Key

• Patients with histologically or cytologically confirmed diagnosis of advanced, epithelial ovarian cancer (except carcinosarcoma), primary peritoneal, or fallopian tube cancer who have all of the following:
  • serum CA-125 level ≥2 x upper limit of normal (ULN) (in screening);
  • has received at least 1 line of platinum-containing therapy or must be platinum-intolerant (applicable for dose escalation and non-randomized dose expansion cohorts);
  • documented relapse or progression on or after the most recent line of therapy;
  • no standard therapy options likely to convey clinical benefit.

2. Adequate organ and bone marrow function as defined in the protocol.

3. Life expectancy of at least 3 months.

4. Randomized phase 2 expansion cohort (Ovarian Cancer only): Platinum-resistant ovarian cancer patients who have had 1 to 3 lines of platinum-based therapy as defined in the
protocol.

Endometrial Cancer Cohorts Only:

• histologically confirmed endometrial cancer that has progressed or recurrent after prior anti-Programmed Cell Death Ligand 1 (PD-1) therapy and platinum-based chemotherapy:
  • MUC16 positivity of tumor cells ≥ 25% by immunohistochemistry (IHC);
  • 1-2 prior lines of systemic therapy.

Key

• Prior treatment with anti-Programmed Cell Death (PD-1)/PD-L1 therapy, as described in the protocol.
• Ovarian Cancer Expansion cohorts only: More than 4 prior lines of cytotoxic chemotherapy.
• Prior treatment with a MUC16
  •targeted therapy.
• Untreated or active primary brain tumor, central nervous system (CNS) metastases, or spinal cord compression, as described in the protocol.
• History and/or current cardiac findings as defined in the protocol.
• Severe and/or uncontrolled hypertension at screening. Patients taking anti-hypertensive medication must be on a stable anti-hypertensive regimen.

Note: Other protocol Inclusion/Exclusion Criteria apply.

Eligibility last updated 1/2/24. Questions regarding updates should be directed to the study team contact.

• Signed and dated IRB approved study consent form prior to study related procedures.
• ≥ 18 years old.
• Chronic symptomatic heart failure (HF) due to non-valvular and non-congenital left heart disease (LHD) documented by the following:
  • A primary diagnosis of mildly reduced or preserved ejection fraction (HFmrEF or HFpEF, LVEF > 40%);
  • NYHA Class II to ambulatory NYHA Class IV (IVa);
  • Documentation of at least one of the following from the date of initial informed consent:
    • An HF hospitalization or HF event* requiring IV HF therapy in the prior 12 months; AND/OR
    • EITHER BNP value > 35 pg/ml or > 125 pg/ml in permanent or long-term persistent atrial fibrillation; OR
    • NT-proBNP > 125 pg/ml or > 375 pg/ml in permanent or longterm persistent atrial fibrillation in the prior 6 months.
  • There is objective evidence of cardiogenic pulmonary congestion based on hemodynamic criteria obtained by right heart catheterization (RHC) at exercise, and confirmed by hemodynamics core lab as:
  • Pulmonary capillary wedge pressure at 20 Watts exercise (PCWP 20W) as measured at end-expiration is elevated to ≥ 25 mmHg and PCWP 20W exceeds right atrial pressure (RAP 20W) by ≥ 8 mmHg.
• In the judgement of the treating physician and the Central Screening Committee (CSC), and according to current 2022 AHA/ACC/HFSA guidelines, the patient is on stable medically optimized guideline-directed medical therapy (GDMT) for HFpEF/HFmrEF, for >30 days prior to screening and baseline assessments, that is expected to be maintained without change for 6 months post index procedure. Where possible, all patients should be on a stable dose of an SGLT2i for >30 days prior to screening and baseline assessments, with exceptions for contraindications, intolerance, and non-coverage, financial, or patient preference decisions. For patients newly started on SGLT2i, all qualifying screening and baseline assessments (including CT, MRI, and RHC), should be performed > 30 days post initiation. †.
• Willing to attend study follow-up assessments for up to 5 years.
• Notes: *Refer to Section 16: Study Definitions for the definition of “(Prior) Heart Failure Hospitalization or Heart Failure Event (Pre-Randomization Inclusion Criterion)”.
• †Any additional medical therapy newly designated as a Class IIA recommendation or higher by Societal Guidelines for HF therapy instituted after the patient receives CSC approval may also be added after the patient reaches 6 months follow-up if patient is not taking the medications at the time of randomization. GDMT Stability = NO cumulative increase ≥ 100% or decrease in HF medications ≥ 50% of baseline dose patient is taking within 30 days prior to screening and baseline assessments. GDMT is expected to be maintained for 6 months post-procedure. Diuretic dosage changes for HF optimization within 30 days before or after the index procedure are allowed.

• Severe heart failure (HF) defined as one or more of the below:
  • ACC/AHA/ESC Stage D HF, non-ambulatory NYHA Class IV HF;
  • If Body Mass Index (BMI) < 30, cardiac index < 2.0 L/min/m^2;
  • If BMI ≥ 30, cardiac index < 1.8 L/min/m^2;
  • Inotropic infusion (continuous or intermittent) within the past 6 months;
  • Patient is on the cardiac transplant waiting list;
  • Prior diagnosis of HF with reduced ejection fraction (HFrEF), including patients with improvement in LVEF to > 40% (i.e., HF with improved ejection fraction, HFimpEF)
• Presence of significant native valve disease, defined by the echo core lab as:
  • Degenerative mitral regurgitation > moderate;
  • Functional or secondary mitral regurgitation defined as grade > moderate;
  • Mitral stenosis > mild; 
  • Primary or secondary tricuspid regurgitation defined as grade > moderate;
  • Aortic valve disease defined as: aortic regurgitation grade > moderate or aortic stenosis > moderate.
• More than mild right ventricular (RV) dysfunction as determined by the echo core lab, taking into account the following available parameters:
  • Tricuspid Annular Plane Systolic Excursion (TAPSE) < 1.4 cm by transthoracic echocardiogram (TTE); or
  • RV ≥ LV size; or
  • Right ventricular ejection fraction (RVEF) 15 mmHg at rest on right heart catheterization (RHC), confirmed by hemodynamics core lab. 
• Pulmonary vascular resistance (PVR) ≥ 5.0 WU at rest on RHC, confirmed by hemodynamics core lab.
• BMI ≥ 45.
• Myocardial infarction (MI) and/or any therapeutic invasive, non-valvular cardiovascular procedure within past 3 months or current indication for coronary revascularization.
• Prior sternotomy or surgical valve repair or replacement within the past 12 months; prior transcatheter valve repair or replacement within the past 6 months.
• Prior placement of CS lead or cardiac resynchronization therapy (CRT).
• Stroke, transient ischemic attack (TIA), deep vein thrombosis (DVT) or pulmonary embolus within the past 6 months.
• Known untreated severe carotid artery stenosis (> 90%).
• Untreated severe sleep apnea.
• Severe lung disease, requiring continuous or PRN home O2 or forced expiratory volume-one second (FEV1) < 1L.
• Hemodynamic instability within 30 days.
• Patient requiring surgery under general anesthesia for any reason within 30 days or patient is expected to undergo elective major surgery within 6 months.
• Ongoing clinically relevant hypertrophic obstructive cardiomyopathy, constrictive pericarditis, or infiltrative cardiomyopathy (including amyloidosis, sarcoidosis, hemochromatosis, etc.) .
• HF due to prior cancer therapy.
• Renal insufficiency as determined by creatinine (sCr) level > 2.5 mg/dL or estimated glomerular filtration rate (eGFR) < 25ml/min/1.73 m^2 by CKD-EPI equation; or currently requiring dialysis.
• Significant hepatic impairment defined as 3x upper limit of normal of transaminases, total bilirubin, or alkaline phosphatase.
• Performance of the six-minute walk test (6MWT) with a distance < 50m OR > 450m.
• Any physical impairment which limits the patient’s capacity to complete functional testing (e.g., 6MWT) due to non-cardiac conditions.
• Patient is contraindicated to receive either dual antiplatelet therapy or oral anticoagulant; or has a documented coagulopathy.
• Known hypersensitivity to anticoagulation therapy or contrast agent, which cannot be adequately medicated.
• Known hypersensitivity to Nickel and/or Tantalum.
• In the judgment of the investigator or CSC, life expectancy < 12 months for non-cardiovascular reasons.
• In the opinion of the CSC, the patient is not an appropriate candidate for the study based on a holistic review of the patient’s medical history at screening, including:
  • Inadequate treatment of hypertension with systolic blood pressure ≥ 170 mmHg regardless of the number of medications;
  • Baseline heart rate > 110 bpm;
  • Untreated anemia with Hgb < 10g/dl;
  • Abnormal resting O2 saturation on room air 3 WU, PCWP < RAP + 5 mmHg at rest.
  • If any of these criteria are met, or the CSC thinks the patient is not an appropriate candidate on other criteria, the patient should be excluded.
• Anatomy (including implantable devices) that is not compatible with the Edwards APTURE transcatheter shunt system (APTURE system)
• Active endocarditis or infection requiring intravenous antibiotics within 3 months.
• Currently participating (e.g., undergoing trial specific exams/treatment/procedures) in an investigational drug or device study. Note: trials requiring extended follow-up for products that were investigational, but have since become commercially available are not considered investigational trials.
• Patient is a current recreational intravenous drug user.
• Positive serum pregnancy test in female patients of child-bearing potential or planning on becoming pregnant during the duration of the trial.
• Known pre-existing shunting or congenital heart disease determined to be clinically significant by the CSC.
• Patient is under guardianship.

