Pembrolizumab/Lenvatinib With and Without Healthy Donor FMT (hdFMT) in Relapsed/ Refractory (R/R) Melanoma

Exclusion Criteria

• •Diagnosis of non-cutaneous melanoma histologies including mucosal melanoma, ocular/choroidal melanoma, and acral-lentiginous melanoma.
• •Prior therapies:
• •* Receipt of prior agent(s) targeting the intestinal microbiome including but not limited to: FMT, defined bacterial consortia, single bacterial species and/or microbiota derived peptides.
• •* Prior chemotherapy, targeted therapy, and/or small molecule therapy within 2 weeks (or 4 half lives) prior to study Day 1.
• •* Prior therapy with lenvatinib or other systemic anti-angiogenic therapy.
• •* Prior radiotherapy within 2 weeks of start of study intervention.
• •* Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis.
• •* A 2-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to disease including CNS disease.
• •Contraindications to receiving lenvatinib:
• •• Has had major surgery within 3 weeks prior to first dose of study interventions.
• •* NOTE: Adequate wound healing after major surgery must be assessed clinically, independent of time elapsed for eligibility.
• •* Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
• •* Has urine protein ≥1 g/24 hours. Note: Participants with proteinuria ≥2+ (≥100 mg/dL) on urine dipstick testing (urinalysis) will undergo 24-hour urine collection for quantitative assessment of proteinuria.
• •* Has a LVEF below the institutional (or local laboratory) normal range, as determined by multigated acquisition (MUGA) or echocardiogram (TTE).
• •* Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation.
• •* NOTE: The degree of proximity to major blood vessels should be considered because of the potential risk of severe hemorrhage associated with tumor shrinkage/necrosis following lenvatinib therapy.
• •• Prolongation of QTcF interval to \>480 ms.
• •* NOTE: If the QTcF is prolonged to \>480 ms in the presence of a pacemaker, contact the Sponsor to determine eligibility.
• •• Has clinically significant cardiovascular disease within 12 months from first dose of study intervention, including New York Heart Association Class III or IV congestive heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or cardiac arrhythmia associated with hemodynamic instability.
• •* NOTE: Medically controlled arrhythmia would be permitted.
• •* Gastrointestinal malabsorption or any other condition that might affect the absorption of lenvatinib
• •* Active hemoptysis (bright red blood of at least 0.5 teaspoon) within 3 weeks prior to the first dose of study drug.
• •Presence of an absolute contraindication(s) to FMT administration
• •* Toxic megacolon
• •* Severe dietary allergies (e.g. shellfish, nuts, seafood)
• •* Inflammatory bowel disease
• •Patients who have not adequately recovered (i.e., ≤Grade 1 or at baseline or ≤Grade 2 endocrinopathy) from adverse events (AEs) due to a previously administered agent
• •A WOCBP who has a positive urine pregnancy test at Screening (see Appendix 3). If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
• •Has received a live vaccine within 30 days prior to the first dose of study drug.
• •* Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
• •* Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (ie. FluMist®) are live attenuated vaccines - Has a diagnosis of immunodeficiency, immunosuppression and/or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 14 days prior to the first dose of study drug.
• •Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• •o Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• •Concurrent non-hematologic malignancy within 3 years of data of first planned dose of therapy except for tumors with a negligible risk of metastasis and/or death as defined below:
• •* Adequately treated non-invasive malignancies including but not limited to melanoma in situ (MIS), cutaneous squamous cell carcinoma (cSCC), in situ cSCC, basal cell carcinoma (BCC), CIS of cervix, or DCIS/LCIS of breast.
• •* Low-risk early-stage prostate adenocarcinoma (T1-T2a N0 M0 and Gleason score ≤6 and PSA ≤10 ng/mL) for which the management plan is active surveillance, or prostate adenocarcinoma with biochemical-only recurrence with documented PSA doubling time of \> 12 months for which the management plan is active surveillance.
• •* Indolent hematologic malignancies for which the management plan is active surveillance including but not limited to CLL/indolent lymphoma.
• •* NOTE: Patients with high-risk hematologic malignancies (CML, ALL, AML, Hodgkin's or non-Hodgkin's lymphoma) are excluded even if the management plan is active surveillance.
• •Active (i.e., symptomatic or growing) central nervous system (CNS) metastases.
• •* Note: Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 2 weeks by repeat imaging (note that the repeat imaging should be performed during Screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study intervention
• •* Note: Patients with leptomeningeal disease are excluded.
• •Has severe hypersensitivity (≥Grade 3) to anti-PD(L)1 inhibitor. Has a systemic disease that requires systemic pharmacologic doses of corticosteroids greater than 10 mg daily prednisone (or equivalent).
• •* Note: Participants who are currently receiving steroids at a dose of ≤10 mg daily do not need to discontinue steroids prior to enrollment.
• •* Note: Participants that require topical, ophthalmologic, injected and/or inhalational steroids are not excluded from the study.
• •* Note: Participants with hypothyroidism stable on hormone replacement or Sjogren's syndrome are not excluded from the study.
• •* Note: Participants who require active immunosuppression (greater than steroid dose discussed above) for any reason are excluded from the study.
• •Has a history of interstitial lung disease or active, non-infectious pneumonitis that required steroids or has current pneumonitis.
• •Active infections:
• •* Any active infection requiring systemic therapy.
• •* Active TB (Bacillus Tuberculosis).
• •* Active COVID-19 infection and/or exposure to SARS-CoV-2 as defined below:
• •* Positive SARS-CoV-2 result on nasopharyngeal and/or stool specimens (by RT-PCR test)
• •* Active COVID-19 infection (per CDC guidelines)
• •* Exposure to active COVID-19 infected patient (as confirmed using SARS-CoV-2 RT-PCR test or other approved test) as defined per CDC guidelines.
• •* Active human immunodeficiency virus (HIV) infection.
• •o Patients will be evaluated for HIV during screening.
• •* 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.
• •Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
• •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• •Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 120 days after the last dose of trial treatment.
• •Has had an allogenic tissue/solid organ transplant.