A Phase Ib Trial to Evaluate the Safety and Efficacy of FMT and Nivolumab in Subjects With Metastatic or Inoperable Melanoma, MSI-H, dMMR or NSCLC

NCT ID: NCT04521075

Last Updated: 2021-08-16

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 42 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-11-01
• Study Completion Date: 2023-07-01

Brief Summary

A Phase Ib trial to evaluate the safety and efficacy of Fecal Microbial Transplantation (FMT) in combination with Nivolumab in subjects with metastatic or inoperable melanoma, microsatellite instability-high (MSI-H) or mismatch-repair deficient (dMMR) cancer, or Non-Small Cell Lung Cancer (NSCLC)

Detailed Description

This study is a Phase I single-center adaptive design study to evaluate the safety and efficacy of FMT in combination with Nivolumab for adult subjects with treatment-refractory or inoperable melanoma, MSH-H, dMMr or NSCLC.

FMT will be conducted with fecal capsules, originating from patients that have achieved a durable complete response with immune checkpoint inhibitors. The study will evaluate the safety and efficacy of the combination of FMT with Nivolumab, a human immunoglobulin G4 (IgG4) monoclonal antibody that blocks PD-1 (anti PD-1) treatment and explore different biomarkers.

Conditions

Melanoma Stage IV; Unresectable Melanoma; NSCLC Stage IV

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Treatment Arm

Combination treatment: anti PD1 + FMT by capsules

Group Type: EXPERIMENTAL

Fecal Microbial Transplantation by capsules

Intervention Type: BIOLOGICAL

Cohorts A and B - Patients will receive 30 oral capsules per administration for two consecutive days (Days 1-2) Cohort C - Patients will receive FMT via colonscopy (Day 1), followed the day after by adnistration of 12 oral capsules (Day 2)

Combination cycles: 6 combined cycles Q2W of FMT maintenance followed by treatment with anti-PD1. Anti-PD-1 will be administered at least one day and up to 3 days after the FMT.

Maintenance of FMT by oral capsules: 12 capsules per administration. Anti PD-1 therapy: A dose of 240 mg Nivolumab will be administrated by intravenous infusion.

Interventions

Fecal Microbial Transplantation by capsules

Cohorts A and B - Patients will receive 30 oral capsules per administration for two consecutive days (Days 1-2) Cohort C - Patients will receive FMT via colonscopy (Day 1), followed the day after by adnistration of 12 oral capsules (Day 2)

Combination cycles: 6 combined cycles Q2W of FMT maintenance followed by treatment with anti-PD1. Anti-PD-1 will be administered at least one day and up to 3 days after the FMT.

Maintenance of FMT by oral capsules: 12 capsules per administration. Anti PD-1 therapy: A dose of 240 mg Nivolumab will be administrated by intravenous infusion.

Intervention Type: BIOLOGICAL

Other Intervention Names

Nivolumab

Eligibility Criteria

Inclusion Criteria

1. Age and gender: 18 and older, all genders

2. Signed written informed consent . Participants must be willing to participate in the study and provide written and signed informed consent (ICF) for the study.

Participants must be willing and able to complete all study specific procedures and visits

3. Diagnosis:

For NSCLC patients Histologically or cytologically confirmed metastatic or locally advanced non-small cell lung cancer not amenable to curative treatment that have a confirmed progression on anti-PD-1/PDL1 therapy:

Subjects may have had a maximum of one prior line of therapy after failure of anti-PD-1/ Programmed death-ligand 1 (PDL1) therapy Received a platinum based chemotherapy for non-small cell lung cancer; or, Subjects with a documented activating mutation {e.g., against epidermal growth factor receptor (EGFR), against rearranged anaplastic lymphoma kinase (ALK), Proto-oncogene tyrosine-protein kinase (ROS)} must have received the appropriate targeted therapy.

For Melanoma patients Histologically confirmed unresectable or metastatic melanoma not amenable to curative treatment that have a confirmed progression on anti-PD-1/PD-L1 therapy: a. Subjects may have had a maximum of one prior line of therapy after failure of anti-PD-1/PDL1 therapy b. Subjects with a documented B-Raf (BRAF) mutation must have received the appropriate targeted therapy

For MSI-H/dMMR patients -Histologically confirmed MSI-H/dMMR metastatic solid tumors including the following indications: colorectal adenocarcinoma, gastric adenocarcinoma, esophageal adenocarcinoma, endometrial carcinoma, ovarian carcinoma, pancreatic ductal adenocarcinoma and urothelial carcinoma that had a confirmed progression on anti-PD-1/PD-L1-based therapy.

4. Biopsies Patients must agree to study biopsies at two time points: a. Pretreatment and on treatment gut biopsies. b. Pretreatment and on treatment tumor biopsies.

5. Measurable disease by RECIST v1.1.

6. Patient status: a. Eastern Cooperative Oncology Group (ECOG) status of 0-1 b. Liver function: Total bilirubin ≤ 2 Upper limit of normal (ULN), Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST) ≤ 2.5 ULN (or < 5 in case of present liver metastasis) c. Neutrophils ≥ 1,000/mm3, platelets ≥ 100,000/mm3, Hb>8 g/dL d. Serum creatinine ≤ 1.5 ULN e. International normalized ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤1.5x ULN

7. Pregnancy a. Negative urine or serum pregnancy test within 72 hours prior to receiving first dose of study procedure in women of childbearing potential. b. Use of an effective contraceptive method throughout the entire treatment period and up to 6 months after the completion of treatment in both males and females of child bearing potential.

Exclusion Criteria

1. Medical Conditions :

1.1 History of chronic or active colitis 1.2. Tumor involvement of the esophagus, stomach, small intestine or colo-rectum. Note: not applicable for patients with MSI-H or dMMR colorectal , gastric or esophageal adenocarcinoma 1.3. Has a current active or a past known additional malignancy within the last 5 years.

1.4. Has an active or a documented history of autoimmune disease that required treatment in the past 2 years.

1.5. Known food allergy to eggs, nuts, peanuts 1.6. Known allergy to neomycin,vancomycin or metronidazole 1.7. Pregnant or breastfeeding women 1.8. Has known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies) 1.9 Has known history of or is positive for hepatitis B or Hepatitis C.

2. Prior/Concomitant Therapy and medical procedure 2.1 Has ongoing immune-related adverse effects from previous immunotherapy treatments that are of Grade ≥2, excluding endocrine adverse effects 2.2 Immunosuppressive chronic treatments. Patients treated with Prednisone ≤10mg per day may be included.

2.3 Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with i.v. antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 28 days prior to the start of Day 1 2.4 Medical condition that requires chronic treatment with antibiotics 2.5 Vaccination with live vaccines within 28 days prior to start of Cycle 1, Day 1.

2.6 Has received major surgery (within 28 days prior to the start of Cycle 1, Day 1), other than for diagnosis. Patient must have recovered from all surgery-related toxicities.

2.7 Patient has a known intolerance to anti-PD-L1 or anti-PD1.

3. Prior/Concurrent Clinical Study Experience 3.1 Participation in another clinical trial with anti-neoplastic intervention up to 14 days prior to study entry

4. Other Exclusions 4.1 Any other serious uncontrolled medical condition (including active bleeding or non-healing wound) 4.2 Has known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ella Therapeutics Ltd

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Guy Ben-Betzalel, MD

Role: PRINCIPAL_INVESTIGATOR

Sheba Medical Center

Locations

Sheba Medical Center

Ramat Gan, , Israel

Site Status: RECRUITING

Countries

Israel

Central Contacts

Elizbeth Tarshish, Msc

Role: CONTACT

elizabeth@ellatherapeutics.com

+972-504048559

Facility Contacts

Meital Bar

Role: primary

Bar Meital <Meital.Bar@sheba.health.gov.il>

Nili Golan

Role: backup

Nili.Golan@sheba.health.gov.il

Other Identifiers

6735-19

Identifier Type: -

Identifier Source: org_study_id