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Fecal Microbiota Transplant and Re-introduction of Anti-PD-1 Therapy (Pembrolizumab or Nivolumab) for the Treatment of Metastatic Colorectal Cancer in Anti-PD-1 Non-responders

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ClinicalTrials.gov Identifier: NCT04729322
Recruitment Status : Recruiting
First Posted : January 28, 2021
Last Update Posted : August 4, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
This phase II trial studies the effect of fecal microbiota transplant and re-introduction of anti-PD-1 therapy (pembrolizumab or nivolumab) in treating anti-PD-1 non-responders with colorectal cancer that has spread to other places in the body (metastatic). Fecal microbiota transplants contain the normal bacteria and viruses found in fecal (stool) material. Immunotherapy with monoclonal antibodies, such as pembrolizumab and nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving pembrolizumab or nivolumab with fecal microbiota transplants may help to control the disease.

Condition or disease Intervention/treatment Phase
Metastatic Colorectal Adenocarcinoma Metastatic Small Intestinal Adenocarcinoma Stage IV Colorectal Cancer AJCC v8 Stage IV Small Intestinal Adenocarcinoma AJCC v8 Stage IVA Colorectal Cancer AJCC v8 Stage IVB Colorectal Cancer AJCC v8 Stage IVC Colorectal Cancer AJCC v8 Procedure: Biopsy Procedure: Fecal Microbiota Transplantation Drug: Fecal Microbiota Transplantation Capsule Drug: Metronidazole Drug: Neomycin Biological: Nivolumab Biological: Pembrolizumab Other: Questionnaire Administration Drug: Vancomycin Early Phase 1

Detailed Description:

PRIMARY OBJECTIVE:

I. To evaluate the efficacy of pembrolizumab or nivolumab in conjunction with fecal microbiota transplant (FMT) from PD-1 responding mismatch-repair deficiency (dMMR) colorectal cancer (CRC) patients for treatment of PD-1 non-responding dMMR CRC patient.

OUTLINE:

Patients receive metronidazole orally (PO) every 8 hours (Q8H) on days -14 to -8 and then vancomycin PO every 6 hours (Q6H) and neomycin PO Q6H on days -8 to -6. Patients then undergo colonoscopic FMT on day -5.

Patients are then assigned to 1 of 2 arms.

ARM I: Patients receive standard of care pembrolizumab intravenously (IV) over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients receive fecal microbiota transplantation capsule PO on day 1. Cycles repeat every 21 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive standard of care nivolumab IV over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1 and 8 of cycles 1-2. Beginning in cycle 4, patients receive fecal microbiota transplantation capsule PO on day 1 of every other cycle. Cycles repeat every 14 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 24 weeks for up to 3 years.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pilot Trial of Fecal Microbiota Transplantation and Re-Introduction of Anti-PD-1 Therapy in dMMR Colorectal Adenocarcinoma Anti-PD-1 Non-Responders
Actual Study Start Date : February 22, 2021
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Bowel Movement

Arm Intervention/treatment
Experimental: Arm I (FMT, pembrolizumab)

Patients receive metronidazole PO Q8H on days -14 to -8 and then vancomycin PO Q6H and neomycin PO Q6H on days -8 to -6. Patients then undergo colonoscopic FMT on day -5.

POST-COLONOSCOPIC FMT: Patients receive standard of care pembrolizumab IV over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1, 8, and 15 of cycle 1. Beginning in cycle 2, patients receive fecal microbiota transplantation capsule PO on day 1. Cycles repeat every 21 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

Procedure: Biopsy
Undergo biopsy
Other Names:
  • BIOPSY_TYPE
  • Bx

Procedure: Fecal Microbiota Transplantation
Undergo colonoscopic FMT
Other Names:
  • Fecal Material Transplantation
  • Fecal Transplantation
  • FMT
  • Poo Transplant
  • Poop Transplant
  • Stool Transplant

Drug: Fecal Microbiota Transplantation Capsule
Given PO
Other Names:
  • Fecal Microbiota Preparation Delivery Capsule
  • FMPCapDE
  • FMT Capsule DE
  • FMT Capsule Delivery
  • FMT DE Capsule

Drug: Metronidazole
Given PO
Other Names:
  • Flagyl
  • Flagyl I.V. RTU
  • Tricom

Drug: Neomycin
Given PO
Other Name: Neomycin Complex

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Other: Questionnaire Administration
Ancillary studies

Drug: Vancomycin
Given PO

Experimental: Arm II (FMT, nivolumab)

Patients receive metronidazole PO Q8H on days -14 to -8 and then vancomycin PO Q6H and neomycin PO Q6H on days -8 to -6. Patients then undergo colonoscopic FMT on day -5.

POST-COLONOSCOPIC FMT: Patients receive standard of care nivolumab IV over 30 minutes on day 1. Patients also receive fecal microbiota transplantation capsule PO on days 1 and 8 of cycles 1-2. Beginning in cycle 4, patients receive fecal microbiota transplantation capsule PO on day 1 of every other cycle. Cycles repeat every 14 days for up to 6 months in the absence of disease progression or unacceptable toxicity.

