MelanomaPhase 2NCT03341143
Fecal Microbiota Transplant (FMT) in Melanoma Patients
A Phase 2 study testing Fecal Microbiota Transplant with Pembrolizumab in people with Melanoma, run by Zarour, Hassane, MD at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma
- What is being tested?
- Fecal Microbiota Transplant with Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Mar 2018to 30 Sep 2024
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
- 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.
Who cannot join
- 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).
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- 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).
- 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.
Trial locations and contacts
1 site in 1 country.
United States1 site
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
About this study
Official title: Phase II Feasibility Study of Fecal Microbiota Transplant (FMT) in Advanced Melanoma Patients Not Responding to PD-1 Blockade
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.
Read the detailed description
This is a phase II Simon two-stage single-center study of concurrent fecal microbiota transplant (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 must have received a minimum of 2 cycles to be considered eligible. 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 on a restaging scan. Other eligibility criteria include absence of CNS disease, presence of disease amenable to biopsy and lack of contra-indications to FMT administration. Patients will be stratified on the presence or absence of liver metastases.
Suitable patients will be identified following first (or subsequent) restaging study that documents progressive disease (RECIST v1.1). Patients will undergo a screening evaluation consisting of imaging (including CNS 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 until disease progression or up to two years from FMT administration.
In August of 2026 the outcome measures were updated clarify the specific analyses that were performed in accordance with the stated protocol endpoints. The "Change in T-Cells Composition", "Change in Innate/Adaptive Immune System Subsets", and "Function of T-Cells" outcome measures were removed. These were replaced with the more specific outcomes: "Change in CD8+CD56+ T Cells", "Change in [TIGIT/LAG-3/CD27/Tbet] Expression in CD8+ T Cells", and "Change in Prevalence of [Naive/EM/CM/TEMRA] CD8+ T Cells" outcome measures.
- Conditions
- Melanoma
- Being tested
- Fecal Microbiota Transplant with Pembrolizumab
- Keywords
- Unresectable, Stage III, Stage IV
- Medical subject headings
- Melanoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Fecal Microbiota Transplant with PembrolizumabDrug
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).
| Study group | Role | What they receive |
|---|---|---|
| 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). Receives: Drug: Fecal Microbiota Transplant with Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 3 years
Secondary outcomes (19)
Disease Control Rate (DCR)
Number of patients with patients with Complete Response (CR), Partial Response (PR), or Stable Disease (SD) 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. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.
Measured: Up to 3 years
Incidence of Grade III/IV Toxicities
Number of patients who experienced grade III or grade IV toxicities per CTCAE v5.0, related to study treatment.
Measured: Up to 4 years
Progression-free Survival (PFS)
Time from first response to to treatment until documented disease progression by RECIST v1.1 or death due to any cause. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Measured: Up to 4 years
6-month Progression-free Survival (PFS)
Percentage of patients who did not experience documented disease progression by RECIST v1.1 or death due to any cause from start of treatment until 6 months post treatment initiation. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Measured: At 6 months
12-month Progression-free Survival (PFS)
Percentage of patients who did not experience documented disease progression by RECIST v1.1 or death due to any cause from start of treatment until 12 months post treatment initiation. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Measured: At 12 months
24-month Progression-free Survival (PFS)
Percentage of patients who did not experience documented disease progression by RECIST v1.1 or death due to any cause from start of treatment until 24 months post treatment initiation. Progression as defined by RECIST v1.1 for target lesions: Progressive Disease (PD): smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). For non-target lesions: Appearance of one or more new lesions and/or unequivocal progression of existing nontarget lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
Measured: At 24 months
Overall Survival (OS)
Overall survival (OS), defined as time from first dose of study treatment until death due to any cause.
Measured: Up to 6.5 years
6-month Overall Survival (OS)
Percentage of patients alive at 6 months from first dose of study treatment.
Measured: At 6 months
12-month Overall Survival (OS)
Percentage of patients alive at 12 months from first dose of study treatment.
