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Microbiota Transplant to Cancer Patients Who Have Failed Immunotherapy Using Faeces From Clinical Responders (MITRIC)

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ClinicalTrials.gov Identifier: NCT05286294
Recruitment Status : Recruiting
First Posted : March 18, 2022
Last Update Posted : April 1, 2022
Sponsor:
Information provided by (Responsible Party):
Jon Amund Kyte, Oslo University Hospital

Brief Summary:
This is a single-arm, single-center, open-label, phase IIa study evaluating the safety, feasibility and efficacy of Faecal Microbiota Transplant (FMT) to cancer patients not responding to ICI therapy, using ICI-responders as donors.

Condition or disease Intervention/treatment Phase
Melanoma Stage IV Head and Neck Squamous Cell Carcinoma Cutaneous Squamous Cell Carcinoma MSI-High Clear Cell Renal Cell Carcinoma Biological: Fecal Microbiota Transplant (FMT) Phase 2

Detailed Description:
Immunotherapy with immune checkpoint inhibitors (ICI) has shown remarkable clinical efficacy against several cancer forms. This includes durable responses in patients with metastatic cancers and no other effective treatment options. However, many patients do not respond. This leaves a major challenge; how to turn non-responders into responders. Herein, this challenge is addressed, by attempting to modulate patients' intestinal microbiota through Faecal Microbiota Transplant (FMT). Data from several preclinical and translational studies have indicated that the microbiota composition is important for the effect of ICIs. Moreover, two recent trials exploring FMT for melanoma patients have suggested acceptable safety and a potential clinical benefit.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: MITRIC: Microbiota Transplant to Cancer Patients Who Have Failed Immunotherapy Using Faeces From Clincal Responders
Estimated Study Start Date : March 2022
Estimated Primary Completion Date : March 2034
Estimated Study Completion Date : December 2034


Arm Intervention/treatment
Experimental: Treatment
Fecal Microbiota Transplant (FMT)
Biological: Fecal Microbiota Transplant (FMT)
Fecal Microbiota Transplant (FMT)




Primary Outcome Measures :
  1. Safety evaluation of Fecal Microbiota Transplant (FMT) in advanced cancer patients [ Time Frame: 10 years ]
    Safety of the intervention (FMT) as assessed by the incidence, nature, and severity of Adverse Events (AE) according to NCI CTCAE, version 5.0

  2. Tumor response evaluation [ Time Frame: 10 years ]
    Objective Tumor Response Rate (ORR) as assessed by iRECIST in PP population


Secondary Outcome Measures :
  1. Feasibility evaluation of FMT for advanced cancer patients [ Time Frame: 10 years ]
    The percentage of included patients that receive i) at least two FMT, ii) the scheduled number of FMT until End of Intervention (EOI)

  2. Overall survival (OS) [ Time Frame: 10 years ]
    Clinical response estimation

  3. Objective Tumor Response Rate (ORR) [ Time Frame: 10 years ]
    Clinical response estimation

  4. Progression Free Survival (PFS) [ Time Frame: 10 years ]
    Clinical response estimation

  5. Durable response rate (DRR) [ Time Frame: 10 years ]
    Clinical response estimation

  6. Clinical benefit range (CBR) [ Time Frame: 10 years ]
    Clinical response estimation

  7. Duration of objective response (DOR) [ Time Frame: 10 years ]
    Clinical response estimation

  8. Implant engraftment estimation, and the effect of repeated FMT [ Time Frame: 10 years ]
    Comparison of the patients' gut bacterial composition before and after FMT and in relation to their donors

  9. Evaluation of the effect of therapy on quality of life [ Time Frame: 10 years ]
    Patient reported outcomes (PRO) as assessed by EORTC quality of life questionnaire (QLQ-C30)

  10. Evaluation of the effect of therapy on fatigue [ Time Frame: 10 years ]
    Patient reported outcomes (PRO) as assessed by Chalder Fatigue Questionnaire (FQ)

  11. Evaluation of the effect of therapy on pain [ Time Frame: 10 years ]
    Patient reported outcomes (PRO) as assessed by an 11-point Numerical Rating Scale (NRS) for pain intensity


Other Outcome Measures:
  1. Immunological response evaluation [ Time Frame: 10 years ]
    Immunological changes in blood (PBMC, serum/plasma), gut and tumor tissue

