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

Eligibility last updated 12/6/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 9/2/22. Questions regarding updates should be directed to the study team contact.

- Karnofsky performance status ≥ 60% (Eastern Cooperative Oncology Group [ECOG] ≤ 2).

- Absolute neutrophil count ≥ 1,500/mcL.

- Platelets ≥ 100,000/mcL.

- Hemoglobin ≥ 10 g/dL.

- Total bilirubin ≤ 2 x institutional upper limit of normal (ULN).

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine transaminase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3 x
institutional ULN.

- Glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m^2.

- Human immunodeficiency virus (HIV)-infected patients on effective anti-retro-viral therapy with undetectable viral load within 6 months are eligible for this trial.

- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

- Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

- Patients 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.

- 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.

- The effects of selinexor (KPT-330) and temozolomide on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as
deoxyribonucleic acid (DNA) alkylating 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, and for 180 days after the last dose of temozolomide. 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 treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of study treatment administration.

- Ability to understand and the willingness to sign a written informed consent document.  Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible.

• Volar reconstruction of the scapholunate ligament

• Institutional follow-up <12 months

•  Patients must have a pre-identified:
  • Heterozygous genetic variant in the POMC gene or PCSK1 gene;
  • Heterozygous genetic variant in the LEPR gene;
  • Homozygous, heterozygous, or compound heterozygous variant in the SRC1;
  • Homozygous, heterozygous, or compound heterozygous variant in SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene;
  • Heterozygous N221D variant in the PCSK1 gene; OR
  • Be an N221D variant of the PCSK1 gene If a patient has composite heterozygous variants eligible for the study she/he will be accounted for the higher category based on ACMG classification;
    • Example: If a patient is a composite heterozygous for POMC pathogenic variant, and LEPR VOUS, the patient will be categorized as POMC pathogenic.
  • If the 2 variants have the same ACMG classification, adjudication will be assigned to the less prevalent gene sub-study;
    • Example:
      • If a patient is a composite heterozygous for LEPR VOUS and SRC1 VOUS, the patient will be categorized as SRC1(sub-study 35c);
      • If a patient is a composite heterozygous for SH2B1 VOUS and SRC1 VOUS, the patient will be assigned to SRC1 (sub-study 35c).
  • If the investigator has genetics results on a patient who may be eligible for the study, but the genetics have not yet been categorized by a CLIA/CAP/ISO15189 certified laboratory, then Rhythm may provide testing and/or categorization through a third-party laboratory.
• Between 6 and 65 years of age at the time of provision of informed consent/assent.
• Obesity, defined as BMI ≥ 30 kg/m^2 for patients ≥ 18 years of age or BMI ≥ 95th percentile for age and gender for patients 6 up to 17 years of age, based on the United States (US) Centers for Disease Control and Prevention criteria.
• Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the study (including once daily [QD] injection regimen and all other study procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all study procedures due to cognitive limitations or any other reason should not be enrolled into the study.
• Patient and/or parent or guardian reports that patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient was significantly overweight during childhood.
• For women of child-bearing potential (WOCBP), agrees to use a highly effective form of contraception throughout the study and for 30 days following the study:
  •  Highly effective forms of contraception include:
    • Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal);
    • Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
    • Intrauterine device (IUD);
    • Sexual abstinence only if it is the preferred and usual lifestyle of the patient.
• Reported history of lifestyle intervention of diet and exercise.
• Reported history of hyperphagia.

• Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents including herbal medications that has resulted in > 2% weight loss.
• Use of any medication that is approved to treat obesity within 3 months of first dose of study drug (e.g., orlistat, phentermine-topiramate, naltrexone-bupropion) if >2% weight loss in the last 3 months.
• History of Bariatric surgery with evidence of weight loss of > 2% in the last 3 months.
• Documented diagnosis of any psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance.
• Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS) during Screening, any suicide attempt in the past 5 years, or any suicidal behavior in the last month.
• Current, clinically significant pulmonary, cardiac or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with Rhythm to determine eligibility.
• HbA1C > 10% at Screening.
• History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
• Glomerular filtration rate (GFR) < 30 mL/min at Screening.
• History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
• Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. Any concerning lesions identified during Screening will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
• Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
• Participation in any clinical study with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing.
• Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
• Significant hypersensitivity to any excipient in the study drug.
• If female, pregnant or breastfeeding.

