Melanoma Checkpoint and Gut Microbiome Alteration With Microbiome Intervention (MCGRAW)

• ClinicalTrials.gov Identifier: NCT03817125
• Recruitment Status: Completed
• First Posted: January 25, 2019
• Last Update Posted: June 9, 2022
• Sponsor: Parker Institute for Cancer Immunotherapy
• Collaborator: Seres Therapeutics, Inc.
• Information provided by (Responsible Party): Parker Institute for Cancer Immunotherapy

Study Description

Brief Summary:

This study is designed to evaluate the safety and tolerability of treatment with oral microbiome study intervention (SER-401) or matching placebo in combination with anti-programmed cell death 1 (anti-PD-1) therapy (nivolumab) in participants with unresectable or metastatic melanoma. The study also intends to assess clinical outcomes, the impact of microbiome study intervention administration on the microbiome profile, and its association with clinical and immunological outcomes.

Condition or disease	Intervention/treatment	Phase
Metastatic Melanoma	Drug: Placebo for antibiotic; Drug: Vancomycin pretreatment; Drug: Nivolumab; Drug: Matching Placebo for SER-401; Drug: SER-401	Phase 1

Detailed Description:

This is a Phase 1b, multicenter, randomized, placebo-controlled, blinded study in adult participants with anti-PD-1 therapy naïve, unresectable or metastatic melanoma to evaluate the safety and tolerability of SER-401, or matching placebo in combination with anti-PD-1 therapy (nivolumab). Prior to initiating microbiome study intervention and nivolumab, participants will undergo an antibiotic or antibiotic placebo treatment lead-in to prime the gut microbiome for engraftment of the oral microbiome study intervention. Study intervention groups will be assessed for safety, changes in the microbiome, changes in the percentage of tumoral CD8 T cells, and antitumor activity. Participants must have measurable disease that can be biopsied and consent to baseline and on-treatment biopsies, as well as stool and blood biomarker collection throughout the study.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Masking Description: Participants will be randomly assigned in a 2:1 ratio to oral microbiome study intervention or matching placebo. Nivolumab will be administered open-label as standard of care to all groups. Investigators, site personnel, and participants will remain blinded to the assignment of microbiome study intervention throughout the course of the study. Select Sponsor personnel, including but not limited to the Medical Monitor, Clinical Scientists, Biostatistician, and Patient Safety, will be unblinded to treatment assignment for ongoing safety monitoring.
• Primary Purpose: Treatment
• Official Title: A Multicenter Phase 1b Randomized, Placebo-controlled, Blinded Study to Evaluate the Safety, Tolerability and Efficacy of Microbiome Study Intervention Administration in Combination With Anti-PD-1 Therapy in Adult Patients With Unresectable or Metastatic Melanoma
• Actual Study Start Date: January 28, 2019
• Actual Primary Completion Date: March 4, 2022
• Actual Study Completion Date: March 4, 2022

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: SER-401 Matching Placebo/ Nivolumab; Participants will undergo a 4-day lead-in pretreatment with antibiotic placebo, then matching placebo for SER-401 and nivolumab (480 mg) treatment.	Drug: Placebo for antibiotic; Placebo for antibiotic will be administered orally four times a day for 4 days, followed by a 2-3 day washout.; Drug: Nivolumab; Nivolumab (480 mg) will be administered intravenously (IV) according to institutional guidelines every 4 weeks for up to 12 cycles. A cycle is defined as 4 calendar weeks.; Other Name: Opdivo; Drug: Matching Placebo for SER-401; Administered once a day for 7 days during the lead-in phase, followed by once a day for 8 weeks during the microbiome/anti-PD-1 treatment phase.
Experimental: SER-401/ Nivolumab; Participants will undergo a 4-day lead-in pretreatment with antibiotic (vancomycin) to prime the gut microbiome for engraftment of the oral microbiome study intervention, then SER-401 and nivolumab treatment.	Drug: Vancomycin pretreatment; Vancomycin (125mg) will be administered orally four times a day, followed by a 2-3 day washout.; Drug: Nivolumab; Nivolumab (480 mg) will be administered intravenously (IV) according to institutional guidelines every 4 weeks for up to 12 cycles. A cycle is defined as 4 calendar weeks.; Other Name: Opdivo; Drug: SER-401; Administered once a day for 7 days during the lead-in phase, followed by once a day for 8 weeks during the microbiome/anti-PD-1 treatment phase.