Measured: At 12 months
24-month Overall Survival (OS)
Percentage of patients alive at 24 months from first dose of study treatment.
Measured: At 24 months
Change in CD8+CD56+ T Cells
Change in cytolytic CD8+CD56+ T cell frequency (as a percentage of all PBMCs) at Day 0, 21, and 42 of treatment. Results will be broken down by response status (responders vs. non-responders).
Measured: Day 0, Day 21, and Day 42
Change in TIGIT Expression in CD8+ T Cells
TIGIT expression on CD8+ T cells was quantified by flow cytometry and normalized within each experimental batch using z-score normalization to account for batch-to-batch variation in fluorescence intensity. A z-score of 0 represents the mean fluorescence intensity for the marker within a given experimental batch. Positive z-scores indicate fluorescence intensity above the batch mean, whereas negative z-scores indicate fluorescence intensity below the batch mean. The magnitude of the z-score reflects the number of standard deviations from the batch mean (e.g., +1 = one standard deviation above the mean; -2 = two standard deviations below the mean).
Because this is a biomarker measurement rather than a clinical outcome, higher or lower z-scores should not be characterized as inherently "better" or "worse"; they simply indicate higher or lower TIGIT expression relative to the batch mean.
Measured: Day 0, Day 21, and Day 42
Change in LAG-3 Expression in CD8+ T Cells
LAG-3 expression on CD8+ T cells was quantified by flow cytometry and normalized within each experimental batch using z-score normalization to account for batch-to-batch variation in fluorescence intensity. A z-score of 0 represents the mean fluorescence intensity for the marker within a given experimental batch. Positive z-scores indicate fluorescence intensity above the batch mean, whereas negative z-scores indicate fluorescence intensity below the batch mean. The magnitude of the z-score reflects the number of standard deviations from the batch mean (e.g., +1 = one standard deviation above the mean; -2 = two standard deviations below the mean).
Because this is a biomarker measurement rather than a clinical outcome, higher or lower z-scores should not be characterized as inherently "better" or "worse"; they simply indicate higher or lower LAG-3 expression relative to the batch mean.
Measured: Day 0, Day 21, and Day 42
Change in CD27 Expression in CD8+ T Cells
CD27 expression on CD8+ T cells was quantified by flow cytometry and normalized within each experimental batch using z-score normalization to account for batch-to-batch variation in fluorescence intensity. A z-score of 0 represents the mean fluorescence intensity for the marker within a given experimental batch. Positive z-scores indicate fluorescence intensity above the batch mean, whereas negative z-scores indicate fluorescence intensity below the batch mean. The magnitude of the z-score reflects the number of standard deviations from the batch mean (e.g., +1 = one standard deviation above the mean; -2 = two standard deviations below the mean).
Because this is a biomarker measurement rather than a clinical outcome, higher or lower z-scores should not be characterized as inherently "better" or "worse"; they simply indicate higher or lower CD27 expression relative to the batch mean.
Measured: Day 0, Day 21, and Day 42
Change in Tbet Expression in CD8+ T Cells
Tbet expression on CD8+ T cells was quantified by flow cytometry and normalized within each experimental batch using z-score normalization to account for batch-to-batch variation in fluorescence intensity. A z-score of 0 represents the mean fluorescence intensity for the marker within a given experimental batch. Positive z-scores indicate fluorescence intensity above the batch mean, whereas negative z-scores indicate fluorescence intensity below the batch mean. The magnitude of the z-score reflects the number of standard deviations from the batch mean (e.g., +1 = one standard deviation above the mean; -2 = two standard deviations below the mean).
Because this is a biomarker measurement rather than a clinical outcome, higher or lower z-scores should not be characterized as inherently "better" or "worse"; they simply indicate higher or lower Tbet expression relative to the batch mean.
Measured: Day 0, Day 21, and Day 42
Change in Prevalence of Naive CD8+ T Cells
Change in prevalence of naive CD8+ T cells (expressed as a percentage of all CD8+ T cells), as indicated by the markers CCR7 and CD45RA, at Days 0, 21, and 42 of treatment. Results are broken down in accordance with response status (responders vs. non-responders).
Naive CD8+ T cells are designated by CCR7 and CD45RA positivity (naive = CCR7+CD45RA+). Effector Memory (EM) CD8+ T cells are designated by CCR7 positivity and CD45RA negativity (EM = CCR7+CD45RA-). Terminally Differentiated Effector Memory (TEMRA) CD8+ T cells are designated by CCR7 negativity and CD45RA positivity (TEMRA = CCR7-CD45RA+). Central Memory (CM) CD8+ T cells are designated by CCR7 and CD45RA negativity (CM = CCR7-CD45RA-).
Measured: Day 0, Day 21, and Day 42
Change in Prevalence of Effector Memory (EM) CD8+ T Cells
Change in prevalence of Effector Memory (EM) CD8+ T cells (expressed as a percentage of all CD8+ T cells), as indicated by the markers CCR7 and CD45RA, at Days 0, 21, and 42 of treatment. Results are broken down in accordance with response status (responders vs. non-responders).
Naive CD8+ T cells are designated by CCR7 and CD45RA positivity (naive = CCR7+CD45RA+). Effector Memory (EM) CD8+ T cells are designated by CCR7 positivity and CD45RA negativity (EM = CCR7+CD45RA-). Terminally Differentiated Effector Memory (TEMRA) CD8+ T cells are designated by CCR7 negativity and CD45RA positivity (TEMRA = CCR7-CD45RA+). Central Memory (CM) CD8+ T cells are designated by CCR7 and CD45RA negativity (CM = CCR7-CD45RA-).
Measured: Day 0, Day 21, and Day 42
Change in Prevalence of Central Memory (CM) CD8+ T Cells
Change in prevalence of Central Memory (CM) CD8+ T cells (expressed as a percentage of all CD8+ T cells), as indicated by the markers CCR7 and CD45RA, at Days 0, 21, and 42 of treatment. Results are broken down in accordance with response status (responders vs. non-responders).
Naive CD8+ T cells are designated by CCR7 and CD45RA positivity (naive = CCR7+CD45RA+). Effector Memory (EM) CD8+ T cells are designated by CCR7 positivity and CD45RA negativity (EM = CCR7+CD45RA-). Terminally Differentiated Effector Memory (TEMRA) CD8+ T cells are designated by CCR7 negativity and CD45RA positivity (TEMRA = CCR7-CD45RA+). Central Memory (CM) CD8+ T cells are designated by CCR7 and CD45RA negativity (CM = CCR7-CD45RA-).
Measured: Day 0, Day 21, and Day 42
Change in Prevalence of Terminally Differentiated Effector Memory (TEMRA) CD8+ T Cells
Change in prevalence of Terminally Differentiated Effector Memory (TEMRA) CD8+ T cells (expressed as a percentage of all CD8+ T cells), as indicated by the markers CCR7 and CD45RA, at Days 0, 21, and 42 of treatment. Results are broken down in accordance with response status (responders vs. non-responders).
Naive CD8+ T cells are designated by CCR7 and CD45RA positivity (naive = CCR7+CD45RA+). Effector Memory (EM) CD8+ T cells are designated by CCR7 positivity and CD45RA negativity (EM = CCR7+CD45RA-). Terminally Differentiated Effector Memory (TEMRA) CD8+ T cells are designated by CCR7 negativity and CD45RA positivity (TEMRA = CCR7-CD45RA+). Central Memory (CM) CD8+ T cells are designated by CCR7 and CD45RA negativity (CM = CCR7-CD45RA-).
Measured: Day 0, Day 21, and Day 42
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2017
- Study start19 Mar 2018
- Primary completion30 Sep 2023
- Study completion30 Sep 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- Zarour, Hassane, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, Diwakar Davar, University of Pittsburgh
- Investigators
- Diwakar Davar, MD, Principal investigator, Univ of Pittsburgh
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03341143
- Sponsor's protocol ID
- HCC 17-034
- Status last verified
- Oct 2026
- First submitted
- 28 Sep 2017
- Last updated
- 27 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 33542131Villemin 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.
PubMed 36464584
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Feasibility Study of Fecal Microbiota Transplant (FMT) in Advanced Melanoma Patients Not Responding to PD-1 Blockade
- ClinicalTrials.gov ID
- NCT03341143
- Acronym / sponsor ID
- HCC 17-034
- Conditions
- Melanoma
- Keywords
- Unresectable, Stage III, Stage IV
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- Zarour, Hassane, MDUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 19 Mar 2018 (actual)
- Primary completion
- 30 Sep 2023 (actual)
- Study completion
- 30 Sep 2024 (actual)
- First posted
- 14 Nov 2017 (actual)
- Results
- Posted 30 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 transplant (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 must have received a minimum of 2 cycles to be considered eligible. 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 on a restaging scan. Other eligibility criteria include absence of CNS disease, presence of disease amenable to biopsy and lack of contra-indications to FMT administration. Patients will be stratified on the presence or absence of liver metastases.
Suitable patients will be identified following first (or subsequent) restaging study that documents progressive disease (RECIST v1.1). Patients will undergo a screening evaluation consisting of imaging (including CNS 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 until disease progression or up to two years from FMT administration.
In August of 2026 the outcome measures were updated clarify the specific analyses that were performed in accordance with the stated protocol endpoints. The "Change in T-Cells Composition", "Change in Innate/Adaptive Immune System Subsets", and "Function of T-Cells" outcome measures were removed. These were replaced with the more specific outcomes: "Change in CD8+CD56+ T Cells", "Change in [TIGIT/LAG-3/CD27/Tbet] Expression in CD8+ T Cells", and "Change in Prevalence of [Naive/EM/CM/TEMRA] CD8+ T Cells" outcome measures.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Fecal Microbiota Transplant (FMT) with Pembrolizumab | Experimental | Drug: Fecal Microbiota Transplant with PembrolizumabThe 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). |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (23 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Fecal Microbiota Transplant with PembrolizumabFMT 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). | Drug | Fecal Microbiota Transplant (FMT) with Pembrolizumab |
Primary outcome
Objective Response Rate (ORR)
Time frame: Up to 3 years
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.
19 secondary outcomes
Disease Control Rate (DCR)
Time frame: Up to 3 years
Incidence of Grade III/IV Toxicities
Time frame: Up to 4 years
Progression-free Survival (PFS)
Time frame: Up to 4 years
6-month Progression-free Survival (PFS)
Time frame: At 6 months
12-month Progression-free Survival (PFS)
Time frame: At 12 months
24-month Progression-free Survival (PFS)
Time frame: At 24 months
Overall Survival (OS)
Time frame: Up to 6.5 years
6-month Overall Survival (OS)
Time frame: At 6 months
12-month Overall Survival (OS)
Time frame: At 12 months
24-month Overall Survival (OS)
Time frame: At 24 months
Change in CD8+CD56+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in TIGIT Expression in CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in LAG-3 Expression in CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in CD27 Expression in CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in Tbet Expression in CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in Prevalence of Naive CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in Prevalence of Effector Memory (EM) CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in Prevalence of Central Memory (CM) CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Change in Prevalence of Terminally Differentiated Effector Memory (TEMRA) CD8+ T Cells
Time frame: Day 0, Day 21, and Day 42
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2026.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 33542131Davar 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.
- Derived from this study: PubMed 36464584Villemin 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Diwakar Davar, MD principal investigator
Univ of Pittsburgh
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Fecal Microbiota Transplant with Pembrolizumab in people with Melanoma, run by Zarour, Hassane, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 23 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 30 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) (time frame: Up to 3 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03341143, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2026.