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.

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.

Eligibility last updated 3/6/23.  Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 10/18/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 6/10/22. Questions regarding updates should be directed to the study team contact.

• Male and female patients aged ≥ 18 years at the time of informed consent form (ICF) signature.
• Received allogeneic HSCT from a related or unrelated, human leukocyte antigen-matched or mismatched donor. Patients having received any of the following stem cell sources are eligible: granulocyte colony stimulating factor mobilized peripheral blood stem cells, bone marrow, umbilical cord blood.
• Diagnosis of TA-TMA established by histologic evidence of microangiopathy in any biopsied organ OR, as per the laboratory markers below, indicating TMA:
  • De novo or progressing thrombocytopenia (platelet count < 50 x 10^9/L or > 50 % decrease in platelet count from the highest value achieved after transplantation); AND
  • Elevated LDH (> 1.5 x ULN); AND
  • At least 1 additional laboratory criteria among the following:
  • Schistocytes on the peripheral blood smear (≥ 2 per hpf); OR
  • De novo anemia (hemoglobin < LLN or anemia requiring PRBC transfusion support as per local institutional standard); OR
  • Proteinuria (rUPCR ≥ 2 mg/mg); OR
  • Elevated plasma concentration of sC5b-9 above ULN.
• Have a diagnosis of TA-TMA that persists despite initial management of any triggering condition.
• Have at least 1 sign/symptom of organ dysfunction:
  • Kidney: doubling of serum creatinine compared with pre-HSCT level or patient receiving renal replacement therapy or proteinuria ≥ 30 mg/dL AND rUPCR ≥ 2 mg/mg;
  • Lungs: hypoxemia or any need for noninvasive or invasive positive pressure ventilation;
  • Cardiovascular: pulmonary hypertension diagnosed by a cardiologist using cardiac catheterization, or pulmonary hypertension criteria on echocardiography or arterial hypertension, defined by systolic blood pressure (BP) ≥ 140 mmHg and/or diastolic BP ≥ 90 mmHg at baseline or hypertension requiring > 2 medications (excluding diuretics);
  • Serositis: clinically significant pleural effusion or pericardial effusion requiring surgical therapy (e.g., pericardiocentesis/ thoracocentesis);
  • CNS: seizures attributable to posterior reversible encephalopathy syndrome;
  • GI tract: presence of biopsy-proven GI TA-TMA. Patients with GI bleeding (hematemesis or hematochezia) will be excluded.
• Women of childbearing potential, defined as any women who have experienced menarche and who are NOT permanently sterile or postmenopausal, must have a negative serum pregnancy test at screening and agree to use protocol-defined methods of contraception for the duration of the study and 8 weeks after their last IMP dose.
  • Note: Postmenopausal is defined as having had 12 consecutive months with no menses without an alternative medical cause.
• Men must agree to the following for the duration of the study and 8 weeks after their last dose of IMP:
  • Avoid fathering a child;
  • Use protocol-defined methods of contraception;
  • Refrain from donating sperm.
• Patient and/or legally authorized representative must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF.