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

Eligibility last updated 11/7/23. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria

• 18 years of age or older.
• Histologically or cytologically confirmed unresectable advanced, metastatic, or recurrent biliary tract cancers (including intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, gallbladder cancer, and ampullary carcinoma).
• Patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as initial therapy for locally advanced or metastatic disease. Patients who relapse within 6 months of receiving gemcitabine and platinum containing chemotherapy regimen in the adjuvant setting are also eligible.
• At least one lesion measurable as defined by RECIST v1.1.
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
• Predicted life expectancy of at least 12 weeks.
• No evidence of ongoing infection and adequate biliary excretion or patients whose adequate biliary excretion can be confirmed with the following procedures:
  • Patients who underwent endoscopic retrograde biliary drainage (ERBD) at least 1 week before the investigational drug treatment;
  • Patients who underwent percutaneous transhepatic biliary drainage (PTBD) at least 4 weeks before the investigational drug treatment;
  • Patients free of any signs of active or suspected uncontrolled infection after a drainage procedure;
  • Patients free of any risk of hemorrhage and with incision completely healed.
• Adequate bone marrow, hepatic, and renal function within 14 days of randomization as described below. (Patient must be free of granulocyte colony-stimulating factor (G-CSF) treatment and blood transfusion within 14 days prior to the lab test):
  • Absolute neutrophil count (ANC) ≥ 1,500/mm^3;
  • Hemoglobin ≥ 9.0 g/dL;
  • Platelet count ≥ 100,000/mm^3;
  • White Blood Cell ≥ 3,000/mm^3;
  • Total bilirubin ≤ 1.5 X Upper Limit of Normal (ULN);
  • Aspartate aminotransferase (AST)/ alanine transaminase (ALT) ≤ 3.0 X ULN (≤ 5 X ULN in case of hepatic metastasis);
  • Estimated creatinine clearance ≥ 30 mL/min based on Cockcroft-Gault;
  • Urine protein ≤ 1+ by Dipstick (Only when urinalysis shows a protein dipstick result of > 1 positive (+), the total protein volume (< 1.0 g/24hr) can be confirmed with a 24-hour urine test.);
  • Serum amylase and lipase level ≤ 1.5 X ULN;
  • Serum Albumin ≥ 3.0 g/dL.
• Female patients who are women of childbearing potential (WCBP) must have a negative pregnancy test (serum-human chorionic gonadotropin (hCG) or urine-hCG performed at the Investigator's discretion) within 14 days of randomization.
• Female patients must be surgically sterile (or have a monogamous partner who is surgically sterile) or be at least 2 years postmenopausal or commit to use 2 acceptable forms of birth control (defined as the use of an intrauterine device (IUD), a barrier method with spermicide, condoms, any form of hormonal contraceptives, or abstinence) for the duration of the study and for 4 months following the las t dose ofstudy treatment. Male patients must be sterile (biologically or surgically) or commit to the use of a reliable method of birth control (condoms with spermicide) for the duration of the study and for 4 months following the last dose of study treatment.
• Signed and dated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved Informed Consent Form (ICF) before any protocol-directed screening procedures are performed.

• Patients who are eligible to be treated with a molecularly targeted therapy on a labelled regimen after receiving first-line chemotherapy. Patients who received a molecularly targeted therapy as part of their first line treatment may be eligible, as determined by the Sponsor Medical Monitor.
• From the time point of screening.
• Less than 4 weeks have elapsed since patients had a surgery or major procedure.
• Less than 2 weeks have elapsed from the last treatment date since patients had any radiation therapy.
• Patients with percutaneous transhepatic biliary drains (PTBD).
• Prior to the initial treatment of study drug.
• Less than 2 weeks have elapsed since patients had chemotherapy or hormone therapy.
• Less than 2 weeks have elapsed since patients had anticancer immunotherapy or investigational drug treatment.
• Less than 4 weeks since cryotherapy, radiofrequency ablation, anhydrous alcohol therapy, or photodynamic therapy, including TACE and TARE.
• A history of the following cardiovascular diseases (please, consult the Sponsor Medical Monitor for a case by case evaluation):
  • Congestive heart failure (CHF) that corresponds to Class II or a higher class under New York Heart Association (NYHA) classification, or less than 50% of left ventricular ejection fraction (LVEF);
  • Uncontrolled hypertension (SBP/DBP > 140/90 mmHg) (e.g., patient with SBP/DBP > 140/90 mmHg despite the best care including optimizing the anti-hypertensive medication regimen);
  • Patients with any history of hypertensive crisis or pre-existing hypertensive encephalopathy;
  • Pulmonary hypertension;
  • Myocardial infarction;
  • Uncontrolled arrhythmia;
  • Unstable angina;
  • Patients with any significant vascular diseases (e.g., aortic aneurysm requiring surgery or recent peripheral artery thrombosis) within 6 months prior to the initial treatment of the investigational product.
• History of hypersensitivity reactions to any components of the investigational product or other drugs of the same class (humanized/human monoclonal antibody drugs) or paclitaxel.
• Patients with contraindications to paclitaxel therapy.
• Patients with persistent, clinically significant toxicities (excluding hair loss) from previous anticancer treatment that corresponds to Grade 2 or a higher grade under NCI-CTCAE v5.0.
• Symptomatic or uncontrolled central nervous system (CNS) metastasis (However, patients with asymptomatic CNS metastasis that have been treated with either surgery or radiation can participate provided that systemic corticosteroid treatment was discontinued at least 4 weeks prior to screening and that the patient is radiologically and neurologically stable or improving).
• A history of the following hemorrhage-related or gastroenterological disease:
  • Active hemorrhage, hemorrhagic diathesis, coagulopathy or tumor in great arteries.
  • History of clinically significant gastroenterological disease, such as peptic ulcer, GI bleeding, GI or non-GI fistula, perforation, abdominal abscess, clinical symptoms, and signs of GI obstruction, need for parenteral hydration or nutrition, or inflammatory bowel disease (IBD).
  • Current or recent (within 10 days prior to study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose will be excluded.
• Prophylactic (i.e., for the patency of venous access devices) use of low molecular weight heparin (i.e., enoxaparin 40 mg/day) is allowed if patient has INR < 2 or aPTT </=2x ULN within 14 days of study treatment.
• Patients with current or recent (within 10 days of study treatment) use of aspirin (>81 mg/day), or other nonsteroidal anti-inflammatory drugs (NSAIDs), or other antiplatelets (i.e., dipyramidole, ticlopidine, clopidogrel, and cilostazol) will be excluded.
• Severe infection requiring ongoing systemic antibiotics, antivirus drugs, etc., or other uncontrolled acute active infectious diseases.
• Patients with evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Patients with positive HBsAg and/or detectable HBV DNA are eligible only if adequately controlled on antiviral therapy according to institutional standards and liver function eligibility criteria are also met. HCV patients showing sustained viral response or patients with immunity to HBV infection may enroll.
• Patients with other severe diseases or uncontrolled illnesses that warrant the exclusion from the study (permitted only if medically controlled) including but not limited to:
  • Pre-existing hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 28 days prior to screening;
  • Major, unhealed injury, active ulcer, or untreated fracture;
  • Pre-existing conditions of cerebrovascular incident (ischemic or hemorrhagic stroke), transient ischemic attack or subarachnoid hemorrhage within 6 months prior to screening;
  • Moderate to severe ascites and/or pleural effusion. However, enrollment is permitted for patients with ascitic fluid as long as paracentesis is not required to improve the condition;
  • Interstitial lung disease or pulmonary fibrosis;
  • Patients expected to require anticancer treatment other than the investigational product during the clinical study.
• Pregnant or lactating patients, or patients planning to become pregnant during the clinical study.
• A history of primary malignancy other than BTC will be excluded, except for malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate >90%). Prior malignancy history will be evaluated on a case-by-case basis by the Sponsor Medical Monitor.
• Clinically significant abnormal ECG findings or history determined as clinically significant by the Investigator.
• QT interval (Fridericia's formula) (QTcF) interval > 450 msec at the time of screening.

