Fecal Microbiota Transplant (FMT) in Melanoma Patients

NCT03341143 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: HCC 17-034
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

The main goal of this research study is to determine if the fecal microbiota transplant (FMT) improves the body's ability to fight your cancer.

Conditions

Melanoma

Keywords

Unresectable; Stage III; Stage IV

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR)

  Number of patients with patients with objective responses (Complete Response (CR) + Partial Response (PR), per RECIST 1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  Up to 3 years

Secondary Outcomes (13)

• Disease Control Rate (DCR)

  Up to 3 years

• Incidence of Grade III/IV Toxicities

  Up to 4 years

• Progression-free Survival (PFS)

  Up to 4 years

• 6-month Progression-free Survival (PFS)

  At 6 months

• 12-month Progression-free Survival (PFS)

  At 12 months

Other Outcomes (1)

• Association of PD-1 Response With (Common) Gut Microbiota

  4 years

Study Arms (1)

Fecal Microbiota Transplant (FMT) with Pembrolizumab

EXPERIMENTAL

The FMT along with an intestinal biopsy will be performed as outpatient by a gastroenterologist. The FMT is infused into the colon by performing a colonoscopy. FMT will be performed on Cycle 1 Day 1 and will take 15 to 30 minutes. Pembrolizumab, 200mg, through an IV over 30 minutes on Cycle 1 Day 1 (same day as the FMT), and then again on Day 1 of each 21-day cycle for an additional 3 cycles (Cycles 2 - 4).

Drug: Fecal Microbiota Transplant with Pembrolizumab

Interventions

Fecal Microbiota Transplant with Pembrolizumab DRUG

FMT is a procedure in which fecal matter or stool is collected from a tested donor, mixed with a saline or other solution, strained and infused into the colon by doing a colonoscopy. The FMT consists of introducing normal bacterial flora contained in stool collected from a donor into your small intestine. In this case, the donor is patient with advanced melanoma who has been treated with a PD-1 inhibitor (nivolumab or pembrolizumab) and has been rendered disease-free as a result. The FMT will be performed on Cycle 1 Day 1. Pembrolizumab, 200mg, through an IV over 30 minutes on Cycle 1 Day 1 (same day as the FMT, and then again on Day 1 of each 21-day cycle for an additional 3 cycles (Cycles 2 - 4).

Fecal Microbiota Transplant (FMT) with Pembrolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Have a histologically or cytologically confirmed diagnosis of unresectable stage III or IV melanoma. Patient may not have a diagnosis of uveal or mucosal melanoma.
• Have received any number of prior systemic therapies for metastatic disease. Prior radiation therapy (any number) and interferon use (any formulation and/or duration) in the adjuvant or metastatic disease settings is permitted. Vaccine therapy will be counted as systemic therapy.
• Patient must currently be receiving systemic PD-1 immunotherapy with pembrolizumab or nivolumab to be eligible. Patients who have received PD-1 immunotherapy in the adjuvant setting and then replaced are eligible.
• Must be PD-1 inhibitor refractory/resistant - defined as having received at least 2 doses of pembrolizumab with documented systemic disease progression on staging imaging. PD will be defined as increase in tumor burden \> 20% relative to nadir (minimum recorded tumor burden) by RECIST v1.1. Once PD is confirmed, initial date of PD documentation will be considered as the date of disease progression. Patients can be enrolled at any time following initiation of PD-1 therapy assuming they have not had (at any time) a record of response to PD-1 therapy (prior best response of stable disease - acceptable; prior best response of complete/partial response - unacceptable). For patients receiving adjuvant PD-1 inhibitor therapy, initial date of PD documentation will be considered as the date of disease progression.
• Patients with CNS progression (parenchymal but not leptomeningeal) are eligible if CNS metastases are treated and deemed stable (with a repeat CT/MRI imaging study) prior to the enrollment date. If radiation is used to treat CNS parenchymal disease, a 2 week washout period will apply (counted from Day 1 treatment). Stability must be confirmed with a repeat CT/MRI imaging study performed as part of the screening evaluation (at least 2 weeks after radiation). Patients with new CNS metastases identified during screening are ineligible.
• Consent to receive FMT administered endoscopically (colonoscopically) and undergo necessary bowel preparation pre-procedure.
• Understand infectious risks associated with FMT administration. Although FMT infusate has been screened for bacteria, viruses, fungi and parasites there is a risk of transmission of known and unknown infectious organisms contained in the donor stool. Post-FMT bacteremia (e.g. E. coli), sepsis and fatal events may rarely occur.
• Understand non-infectious risks associated with FMT administration. Possible allergy and/or anaphylaxis to antigens in donor stool; theoretical risk of developing disease possibly related to donor gut microbiota including but not limited to: obesity, metabolic syndrome, cardiovascular disease, autoimmune conditions, allergic/atopic disorders, neurologic disorders, psychiatric conditions and malignancy.
• Understand risks associated with colonoscopy including risk of infection transmission, colonic perforation, aspiration pneumonia, and death.
• Understand that data regarding the long-term safety risk of FMT are lacking.
• Consent to participate in the correlative studies and should have available tumor tissue for tumor biopsies. Acceptable biopsies include surgical biopsy, core biopsy or punch/surgical tumor biopsies (of accessible lesions).
• Have measurable disease as per RECIST version 1.1. At least 1 of the tumor sites must be amenable to biopsy and this may not be the site of disease used to measure antitumor response.
• Be willing and able to provide written informed consent for the trial.
• Be 18 years of age or older on day of signing informed consent.
• Have a performance status of 0 or 1 on the ECOG Performance Scale.

