or systemic corticosteroids within 4 weeks prior to start of treatment.
• Previous treatment with PTH/parathyroid hormone-related protein-like drugs, including PTH(1-84) and PTH(1-34) within 3 months of screening.
• Use of other drugs known to influence calcium and bone metabolism within 4 weeks of screening.
• Use of oral bisphosphonates within 6 months of screening or intravenous bisphosphonate within 12 months of screening.
• Use of denosumab within 18 months of screening.
• Seizure disorder/epilepsy with history of a seizure within 6 months of screening.
• History of symptomatic urinary tract calculi within 3 months of screening.
• Irradiation to the skeleton within 2 years of screening.
• Pregnant or breastfeeding female patients.
• Participation in any other interventional study in which the patient received an investigational drug or device within 2 months or within 5 times the half-life of the investigational drug (whichever comes first) prior to screening.
• Any disease or condition that, in the opinion of the investigator, may require treatment or make the subject unlikely to fully complete the trial, or any condition that presents undue risk from the study treatment or procedures, including treated malignancies that are likely to recur within the approximate duration of the trial.
• Any other reason that in the opinion of the investigator would prevent the subject from completing participation or following the trial schedule.
• Known allergy or sensitivity to PTH or any of the excipients.

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

Eligibility last updated 4/27/23. Questions regarding updates should be directed to the study team contact.

• Patients with a presumptive diagnosis of EPH determined by the group of clinicians who participate in patient management conference.
• Ability to comply with test directions and provide informed consent or assent to the study; i.e. cognitively able to participate in studies (typically IQ of 65 or above).
• Relatively preserved verbal memory – as determined via formal neuropsychological evaluation performed by the neuropsychologist. The values must within 1 SD of the mean for verbal memory.
• Proficient in English, as all of our tasks and consent forms will be in English and the inclusion of non-English speakers will introduce another confound in this small sample size and preclude grouped analysis.
• Age 18 – 65 years (we expect the trial to take 5 years and wish to target patients with minimal medical comorbidities).
• Must have a minimum of 2 seizures per month
  •this is essential to be able to detect the impact of neuromodulation on the epilepsy over relatively short intervals of time.

• Impaired reading and cognitive functions (more than 3 standard deviations below the mean, usually an IQ < 60), as determined by preoperative neuropsychological testing.
• Patients with gross structural abnormalities (hamartomata, tumors, vascular malformations, diffuse malformations of cortical development) in the brain that raise the possibility of dual pathology resulting in the epilepsy and by derivation, a larger epilepsy network.
• Patients with uncontrolled prominent psychiatric comorbidity that will preclude their meaningful participation.
• Patients who are unable to speak or comprehend English. The inclusion of multiple languages will make task development and grouped comparisons of neuro-psychology data difficult.
• Patients with cardiac pacemakers, intracranial aneurysm clips, or other potentially mobile implanted metallic devices that are deemed MRI incompatible by the manufactures – The absence of high resolution structural imaging precludes appropriate targeting of the regions of interest.
• Classic hippocampal sclerosis (equivalent to ILAE type 1) by imaging.
• Prior brain surgery for any reason or failed prior brain neuromodulation (prior VNS therapy is acceptable so long as it is held constant for the duration of the trial).
• History of or current non-epileptic spells (will confound accuracy of seizure detection with ANT Percept PC and the precision of the estimate of the neuromodulation effect).
• Patients who are pregnant. 

Eligibility last updated 8/26/22. Questions regarding updates should be directed to the study team contact.

- PT/INR, aPTT ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy and the PT/INR or aPTT is within the intended therapeutic range of the anticoagulant.

- Participants must have adequately controlled blood pressure (BP) with or without antihypertensive medications, defined as a BP ≤ 140/90 at screening and no change in
antihypertensive medications within 2 weeks prior to Cycle 1 Day 1.

- Participants with known brain metastases are eligible if they have completed primary CNS-directed therapy (such as surgical resection or radiotherapy) and if they have
remained clinically stable, asymptomatic, radiologically stable without evidence of progression for at least 4 weeks by repeat imaging, and have been off of steroids for
at least 4 weeks prior to starting study treatment.

- Participants 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, as determined after discussion with the PI, are eligible for this trial.