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

Eligibility last updated 9/26/23. Questions regarding updates should be directed to the study team contact.

• Participant must have a BMI between 18.5 and 40.
• Participant be aged between 18 and 80.
• Participant must use the Mayo Clinic patient online portal.
• Participant must be able to understand English without the need of an interpreter.
• Must be willing to be contacted for research.
• Participant must be willing and capable to provide consent.
• Participants shall be generally healthy as deemed acceptable by the principal investigator.
• Men and women will be participant in this study. Women cannot be pregnant during this study.

• Gastric surgery, pacemaker placement, weight loss surgery, metabolic and obstetric surgery.
• Smokers will be excluded from the study.
• Insulins, common diabetic drugs, anti-hyperglycemic drugs, beta blockers cardiac selective, beta-blockers noncardiac selective, oral steroids, opioids anti-depressants, and hormones.
• Disorder of coronary artery, hepatic failure, gastroparesis, disorder of the adrenal gland, drug related disorders, substance abuse, malignant neoplastic disease, psychotic disorders, disorder of skeletal muscle, finding of brain, chronic kidney disease, renal failure syndrome, disorder of pulmonary circulation, cerebrovascular disease, neuro developmental disorder, disorder of immune function, disorder of central nervous system.
• Participants are not to have an abnormal value as part of a lipid panel within the past 6 months.
• Participant will be excluded if they have recreational drug use or a history of alcohol abuse.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent.
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention.
• Participant will be excluded if they have epilepsy.
• Participant will be excluded if they have cranial metal/device implants.
• Participant will be excluded if they are pregnant.

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

Eligibility last updated 10/4/23. Questions regarding updates should be directed to the study team contact.

Key

• Moderate AS, defined as follows by transthoracic echo (TTE)
  • AVA >1.0 cm^2 and < 1.5 cm^2, and
  • Max aortic velocity ≥ 3.0 m/sec and < 4.0 m/sec OR mean aortic gradient ≥ 20.0 mmHg and < 40.0 mmHg
• Symptoms of AS, defined as:
  • NYHA ≥ II; or'
  • Reduced functional capacity, defined a
  • 6MWT < 300 meters; or
  • < 85% of age-sex predicted METs on exercise tolerance testing.
• Any of the following:
  • HF event or hospitalization for heart failure within 1 calendar year prior to consent;
  • NT-proBNP ≥ 600 pg/ml (or BNP ≥ 80 pg/ml if NT-proBNP not available).
• Any of the following by TTE:
  • Global longitudinal strain ≤ 16.0 % (absolute value);
  • E/e’ > 14.0;
  • Diastolic dysfunction ≥ Grade II;
  • LVEF < 60%;
  • Stroke volume index < 35 ml/m^2;
  • Paroxysmal AF or persistent AF episode within 6 months prior to consent;
  • Elevated aortic valve calcium score (> 1200 AU for females and > 2000 AU for males).

Key

• Age < 65 years.
• LVEF ≤ 20% by 2-D echo.
• Class I indication for cardiac surgery.
• Sievers Type 0 or Type 2 bicuspid aortic valve or Sievers Type 1 bicuspid aortic valve with ascending aorta diameter > 4.5 cm.
• Not anatomically suitable for transfemoral TAVR with the trial device.
• In need of and suitable for coronary revascularization per Heart Valve Team.
• Documented history of cardiac amyloidosis.

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

Eligibility last updated 12/27/23. Questions regarding updates should be directed to the study team contact.

• For Enrollment to Phase 1b: Participants must have histologically confirmed advanced or metastatic soft-tissue sarcoma and no curative multimodality treatment options available.
• For Enrollment to Phase 2: Participants must have histologically confirmed advanced or metastatic leiomyosarcoma (LMS) and no curative multimodality treatment options available.
• Participants must have measurable disease per RECIST 1.1 criteria.
• Age ≥ 18 years. Because no dosing or adverse event data are currently available on the use of lurbinectedin in combination with doxorubicin in participants < 18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%).
• Participants must have adequate organ and marrow function as defined below:
  • Absolute Neutrophil Count ≥ 1,500/mcL;
  • Hemoglobin (Hgb) ≥ 8 g/dl (transfusion support permitted);
  • Platelet Count ≥ 100,000/mcL;
  • Total Bilirubin ≤ 1.5 × institutional upper limit of normal (ULN);
  • AST (SGOT) / ALT(SGPT) ≤ 2.5 × institutional ULN, OR ≤ 5 × institutional ULN if elevation is a result of metastases;
  • Creatinine ≤ 1.5 × institutional ULN, OR Creatinine Clearance ≥ 60 mL/min/1.73 m^2 for participants with creatinine levels above 1.5 × institutional normal (calculated via the Cockcroft-Gault equation);
  • Creatine Phosphokinase (CPK) < 2.5 × institutional ULN on two different determinations performed one week (± 1 day) apart.
• For participants with known chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
• Participants with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with known HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
• Left ventricular ejection fraction (LVEF) ≥ 50% on screening echocardiogram (ECHO) or multigated acquisition (MUGA) scan.
• The effects of lurbinectedin or doxorubicin on the developing human fetus are unknown. For this reason and because anti-cancer agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of study agent administration.
• Ability to understand and the willingness to sign a written informed consent document.
• Participants must have archival tissue available for analysis in the form of a formalin-fixed paraffin embedded (FFPE) block or unstained slides. Participants without archival tissue available may be enrolled with approval of the Sponsor-Investigator. Note: confirmation of availability of archival tissue is the only requirement for eligibility, archival tissue does not need to be received by the study team or site prior to enrollment.
• 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 as assessed by the treating investigator may be included with the approval of the Sponsor-Investigator.