You may not qualify if:

• \- Presence of absolute contra-indications to FMT administration: Toxic megacolon Severe dietary allergies (e.g. shellfish, nuts, seafood) Inflammatory bowel disease Anatomic contra-indications to colonoscopy
• Patients receiving PD-1 therapy whose disease is responding or stable (as defined by RECIST v1.1).
• Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
• Highly symptomatic patients (e.g., declining ECOG performance status; rapidly worsening symptoms; rapid progression of disease; progression of tumor at critical anatomical sites (e.g., spinal cord compression) requiring urgent alternative medical intervention) are not eligible.
• Expected to require any other form of systemic or localized antineoplastic therapy while on study.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy (\> 10 mg prednisone daily or equivalent) or any other form of immunosuppressive therapy prior to trial treatment. Patients receiving systemic steroids at physiologic doses are permitted to enroll assuming steroid dose is not above the acceptable threshold (\> 10 mg prednisone daily or equivalent).
• Has a known history of a hematologic malignancy, primary brain tumor or sarcoma, or of another primary solid tumor, unless the patient has undergone potentially curative therapy with no evidence of that disease for five years. NOTE: The time requirement also does not apply to patients who underwent successful definitive resection of basal or squamous cell carcinoma of the skin, superficial bladder cancer, in situ cancers including cervical cancer, breast cancer, melanoma, or other in situ cancers.
• Active central nervous system (CNS) metastases and/or leptomeningeal involvement. Patients with treated brain metastases will be re-screened (MRI brain or CT head with IV contrast). Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by MRI/CT for at least two weeks prior to the first dose of study drug), have no evidence of new or enlarging brain metastases and are off systemic steroids (≤ 10 mg/day prednisone or equivalent) for at least one weeks prior to enrollment. Patients with leptomeningeal disease (leptomeningeal enhancement on MRI/CT imaging and/or positive CSF cytology) are not eligible to enroll. Patients with no history of CNS disease will not require a repeat MRI brain unless they have symptoms to suggest new brain metastases.
• Had a severe hypersensitivity reaction to treatment with pembrolizumab or any of its excipients.
• Has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo, type I diabetes, resolved childhood asthma/atopy are exceptions to this rule. Patients who require intermittent use of bronchodilators or local steroid injections are not excluded from the study. Patients with hypothyroidism stable on hormone replacement are not excluded from the study.
• Has a history of (non-infectious) pneumonitis that was life-threatening and/or required invasive support (CTCAE grade 4 or greater) or current pneumonitis.
• Has serious concomitant illnesses, such as: cardiovascular disease (uncontrolled congestive heart failure, hypertension, cardiac ischemia, myocardial infarction, and severe cardiac arrhythmia), bleeding disorders, autoimmune diseases, severe obstructive or restrictive pulmonary diseases, active systemic infections, and inflammatory bowel disorders. This includes HIV or AIDS-related illness, or active HBV and HCV.
• Has an active infection requiring systemic therapy.
• Has active COVID-19 infection and/or exposure to SARS-CoV-2 defined as Positive SARS-CoV-2 result on nasopharyngeal and/or stool specimens (by RT-PCR test), Active COVID-19 infection (per CDC guidelines), Exposure to active COVID-19 infected patient (as confirmed using SARS-CoV-2 RT-PCR test or other approved test) as defined per CDC guidelines
• Has active human immunodeficiency virus (HIV) infection (as manifested by presence of HIV 1/2 antibodies and/or positive HIV ELISA/Western Blot assays).

Sponsors & Collaborators

• Zarour, Hassane, MD: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (2)

• Davar D, Dzutsev AK, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, Deblasio RN, Menna C, Ding Q, Pagliano O, Zidi B, Zhang S, Badger JH, Vetizou M, Cole AM, Fernandes MR, Prescott S, Costa RGF, Balaji AK, Morgun A, Vujkovic-Cvijin I, Wang H, Borhani AA, Schwartz MB, Dubner HM, Ernst SJ, Rose A, Najjar YG, Belkaid Y, Kirkwood JM, Trinchieri G, Zarour HM. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021 Feb 5;371(6529):595-602. doi: 10.1126/science.abf3363.

  PMID: 33542131 RESULT

• Villemin C, Six A, Neville BA, Lawley TD, Robinson MJ, Bakdash G. The heightened importance of the microbiome in cancer immunotherapy. Trends Immunol. 2023 Jan;44(1):44-59. doi: 10.1016/j.it.2022.11.002. Epub 2022 Dec 1.

  PMID: 36464584 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

Fecal Microbiota Transplantation; pembrolizumab

Condition Hierarchy (Ancestors)

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; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Biological Therapy; Therapeutics

Results Point of Contact

• Title: Barbara Stadterman, MPH, CCRP
• Organization: UPMC Hillman Cancer Center

stadtermanbm@upmc.edu

4126475554

Study Officials

• Diwakar Davar, MD

  Univ of Pittsburgh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine

Study Record Dates

• First Submitted: September 28, 2017
• First Posted: November 14, 2017
• Study Start: March 19, 2018
• Primary Completion: September 30, 2023
• Study Completion: September 30, 2024
• Last Updated: October 30, 2024
• Results First Posted: October 30, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)