Procedure: Biopsy
Undergo biopsy
Other Names:
  • BIOPSY_TYPE
  • Bx

Procedure: Fecal Microbiota Transplantation
Undergo colonoscopic FMT
Other Names:
  • Fecal Material Transplantation
  • Fecal Transplantation
  • FMT
  • Poo Transplant
  • Poop Transplant
  • Stool Transplant

Drug: Fecal Microbiota Transplantation Capsule
Given PO
Other Names:
  • Fecal Microbiota Preparation Delivery Capsule
  • FMPCapDE
  • FMT Capsule DE
  • FMT Capsule Delivery
  • FMT DE Capsule

Drug: Metronidazole
Given PO
Other Names:
  • Flagyl
  • Flagyl I.V. RTU
  • Tricom

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Other: Questionnaire Administration
Ancillary studies

Drug: Vancomycin
Given PO




Primary Outcome Measures :
  1. Objective response rate [ Time Frame: Up to 3 years post-treatment ]
    Assessed by Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST). Will be summarized by mean, standard error, and 95% confidence interval.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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:

  • At least 18 years of age on the day of signing informed consent
  • Histologically/cytologically confirmed diagnosis of colorectal adenocarcinoma (in addition patients with small bowel adenocarcinoma will be allowed given rarity and management similar to colorectal adenocarcinoma)
  • Tumor that is deficient in mismatch repair (dMMR) or microsatellite instability high (MSI-H) as determined by one of three methods:

    • Immunohistochemistry determined dMMR by complete loss of MLH1, PMS2, MSH2 or MSH6
    • Polymerase chain reaction (PCR) determined microsatellite instability at > 30% of tested microsatellites
    • Next-generation determined MSI-H based upon instability at multiple microsatellites as determined by the specific next generation sequencing panel
  • Have metastatic disease that is measurable based on Immune-Modified Response Evaluation Criteria in Solid Tumors (iRECIST) version (v)1.1
  • Demonstrated prior progression on anti-PD1/L1 based therapy by radiographic progression. The potential for pseudoprogression should be excluded by concurrent carcinoembryonic antigen (CEA) or other tumor marker or circulating tumor-derived deoxyribonucleic acid (ctDNA) elevation, or clinical symptom progression, or short interval repeat imaging confirming progression

    • Must have received at least 2 doses of a PD1/PD-L1 inhibitor
    • Progressive disease either during therapy or within 2 months of last dose of therapy
  • An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Evaluation of ECOG is to be performed within 7 days prior to the date of signing study consent
  • Patients must be willing to undergone mandatory tumor biopsies at pre-treatment, at time of colonoscopy if possible and on-treatment (unless deemed unsafe by interventional radiology or by approval by study principal investigator [PI])
  • The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
  • Estimated life-expectancy of > 4 months
  • White blood cell (WBC) count >= 3,000/microL
  • Platelet count >= 75,000/microL
  • Hemoglobin (Hgb) >= 8 g/dL
  • Total bilirubin level =< 1.5 x the upper limit of normal (ULN) (except if Gilberts syndrome and then total bilirubin =< 3 x is allowed)
  • Aspartate aminotransferase (AST), level =< 2.5 x ULN, and an alanine aminotransferase (ALT) level =< 2.5 x ULN. If liver metastases are present, then AST and ALT levels must be =< 4 x ULN
  • Estimated creatinine clearance > 30 mL/min according to the Cockcroft-Gault formula or by a creatinine clearance measurement from a 24-hour urine collection
  • Highly effective contraception for both male and female subjects if the risk of conception exists. Highly effective contraception must be used 30 days prior to first study-drug administration, for the duration of trial treatment, and for at least for 6 months (women and men after taking your last dose of any of the trial drugs. Should a female patient (or male patient's sexual partner) become pregnant or should either the female patient (or male patient's partner) suspect she is pregnant while the patient's study-participation is ongoing, the treating physician should be informed immediately

Exclusion Criteria:

  • Has received prior systemic anti-cancer therapy including investigational agents within 2 weeks of study treatment (excluding continuation of ongoing nivolumab or pembrolizumab therapy)
  • If participant received major surgery within last 4 weeks, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
  • Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities (excluding skin toxicity), not require corticosteroids, and not have had radiation pneumonitis
  • Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
  • Has a diagnosis of immunodeficiency (excluding immunoglobulin A [IgA] deficiency)
  • Has an active autoimmune condition and is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug

    • Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses =< 10 mg of prednisone or equivalent per day
    • Administration of steroids for other conditions through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable
  • Has severe hypersensitivity (>= grade 3) to pembrolizumab or nivolumab and/or any of its excipients
  • Serious adverse immune related adverse events (grade 3 or 4) with previous immune checkpoint therapy, that were symptomatic and required prolong immunosuppression (> 6 weeks)
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the study subject's best interest to participate, in the opinion of the treating investigator
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Pregnant or nursing women
  • For women of childbearing age, a positive urine pregnancy test within 72 hours prior to enrollment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

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): NCT04729322


Contacts
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Contact: Michael J. Overman 713-792-2828 moverman@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Michael J. Overman    713-792-2828    moverman@mdanderson.org   
Principal Investigator: Michael J. Overman         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Layout table for investigator information
Principal Investigator: Michael J Overman M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04729322    
Other Study ID Numbers: 2020-0186
NCI-2020-13897 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0186 ( Other Identifier: M D Anderson Cancer Center )
P50CA221707 ( U.S. NIH Grant/Contract )
First Posted: January 28, 2021    Key Record Dates
Last Update Posted: August 4, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
Layout table for MeSH terms
Colorectal Neoplasms
Adenocarcinoma
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Metronidazole
Vancomycin
Neomycin
Pembrolizumab
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action
Anti-Infective Agents
Anti-Bacterial Agents
Antiprotozoal Agents
Antiparasitic Agents
Protein Synthesis Inhibitors
Enzyme Inhibitors