- Archival tumor tissue must be available as 27 (25 unstained + 2 H&E) freshly serially cut slides from formalin-fixed, paraffin-embedded (FFPE) tissue blocks. The most
recent available tissue is preferred to archived tissue. If fewer than 27 slides are available, the participant may still be eligible pending discussion with the Sponsor-Investigator.

- The effects of pembrolizumab and lenvatinib on the developing human fetus are unknown.  For this reason and because these agents are known to be teratogenic, women of child-bearing potential* must have a negative serum or urine pregnancy test at the Screening and Cycle 1 Day 1 visits. Women of child-bearing potential and men must
agree to use adequate contraception (see Appendix D) prior to study entry, for the duration of study participation, and for at least 30 days after last receipt of study therapy. Should a woman become pregnant or suspect she is pregnant while she is participating in this study, she should inform her treating physician immediately.

-- Female participants are NOT considered to be of childbearing potential if they meet either criteria:

- Post-menopausal, defined as amenorrheic for at least 12
consecutive months within the appropriate age group and without an alternative medical cause; OR;

- Surgically sterilized (i.e., bilateral oophorectomy, bilateral tubal ligation or salpingectomy, or total hysterectomy).

- Ability to understand and the willingness to sign a written informed consent document.

• Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic.

Dose-Escalation Cohorts:

• Subjects with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.

Expansion Cohort 1 (ccRCC):

• Subjects with unresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy.

Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose.

Expansion Cohort 2 (ccRCC):

• Subjects with unresectable advanced or metastatic RCC with a clear cell component.
• Must have radiographically progressed after a combination therapy consisting of a PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy. 

Expansion Cohort 3 (mCRPC):

• Men with metastatic adenocarcinoma of the prostate.
• Must have progressed after one NHT given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC.

Expansion Cohort 4 (UC, ICI-naive):

• Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
• Must have progressed during or after prior first-line platinum-based combination therapy, including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence < 12 months from the end of last therapy.

Expansion Cohort 5 (UC, ICI-experienced):

• Subjects with histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra).
• Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapy given as monotherapy, combination therapy, or maintenance therapy.

Expansion Cohort 6 (nccRCC):

• Subjects with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary RCC (any type), unclassified RCC, sarcomatoid RCC (≥ 50% of the tumor has sarcomatoid features).
• No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant therapy if disease recurrence occurred at least 6 months after the last dose.

Expansion Cohorts 1, 2, 4, 5, 6:

• Measurable disease per RECIST 1.1 as determined by the Investigator.
• For expansion cohorts only: Archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained.
• Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
• Karnofsky Performance Status (KPS) ≥ 70%.
• Adequate organ and marrow function.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

• Prior treatment with XL092, nivolumab, ipilimumab, or agents targeting the IL-2 pathway such as bempegaldesleukin.

For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC):

• Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.

For Cohort 3 (mCRPC):

• Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment. 

For Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC):

• Receipt of any type of anticancer antibody or systemic chemotherapy within 3 weeks before first dose of study treatment.
• Prior external radiation therapy within 2 weeks and prior radium-223 therapy within 6 weeks before first dose of study treatment. 
• Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy (including radiosurgery) or surgically removed and stable for at least 4 weeks before first dose of study treatment.
• Concomitant anticoagulation with oral anticoagulants and platelet inhibitors.
• Uncontrolled, significant intercurrent or recent illness.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment.
• Pregnant or lactating females.
• Any other active malignancy within two years before first dose of study treatment, except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

Note: Additional Inclusion and Exclusion Criteria may apply.

Eligibility last updated 6/14/22. Questions regarding updates should be directed to the study team contact.

