Clinical Trials /

Fecal Microbiota Transplant (FMT) in Melanoma Patients

NCT03341143

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Fecal Microbiota Transplant (FMT) in Melanoma Patients
  • Official Title: Phase II Feasibility Study of Fecal Microbiota Transplant (FMT) in Advanced Melanoma Patients Not Responding to PD-1 Blockade

Clinical Trial IDs

  • ORG STUDY ID: 17-034
  • NCT ID: NCT03341143

Conditions

  • Melanoma

Interventions

DrugSynonymsArms
Fecal Microbiota Transplant with PembrolizumabFecal Microbiota Transplant (FMT) with Pembrolizumab

Purpose

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.

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
      first (or subsequent) restaging scans from week 12 up to week 52. Patients who have received
      either nivolumab or pembrolizumab are eligible. Patients who have received
      pembrolizumab/nivolumab in combination with other investigational agent(s) may be eligible at
      the discretion of the treating investigator. 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 if
      clinically suspected, tumor biopsy, and serological/stool studies to confirm suitability for
      FMT administration. Eligible patients will receive FMT endoscopically (along with intestinal
      biopsy) (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.
    

Trial Arms

NameTypeDescriptionInterventions
Fecal Microbiota Transplant (FMT) with PembrolizumabExperimentalThe 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).
  • Fecal Microbiota Transplant with Pembrolizumab

Eligibility 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.

          -  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 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. Patients with prior adverse events on
             replacement therapy who are asymptomatic or minimally symptomatic are not excluded
             from the study (i.e. hypothyroidism, hypopituitarism, adrenal insufficiency).

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:3 years
Safety Issue:
Description: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

Measure:Change in T-cells Composition
Time Frame:4 years
Safety Issue:
Description: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
Measure:Change in Innate/adaptive immune system subsets
Time Frame:4 years
Safety Issue:
Description: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.
Measure:Function of T-cells
Time Frame:4 years
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Zarour, Hassane, MD

Trial Keywords

  • Unresectable
  • Stage III
  • Stage IV

Last Updated

May 2, 2019