NCT06030037

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

• Status: Withdrawn
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Diwakar Davar · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

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).

Conditions

• PD-1 Refractory Advanced Melanoma

Interventions

Type	Name	Description
BIOLOGICAL	Healthy Donor Fecal Microbiota Transplantation (hdFMT)	hdFMT (induction) via colonoscopy or oral capsule on C1D1 and C3D1. hdFMT (maintenance) via sigmoidoscopy or oral capsules will be repeated every 9 weeks.
DRUG	Pembrolizumab	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)
DRUG	Lenvatinib	Lenvatinib will be administered at 20 mg daily

Timeline

• Start date: 2025-03-11
• Primary completion: 2029-12-31
• Completion: 2029-12-31
• First posted: 2023-09-08
• Last updated: 2025-09-29

Regulatory

• FDA-regulated drug study