• Male or female patients ≥ 18 years of age with a life expectancy of at least 3 months.
• Histologic or cytologic evidence of NSCLC, without histological evidence of a small cell or neuroendocrine components, that are either metastatic (Stage 4) or locally advanced (Stage 3B-C) and unresectable (IASLC 8th edition).
• Patients must have a known somatic KRAS G12C mutation determined using a validated next-generation sequencing (NGS) test (tumor tissue or circulating tumor DNA [ctDNA]) prior to enrollment. Adequate material (as defined in the lab manual) must be available prior to study therapy to be used for central confirmation of KRAS mutation status. Central confirmation does not need to be completed prior to enrollment.
• The patient must have received prior therapy with a KRAS G12C inhibitor and experienced progressive disease.
• The patient must have received anti-programmed cell death protein 1 or anti-programmed death-ligand 1 immunotherapy (unless contraindicated) AND/OR platinum-based combination chemotherapy AND targeted therapy if actionable oncogenic driver mutations were identified (i.e., EGFR, ALK, and ROS1).
• The patient must have received appropriate treatment with at least 1 prior systemic regimen, but no more than 3 prior regimens, for Stage 3B-C or 4 NSCLC.
• The patient may have previously received adjuvant/neoadjuvant chemotherapy for earlier-stage disease. Adjuvant/neoadjuvant chemotherapy in early stages will not count as a prior regimen unless disease progression occurred during or within 6 months following adjuvant/neoadjuvant therapy.
• Measurable disease according to RECIST 1.1 with at least 1 measurable disease lesion.
• An Eastern Cooperative Group (ECOG) performance status ≤ 1.
• Must have adequate organ function defined by the following laboratory parameters:
  • Adequate hematologic function including: hemoglobin (Hb) ≥ 9.0 g/dL; platelets ≥ 100,000/mm^3; and absolute neutrophil count (ANC) ≥ 1500/mm^3. If a red blood cell transfusion has been administered the Hb must remain stable and ≥ 9 g/dL for at least 1 week prior to first dose of study therapy;
  • Adequate hepatic function: (i) total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 μmol/L) upon discussion with Medical Monitor; (ii) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (or < 5 x ULN in patients with liver metastases);
  • Adequate renal function with creatinine clearance rate of ≥ 50 mL/min as calculated by the Cockcroft-Gault formula, or serum creatinine ≤ 1.5 x ULN;
  • International normalized ratio (INR) ≤ 1.5 and partial thromboplastin time (PTT) ≤ 1.5 x ULN in the absence of anticoagulation or therapeutic levels in the presence of anticoagulation;
  • Albumin ≥3.0 g/dL (451 μmol/L);
  • Creatine phosphokinase (CPK) ≤ 2.5 x ULN;
  • Adequate cardiac function with left ventricular ejection fraction ≥ 50% by echocardiography (ECHO) or multiple-gated acquisition (MUGA) scan.
• Adequate recovery from toxicities related to prior treatments to at least Grade 1 by CTCAE v5.0. Exceptions include alopecia and peripheral neuropathy Grade ≤ 2. Patients with other toxicities that are stable on supportive therapy may be allowed to participate with prior approval by the Sponsor.
• Male and female patients with reproductive potential agree to use a highly effective method of contraceptive during the trial and for at least 6 months following the last dose of study interventions.

• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational agent within 14 days of first receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 (C1D1) for chest radiation > 30Gy).
  • Note: palliative radiation, other than to target lesions, is permitted during the study except during the DLT assessment period. Patients receiving palliative radiation during the DLT assessment period will be replaced. Prior G12C therapy must be discontinued at least 6 days prior to Day 1 of study therapy for PK lead-in.
• Presence of other malignancy that could be mistaken for the malignancy under study during disease assessments.
• History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy.
• Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
• Prior chemotherapy, targeted therapies, radiotherapy, immunotherapy, or treatment with an investigational agent within 14 days of first receipt of study drug (within 6 weeks for nitrosoureas, mitomycin C and chest radiation; within 6 months prior to Cycle 1 Day 1 (C1D1) for chest radiation > 30Gy).
  • Note: palliative radiation, other than to target lesions, is permitted during the study except during the DLT assessment period. Patients receiving palliative radiation during the DLT assessment period will be replaced. Prior G12C therapy must be discontinued at least 6 days prior to Day 1 of study therapy for PK lead-in.
• Presence of other malignancy that could be mistaken for the malignancy under study during disease assessments.
• History of prior malignancy, with the exception of curatively treated malignancies or malignancies with very low potential for recurrence or progression.
• Major surgery within 4 weeks (excluding placement of vascular access), minor surgery within 2 weeks, or palliative radiotherapy within 1 week of the first dose of study therapy.
• Treatment with warfarin. Patients on warfarin for deep vein thrombosis/pulmonary embolism can be converted to low-molecular-weight heparin or direct oral anticoagulants.
• Exposure to QT-prolonging medications within 14 days prior to the first dose and during the course of therapy. 
• Use of proton pump inhibitors (PPI) within 3 days and H2 receptor antagonists within 1 day prior to study Day 1.
• exposure to strong CYP3A4 inhibitors, inducers, or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
• Exposure to P-glycoprotein (P-gp) inhibitors or inducers or sensitive substrates with narrow therapeutic index within 14 days prior to the first dose and during the course of therapy.
• Exposure to strong inhibitors or inducers of breast cancer resistance protein (BCRP) within 14 days prior to the first dose and during the course of therapy. 
• Exposure to CYP2C9 and CYP2D6 sensitive substrates with narrow therapeutic index during the course of therapy.
• Part A: Leptomeningeal metastases or any central nervous system (CNS) metastases. Part B: Leptomeningeal metastases or active CNS metastases 480 msec using Fridericia’s formula.
• Weight loss > 10% within 4 weeks prior to first dose of study therapy.
• Known severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (clinical symptoms) ≤ 28 days prior to first dose of study therapy.
• Known hepatitis B, hepatitis C, or human immunodeficiency virus infection that is active and/or requires therapy.
• Active skin disorder that has required systemic therapy within the past 1 year.
• History of rhabdomyolysis.
• History of interstitial lung disease (ILD) or pneumonitis.
• Concurrent ocular disorders:
  • Patients with history of glaucoma, history of retinal vein occlusion (RVO), predisposing factors for RVO, including uncontrolled hypertension, uncontrolled diabetes;
  • Patient with history of retinal pathology or evidence of visible retinal pathology that is considered a risk factor for RVO, intraocular pressure > 21 mm Hg as measured by tonometry, or other significant ocular pathology, such as anatomical abnormalities that increase the risk for RVO;
  • Patients with active or chronic visually significant corneal disorders, other active ocular conditions requiring ongoing therapy or clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy. Examples of visually significant corneal disorders include corneal degeneration, active or recurrent keratitis, and other forms of serious ocular surface inflammatory conditions. Visually significant corneal disorders do NOT include dry eyes, blepharitis, and uncomplicated corneal erosions.
  • Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart Association [NYHA], myocardial infarction, cerebrovascular stroke or transient ischemic attack within the last 6 months, unstable arrhythmias, unstable angina or severe obstructive pulmonary disease. 22. Patients with the inability to swallow oral medications or impaired gastrointestinal absorption due to gastrectomy or active inflammatory bowel disease.
  • Patients with a history of hypersensitivity to any of the active (avutometinib, adagrasib) or inactive (croscarmellose sodium, hydroxypropylmethylcellulose, lactose monohydrate, mannitol, magnesium stearate, microcrystalline cellulose) ingredients of the investigational products.
  • Female patients who are pregnant or breastfeeding.
  • Any other medical condition (e.g., cardiac, gastrointestinal, pulmonary, psychiatric, neurological, genetic, etc.) that in the opinion of the investigator would place the patient at unacceptably high risk for toxicity.

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

Eligibility last updated 9/18/23 Questions regarding updates should be directed to the study team contact.

• Male or female subjects between 28 days and < 12 weeks of age, inclusive.
• Must have clinical and imaging features that are consistent with a diagnosis of ARPKD with all the following characteristics:
  • Nephromegaly (> 2 standard deviations from age appropriate standard via ultrasound);
  • Multiple renal cysts;
  • History of oligohydramnios or anhydramnios.
• Ability for parent or guardian to provide written, informed consent prior to initiation of any trial-related procedures, and ability, in the opinion of the principal investigator, to comply with all the requirements of the trial.

• Premature birth (≤ 32 weeks gestational age).
• Anuria or RRT.
• Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
• Abnormal liver function tests including ALT and AST, > 1.2 × ULN.
• Parents with renal cystic disease.
• Need for chronic diuretic use.
• Cannot be monitored for fluid balance.
• Critical electrolyte imbalances, as determined by the investigator.
• Has or at risk of having significant hypovolemia as determined by investigator.
• Clinically significant anemia, as determined by investigator.
• Severe systolic dysfunction defined as ejection fraction < 14%.
• Serum sodium levels < 130 mmol/L.
• Cannot be taking any other experimental medications.
• Require ventilator support.
• Taking medications known to induce CYP3A4.
• Having an infection including viral that would require therapy disruptive to IMP dosing.
• Platelet count < 50,000 µL.