Pembrolizumab/Lenvatinib With and Without Responder-derived FMT in Relapsed/Refractory Melanoma

Study Overview
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Brief Summary
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In this is a randomized phase II study the addition of R-FMT to pembrolizumab /lenvatinib in PD-1 R/R melanoma will be evaluated over a 104-week period in patients with anti-PD-1 R/R disease. Patients with PD-1 refractory advanced melanoma are eligible to enroll, excluding patients with prior lenvatinib (or other TKI) exposure. Intestinal microbiome composition mediates response to anti-PD-1 by affecting systemic inflammatory tone.

Detailed Description
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Despite treatment advances, 40-60% of melanoma patients do not respond or fail to respond durably; and the management of relapsed/refractory (R/R) disease remains an important problem for the field. The importance of intact immune surveillance function in controlling outgrowth of neoplastic transformations has been known for decades. Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma. Targeting TAMs (tumor associated macrophages, which are innate immune cells of heterogeneous origins that accumulate within the tumor microenvironment (TME) as tumors progress and interfere with antitumor T cell mediated responses) via targeted depletion, inhibition of active migration, and/or promotion of activation and differentiation have been pursued as therapeutic strategies to increase efficacy of ICI therapy clinically and preclinically. The pembrolizumab/lenvatinib combination has been explored in several clinical settings and been granted approval for two indications including advanced endometrial carcinoma and RCC. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1.

Official Title
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Randomized Phase II Study of Pembrolizumab/Lenvatinib With and Without Responder-derived FMT (R-FMT) in Relapsed/Refractory Melanoma

Conditions
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PD-1 Refractory Advanced Melanoma