• Participants who have received prior anthracycline or trabectedin (Yondelis, ET-743), including prior exposure to doxorubicin or liposomal doxorubicin.
• Participants who have received more than 2 prior lines of cytotoxic chemotherapy for the phase 1b study and no more than 1 prior line of cytotoxic chemotherapy for the phase 2 study. There is no limit on the number of prior lines of non-cytotoxic chemotherapy (e.g., pazopanib, immunotherapy).
• Prior exposure to lurbinectedin (PM01183).
• Participants who have received or undergone prior chemotherapy within 14 days of cycle 1 day 1, therapeutic radiation therapy within 21 days of cycle 1 day 1 or major surgery within 21 days of cycle 1 day 1.
• Participants who have received prior palliative radiation therapy within 7 days of cycle 1 day 1.
• Participants who have received prior antibody-based therapy (e.g., nivolumab) within 4 weeks or 3 half-lives (whichever is shorter) of cycle 1 day 1.
• Participants who have received prior oral small molecule or tyrosine kinase inhibitor (TKI) therapy within 2 weeks or 3 half-lives (whichever is shorter) of cycle 1 day 1.
• Participants who have not recovered to ≤ Grade 1 or baseline from adverse events attributed to any prior anti-cancer therapy, with the exceptions of alopecia, controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity which will be permitted at Grade 2.
• Participants who are receiving any other investigational agents.
• Participants with known CNS disease involvement, with the exception of patients with brain metastases that have been previously treated and have remained stable on MRI ≥ 28 days prior to cycle 1 day 1 without use of steroids or anti-epileptic medications.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lurbinectedin or doxorubicin. 
• Participants receiving any medications or substances that are strong or moderate inhibitors or inducers of CYP3A, CYP2D6, or P-gp are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently updated medical reference. As part of the enrollment/informed consent procedures, the participant must be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
• Uncontrolled intercurrent illness including, but not limited to: ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, chronic indwelling drains, or psychiatric illness/social situations that would limit compliance with study requirements.
• History of interstitial pneumonitis or pulmonary fibrosis.
• Known cardiomyopathy.
• Pregnant women are excluded from this study because lurbinectedin and doxorubicin are anti-cancer agents with the potential for teratogenic or abortifacient effects.  Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with lurbinectedin or doxorubicin, breastfeeding must be discontinued if the mother is treated with lurbinectedin or doxorubicin. A negative pregnancy test is required for women of childbearing potential prior to the first dose of study medication.
• Immunocompromised patients, including patients who are known to be seropositive for human immunodeficiency virus (HIV) due to the increased risk of lethal infections when treated with marrow-suppressive therapy. HIV testing is not required as part of screening. 

Eligibility last updated 8/17/23. Questions regarding updates should be directed to the study team contact.

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

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

Eligibility last updated 2/8/23. Questions regarding updates should be directed to the study team contact.

• Adult patients (≥ 18 years of age) with a diagnosis of bilateral moderate to profound sensorineural hearing loss who are undergoing unilateral cochlear implantation at Mayo Clinic in Rochester, MN.
• Patients must show normal-to-high performance in speech recognition.
• Patient must show an improvement in CNC word scores in quiet of 20% or greater from pre-implantation scores by 3 months post-activation in the implanted ear to proceed with the trial.

• Patients < 18 years of age.
• Patients undergoing revision implantation, completion bilateral cochlear implantation, or implantation for unilateral deafness will be excluded from enrollment.
• Patients unable to provide consent will be excluded.
• No patients will be excluded based on gender or race.

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

Eligibility last updated 11/1/22. Questions regarding updates should be directed to the study team contact.

Inclusion Criteria
•PAD Patients:

• Mild claudication to minor tissue loss (Rutherford 1-5).
• Resting or exercise ankle-brachial index < 0.9 or toe brachial index < 0.6.
• Age 35 or more.

Inclusion Criteria
•Healthy Volunteers:

• Age 35-90.

Exclusion Criteria
•PAD Patients and Healthy Volunteers: 

• Evidence of active infection.
• Chronic liver disease, end-stage renal disease (CKD 5), or chronic inflammatory disease.
• Poorly controlled diabetes (HbA1c > 8%).
• BMI < 18 or > 35.
• Recent other major surgery or illness within 30 days.
• Use of immunosuppresive medications or steroids.
• History of organ transplantation.
• Pregnancy, or plans to become pregnant, or lactating.

Exclusion Criteria - Healthy Volunteers:

• hsCRP > 2 mg/L.

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

Eligibility last updated 5/19/23. Questions regarding updates should be directed to the study team contact.

• Age ≥ 18 years.
• Histological confirmation of prostate cancer.
• Planned definitve dose radiotherapy to the prostate.
• ECOG Performance Status (PS) 0-2.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Provide written informed consent.

• Planned delivery of radiotherapy to pelvic lymph nodes.
• Planned brachytherapy treatment of the prostate.
• Significant urinary incontinence that precludes standard bladder filling.
• Evidence of direct bladder extension or bladder wall metastases from prostate cancer.
• Use of indwelling or intermittent urinary catheterization at baseline.
• Prior pelvic radiotherapy such that any portion of the prostate received > 5 Gy.
• Provide written informed consent.

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

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

• Age ≥ 18 years.
• Histological confirmation of prostate cancer.
• Planned definitve dose radiotherapy to the prostate.
• ECOG Performance Status (PS) 0-2.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Provide written informed consent.

• Planned delivery of radiotherapy to pelvic lymph nodes.
• Planned brachytherapy treatment of the prostate.
• Significant urinary incontinence that precludes standard bladder filling.
• Evidence of direct bladder extension or bladder wall metastases from prostate cancer.
• Use of indwelling or intermittent urinary catheterization at baseline.
• Prior pelvic radiotherapy such that any portion of the prostate received > 5 Gy.
• Provide written informed consent.

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

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

• Age ≥ 18 years.
• Histological confirmation of prostate cancer.
• Planned definitve dose radiotherapy to the prostate.
• ECOG Performance Status (PS) 0-2.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Provide written informed consent.

• Planned delivery of radiotherapy to pelvic lymph nodes.
• Planned brachytherapy treatment of the prostate.
• Significant urinary incontinence that precludes standard bladder filling.
• Evidence of direct bladder extension or bladder wall metastases from prostate cancer.
• Use of indwelling or intermittent urinary catheterization at baseline.
• Prior pelvic radiotherapy such that any portion of the prostate received > 5 Gy.
• Provide written informed consent.

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

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

• Patient is able to communicate well with the Investigator, understands and is willing to comply with all requirements of the study, and understands and signs the written informed consent form (ICF).
• At least 18 years of age.
• Cirrhosis and ascites.
• AKI stage 2 or 3. AKI defined by any of the following:
  • increase in SCr (SCr) ≥ 0.3 mg/dl (or ≥ 26.5 micromolar/L) within 48 h; or
  • increase ≥ 50% in baseline SCr, which is known or presumed to have occurred within the prior seven days.
• QLY SCr ≥ to 1.5 mg/dl.
• No sustained improvement in renal function (less than 20% decrease in SCr and SCr ≥ 1.5 mg/dL) after 48 h of diuretic withdrawal and the beginning of plasma volume expansion with albumin.
• Female patients as well as female partners of male patients must be willing to avoid pregnancy for the duration of the study (> 90 days).

