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Fecal Microbiota Transplant (FMT) in Melanoma Patients

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ClinicalTrials.gov Identifier: NCT03341143
Recruitment Status : Recruiting
First Posted : November 14, 2017
Last Update Posted : March 9, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Diwakar Davar, University of Pittsburgh

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.

Condition or disease Intervention/treatment Phase
Melanoma Drug: Fecal Microbiota Transplant with Pembrolizumab Phase 2

Detailed Description:

This is a phase II Simon two-stage single-center study of concurrent fecal microbiota transplang (FMT) with pembrolizumab in patients with PD-1 resistant/refractory melanoma. The study will be conducted over a 12-week period (and up to 24-weeks in responding patients).

Patient eligibility is based upon prior exposure to PD-1 inhibitor therapy and response at restaging scans at any time up to 1 year from time of initiation of PD-1 therapy. Patients who have received either nivolumab or pembrolizumab are eligible. Patients who have received pembrolizumab/nivolumab in combination with other investigational agent(s) are NOT eligible. PD-1 refractory disease is defined as progressive disease (PD) at the first (or subsequent) radiographic evaluation while receiving PD-1 inhibitor treatment as assessed by RECIST v1.1 or immune-related RECIST criteria. Other eligibility criteria include absence of CNS disease, presence of disease amenable to biopsy and lack of contra-indications to FMT administration.

Suitable patients will be identified following restaging study documenting disease progression. Patients will undergo a rapid screening evaluation consisting of CNS imaging, tumor biopsy, and serological/stool studies to confirm suitability for FMT administration. Eligible patients will receive FMT endoscopically (with cycle 1 pembrolizumab +/- 3 days) followed by 3 further cycles of pembrolizumab (cycles 2-4) following which restaging will be performed. Patients with stable and/or responding disease will continue to receive pembrolizumab on study for 4 cycles. Patients with stable and/or responding disease after 8 cycles of pembrolizumab will continue to receive therapy off study till progression.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase II Feasibility Study of Fecal Microbiota Transplant (FMT) in Advanced Melanoma Patients Not Responding to PD-1 Blockade
Actual Study Start Date : January 10, 2018
Estimated Primary Completion Date : November 30, 2019
Estimated Study Completion Date : November 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Fecal Microbiota Transplant (FMT) with Pembrolizumab

The FMT 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

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).





Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 3 years ]
    Number of patients with patients with objective responses (Complete Response (CR) + Partial Response (PR)) divided by the total number of evaluable patients, per RECIST 1.1.


Secondary Outcome Measures :
  1. Change in T-cells Composition [ Time Frame: 4 years ]
    Quantitative differences in CD8 + PD1+ T cells (measured by percent of total cells) and MFI (staining intensity) between pre- and post- treatment samples from patients that respond and patients that do not respond (per RECIST 1.1), to study treatment

  2. Change in Innate/adaptive immune system subsets [ Time Frame: 4 years ]
    Changes in CD8+ T-cell receptor diversity (quantified/determined by using Immunoseq analyses), CD4 + Foxp3 + T regulatory cells, CD56 + NK cells, CD68+ dendritic cells between pre- and post- treatment samples from patients that respond and patients that do not respond (per RECIST 1.1), to study treatment.

  3. Function of T-cells [ Time Frame: 4 years ]
    Functional analyses (measured by percent of total cells) expressing IFNgamma) and MFI (staining intensity) between pre- and post- treatment samples from patients that respond and patients that do not respond (per RECIST 1.1), to study treatment.


Other Outcome Measures:
  1. Association of PD-1 response with (common) gut microbiota [ Time Frame: 4 years ]
    Changes in bacterial abundance (quantified by the operational taxonomic unit (OTU)) which indicates the number of different species present along with the representative proportion of each species in the sample) and bacterial diversity (quantified by alpha diversity which is defined by the Shannon Index and quantifies both the organismal richness of a sample and the evenness of the organisms' abundance distribution), between pre- and post- treatment samples from patients that respond and patients that do not respond (per RECIST 1.1) to study treatment.



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:

  • 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 are receiving combination Ipilimumab with pembrolizumab or nivolumab are not eligible.
  • Must be pembrolizumab/nivolumab refractory/resistant - defined as having received at least 2 doses of pembrolizumab (or 2 doses of nivolumab) 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 up to 1 year.
  • 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.
  • 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/assent for the trial.
  • Be 18 years of age on day of signing informed consent.
  • Have a performance status of 0 or 1 on the ECOG Performance Scale.
  • Demonstrate adequate organ function:

Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl) - ≤1.5 X upper limit of normal (ULN) OR ≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Serum total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR ≤ 5 X ULN for patients with liver metastases Albumin >2.5 mg/dL International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless patient is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.

  • Female patients of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Female patients of childbearing potential must be willing to use an adequate method of contraception. Contraception, for the course of the study through 120 days after the last dose of study medication. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.
  • Male patients of childbearing potential must agree to use an adequate method of contraception. Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the patient.

Exclusion Criteria:

- 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. 3. 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 required steroids 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 human immunodeficiency virus (HIV) infection (as manifested by presence of HIV 1/2 antibodies and/or positive HIV ELISA/Western Blot assays).
  • Has active Hepatitis B or Hepatitis C infection. Patients with a history of Hepatitis B/C infection who have received anti-viral therapy and are disease free (Hep B - negative HBsAg and HBV DNA; Hep C - negative HCV RNA) may be considered for enrollment after discussion with Principal Investigator.
  • Has a known history of active TB (Bacillus Tuberculosis).
  • Patient has received a live vaccine within 4 weeks prior to the first dose of treatment.

Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

  • Has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  • Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. If the patient received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject 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.
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.

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): NCT03341143


Contacts
Contact: Diwakar Davar, MD 412-623-7368 davard@upmc.edu
Contact: Amy Rose, RN 412-647-8587 kennaj@upmc.edu

Locations
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Amy Rose, RN    412-647-8587    kennaj@upmc.edu   
Sponsors and Collaborators
Zarour, Hassane, MD
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Diwakar Davar, MD Univ of Pittsburgh

Responsible Party: Diwakar Davar, Assistant Professor of Medicine, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT03341143     History of Changes
Other Study ID Numbers: 17-034
First Posted: November 14, 2017    Key Record Dates
Last Update Posted: March 9, 2018
Last Verified: March 2018

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

Keywords provided by Diwakar Davar, University of Pittsburgh:
Unresectable
Stage III
Stage IV

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
Pembrolizumab
Antineoplastic Agents