Intervention / Treatment
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* Biological: Responder-Derived Fecal microbiota transplantation (R-FMT
* Drug: Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with cutaneous melanoma or unknown primary melanoma may enroll. Patients with uveal or mucosal or acral-lentiginous melanoma are excluded. A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period. A female participant is eligible to participate if she is not pregnant (see Appendix 3), not breastfeeding, and at least one of the following conditions applies: Not a woman of childbearing potential (WOCBP) as defined in Appendix 3; OR A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and for at least 120 days after the last dose of study treatment. Participants must have progressed on treatment with an anti-PD(L)1 ICI administered either as monotherapy or in combination with other checkpoint inhibitors or other standard/investigational therapies. PD-1 treatment progression is defined by meeting all the following criteria: Has received at least 2 doses of an approved anti-PD(L)1 ICI administered as a single agent, in combination with chemotherapy, and/or in combination with other investigational therapy. Participants who progressed on/within 3 months of adjuvant therapy with anti-PD(L)1 ICI will eligible. Demonstrated disease progression after anti-PD-1/L1 as defined by RECIST v1.1. The initial evidence of PD is to be confirmed by a second assessment no sooner than 4 weeks from the date of the first documented PD. Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/anti-PD-L1 mAb. Patients with CNS disease are eligible if CNS metastases are treated and deemed stable prior to date of enrollment. Willingness to repeatedly receive FMT administered endoscopically (colonoscopy or sigmoidoscopy) following necessary bowel preparation pre-procedure. Presence of measurable disease based on RECIST 1.1. Patients need to have at least one measurable lesion and a separate lesion for biopsy. Patients with only 1 lesion may be enrolled after discussion with Sponsor-Investigator. Able to provide newly obtained core or excisional biopsy of a tumor lesion not previously irradiated to undergo tumor biopsy (core, punch, incisional or excisional). Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Have adequate organ function as defined in Table 4.1.11-1 below. Specimens must be collected within 28 days prior to the start of study intervention. Patients who are hepatitis B positive (i.e. HBsAg positive) or have a history of history of hepatitis B (i.e. HBcAb positive, or history of documented hepatitis B infection) are eligible if they have received hepatitis B directed antiviral therapy for at least 4 weeks and have undetectable HBV viral load (HBV DNA) prior to enrollment Patients who are hepatitis C positive (i.e. HCV antibody reactive) or have a history of history of hepatitis C (i.e. history of documented hepatitis C infection) are eligible if they have received and completed hepatitis C directed antiviral therapy at least 4 weeks and have undetectable HCV viral load (HCV RNA) prior to enrollment Exclusion Criteria: Diagnosis of non-cutaneous melanoma histologies including mucosal melanoma, ocular/choroidal melanoma, and acral-lentiginous melanoma. 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. Has had major surgery within 3 weeks prior to first dose of study interventions. 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. Prolongation of QTcF interval to >480 ms. 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. 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 (eg, FluMist®) are live attenuated vaccines and are not allowed. 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). 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. Active (i.e., symptomatic or growing) central nervous system (CNS) metastases. 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). Has a history of interstitial lung disease or active, non-infectious pneumonitis that required steroids or has current pneumonitis. 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. 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 mighconfound 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R-FMT + pembrolizumab/lenvatinib (Arm A)<br>Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). Lenvatinib will be administered at 20 mg daily. R-FMT (induction) will be administered at C1D1 and C4D1 via colonoscopy. R-FMT (maintenance) will be repeated every 9 weeks starting with C4D1 via sigmodoscopy. | Biological: Responder-Derived Fecal microbiota transplantation (R-FMT<br>* R-FMT (induction) via colonoscopy on C1D1 and C3D1. R-FMT (maintenance) via sigmoidoscopy will be repeated every 9 weeks.<br>Drug: Pembrolizumab<br>* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity)<br>Drug: Lenvatinib<br>* Lenvatinib will be administered at 20 mg daily<br>|
| Active Comparator: pembrolizumab/lenvatinib (Arm B)<br>Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity as described). Lenvatinib will be administered at 20 mg daily. | Drug: Pembrolizumab<br>* Pembrolizumab will be administered at 200 mg every 3 weeks (Q3W) as a 30-minute IV infusion (treatment intervals may be increased due to toxicity)<br>Drug: Lenvatinib<br>* Lenvatinib will be administered at 20 mg daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) per RECIST v1.1 | The proportion of patients with objective response to treatment assessed using Response Evaluation Criteria in Solid Tumors v1.1 (RECIST). Per RECIST v1.1: Complete Response (CR): disappearance of all target lesions. Any pathological lymph nodes (target or nontarget) with reduction in short axis to <10 mm. Partial Response (PR): ≥30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events Related to Treatment | Frequency of Adverse Events (AEs) and/or Serious Adverse Events (SAEs) (specifically ≥grade 2 irAEs) related to study treatment, per NCI Common Terminology Criteria for Adverse Events (CTCAE) v5.0. | Up to 5 years | 
| Objective Response Rate (ORR) per iRECIST | The proportion of patients Complete Response (irCR) or Partial Response (irPR) to treatment as assessed per iRECIST. irCR: Disappearance of non-nodal lesions. All pathologic lymph nodes <10 mm (short axis) (2 consecutive measurements ≥4 weeks apart); irPR:≥30% decrease from baseline (2 consecutive measurements ≥4 weeks apart). Disappearance of all non-nodal lesions. All pathologic lymph nodes <10 mm (Non-Target Lesions: Any other than disappearance of all non-nodal lesions and reduction of pathologic lymph nodes <10 mm). Baseline tumor burden: sum of single diameters (short axis for nodal lesions, longest diameter for other lesions) for target lesions. In subsequent scans, the diameters of new measurable lesions are added to the tumor burden. Re-treatment: ≤5 target lesions (=/≠ original lesions) are selected and a new baseline tumor burden will be established. (no distinct iRECIST assessment until radiographic progression per RECIST 1.1 is observed). | Up to 5 years | 
| 6-month Progression-free Survival | Percentage of patients without disease progression at 6 months after start of treatment, per RECIST v1.1. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 6 months | 
| 1-year Progression-free Survival (PFS) | Percentage of patients without disease progression at 1 year after start of treatment, per RECIST v1.1. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 1 year | 
| 2-year Progression-free Survival (PFS) | Percentage of patients without disease progression at 2 years after start of treatment, per RECIST v1.1. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 2 years | 
| Progression-free Survival (PFS) | The median length of time from initiation of study drug(s) disease progression as defined by RECIST v1.1, or death. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression. | Up to 5 years | 
| 1-year Overall Survival (OS) | Percentage of patients that are alive at 1 year after start of treatment. | Up to 1 year | 
| 2-year Overall Survival (OS) | Percentage of patients that are alive at 2 years after start of treatment. | Up to 2 years | 
| Overall Survival (OS) | The median length of time that patients remain alive after treatment. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CD8+ T-cells, CD8+ effector T cells, FoxP3+ regulatory T-cells (T-regs)