• Significant co-morbidities that in the opinion of the Investigator would preclude study participation.
• QLY SCr level > 5 mg/dL.
• AKI stage 1.
• ACLF stage 3.
• Model for End-Stage Liver Disease (MELD) score > 35.
• At least one event of large volume paracentesis (LVP) > 4 Liters in the last 4 days before enrollment.
• Current or recent (within 4 weeks) treatment with nephrotoxic drugs (e.g., aminoglycosides, amphotericin, cyclosporine, NSAIDS (e.g., ibuprofen, naproxen, celecoxib), significant exposure to radiographic contrast agents (large doses or multiple injections of iodinated contrast media).
• Shock (hypovolemic-, cardiogenic-, or vasodilatory/distributive shock) with mean arterial blood pressure (MAP) ≤ 70 mmHg or systolic blood pressure ≤ 90 mmHg along with hypoperfusion. 
• Sepsis or uncontrolled bacterial infection (e.g., persisting bacteremia, persisting ascitic fluid leucocytosis, fever, increasing leucocytosis with vasomotor instability) as measured with the quick sepsis-related organ dysfunction assessment (qSOFA) score.
• Fewer than two days of anti-infective therapy for documented or suspected infection.
• Superimposed acute liver injury induced by drugs, herbal preparation or dietary supplements, with the exception of alcoholic hepatitis.
• Estimated life expectancy less than 5 days.
• Hypoxia (< 90%) or worsening respiratory symptoms.
• Proteinuria > 500 mg/day.
• Tubular epithelial casts, heme granular casts.
• Haematuria or microhaematuria (more than 50 red blood cells per high power field).
• Abnormal renal ultra-sonography unless there is a known chronic structural disease (e.g., diabetic or hypertensive nephropathy).
• Current or recent (within 4 weeks) renal replacement therapy (RRT).
• Severe cardiovascular and pulmonary diseases including, but not limited to, unstable angina, pulmonary edema, congestive heart failure requiring increasing doses of drug therapy, persisting symptomatic peripheral vascular disease, or any other cardiovascular disease judged by the Investigator to be severe. 
• Transjugular intra-hepatic systemic shunt (TIPS) unless it is known to be non-functioning or occluded.
• Ongoing use of vasopressors, unless used for only 48 h before screening; in this case a wash-out period of 8 h before enrollment will be necessary. Patients receiving midodrine and octreotide may be enrolled but treatment must be discontinued prior to enrollment.
• Known allergy or hypersensitivity to terlipressin or other component of the study treatment.
• Subject is not suitable to participate in the study for any reason (including, but not limited to co-morbidities, history of non-compliance with study visits, procedures, or drug administration) in the opinion of the Investigator.
• Females of childbearing potential (those who are not surgically sterilized or post-menopausal for at least 1 year) are excluded from participation in the study unless they agree to use highly effective contraception.
• Males who have no sterilization history and whose female partners have child-bearing potential must agree to use a highly effective method of contraception during the  period from the time of signing the informed consent form (ICF) through 90 days after the last dose of study drug. A male patient must agree to immediately inform the Investigator if his partner becomes pregnant during the study.

Eligibility last updated 5/30/23. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 3/10/23. Questions regarding updates should be directed to the study team contact.

• Signed Informed Consent/Assent Form.
• Age ≥ 18 years at time of signing Informed Consent Form.
• Ability to comply with the study protocol, in the investigator's judgment.
• Diagnosis of AHA based on a reduced FVIII activity ( < 50 %) and positive FVIII inhibitor  (> 0.6 BU/ml) at screening (local laboratory).
• Current bleeding due to AHA at the time of screening.
• Plan to be adherent to emicizumab prophylaxis during the study.
• For women of childbearing potential who meet the following criteria:
  • Refrain from heterosexual intercourse or use contraceptive methods that result in a failure rate of < 1% per year during the study period;
  • A woman with ≥ 12 continuous months of amenorrhea with no identified cause other than menopause and has not undergone surgical sterilization (removal of ovaries and/or uterus);
  • Use of combined oral or injected hormonal contraceptive, bilateral tubal ligation, male sterilization, hormone- releasing intrauterine devices, and copper intrauterine devices.

• Congenital hemophilia A.
• Treatment with aPCC within the last 24 hours before first study treatment or planned treatment with aPCC during the course of the study.
• Known positive lupus anticoagulant at the time of screening.
• Severe uncontrolled infection at the time of screening.
• Signs of active disseminated intravascular coagulation at the time of screening.
• Current treatment for thromboembolic disease or signs of current thromboembolic disease at time of screening.
• Patients who are at high risk for TMA (e.g., have a previous medical or family history of TMA), in the investigator's judgment.
• Known severe congenital or acquired thrombophilia.
• Life expectancy < 3 months at the time of screening.
• Other conditions that substantially increase risk of bleeding or thrombosis by the discretion of the investigator.
• Contraindications according to the Investigator's Brochure of emicizumab.
• Current treatment with emicizumab at time of screening.
• History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection by the discretion of the investigator.
• Concurrent disease, treatment, or abnormality in clinical laboratory tests that could interfere with the conduct of the study, may pose additional risk, or would, in the opinion of the local investigator, preclude the patient's safe participation in and completion of the study.
• Addiction or other diseases that preclude the patient from appropriately assessing the nature and scope as well as possible consequences of the clinical study by the discretion of the investigator.
• Pregnant or breast-feeding women.
• Would refuse treatment with blood or blood products, if necessary.
• Subject is in custody by order of an authority or a court of law.
• Treatment with any of the following:
  • An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration before Study Day 1;
  • A non-hemophilia-related investigational drug within the last 30 days or 5 half-lives-before Study Day 1, whichever is longer;
  • An investigational drug concurrently;
  • History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection.

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

In order to be eligible to participate in this study, participants must meet all of the following criteria:

• Age ≥ 18 years old at the date of screening
• Have both clinical and radiographic findings consistent with osteoarthritis of the knee:
  • Participant has clinical findings including (but not limited to) tendernessto palpation, swelling/effusion, stiffness, chronic limited range of motion;
  • Participant has a diagnosis of knee OA defined as Grade 2 to 3 by (K/L) weight bearing X-ray and physician review within the past 3 months.
• The index knee must present with symptomatic knee pain using WOMAC-A Visual Analog Scale (VAS) of 40mm or greater despite conservative therapies for 3 months prior to enrollment:
  • Failure of conservative therapies include the following: Participants must have failed a minimum of at least 3 months, including (1) physical therapy, and (2) oral OTC pain medications such as an NSAID (Aleve® or Advil®) or Acetaminophen (Tylenol®), or a prescription NSAID, for a period of 90 days at the Maximum Tolerable Dose according to the respective manufacturer's instructions on dose and duration, or their physician's over-riding guidance. Patients who are unable to tolerate this dosing regimen for 90 days, or those in whom NSAIDS or Acetaminophen are contraindicated, shall be deemed to have satisfied this inclusion criteria.
• Willing to give written Informed Consent to voluntarily participate in the study and sign the Health Insurance Portability and Accountability Act (HIPAA) Authorization prior to study participation
• Ability to return for multiple follow-up visits
• Ability read and understand English language
• Females must have a negative urine pregnancy test performed within 7 days of study enrollment

• Diagnosis of knee OA defined as K/L grade 1 or 4.
• BMI greater than 35 kg/m^2.
• Diagnosis of rheumatoid arthritis, psoriatic arthritis, or any other disorder which attributes to the primary source of their knee pain, including but not limited to: osteonecrosis, radiculopathy, bursitis, tendinitis, tumor, cancer.
• Presence of any clinically observed active infection including in the index knee joint, infection at the site of adipose tissue harvest, and/or any active systemic or local infection.
• Undergone injection in target knee within 6 months prior to screening visit, including but not limited to corticosteroids, hyaluronic acid (HA), bone marrow concentrate (BMAC) platelet rich plasma (PRP), human cellular exosomes, amniotic fluid or any human birth tissue.
• Undergone surgical procedures of either knee within 6 months prior to the screening visit.
• Bilateral knee pathology can only be treated in one knee for the study. The contralateral knee must have a WOMAC-A Visual Analog Scale (VAS) pain score of no more than 20mm for the past 3 months prior to enrollment. 
• Index knee greater than 10 degrees varus/valgus deformities.
• Knee pain associated with osteochondritis dissecans, ligament damage or displaced meniscus tear.
• Current or historical autoimmune disease that requires immunosuppressive medication.
• Any disorder affecting musculoskeletal pain and/or function, including symptomatic OA of the back, hips, or ankle that would interfere with the evaluation of the treated knee.
• Allergy to lidocaine, epinephrine, or valium.
• Diagnosis of HIV or viral hepatitis.
• Use of oral systemic corticosteroids within the last 90 days and for the duration of the study.
• History of any chemotherapy or radiation therapy of the targeted/treatment leg or adipose harvest site.
• Active worker's compensation case.
• Known hypersensitivity/contraindication to corticosteroid injections.
• Diagnosis of coagulation disorders (e.g., Von Willebrand's disease) and/or currently on anti-coagulant therapy.
• Occurrence of knee trauma to the index knee within six months prior to screening.
• Unwilling to stop usage of over-the-counter pain medication (e.g., Acetaminophen or NSAID), "Rescue Analgesics", for 7 days prior to any follow-up visit, with the exception of one "baby aspirin" per day for cardiovascular therapy or prophylaxis.
• Unwilling to stop taking prescription pain or prescription anti-inflammatory medication for the duration of the study, with the exception of Tramadol during the immediate post-procedure period noted below.
• Unwilling to abstain from NSAIDS for 7 days pre-injection and 2 weeks post-injection. Tramadol is allowed during the 72 hours immediately post-injection, with diary documentation of usage.
• Currently taking prescription pain medication for a condition other than the index knee.
• Currently in prison.
• Untreated symptomatic injury of the index knee (e.g., acute traumatic injury, anterior cruciate ligament injury, clinically symptomatic meniscus injury characterized by mechanical issue such as locking or catching).
• Impossibility to harvest enough adipose tissue.
• Any medical issue that the clinician feels would be a contraindication to the study treatment including, but not limited to:
  • Uncontrolled diabetes defined as HbA1c > 7%;
  • History of uncontrolled hypertension defined by average systolic BP > 140 mmHg or diastolic BP > 90 mmHg on ≥ 3 blood pressure medications;
  • History of cardiovascular disease;
  • History of cerebrovascular disease;
  • Uncontrolled asthma, defined as symptomatic (i.e., shortness of breath and/or wheezing) despite therapy;
  • History of solid organ or hematologic transplantation;
  • Diagnosis of non-basal cell malignancy within preceding 5 years;
  • Change in prescription medication within 1 month prior to enrollment;
  • Clinically significant abnormalities in vital signs at the time of screening defined by:
    • Systolic BP > 140 or < 90 mmHg or diastolic BP > 90 or < 60 mmHg;
    • Pulse < 60 or > 100 bpm;
    • Respiratory Rate < 9 or > 20;
    • Temperature  >99 °F.
• History of septic arthritis or sepsis/bacteremia in the affected knee within 6 months prior to screening, or infection requiring antibiotic treatment within the preceding 3 months. 
• Women who are breastfeeding.
• Unwilling to use contraception for 3 months post procedure.