• Positive direct Coombs test.
• Known familial or acquired ADAMTS13 deficiency.
• Known Shiga toxin‐related hemolytic uremic syndrome.
• Known bone marrow or graft failure.
• Diagnosis of disseminated intravascular coagulation.
• Diagnosis of VOD.
• Active GI bleeding (hematemesis or hematochezia) at baseline.
• Body weight < 30 kg and > 100 kg.
• Uncontrolled systemic bacterial or fungal infection, presence or suspicion of sepsis.
• Previously or currently treated with a complement inhibitor (approved or investigational).
• Pregnancy or breastfeeding.
• Positive human immunodeficiency virus antibody at screening or documented in pre-HSCT medical record.
• Hepatitis C virus detectable by polymerase chain reaction at screening or documented in pre-HSCT medical record.
• Chronic inactive hepatitis B virus with viral loads > 1000 IU/mL (> 5000 copies/mL) at screening or documented in pre-HSCT medical record. Eligible patients who are chronic active carriers (≤ 1000 IU/mL) must receive prophylactic antiviral treatment (e.g., entecavir, tenofovir, lamivudine) according to local country guidelines.
• Inability to cooperate with study procedures or any condition that, in the opinion of the investigator, could increase the patient’s risk by participating in the study or confound the outcome of the study.

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

• Has a histologically or cytologically confirmed diagnosis of Stage IV (T any, N any, M1a, M1b, M1c
  •AJCC eighth Edition) squamous or nonsquamous NSCLC.
  • Note: Mixed tumors will be characterized by the predominant cell type; if small cell elements are present, the participant is ineligible.
• Has measurable disease based on RECIST 1.1, as determined by the local site assessment.
  • Note: Measurable disease is defined as having at least 1 measurable lesion by CT or MRI per RECIST 1.1. Lesions that appear measurable but are situated in a previously irradiated area can be considered measurable (eligible for selection as target lesions) if they have shown documented growth since the completion of radiation.
• Has provided tumor tissue (post diagnosis of metastatic disease is preferred) for determination of PD-L1 status before randomization.
  • Note: Assessment of PD-L1 expression must be made from provided archival tumor tissue sample or newly obtained core or incisional or excisional biopsy of a tumor lesion not previously irradiated. FFPE tissue blocks are preferred to slides. Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
• Has confirmation that EGFR-, ALK-, or ROS1-directed therapy is not indicated as primary therapy (documentation of the absence of tumor-activating EGFR mutations [e.g., DEL19 or L858R], AND absence of ALK and ROS1 gene rearrangements).
  • Note: If participant’s tumor is known to have a predominantly squamous histology, molecular testing for EGFR mutation and ALK and ROS1 translocations will not be required, as this is not part of current diagnostic guidelines.
• Has not received prior systemic treatment for metastatic NSCLC.
• Is male or female, from ≥ 18 years of age inclusive, at the time of signing the informed consent.
• Has an ECOG PS of 0 or 1 assessed within 7 days before randomization.
• Has a life expectancy of at least 3 months.
• If male, agrees to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is as follows:
  • Chemotherapy: at least 95 days from the last dose;
  • Refrain from donating sperm; PLUS either:
  • Abstains from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent; OR
  • Uses contraception unless confirmed to be azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview as detailed below:
  • Uses a male condom plus partner use of an additional contraceptive method when having penile-vaginal intercourse with a WOCBP who is not currently pregnant.
  • Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-vaginal intercourse or use a male condom during each episode of penilevaginal penetration.
• Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• A female participant is eligible to participate if she is not pregnant or breastfeeding and at least one of the following conditions applies:
  • Not a WOCBP; OR
  • Is a WOCBP and:
  • Uses a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during this period. The length of time required to continue contraception for each study intervention is as follows:
    • MK-7684A/pembrolizumab: 120 days;
    • Chemotherapy: 180 days.
• The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention. Contraceptive use by women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study interventions is more stringent than the requirements above, the local label requirements are to be followed.
• Has a negative highly sensitive pregnancy test ( as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention. If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. 
• Abstains from breastfeeding during the study intervention period and for at least 120 days after the last dose of study intervention.
• Medical history, menstrual history, and recent sexual activity has been reviewed by the investigator to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• The participant (or legally acceptable representative) has provided documented informed consent/assent for the study. The participant may also provide consent/assent for FBR.  However, the participant may participate in the study without participating in FBR.
• Has adequate organ function. Specimens must be collected within 10 days before the start of study intervention.
• Absolute neutrophil count (ANC) ≥ 1500/μL.
• Platelets ≥ 100 000/μL.
• Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/La.
• Estimated creatinine clearance using the Cockcroft-Gault equation.
• To initiate treatment with carboplatin or cisplatin, CrCl must be ≥ 60 mL/min
• Total bilirubin ≤ 1.5 ×ULN OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN.
• AST (SGOT) and ALT (SGPT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases).
• International normalized ratio (INR) OR prothrombin time (PT).
• Activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
• Abbreviations: ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=absolute neutrophil count; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of normal.
• Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks.
• Estimated creatinine clearance using Cockcroft-Gault:
  • (140-age [years] × weight (kg) (×F)*Serum creatinine (mg/dL) × 72 *where F = 0.85 for females and F = 1 for males
  • Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements are to be adapted according to local regulations and guidelines for the administration of specific chemotherapies.

