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FMT to Convert Response to Immunotherapy

Primary Purpose

Melanoma Stage III, Melanoma Stage IV

Status

Recruiting

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

Fecal microbiota transplantation

About this trial

This is an interventional treatment trial for Melanoma Stage III

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Patients should be 18 years or older
Patients have pathologically confirmed advanced stage cutaneous melanoma (stage III or IV) requiring systemic treatment with anti-PD-1
- In case of stage IV disease, only patients with M1a or M1b disease are eligible.
Patients have confirmed disease progression (≥20% increase according to RECIST1.1) on two consecutive scans with a four week interval while on anti-PD-1 treatment, of which the second scan has to be performed within 3 weeks prior to signing informed consent.
Patients must have measurable disease per RECIST 1.1 criteria
Patients have an ECOG performance status of 0-1 (appendix D)
Patients have a life expectancy of >3 months
Patients have adequate organ function as determined by standard-of-care pre-checkpoint inhibitor infusion lab (including serum ALAT/ASAT less than three times the upper limit of normal (ULN); serum creatinine clearance 50ml/min or higher; total bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 50 micromol/L)
Patients have an LDH level of ≤1 times ULN
Patients of both genders must be willing to use a highly effective method of birth control during treatment
Patients must be able to understand and sign the Informed Consent document

Exclusion Criteria:

Patients with acral, uveal or mucosal melanoma, or patients with an unknown primary
Patients who have received treatment for their melanoma other than anti-PD-1 treatment.
Stage IV patients with M1c or M1d disease.
Patients with autoimmune diseases: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study (except Hashimoto thyroiditis, vitiligo, history of psoriasis, but no active disease)
Patients with any grade 3 or 4 immune-related adverse events still requiring active immunosuppressive medication, apart from endocrinopathies that are stable under hormone replacement therapy. Patients who had developed grade 3-4 immune related toxicity, which has reverted to grade I with immunosuppressive drugs and who are off immunosuppression at least two weeks prior to enrollment are eligible
Patients with brain or LM metastasis.
Patients with an elevated LDH level
Patients that have undergone major gastric/esophageal/bowel surgery (like Wipple, subtotal colectomy)
Severe food allergy (e.g. nuts, shellfish)
Patients with a swallowing disorder or expected bowel passage problems (ileus, fistulas, perforation)
Severe dysphagia with incapability of swallowing 2 liters of bowel lavage
Patients with a life expectancy of less than three months
Patients with severe cardiac or pulmonary comorbidities (per judgement of the investigator)
Women who are pregnant or breastfeeding
Patients with any active systemic infections, coagulation disorders or other active major medical illnesses
Patients with other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years
Patients who received treatment with antibiotics in the three months prior to study enrolment, or patients we are expected to receive systemic antibiotics during the course of this study

Sites / Locations

Antoni van LeeuwenhoekRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

A: FMT from an ICI non-responding donor

B: FMT from an ICI responding donor

Arm Description

Patients will receive FMT from an ICI non-responding donor (defined as ≥20% increase according to RECIST 1.1 criteria within the past 3 months). Patients will continue their anti-PD-1 treatment.

Patients will receive FMT from an ICI responding donor (defined as ≥30% decrease or disappearance of all lesions according to RECIST 1.1 criteria within the past 24 months). Patients will continue their anti-PD-1 treatment.

Outcomes

Primary Outcome Measures

Efficacy, defined as clinical benefit (stable disease (SD), partial response (PR), complete response (CR)

Secondary Outcome Measures

Safety, measured as the occurrence of toxicity of grade 3 or higher

Progression free survival (PFS)

PFS will be calculated from the date of registration to the date of progression or death, whichever occurs first, censoring patients without progression and who are still alive at last follow-up

The change in gut microbiome following FMT and the duration and stability over time

To assess the fecal microbiome (which includes bacteria, archaea, viruses, parasites and fungi), nucleotides will be isolated for next generation sequencing and molecular methodologies (e.g. PCR, qPCR). Initially, whole genomic DNA (metagenomics) and the ITS2 region or the rRNA gene will be will be sequenced, giving insights in the overall microbiota's structural and functional features and in the structural features of the fungal microbiota, respectively, which both will be associated to clinical variables.

The change in metabolome following FMT and the duration and stability over time

To assess the metabolome in feces (which includes amino acids, short lipids, sugars and nucleotides), samples will be processed and analyzed by Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) or Nuclear magnetic resonance (NMR). The identified metabolic profile will be associated with the microbiome data and clinical variables.

The immune changes; changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment

Tumor biopsies and blood samples will be analyzed to investigator the local and systemic immune changes: changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment (TME). If possible, results will be linked to response.

Full Information

NCT ID

NCT05251389

First Posted

December 20, 2021

Last Updated

July 8, 2022

Sponsor

The Netherlands Cancer Institute

1. Study Identification

Unique Protocol Identification Number

NCT05251389

Brief Title

FMT to Convert Response to Immunotherapy

Official Title

Conversion of Unresponsiveness to Immunotherapy by Fecal Microbiota Transplantation in Patients With Metastatic Melanoma: a Randomized Phase Ib/IIa Trial

Study Type

Interventional

2. Study Status

Record Verification Date

July 2022

Overall Recruitment Status

Recruiting

Study Start Date

July 2022 (Anticipated)

Primary Completion Date

April 2024 (Anticipated)

Study Completion Date

April 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Netherlands Cancer Institute