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

Eligibility last updated 3/17/23. Questions regarding updates should be directed to the study team contact.

• 18 years or older.
• Biological female or male.
• Patients scheduled with a surgical consultation with a plastic surgeon (Dr. Nho V. Tran and/or Dr. Vahe Fahradyan-Part 2).
• Unilateral lymphedema in the upper or lower extremity (Part 2).
• Patient must be able to come to the 6-month clinical follow-up appointment (Part 2).
• Patients must be able to understand the study procedures and comply with them for the entire length of the study.

• Pregnant or nursing women, as self-reported.
• Known or suspected cardiac shunts.
• Prior lymphedema surgery in the upper extremity.
• Patients with documented history of congestive heart failure, nephrotic syndrome, venous insufficiency or other confounding disease.
• Tattoo or scar on either upper extremity.
• Patient conditions that would interfere with compliance to the study elements in the opinion of the study investigators
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent. Patient must be able to produce a written signature.
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention, at the PIs discretion.

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

Eligibility last updated 4/17/23. Questions regarding updates should be directed to the study team contact.

Inclusion criteria

• Prior diagnosis of bile acid diarrhea as documented by either.
  • total bile acid in 48 hour stool excretion of 2337 micromoles per 48 hours; or
  • greater than 1000 micromoles per 48 hours with greater than 4% primary bile acids in stool; or
  • greater than 10% primary bile acid (CA and CDCA) in stool 48 hour collection; or
  • serum 7 alpha C4 greater than 52 ng/mL.
• Age 18-70 years old.
• BMI <40 kg/m^2.
• Prior cholecystectomy, appendectomy, and tubal ligation or hysterectomy will all be permissible for participation in the study. 
• Participants receiving bile acid sequestrant will not be permitted to continue therapy and need to stop one week before baseline test.
• No use of oral antibiotics and NSAIDs for 2 weeks prior to study treatment.

Exclusion criteria

• Diabetes mellitus (type 1).
• Diabetes mellitus type 2 if taking metformin or GLP-1 agonist treatment (exenatide, liraglutide, semaglutide).
• Uncontrolled hypertension (with BP measured > 140/90mmHg in the CRTU).
• BMI ≥ 40 kg/m^2
• Chronic NSAID use (>1 day/week).
• Use of oral antibiotics and NSAIDs for 2 weeks prior to and during the entire 28 day study period.
• Diagnosis of gastrointestinal diseases that are associated with inflammation such as inflammatory bowel diseases and celiac disease or gastrointestinal infection in the prior 4 weeks.
• Prior intestinal or colonic resection; note prior cholecystectomy, appendectomy, and tubal ligation or hysterectomy will all be permissible for participation in the study.
• Participation in highly vigorous exercise such as running >5 miles per day in week prior to the permeability test.

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

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

• Branch 1: People who are older than 18 years old, with low vision, and those with a stable internet connection.
• Branch 2: People who are older than 18 years old, with VA poorer than or equal to 20/1,000, and those with a stable internet connection.

• Anyone with normal vision will be excluded from branch 1 studies, and anyone with vision better than ULV will be excluded from branch 2 studies.  

Eligibility last updated 5/6/22. Questions regarding updates should be directed to the study team contact.

• Satisfactory completion of Treatment Period and the End of Treatment Visit of the Index Study (ION-682884-CS2) OR diagnosis of ATTR-CM and satisfactory participation on ISIS 420915- CS101 study as judged by the Investigator and Sponsor.
• Investigator is willing to treat the participant with open-label eplontersen.
• Willingness to adhere to vitamin A supplementation per protocol.

• Permanently discontinued study drug administration while participating in the Index Study (ION 682884-CS2) or IST (ISIS 420915-CS101 Study).
• Have any new condition or worsening of an existing condition that in the opinion of the Investigator or Sponsor would make the participant unsuitable for enrolment, or which could interfere with the participant participating in or completing the study, including the need for treatment with medications disallowed in the Index Study. 

Eligibility last updated 5/25/23.   Questions regarding updates should be directed to the study team contact.

• 18-21 years old.
• Fluent English speaker.
• Medically cleared to play ice hockey.

• Clinically documented hearing issues.
• In-ear hearing aid or cochlear implant.
• Implanted pacemaker or defibrillator.
• Metal or plastic implants in skull.
• lack of verbal fluency in the English language.
• History of seizures.
• Allergy to rubbing alcohol or EEG gel.

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

Eligibility last updated 5/17/23. Questions regarding updates should be directed to the study team contact.

• Male or female subjects between 28 days and less than 18 years of age, with clinical features that are consistent with a diagnosis of ARPKD.
• Ability for parent/legal 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. Ability to provide written informed assent from all subjects old enough per local laws to provide assent.

• Premature birth (≤ 32 weeks gestational age) for infants 28 days to < 12 weeks of age.
• Anuria or RRT defined as intermittent or continuous hemodialysis, peritoneal dialysis, hemofiltration, hemodiafiltration or history of kidney transplantation.
• Evidence of syndromic conditions associated with renal cysts (other than ARPKD).
• Abnormal liver function tests including ALT and AST, > 1.2 × ULN (upper limit of normal).
• Has splenomegaly or portal hypertension (HTN).
• Parents with renal cystic disease.
• Receiving chronic diuretic that could not be adjusted after tolvaptan initiation.
• Cannot be monitored for fluid balance. 
• Has or at risk of having sodium and potassium 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.
• Platelets < 50000 µL.
• Severe systolic dysfunction defined as ejection fraction < 14%.
• Serum sodium levels < 130 mmol/L or >145 mmol/L.
• Taking any other experimental medications.
• Require ventilator support.
• Taking medications known to induce CYP3A4 (CYP = Cytochrome P).
• Having an infection including viral that would require therapy disruptive to IMP dosing.
• Females who are breast-feeding or who have a positive pregnancy test result prior to receiving IMP.
• Subjects with a history of substance abuse (within the last 6 months).
• Subjects who have bladder dysfunction and/or difficulty voiding.
• Subjects taking a vasopressin agonist (e.g., desmopressin).
• Subjects with a history of persistent noncompliance with antihypertensive or other important medical therapy.
• Subjects taking medications or having concomitant illnesses likely to confound endpoint assessments, including taking approved (i.e., marketed) therapies for the purpose of affecting PKD cysts such as tolvaptan, vasopressin antagonists, anti-sense ribonucleic acid (RNA) therapies, rapamycin, sirolimus, everolimus, or somatostatin analogs (i.e., octreotide, sandostatin).
• Received or are scheduled to receive a liver transplant.
• History of cholangitis within the last 6 months.
• Has findings consistent with clinically significant portal hypertension (e.g., varices, variceal bleeding, hypersplenism indicated by thrombocytopenia).