• Known additional malignancy that is progressing or has required active treatment within the past 3 years.
  • Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded.
• Known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, (i.e., without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study intervention.
• Participants with asymptomatic brain metastases (i.e., no neurological symptoms, no requirements for corticosteroids, no or minimal surrounding edema, and no lesion >1.5 cm) may participate.
• Severe hypersensitivity (≥ Grade 3) to MK-7684, MK-7684A, pembrolizumab, chemotherapy components, and/or any of its excipients.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days before the first dose of study medication.
• Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs).  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.
• History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Note: Lymphangitic spread of the NSCLC is not exclusionary.
• Active infection requiring systemic therapy.
• Known history of HIV infection. No HIV testing is required unless mandated by local health authority.
• Has a known history of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
  • Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• History or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• Known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
• Received prior therapy with an anti-TIGIT, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or coinhibitory T-cell receptor (e.g., CTLA-4, OX-40, CD137).
• Received prior systemic anticancer therapy for metastatic disease.
  • Note: Participants who received adjuvant or neoadjuvant therapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months before the development of metastatic disease.
• If the participant had major surgery, the participant must have recovered adequately from the procedure and/or any complications from the operation before starting study intervention.
• Received prior radiotherapy within 2 weeks of start of study intervention or have had a history of radiation pneumonitis. 
  • Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
• Received radiation therapy to the lung that is > 30 Gray within 6 months of the first dose of study intervention.
• Received a live or live attenuated vaccine within 30 days before the first dose of study
• intervention. Administration of killed vaccines are allowed. 
• Is unable to interrupt aspirin or other NSAIDs, other than an aspirin dose ≤ 1.3 g/day, for a 5-day period (8-day period for long-acting agents, such as piroxicam).
• Is unable or unwilling to take folic acid or vitamin B12 supplementation.
• Currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
  • Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
• History of allogenic tissue/solid organ transplant.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.

