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

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ClinicalTrials.gov Identifier: NCT03817125
Recruitment Status : Recruiting
First Posted : January 25, 2019
Last Update Posted : February 8, 2019
Sponsor:
Collaborator:
Seres Therapeutics, Inc.
Information provided by (Responsible Party):
Parker Institute for Cancer Immunotherapy

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 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
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma
Drug Information available for: Nivolumab

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.




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) ]


Information from the National Library of Medicine

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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.
    2. Prior BRAF-targeted therapy in the neoadjuvant, adjuvant, or metastatic setting is allowed if completed at least 4 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.
  5. Prior systemic treatment (ie, anticancer chemotherapy, immunotherapy, or investigational agents) for unresectable or metastatic melanoma.

    a. 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.

  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. Has a transplanted organ or has undergone allogeneic bone marrow transplant.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03817125


Contacts
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Contact: Recruiting sites have contact information. Please contact the site directly. If there is no contact info, please email mcgraw0014@parkerici.org

Locations
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United States, California
The Angeles Clinic and Research Institute Recruiting
Los Angeles, California, United States, 90025
Contact: Saba Mukarram    310-231-2181    smukarram@theangelesclinic.org   
Principal Investigator: Omid Hamid, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Suzanne Cain    713-792-8874    scain@mdanderson.org   
Principal Investigator: Isabella C Glitza, MD PhD         
Principal Investigator: Hussein A Tawbi, MD PhD         
Sponsors and Collaborators
Parker Institute for Cancer Immunotherapy
Seres Therapeutics, Inc.
Investigators
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Study Director: Ramy Ibrahim, MD Parker Institute for Cancer Immunotherapy

Additional Information:
Publications:
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2.

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Responsible Party: Parker Institute for Cancer Immunotherapy
ClinicalTrials.gov Identifier: NCT03817125     History of Changes
Other Study ID Numbers: PICI0014
First Posted: January 25, 2019    Key Record Dates
Last Update Posted: February 8, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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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:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Anti-Bacterial Agents
Vancomycin
Antibiotics, Antitubercular
Nivolumab
Anti-Infective Agents
Antitubercular Agents
Antineoplastic Agents, Immunological
Antineoplastic Agents