Eligibility last updated 6/2/23. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years of age.

• Coronary artery disease.
• Heart failure.
• Pregnancy.
• Diabetes.
• Sleep disorders.
• Shift workers.
• Individuals who typically go to sleep after midnight.
• Individuals who traveled across ≥2 time zones within one week of study visits.
• BMI ≥ 35.0kg/m^2.
• Use of nicotine-containing products within the two years preceding study visits.
• Use of allopurinol, proton pump inhibitors, or other medications/supplements which interfere with the nitrate-nitrite-nitric oxide pathway or outcome measures.

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

Eligibility last updated 1/24/23. Questions regarding updates should be directed to the study team contact.

• ≥  18 years of age.  
• Capacity to consent.
• BMI ≤ 30.
• Systolic BP ≤ 140mmHg.
• Diastolic BP ≤ 90.
• eGFR > 30 (within prior 3 months).
• Able to undergo an MRI.

• History of Cardiovascular disease that may affect the results of the testing performed.
•  Any Current orthopedic limitations.
• Currently taking any cardiac medication.
• Pregnancy.

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

Eligibility last updated 2/21/23. Questions regarding updates should be directed to the study team contact.

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.

- Not pregnant and not nursing, because this study involves agents that
have 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.

- Patients may not have received prior treatment with any PARP inhibitor, temozolomide
or dacarbazine (IV analogue of temozolomide).

- Patients may not have had prior treatment with at least one of the agents included on
the investigator's choice arm: trabectedin or pazopanib. If the patient has had prior
treatment with one of these agents, they must be assigned to the other agent for
investigator's choice. That is, patients who have received prior pazopanib must be
assigned to trabectedin, and patients who have received prior trabectedin must be
assigned to pazopanib.

- Patients may not have undergone major surgery (related or unrelated to their cancer
diagnosis) ≤ 28 days of registration. Subjects with clinically relevant ongoing
complications from prior surgery are not eligible.

- Patients may not have uncontrolled hypertension defined as a blood pressure (BP) >
150/90 on two consecutive assessments during the screening period. If a patient is
found to have a BP > 150/90 on two consecutive assessments during the screening
period, the patient may be started on an anti-hypertensive regimen, and will be
considered eligible if two subsequent measurements are performed and the BP is ≤
150/90.

- Patients may not have an uncontrolled ventricular arrhythmia or recent (within 3
months) myocardial infarction.

- In addition to the above, patients with known history or current symptoms of cardiac
disease, or history of treatment with cardiotoxic agents, should have a clinical risk
assessment of cardiac function using the New York Heart Association Functional
Classification. To be eligible, patients should be class 2B or better.

- Patients may not have a history of active or unresolved: perforation, abscess or
fistula within 28 days prior to registration (either clinically or radiographically).

- Patients must not have myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or
a history of bone marrow biopsy findings at any time consistent with MDS and/or AML.

- Patients must not have an uncontrolled intercurrent illness including, but not limited
to, ongoing or active infection, uncontrolled major seizure disorder, unstable spinal
cord compression, superior vena cava syndrome, extensive interstitial bilateral lung
disease on high resolution computed tomography (HRCT) scan or any other condition that
would limit compliance with study requirements.

- Patients may not require concomitant use of known strong CYP3A inhibitors (e.g.,
itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with
ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or
moderate CYP3A inhibitors (e.g., ciprofloxacin, erythromycin, diltiazem, fluconazole,
verapamil). The required washout period prior to starting study treatment is 2 weeks.

- Patients may not require concomitant use of known strong (e.g., phenobarbital,
enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine
and St John's Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil).
The required washout period prior to starting study treatment is 5 weeks for
enzalutamide or phenobarbital and 3 weeks for other agents.

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

Eligibility last updated 6/9/23. Questions regarding updates should be directed to the study team contact.

• Adults age 65 and above.
• Men and women.
• Sarcoma diagnosis.

• Children.

Eligibility last updated 8/20/21. Questions regarding updates should be directed to the study team contact.

NOTE: Histologic confirmation of the primary tumor or recurrent tumor per pathology report is required. Eligible histotypes include high grade serous; endometrioid; and clear cell carcinoma, as these histotypes have high expression of FRalpha (Kalli, Oberg, Keeney, & et al., 2008). Mixed carcinomas, including carcinosarcomas, with >= 50% of the tumor comprised of high grade serous; and/or
endometrioid; and/or clear cell carcinoma are eligible

- Ovarian cancer (OC) recurrence
•Platinum sensitivity/resistance

- Platinum-refractory (defined as recurrence or progression of OC =< 30 days of the last dose of platinum-based chemotherapy)

- Platinum-resistant (defined as recurrence or progression of OC between 31-180 days of the last dose of platinum-based chemotherapy)

- Platinum-sensitive (defined as recurrence or progression >=181 days after the last dose of platinum-based chemotherapy). NOTE: Patients with platinum-sensitive
recurrent OC must have either received at least two prior courses of platinum-based chemotherapy AND/OR have a documented allergy to carboplatin

NOTE: Any number of prior therapies or maintenance regimens for OC are allowed

- At least one of the following:

- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria AND/OR

- CA-125-evaluable disease, as defined by the Gynecologic Cancer InterGroup (GCIG)

- Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1

- Hemoglobin >= 8.5 g/dL (obtained =< 15 days prior to registration)

- Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 15 days prior to registration)

- Platelet count >= 75,000/mm^3 (obtained =< 15 days prior to registration)

- Lymphocytes >= 0.3 x 10^9/L (obtained =< 15 days prior to registration)

- Monocytes >= 0.25 x 10^9/L (obtained =< 15 days prior to registration) 
- Total bilirubin =< 1.5 x upper limit of normal (ULN), unless patient has a documented history of Gilbert's disease, then direct bilirubin must be =< ULN (obtained =< 15 days prior to registration)

- Aspartate transaminase (AST) =< 3 x ULN (obtained =< 15 days prior to registration)

- Creatinine clearance >= 30 mL/min per Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation (obtained =< 15 days prior to registration)

- Negative pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only

- Provide written informed consent

- Willing to provide mandatory blood and tissue specimens for correlative research

- Willing to provide archival tissue specimen for correlative research

- Willing to return to Mayo Clinic for follow-up (during the active monitoring phase of the study)

- Willing to undergo a tetanus vaccination (if not performed =< 365 days prior to registration)

- Willing to have a central access line placed, if needed (as determined during venous access assessment)

NOTE: Since treatment will begin no sooner than 4 weeks after registration due to the need for apheresis and
manufacturing of the FRalphaDC product, a "wash-out" period of 3 or 1 week(s) prior to registration will cause a gap of at least 7 or 5 weeks between the last anti-cancer
treatment and initiation of protocol therapy

- Grade 2 or higher symptoms attributed to OC OR disease measuring > 5 cm in long axis (non-nodal lesions), or > 5 cm in short axis (nodal lesions) OR disease that, in the
judgement of the treating investigator, is likely to become symptomatic in the next 8 weeks (ex. moderate ascites)

NOTE: Since patients will not receive therapy for cancer
until 3-4 weeks after apheresis-potentially 6-8 weeks after registration-patients with symptomatic OC or an elevated tumor burden may experience significant progression
prior starting therapy and should not be treated on this protocol.)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or
interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens

- Known history of human immunodeficiency virus (HIV) infection

NOTE: No HIV testing is required unless mandated by local health authority

- Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active serious infections (e.g., pneumonia, sepsis) requiring systemic therapy