• Male or female ages 18-50 years.
• Persons of childbearing potential must have a negative pregnancy test prior to receiving the study drug and will agree to use adequate contraception (hormonal or barrier method or abstinence) from the time of screening to a period of 2 years following treatment. Females of childbearing potential are defined as premenopausal and not surgically sterilized, or post-menopausal for fewer than 2 years. A urine pregnancy test will be performed prior to the administration of the study drug to confirm negative results. If the urine pregnancy test is positive, the study drug will not be administered and the result will be confirmed by a serum pregnancy test. Urine pregnancy tests will be performed by qualified personnel using kit.
• Persons becoming pregnant during the study will continue to be monitored for the duration of the study or completion of the pregnancy, whichever is longer. Monitoring will include perinatal and neonatal outcome. Any SAEs associated with pregnancy will be recorded.
• Chronic (> 3 months), unilaterally symptomatic, ICRS Grade III or IV cartilage lesions ranging in size from 2 to 8 cm^2. Patients with episodes of contralateral knee pain that is asymptomatic at the time of enrollment will be eligible for inclusion.  However, as outlined in the primary study endpoints, patients with previous episodes of contralateral knee pain who experience a repeat episode of contralateral pain similar to their established pattern of pain during the course of the trial will not be considered as having experienced an adverse event.
• Radiographic knee OA of Kellgren-Lawrence Grade 1 or less, consisting of normal knee radiographs (Grade 0) or doubtful narrowing of the joint space and possible osteophytic lipping (Grade 1).
• Previous 6 week or longer trial of one of the following conservative treatments:
  • activity modification;
  • weight loss;
  • physical therapy;
  • anti-inflammatory medications; or
  • injection therapy (e.g., cortisone).
• If applicable, at least 3 months will have passed since the last target knee intraarticular injection prior to undergoing RECLAIM therapy and at least 6 months will have passed between any prior arthroscopic or open knee procedures.
• Able to routinely walk without assistance (e.g., cane, walker).
• Clinically stable target knee. Patients undergoing primary anterior crucial ligament (ACL) reconstruction will be eligible for inclusion if their target knee is otherwise stable and well-aligned.
• No additional surgery planned in the target knee for at least 12 months following RECLAIM therapy.
• Completed general physical and well-being evaluation with primary care provider within 12 months of enrollment.
• Fully understanding of the requirements of the study and willingness to comply with the treatment plan, including laboratory tests, diagnostic imaging, and follow-up visits and assessments.
• Can provide written informed consent and complete HIPAA documentation after the nature of the study is fully explained and prior to any study-related procedure.

• Pregnant or nursing, or planning on becoming pregnant during the study period.
• Congenital or acquired malformation of the target knee resulting in significant deformity or leading to problems with the study treatment or analysis of the results.
• Significant knee malalignment that is not corrected at the time of RECLAIM surgery.
• Injections of any kind into the target knee within 3 months prior to study enrollment.
• Greater than 50% preoperative loss in native meniscus volume (i.e., meniscectomy, degenerative loss) in the surgical knee compartment. Patients undergoing repair of meniscus tears without > 50% meniscus volume loss will remain eligible for inclusion.
• History of intra-articular infection in the target knee.
• History of superficial infection in the target knee within 6 months of study enrollment, or evidence of current superficial infection affecting the target knee.
• History of falls requiring medical attention, or gait instability.
• Clinically significant abnormal hematology (complete blood count with differential), blood chemistry, or urinalysis screening laboratory results.
• Body mass index (BMI) > 35 kg/m^2.
• Taking anticoagulant medications (e.g., warfarin, heparin or clopidogrel) which may pose a clinically-significant contraindication to surgical RECLAIM therapy.
• Taking herbal therapies or supplements within 4 weeks of enrollment or unwilling to avoid use of herbal therapies or supplements until at least 30 days following  completion of the RECLAIM treatment cycle (includes, but not limited to chondroitin sulfate, diacerein, n-glucosamine, piascledine, and capsaicin).
• Taking non-steroidal anti-inflammatory medications (e.g., COX-2 inhibitors) without a stable dosing regimen for at least 4 weeks before baseline evaluation, or anticipating not remaining on a stable dose until at least 30 days following completion of the study drug treatment cycle.
• Use of electrotherapy or acupuncture for knee pain, unless there is a stable regimen for at least 4 weeks before baseline assessment.
• Taking anti-rheumatic disease medication (including methotrexate or other antimetabolites) within 3 months prior to study enrollment.
• On chronic, immunosuppressive transplant therapy or having a chronic, immunosuppressive state, including use of systemic steroids/corticosteroids.
• Current tobacco product use, including nicotine patch or other nicotine products.
• Clinically significant systemic inflammatory, rheumatological or connective tissue disorder including but not limited to rheumatoid arthritis, systemic sclerosis, system lupus erythematosus, and Ehlers-Danlos Syndrome.
• Clinically significant rheumatological or inflammatory disease of the knee or chondrocalcinosis/calcium pyrophosphate disease (CPPD), hemochromatosis, inflammatory arthritis, arthropathy of the knee associated with juxta-articular Paget's disease of the femur or tibia, ochronosis, hemophilic arthropath.