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In this study the aim is to investigate whether transfer of the microbiota of either responder or non-responder patients via fecal microbiotica transplantation (FMT) can convert the response to immunotherapy in immune checkpoint inhibitors (ICI) refractory metastatic melanoma patients. This is a randomized double-blind intervention phase Ib/IIa trial in ICI refractory metastatic melanoma patients receiving either FMT of an ICI responding or FMT from an ICI non-responding donor, in combination with ICI. Following randomization, patients will receive vancomycin 250 mg, four times daily for 4 days (day -5 up until day -2), and undergo bowel clearance on day -1 (in total 1L MoviPrep). The FMT, either derived from donor group R (who showed a good response on anti-PD-1 therapy) or donor group NR (who showed progression on anti-PD-1 therapy), will be performed by a gastroenterologist using esophagogastroduodenoscopy. A total amount of 198mL (containing a total of 60 gram feces) will be used for transplantation. Anti-PD-1 treatment will be continued according to the patient's regular treatment schedule. Evaluation of safety and response to treatment will be performed.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Melanoma Stage III, Melanoma Stage IV

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Model Description

a randomized double-blind intervention trial

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

A: FMT from an ICI non-responding donor

Arm Type

Experimental

Arm Description

Patients will receive FMT from an ICI non-responding donor (defined as ≥20% increase according to RECIST 1.1 criteria within the past 3 months). Patients will continue their anti-PD-1 treatment.

Arm Title

B: FMT from an ICI responding donor

Arm Type

Experimental

Arm Description

Intervention Type

Other

Intervention Name(s)

Fecal microbiota transplantation

Intervention Description

Fecal microbiota transplantation of an ICI responding or Fecal microbiota transplantation from an ICI non-responding donor, in combination with ICI.

Primary Outcome Measure Information:

Title

Efficacy, defined as clinical benefit (stable disease (SD), partial response (PR), complete response (CR)

Time Frame

At 12 weeks after FMT

Secondary Outcome Measure Information:

Title

Safety, measured as the occurrence of toxicity of grade 3 or higher

Time Frame

At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT

Title

Progression free survival (PFS)

Description

PFS will be calculated from the date of registration to the date of progression or death, whichever occurs first, censoring patients without progression and who are still alive at last follow-up

Time Frame

Up to one year post-FMT

Title

The change in gut microbiome following FMT and the duration and stability over time

Description

Time Frame

At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT

Title

The change in metabolome following FMT and the duration and stability over time

Description

Time Frame

At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT

Title

The immune changes; changes in cell populations (absolute, relative, phenotypical), in chemokine/cytokine levels and in the tumor-microenvironment

Description

Time Frame

At screening, and 2 weeks, 6 weeks, 12 weeks and 16 weeks after FMT

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Patients should be 18 years or older Patients have pathologically confirmed advanced stage cutaneous melanoma (stage III or IV) requiring systemic treatment with anti-PD-1 In case of stage IV disease, only patients with M1a or M1b disease are eligible. Patients have confirmed disease progression (≥20% increase according to RECIST1.1) on two consecutive scans with a four week interval while on anti-PD-1 treatment, of which the second scan has to be performed within 3 weeks prior to signing informed consent. Patients must have measurable disease per RECIST 1.1 criteria Patients have an ECOG performance status of 0-1 (appendix D) Patients have a life expectancy of >3 months Patients have adequate organ function as determined by standard-of-care pre-checkpoint inhibitor infusion lab (including serum ALAT/ASAT less than three times the upper limit of normal (ULN); serum creatinine clearance 50ml/min or higher; total bilirubin less than or equal to 20 micromol/L, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 50 micromol/L) Patients have an LDH level of ≤1 times ULN Patients of both genders must be willing to use a highly effective method of birth control during treatment Patients must be able to understand and sign the Informed Consent document Exclusion Criteria: Patients with acral, uveal or mucosal melanoma, or patients with an unknown primary Patients who have received treatment for their melanoma other than anti-PD-1 treatment. Stage IV patients with M1c or M1d disease. Patients with autoimmune diseases: patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's disease, are excluded from this study (except Hashimoto thyroiditis, vitiligo, history of psoriasis, but no active disease) Patients with any grade 3 or 4 immune-related adverse events still requiring active immunosuppressive medication, apart from endocrinopathies that are stable under hormone replacement therapy. Patients who had developed grade 3-4 immune related toxicity, which has reverted to grade I with immunosuppressive drugs and who are off immunosuppression at least two weeks prior to enrollment are eligible Patients with brain or LM metastasis. Patients with an elevated LDH level Patients that have undergone major gastric/esophageal/bowel surgery (like Wipple, subtotal colectomy) Severe food allergy (e.g. nuts, shellfish) Patients with a swallowing disorder or expected bowel passage problems (ileus, fistulas, perforation) Severe dysphagia with incapability of swallowing 2 liters of bowel lavage Patients with a life expectancy of less than three months Patients with severe cardiac or pulmonary comorbidities (per judgement of the investigator) Women who are pregnant or breastfeeding Patients with any active systemic infections, coagulation disorders or other active major medical illnesses Patients with other malignancies, except adequately treated and a cancer-related life-expectancy of more than 5 years Patients who received treatment with antibiotics in the three months prior to study enrolment, or patients we are expected to receive systemic antibiotics during the course of this study

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

John Haanen, Prof

Phone

+31205129111

j.haanen@nki.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Femke Burgers, MD

Phone

+31205129111

f.burgers@nki.nl

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John Haanen, Prof

Organizational Affiliation

Medical Oncologist

Official's Role

Principal Investigator

Facility Information:

Facility Name

Antoni van Leeuwenhoek

City

Amsterdam

ZIP/Postal Code

1066CX

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Femke Burgers

Phone

+31 20 512 9111

f.burgers@nki.nl

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

FMT to Convert Response to Immunotherapy

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