- Current diagnosis or previous history of immune-related (non-infectious) pneumonitis or interstitial lung disease that requires or required steroids

- Active autoimmune disease that required systemic treatment other than replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroids) =< 2 years
prior to registration

- Psychiatric illness/social situations that would limit compliance with study requirements

- Concurrent active hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. EXCEPTIONS:

- For patients with evidence of hepatitis B virus (HBV) infection (hepatitis B surface antigen [HBsAg] positive), patients must have completed at least 4 weeks of hepatitis B virus (HBV) antiviral therapy and the HBV viral load
must be undetectable at the time of registration

- Patients with a history of hepatitis C virus (HCV) are eligible if they have an undetectable HCV viral load. Patients must have completed curative anti-viral treatment >= 4 weeks prior to registration

- NOTE: Patients without symptoms or prior history do not require testing prior to registration

- Other active malignancy either requiring palliative systemic therapy =< 3 years prior to registration, or likely to require treatment in the next 2 years EXCEPTIONS:
Patients with non-melanotic skin cancer, papillary thyroid cancer not requiring therapy or carcinoma-in-situ are eligible for this trial. 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

- History of myocardial infarction =< 6 months prior to registration, or congestive heart failure requiring use of ongoing maintenance therapy for life-threatening
ventricular arrhythmias 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. To be eligible for this trial, patients should be class 2B or better

- Treatment with systemic immunosuppressive medication (including, but not limited to, prednisone >10 mg/day or equivalent, cyclophosphamide, azathioprine, methotrexate,
thalidomide, and anti-tumor necrosis factor [TNF]-alpha agents) =< 7 days prior to registration, or anticipation of need for systemic immunosuppressive medication during
the course of the study

NOTE: Patients who have received acute, low-dose systemic steroids (=< 10 mg/day oral prednisone or equivalent) prior to registration or a one-time pulse dose of systemic immunosuppressant medication (e.g., =< 48 hours of corticosteroids for a contrast allergy) are eligible for the study

NOTE: The use of inhaled corticosteroids for chronic obstructive pulmonary disease or asthma, mineralocorticoids (e.g., fludrocortisone), or low-dose corticosteroids for patients with orthostatic hypotension or adrenocortical insufficiency is allowed

- History of allogeneic stem cell transplant

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

• Participant must be at least 16 years of age, at the time of signing the informed consent or assent.
• Participants must have a documented pathogenic activating variant, or variant of uncertain significance, of the CASR gene associated with biochemical findings of hypoparathyroidism either present at Screening or a documented history of both:
  • cCa < 8.6 mg/dL (2.2 mmol/L) in participants 16 to < 18 years, or < 8.5 mg/dL (2.1 mmol/L) in participants ≥ 18 years iPTH < 40 pg/mL (4.2 pmol/L);
  • Note: A genetic analysis report for CASR will be acceptable. In the absence of any documentation for the CASR variant, participants must be willing to undergo CASR variant analysis. Participants who have undergone an allogeneic bone marrow transplant must provide either CASR variant analysis report performed prior to the bone marrow transplant or provide a buccal swab for variant analysis. Participants who have received a blood transfusion must wait 2 weeks following the blood transfusion before undergoing CASR variant analysis.
• Participants must have a documented history of symptoms or signs of ADH1. Symptoms of ADH1 include agitation, anxiety, back pain, brain fog, bronchospasm, blepharospasm, cardiac failure, cognitive impairment, difficulty focusing/concentration, esophageal spasm, facial spasm, headaches, hypoesthesia (including facial and oral), irritability, laryngospasm, muscle cramping, muscle fatigue, muscle spasms, muscle tightness, muscle twitching, musculoskeletal pain, musculoskeletal stiffness, myalgia, nephrolithiasis, nervousness, paresthesia (including oral), polydipsia, polyuria, seizure, tetany, throat tightness, or tremor. Signs of ADH1 include basal ganglia or other cerebral calcification, Chvostek sign, hypercalciuria, nephrocalcinosis, papilledema, premature cataracts, prolonged QT interval on ECG, pseudotumor cerebri, or Trousseau sign.
• Participants 16 to < 18 years old must have closed growth plates on hand radiograph.
• Participants treated with thiazide diuretics must discontinue thiazides for at least 14 days prior to Screening through Period 3 Week 24. When the thiazide is being used as an antihypertensive, alternative therapy will be prescribed by the Investigator as needed.
• Participants treated with phosphate binders must discontinue the phosphate binders at least one day prior to the Screening Visit.
• Participants treated with magnesium or potassium supplements must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants treated with potassium-sparing diuretics must be willing to discontinue such treatment prior to the first dose of encaleret.
• Participants must meet SoC Optimization criteria.
• Male participants must use highly effective contraceptive method (eg, condoms with spermicidal gel or foam) during vaginal intercourse and should not father a child nor donate sperm while taking encaleret and for 3 months after the last dose of encaleret. Condoms are not required if the participant is vasectomized or if the participant’s partner is not a female of childbearing potential.
• Postmenopausal females and females not of childbearing potential may participate in this study without use of contraception:
  • Females are considered postmenopausal if they have had 12 months of natural (spontaneous) amenorrhea without an alternative medical cause and must be confirmed with plasma FSH;
  • Females are considered not of childbearing potential if they have had surgical bilateral oophorectomy (with or without hysterectomy) or hysterectomy. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, shall she be considered not of childbearing potential.

• Females of childbearing potential, defined as all females physiologically capable of becoming pregnant, must use two highly effective methods of contraception starting at Screening and for 3 months following the last dose of encaleret. Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Capable of giving signed informed consent or assent, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.

• cCa and 24-hr UCa both within the respective reference ranges (cCa = 8.6-10.5 mg/dL in participants 16 to < 18 years or 8.5-10.5 mg/dL in participants ≥ 18 years and UCa < 250 mg/day for women and < 300 mg/day for men) at Screening Visit.
  • Note: Exclusion Criteria only applies to participants on SoC who have not participated in CLTX-305-201.
• History of hypocalcemic seizure within the past 3 months preceding Screening.
• History of thyroid or parathyroid surgery.
• Pregnant or nursing (lactating) women, where pregnancy is confirmed by a positive β-hCG laboratory test.
• History of treatment with PTH 1-84 or 1-34 within the 2 months preceding Screening and requiring SoC doses exceeding > 1.2 × their pre-PTH treatment total daily doses or bone turnover markers, CTx and P1NP, > upper limit of normal for sex, age (men only) and menopausal status (women only).
• Received any investigational medicinal product other than encaleret within 30 days or 5 half-lives, whichever is longer, prior to the first day on study, or are in follow-up for another interventional clinical study during Screening. If the half-life of an investigational medicinal product is unknown, then 30 days prior to Screening.
• Blood 25-OH Vitamin D level < 25 ng/mL.
• If participant has a blood 25-OH Vitamin D level < 25 ng/mL at the Screening Visit, they will be prescribed cholecalciferol or ergocalciferol supplementation per the Investigator. Once the 25-OH Vitamin D level is > 25 ng/mL, the participant will be eligible to enroll in the study (if still within Screening period) or re-screen for the study.
• Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2 using CKD-EPIcr_R (for participants < 18 years old the Bedside Schwartz equation should be used). 
• 12-lead resting ECG with clinically important abnormalities except for asymptomatic QTc prolongation clinically ascribed to hypocalcemia.
• Participants with positive HBsAg, Hepatitis A IgM, or HIV viral serology test at the Screening Visit. Participants who are in complete remission from Hepatitis C as evidence by sensitive assay ≥ 12 weeks after completion of HCV therapy may participate in the study.
• Male or female participants planning to conceive a child prior to the LTE.
• Hypersensitivity to any active substance or excipient of encaleret. 
• Presence or history of any disease or condition (eg, drug or alcohol dependency) that, in the view of the Investigator, would affect the participant’s safety or places the participant at high risk of poor treatment compliance or of not completing the study.

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

Eligibility last updated 11/30/22. Questions regarding updates should be directed to the study team contact.