Eligibility last updated 8/2/22. Questions regarding updates should be directed to the study team contact.

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

Eligibility last updated 12/7/22. Questions regarding updates should be directed to the study team contact.

• Diagnosis of Partial Lipodystrophy.

• Previous treatment with metreleptin.

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

• Primary care clinicians in Rochester/Kasson who complete the pre/posttests, dermoscopy education and conducts skin lesion visits in their practice.  

• Patient refusal for dermoscopy skin lesion photo (skin lesion would then be excluded), dermoscopy image not captured by clinician at visit.

Eligibility last updated 8/18/22. Questions regarding updates should be directed to the study team contact.

• Plain film skeletal survey is the universal screening examination all cases of suspected child abuse in patients aged 24 months and younger.
• All patients who fit these criteria and present to the Rochester, Mayo Clinic site are routinely evaluated by the Child Abuse Team, led by coinvestigators Drs. Arne Graff and Chris Derauf.
• The non-contrast ultra-low dose chest CT will be performed the same day as the plain film skeletal survey, or less optimally within 48 hours. Logistically, many of these patients also receive head CT as part of the initial work-up, which would be the ideal time to add this additional examination, as it would add just seconds to the examination already being performed.
• A follow-up ultra-low dose chest CT will also be performed at the time of follow-up plain film skeletal survey. Follow-up imaging is typically recommended at about 2 weeks, but a wider window of 1-4 weeks will be allowed to capture this patient population, which is a reasonable time-period to evaluate for healing changes of occult fractures on x-ray.

• Patients older than 24 months.

Eligibility last updated 8/25/21. Questions regarding updates should be directed to the study team contact.

- Advanced solid tumor, where standard curative or palliative measures are no longer effective or are not considered appropriate or safe in the opinion of the Investigator.

Note: At the Sponsor’s discretion, enrollment to Phase 1a backfill slots may be limited to select patient populations (e.g., ER+ HER2- advanced breast cancer patients) to ensure adequate evaluation of LOXO-783 safety, PK, pharmacodynamic, and/or clinical activity in populations of interest. \

- Patients may have had up to 5 prior regimens for advanced disease.

- Phase 1b:

- Part A:

- ER+/HER2- advanced breast cancer

- Patients may have had up to 2 to 4 prior regimens for advanced disease,
depending on cohort

- Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required

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

Eligibility last updated 8/25/23. Questions regarding updates should be directed to the study team contact.

- Part B:

- ER+/HER2- advanced breast cancer

- Patients may have had up to 2 prior regimens for advanced disease.

- Part C:

- ER+/HER2- advanced breast cancer

- Patients may have had up to 5 prior regimens for advanced disease.

---- Prior CDK4/6 inhibitor therapy required.

- Have a diagnosis of diabetes mellitus Type 2

- Part D:

- Advanced breast cancer

- Patients may have had up to 5 prior regimens for advanced disease.

- Part E:

- Advanced solid tumor

- Patients may have had up to 3 prior regimens for advanced disease advanced
disease

- Part F:

- ER+/HER2- advanced breast cancer

- Patients may have had up to 2 prior regimens for advanced disease

- Prior cyclin dependent kinase (CDK)4/6 inhibitor therapy required

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.

Either:

• TEGSEDI Exposed Cohort: Patients diagnosed with hATTR-PN who have taken any dose of TEGSEDI within 25 weeks prior to enrollment; or
• TEGSEDI Unexposed Cohort: Patients diagnosed with hATTR-PN who have not taken any dose of TEGSEDI within 25 weeks prior to enrollment and are eligible for TEGSEDI treatment per applicable product label.
• Clinically managed in Canada, Europe, or the US.
• Have provided appropriate written informed consent.