Outcome Measures

Primary Outcome Measures :

1. Percentage of patients with Adverse Events (AEs) [ Time Frame: Up to 2 years ]

Secondary Outcome Measures :

1. Determination of the engraftment of SER-401 bacteria in microbiome study intervention group relative to placebo. [ Time Frame: Up to 2 years ]
2. Objective response rate (ORR) at Weeks 24 and 52 [ Time Frame: Up to week 52 ]
   Defined as complete response (CR) or partial response (PR) as best response by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 assessment.
3. Disease control rate (DCR) at Weeks 24 and 52 [ Time Frame: Up to week 52 ]
   Defined as CR, PR, or stable disease (SD) for ≥ 24 weeks as best response by RECIST v1.1.
4. Progression-free survival (PFS) Progression free survival [ Time Frame: Up to 2 years ]
   Defined as the time from randomization to date of first documented progression of disease, date of death due to any cause, or date of most recent participant contact that documented progression-free status
5. Overall survival [OS] [ Time Frame: Up to 2 years ]
   Defined as the time from randomization until death or last contact if still alive at the time of final data collection (after completion of anti-PD-1 therapy).
6. Duration of response [ Time Frame: Up to 2 years ]
   Defined as time from date of documented CR or PR to date of first documented progression of disease, date of death due to any cause, or date of most recent participant contact that documented response (ie, scan date).
7. Change in the percentage of CD8 cells in tumor tissue from baseline at Cycle 2. [ Time Frame: At cycle 2 (each cycle is 28 days) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Participant must be willing to provide a baseline stool sample.
2. Histologically-confirmed Stage IV cutaneous melanoma or Stage III cutaneous, acral or mucosal melanoma that is judged inoperable. Participants with a history of uveal melanoma are not eligible.

3. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1; ie, defined as at least 1 lesion that can be accurately measured in at least 1 dimension [longest diameter to be recorded] with a minimum size of ≥ 10 mm by computerized tomography [CT] scan or caliper measurement on clinical exam or ≥ 20 mm by chest X-ray).

   1. Malignant lymph nodes must be ≥ 15 mm in short axis when assessed by CT scan to be considered pathologically enlarged and measurable.
   2. Participants must have at least one measurable lesion by RECIST and a separate lesion amenable to biopsy that has not been previously irradiated.

   i. Participants must be willing to undergo a newly-obtained core needle or incisional biopsy at baseline (prior to antibiotic or antibiotic placebo administration). Fine needle aspiration is not acceptable.

4. Participants must be willing to undergo tumor biopsy on treatment.

5. Prior adjuvant or neoadjuvant melanoma therapy is permitted if completed at least 6 weeks prior to randomization and all related AEs have either returned to baseline or stabilized.

   1. Prior anti-CTLA-4 therapy in the adjuvant setting is allowed if completed at least 12 weeks prior to the first dose of anti-PD-1.

Exclusion Criteria:

1. Participants who require hemodialysis.
2. Participants with a history of another cancer in the last 5 years, except for: a) curatively resected non-melanoma skin cancer; b) curatively treated cervical carcinoma in situ; c) localized prostate cancer not requiring systemic therapy; and c) other primary tumors with no known active disease present that, in the opinion of the Investigator and the Sponsor, will not affect participant outcome in the setting of the current diagnosis.

3. Any known, untreated brain metastases. Participants with brain metastases are eligible if these have been treated, and provided:

   1. Brain metastases must be stable (image-documented) 4 weeks after completion of treatment for brain metastases and require treatment with less than 10 mg/day prednisone equivalent for at least 2 weeks prior to study intervention administration.
   2. Neurological symptoms should be absent or returned to baseline.

