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Pembrolizumab/Lenvatinib With and Without Healthy Donor FMT (hdFMT) in Relapsed/ Refractory (R/R) Melanoma | Clinical Trials | Clareo Health

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

Randomized Phase II Study of Pembrolizumab/Lenvatinib With and Without Healthy Donor FMT (hdFMT) in Relapsed/Refractory (R/R) Melanoma

NCT06030037•Diwakar Davar

View on ClinicalTrials.gov

Summary

In this is a randomized phase II study the addition of hd-FMT (healthy donor fecal-microbiota transplant) 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

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; In this trial, that will be in the form of hdFMT (healthy donor fecal-microbiota transplant).

Eligibility

Age

18 - No limit years

Sex

ALL

Healthy Volunteers

Inclusion Criteria

•Patients with cutaneous melanoma or unknown primary melanoma may enroll. Patients with uveal or mucosal or acral-lentiginous melanoma are excluded.
•Male participants:
•• 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.
•Female participants:
•* A female participant is eligible to participate if she is not pregnant; not breastfeeding, and at least one of the following conditions applies:
•* Not a woman of childbearing potential (WOCBP); OR
•* A WOCBP who agrees to follow the contraceptive guidanceper protocol 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.
+32 more criteria

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.
+51 more criteria

Key Dates

Start Date

March 11, 2025

Primary Completion Date

December 31, 2029

Completion Date

December 31, 2029

Last Updated

September 29, 2025

Conditions

PD-1 Refractory Advanced Melanoma

Interventions

Healthy Donor Fecal Microbiota Transplantation (hdFMT)

BIOLOGICAL

Pembrolizumab

DRUG

Lenvatinib

DRUG