• None.

Eligibility last updated 12/2/21. Questions regarding updates should be directed to the study team contact.

• Premenopausal women, ages 18-50 years old.
• Uterine fibroid group (n≈20): These participants will have had a previous or current diagnosis of UF determined by ultrasound, hysteroscopy, or MRI, confirmed with medical documentation within one year of recruitment.
• Control (non-fibroid) group (n≈20): These participants will not have evidence of UF (confirmed by imaging) at the time of study participation.

• History or evidence of:
  • hepatic, renal, or hematological disease;
  • peripheral vascular disease;
  • stroke/neurovascular disease;
  • diabetes;
  • dyslipoproteinemia;
  • hypertension (> 130/80 mmHg brachial cuff pressure); 
  • lung disease;
  • arthritis affecting ability to exercise; or
  • a body mass index > 30 kg/m^2. 
• Participants also will be excluded if taking antihypertensive medication or medication that alters autonomic or vascular function (e.g., tricyclic antidepressants, alpha-blockers, beta-blockers, etc.). 
• Participants will be non-smokers. 
• Subjects must have a negative pregnancy test in order to participate in the study. 
• Participants who are breastfeeding will be excluded.
• Women who have undergone hysterectomy will be excluded.

Eligibility last updated 3/7/22. Questions regarding updates should be directed to the study team contact.

• Healthy volunteers
  or Chronic Kidney Disease (CKD) patients with clinically indicated renal biopsy.
• ≥ 18 years of age.

• Subjects lacking capacity to consent.
• Vulnerable subjects such as prisoners; pregnant women; nursing mother.
• Subjects with history of hypersensitivity allergic reactions to ultrasound contrast agents.
• Patients with high-risk cardiac diseases.

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

• Patients with known or suspected genetic disorders.
• Patients with disorders where the genetic basis is not known.
• Control subjects.

• Patients with no known genetic disorders.

Eligibility last updated 10/20/22 Questions regarding updates should be directed to the study team contact.

- No available autologous iPSC-CL as defined by the manufacturer's release criteria.  (This applies to Part II of the study and applies to the treatment arm only).

- History of symptomatic episodes of cardiac arrythmia requiring cardiac defibrillation or escalation of medications.

- Heart failure with preserved ejection fraction.

- Heart failure due to co-morbid conditions (e.g., amyloidosis, valvular heart disease, refractory anemia).

- QTc greater than 500 ms.

- Stage III or higher chronic kidney disease.

- Decompensated liver cirrhosis.

- History of coronary artery disease.

- Uncontrolled diabetes mellitus.

- Any history of cancer.

- Contraindication for use of amiodarone for up to 3 months (treatment arm only).

- Contraindication for insertion of Insertable Cardiac Monitor.

- Contraindication for placement of LifeVest cardioverter defibrillator.

- Positive serology testing for HIV, Hepatitis B, Hepatitis C or Syphilis.

- Obesity with BMI greater than 30.

- Current alcohol or drug abuse precluding heart transplantation.

- Active infection requiring ongoing treatment.

- Contraindication to anesthesia.

- Past or current medical problems or findings from physical examination or laboratory testing that are not listed above, which, in the opinion of the investigator, may pose
additional risks from participation in the study, may interfere with the participant's ability to comply with study requirements or that may impact the quality of the data
obtained from the study.

- Inability or unwillingness of a participant to give written informed consent or comply with study protocol.

- History of non-compliance.

- Inability to be accompanied around the clock for any part of the first 3 weeks post product administration.

- Uncontrolled depression.

- Denied heart transplant due to social determinants.

- Current participation in another cardiac interventional clinical trial that could confound the results of this study.

- Previous heart transplant.

Eligibility last updated 7/19/23. Questions regarding updates should be directed to the study team contact.

Key

Eligibility last updated 5/11/22. Questions regarding updates should be directed to the study team contact.