4. Prior checkpoint inhibitor therapy with anti-PD-1 or anti-PD-L1 in the adjuvant setting.

   a. Exception: Participants with stage 3 or 4 cutaneous melanoma status post-resection who have received up to one year of adjuvant anti-PD-1 therapy who have recurred > 6 months after their last dose of anti-PD-1 therapy are eligible.

5. Other prior systemic treatment (ie, anticancer chemotherapy, immunotherapy, or investigational agents) for unresectable or metastatic melanoma EXCEPT:

   1. Prior BRAF-targeted therapy (ie, BRAF or BRAF-MEK) in the metastatic setting is allowed if completed at least 4 weeks prior to the first dose of anti-PD-1.
   2. Prior anti-CTLA 4 therapy in the adjuvant setting are allowed if completed at least 12 weeks prior to the first dose of anti-PD-1.
6. History of active inflammatory bowel disease (eg, active Crohn's disease or ulcerative colitis) with diarrhea OR major gastrointestinal surgery (not including appendectomy or cholecystectomy) within 3 months of enrollment (ie, signed informed consent for the study), OR any history of total colectomy or bariatric surgery (bariatric surgery which does not disrupt the gastrointestinal lumen, ie, restrictive procedures such as banding, are permitted).

7. Any diagnosis of autoimmune disease. Participants with Type I diabetes mellitus, hypothyroidism only requiring hormone replacement, adrenal insufficiency on replacement dose steroids, skin disorders (such as vitiligo, psoriasis or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

   a. Participants with controlled Type 1 diabetes mellitus on a stable insulin regimen may be eligible.

8. Has a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study intervention administration or has a contrast allergy requiring premedication with corticosteroids. Inhaled or topical steroids, and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

9. History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (ie, bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan.

   a. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.

10. Has a transplanted organ or has undergone allogeneic bone marrow transplant.
11. Has received a live vaccine within 30 days prior to first dose. Participants must not receive live, attended influenza vaccine (eg, FluMist) within 30 days prior to Cycle 1, Day 1 or at any time during the study and 100 days after last dose of nivolumab.
12. Has used antibiotics within 30 days prior to randomization or has planned or required need for antibiotic prophylaxis for more than 24 consecutive hours during the course of the study.

Contacts and Locations

Locations

United States, California

The Angeles Clinic and Research Institute

Los Angeles, California, United States, 90025

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, Texas

MD Anderson Cancer Center

Houston, Texas, United States, 77030

United States, Utah

Huntsman Cancer Institute

Salt Lake City, Utah, United States, 84112

Sponsors and Collaborators

Parker Institute for Cancer Immunotherapy

Seres Therapeutics, Inc.

Investigators

• Study Director: Parker Institute for Cancer Immunotherapy; Parker Institute for Cancer Immunotherapy

More Information

Additional Information:

NCT02437487: SER-109 Versus Placebo to Prevent Recurrent Clostridium Difficile Infection (RCDI) 

NCT02530385: Fecal Microbiota Transplant for Obesity and Metabolism 

NCT02618187: A Study to Evaluate the Safety, Tolerability and Microbiome Dynamics of SER- 287 in Subjects With Mild-to-Moderate Ulcerative Colitis Patients 

NCT03341143: Fecal Microbiota Transplant (FMT) in Melanoma Patients 

NCT03353402: Fecal Microbiota Transplantation (FMT) in Metastatic Melanoma Patients Who Failed Immunotherapy 

NCT03637803: MRx0518 and Pembrolizumab Combination Study 

Opdivo (nivolumab) US Prescribing Information (USPI), Aug-2018 

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• Responsible Party: Parker Institute for Cancer Immunotherapy
• ClinicalTrials.gov Identifier: NCT03817125
• Other Study ID Numbers: PICI0014
• First Posted: January 25, 2019
• Last Update Posted: June 9, 2022
• Last Verified: June 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Parker Institute for Cancer Immunotherapy:

Metastatic Melanoma; anti-PD1; Nivolumab; Microbiome; SER-401

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Anti-Bacterial Agents; Vancomycin; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents