- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03341143
Fecal Microbiota Transplant (FMT) in Melanoma Patients
Phase II Feasibility Study of Fecal Microbiota Transplant (FMT) in Advanced Melanoma Patients Not Responding to PD-1 Blockade
Study Overview
Status
Conditions
Intervention / Treatment
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 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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
Pennsylvania
-
Pittsburgh, Pennsylvania, United States, 15232
- UPMC Hillman Cancer Center
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
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 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.
- 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. 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Fecal Microbiota Transplant (FMT) with Pembrolizumab
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). |
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). |
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
3 years
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of grade III/IV toxicities
Time Frame: Up to 4 years
|
Frequency of grade III/IV toxicities experienced per CTCAE v5.0
|
Up to 4 years
|
Progression-free survival (PFS)
Time Frame: Up to
|
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.
|
Up to
|
Overall Survival (OS)
Time Frame: Up to
|
Overall survival (OS), defined as time from first dose of study treatment until death due to any cause.
|
Up to
|
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
|
4 years
|
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.
|
4 years
|
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.
|
4 years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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.
|
4 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Diwakar Davar, MD, Univ of Pittsburgh
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Neuroendocrine Tumors
- Nevi and Melanomas
- Melanoma
- Molecular Mechanisms of Pharmacological Action
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Pembrolizumab
Other Study ID Numbers
- 17-034
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Melanoma
-
H. Lee Moffitt Cancer Center and Research InstituteTurnstone Biologics, Corp.RecruitingMetastatic Melanoma | Conjunctival Melanoma | Ocular Melanoma | Unresectable Melanoma | Uveal Melanoma | Cutaneous Melanoma | Mucosal Melanoma | Iris Melanoma | Acral Melanoma | Non-Cutaneous MelanomaUnited States
-
University of Southern CaliforniaNational Cancer Institute (NCI)CompletedRecurrent Melanoma | Stage IV Melanoma | Mucosal Melanoma | Ciliary Body and Choroid Melanoma, Medium/Large Size | Ciliary Body and Choroid Melanoma, Small Size | Iris Melanoma | Metastatic Intraocular Melanoma | Recurrent Intraocular Melanoma | Stage IV Intraocular Melanoma | Stage IIIA Melanoma | Stage... and other conditionsUnited States
-
MelanomaPRO, RussiaRecruitingMelanoma | Melanoma (Skin) | Melanoma Stage IV | Melanoma Stage III | Melanoma, Stage II | Melanoma, Uveal | Melanoma in Situ | Melanoma, OcularRussian Federation
-
National Cancer Institute (NCI)CompletedRecurrent Melanoma | Stage IIIA Melanoma | Stage IIIB Melanoma | Stage IIIC Melanoma | Stage IIB Melanoma | Stage IIC Melanoma | Stage IA Melanoma | Stage IB Melanoma | Stage IIA MelanomaUnited States
-
National Cancer Institute (NCI)CompletedStage IV Melanoma | Ciliary Body and Choroid Melanoma, Medium/Large Size | Iris Melanoma | Stage IIIA Melanoma | Stage IIIB Melanoma | Stage IIIC Melanoma | Extraocular Extension Melanoma | Stage IIB Melanoma | Stage IIC MelanomaUnited States
-
Roswell Park Cancer InstituteNational Cancer Institute (NCI); National Comprehensive Cancer NetworkTerminatedRecurrent Melanoma | Stage IV Melanoma | Metastatic Intraocular Melanoma | Recurrent Intraocular Melanoma | Stage IV Intraocular Melanoma | Stage IIIA Melanoma | Stage IIIB Melanoma | Stage IIIC Melanoma | Extraocular Extension Melanoma | Stage IIIA Intraocular Melanoma | Stage IIIB Intraocular Melanoma | Stage...United States
-
Rutgers, The State University of New JerseyNational Cancer Institute (NCI); University of VirginiaCompletedStage IIIB Skin Melanoma | Stage IIIC Skin Melanoma | Stage III Skin Melanoma | Stage IIA Skin Melanoma | Stage IIB Skin Melanoma | Stage IIC Skin Melanoma | Stage IIIA Skin Melanoma | Stage IA Skin Melanoma | Stage IB Skin Melanoma | Stage 0 Skin Melanoma | Stage I Skin Melanoma | Stage II Skin MelanomaUnited States
-
Mayo ClinicNational Cancer Institute (NCI)CompletedRecurrent Melanoma | Stage IV Melanoma | Stage IIIA Melanoma | Stage IIIB Melanoma | Stage IIIC Melanoma | Stage IIB Melanoma | Stage IIC Melanoma | Stage IIA MelanomaUnited States
-
ECOG-ACRIN Cancer Research GroupNational Cancer Institute (NCI)RecruitingUnresectable Melanoma | Clinical Stage III Cutaneous Melanoma AJCC v8 | Melanoma of Unknown Primary | Pathologic Stage IIIB Cutaneous Melanoma AJCC v8 | Pathologic Stage IIIC Cutaneous Melanoma AJCC v8 | Pathologic Stage IIID Cutaneous Melanoma AJCC v8 | Clinical Stage IV Cutaneous Melanoma AJCC... and other conditionsUnited States
-
BiocadRecruitingMelanoma | Melanoma (Skin) | Melanoma Stage IV | Melanoma Stage III | Melanoma Metastatic | Melanoma Unresectable | Melanoma AdvancedIndia, Russian Federation, Belarus
Clinical Trials on Fecal Microbiota Transplant with Pembrolizumab
-
Massachusetts General HospitalCompletedClostridium Difficile InfectionUnited States
-
Boston Medical CenterBeth Israel Deaconess Medical Center; Brigham and Women's Hospital; Massachusetts...TerminatedCrohn's DiseaseUnited States
-
The University of Hong KongNot yet recruitingFecal Microbiota Transplantation for Decolonization of Carbapenem-resistant Enterobacteriaceae (FMT)Fecal Microbiota Transplantation | Carbapenem-Resistant Enterobacteriaceae Infection
-
Washington University School of MedicineUniversity of Pennsylvania; Duke University; Centers for Disease Control and... and other collaboratorsCompleted
-
Judith KelsenRecruitingCrohn's Disease | Ulcerative Colitis | Inflammatory Bowel Disease | Clostridium DifficileUnited States
-
University of AlbertaCompletedHepatic EncephalopathyCanada
-
University of AlbertaCompletedCrohn's DiseaseCanada
-
Otto HelveKarolinska Institutet; University of HelsinkiNot yet recruitingMicrobial ColonizationFinland
-
McMaster Children's HospitalThe Hospital for Sick ChildrenRecruitingSmall Intestinal Bacterial OvergrowthCanada
-
University of AlbertaCompletedUlcerative ColitisCanada