• ≥ 18 years age.
• Biological female.
• Unilateral lymphedema in the upper extremity (ISL stage 2 or 3) secondary to breast cancer or breast cancer treatment.
• Patient qualifies for LVA surgery as determined by the plastic surgeons performing the surgery (Dr. Bill Tran or Dr. Vahe Fahradyan), and the patient consents to surgery.
• Patient must be able to come to the 6-month clinical follow-up appointment (Part 2 only).
• Patients must be able to understand the study procedures and comply with them for the entire length of the study.
• No contraception is necessary or required.

• Pregnant or nursing women.
• Known or suspected hypersensitivity to microbubble contrast agent, perflutren, blood products, albumin, polyethylene glycol (PEG), or egg.
• Known or suspected cardiac shunts.
• Prior lymphedema surgery in the upper extremity.
• Tattoo or scar on either upper extremity.
• Current drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.
• Inability or unwillingness of individual or legal guardian/representative to give written informed consent..
• Current or past participation within a specified timeframe in another clinical trial, as warranted by the administration of this intervention.

Eligibility last updated 6/24/22. Questions regarding updates should be directed to the study team contact.

• Patients with a diagnosis of soft tissue sarcoma.

• Unable or unwilling to provide informed consent

Eligibility last updated 1/12/22. Questions regarding updates should be directed to the study team contact.

• Ages ≥ 18 years.
• Diagnosis of degenerative thoracolumbar deformity.
• Deformity correction surgery scheduled with either Dr. Elder or Dr. Fogelson, minimum 4-level fusion with fixation to the pelvis.

• Unable to return to Mayo Clinic for follow-up evaluation.
• Patient is immobile (unable to walk independently or with a use of a gait aid)

Eligibility last updated 11/8/23. Questions regarding updates should be directed to the study team contact.

• Restricted to 18 to 80 years of age.
• ECOG performance status ≤ 2.
• Histologic confirmation of gastric adenocarcinoma including all subtypes and Siewert type III GE junction adenocarcinomas
• Adequate renal, and bone marrow function:
  • Leukocytes ≥ 3,000/uL;
  • Absolute neutrophil count ≥ 1,500/uL;
  • Platelets ≥ 50,000/Ul d. Serum creatinine ≤ 1.5 mg/dL.
• Metastasis confined to the peritoneum:
  • Positive peritoneal cytology;
  • Peritoneal metastasis on diagnostic laparoscopy;
  • Peritoneal metastasis on imaging.
• Response to systemic chemotherapy defined as at least one of the following:
  • Reduction (≥ 30%) in SUV max;
  • Reduction in size of primary tumor, regional lymph node or peritoneal metastasis on imaging (≥ 30% decrease in the longest diameter of target lesion) or laparoscopy (reduction in PCI or conversion of peritoneal cytology);
  • Reduction (≥ 30%) in serum tumor markers CEA or CA 19-9.
• Peritoneal Carcinomatosis Index (PCI) ≤ 7 and surgeon deems high likelihood for a complete cytoreduction.
• BMI ≤ 35 kg/m^2.

• Distant metastatic disease not limited to peritoneum, such as solid organ metastases (liver, lung, bone, distant lymph node, etc).
• Malignant ascites at time of study enrollment.
• Comorbidities that would preclude protocol therapy.
• Women with a positive urine or serum pregnancy test are excluded from this study; women of childbearing potential (defined as those who have not undergone a hysterectomy or who have not been postmenopausal for at least 24 consecutive months) must agree to refrain from breast feeding and practice adequate contraception as specified in the informed consent. Adequate contraception consists of oral contraceptive, implantable contraceptives, injectable contraceptives, a double barrier method, or abstinence.
• Subjects deemed unable to comply with study and/or follow-up procedures.
• Subjects with a known hypersensitivity to protocol systemic chemotherapy that was lifethreatening, required hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability or incapacity.