  2. Explorative assessment of biomarkers or clinical responses and toxicity [ Time Frame: 10 years ]
    Microbial gut composition, tumor tissue, blood and gut will be characterized and correlated with treatment outcome. Assessment will include baseline profile and changes after FMT

  3. Investigation of T cell reactivity to neoantigens and microbial antigens [ Time Frame: 10 years ]
    T cell receptor binding and T cell reactivity to selected peptides

  4. Characterization of tumor evolution and changes in immunological milieu induced by the FMT and continued ICI therapy [ Time Frame: 10 years ]
    Comparison of tumor biopsies at baseline and later time points, by gene and protein profiling



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Participant must be 18 years of age, at the time of signing the informed consent
  2. Histologically confirmed malignant melanoma, CSCC, HNSCC, renal clear cell carcinoma or MSI+ solid cancer
  3. Metastatic disease or local recurrence not curable by standard therapy
  4. PD-L1 positivity (>20% combined positive score) is required for subjects with HNSCC
  5. Measurable disease according to iRECIST
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  7. Progressive disease, as considered by the treating physician, on therapy with PD1/PD-L1 blockers and/or CTLA4-blockers. Indication for further treatment with ICI.
  8. No response to ICI at any time point, during the history of the cancer
  9. Mandatory pre-FMT biopsy and lesion accessible for further biopsies
  10. Life expectancy >3 months
  11. Adequate organ function as defined below:

    1. Hemoglobin > 9 g/dL
    2. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
    3. Platelet count ≥80 x 109/L
    4. INR≤1.2
    5. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
    6. AST and ALT ≤2.5 x ULN unless liver metastases are present, in which case it must be ≤5x ULN
    7. Albumin >25 g/L
    8. Serum creatinine ≤1.5 X ULN OR measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance.
  12. Capable of giving signed informed consent

Exclusion Criteria:

  1. Other cancer within 3 years prior to study entry, with the exception of those with a negligible risk of metastasis or death and treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer)
  2. Spinal cord compression not definitively treated with surgery and/or radiation, or previously diagnosed and treated spinal cord compression without evidence that disease has been clinically stable for > 2 weeks prior to first FMT
  3. Uncontrolled pleural effusion, pericardial effusion, or ascites. Patients with indwelling catheters are allowed
  4. Uncontrolled tumor-related pain. Patients requiring narcotic pain medication must be on a stable regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrolment. Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to enrolment.
  5. Significant cardiovascular disease, such as New York Heart Association (NYHA) cardiac disease (Class II or greater), myocardial infarction within 3 months prior to study entry, unstable arrhythmias, or unstable angina. Patients with a known left ventricular ejection fraction (LVEF) < 40% will be excluded. Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
  6. Undergone allogeneic stem cell or solid organ transplantation
  7. A positive test for HIV
  8. Active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HbsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
  9. Active tuberculosis
  10. Ongoing immune-related adverse effects from immunotherapy treatments that are of Grade ≥2, excluding endocrine adverse effects. An ongoing grade 2 cutaneous reaction is allowed.
  11. Severe infection within 14 days prior to first FMT, requiring hospitalization.
  12. Any condition that significantly increases the risk of perforation during endoscopy for FMT.
  13. 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.
  14. Known psychiatric or substance abuse disorders that would interfere with cooperation and the requirements of the trial
  15. A requirement of systemic antibiotics at the time of study entry.
  16. Received oral or IV antibiotics within 5 days prior to first FMT.
  17. Currently receiving other study therapy that may interfere with the interpretation of data in this study.
  18. Received treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 10 days prior to first FMT, or anticipated requirement for systemic immunosuppressive medications during the trial. A daily dose equivalent to ≤10mg prednisolone is allowed.

    1. Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study.
    2. Patients with a history of allergic reaction to IV contrast requiring steroid pre-treatment should have baseline and subsequent tumor assessments performed using MRI.
    3. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
  19. Pregnant or breastfeeding
  20. Any reason why, in the opinion of the investigator, the patient should not participate

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05286294


Contacts
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Contact: Jon Amund Kyte, MD, Ph.D. +4722934000 jonky@ous-hf.no
Contact: Andreas Ullern, MD +4722934000 andull@ous-hf.no

Locations
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Norway
Oslo University Hospital Recruiting
Oslo, Norway, 0379
Contact: Jon Amund Kyte, MD Ph.D.         
Contact: Andreas Ullern, MD       andull@ous-hf.no   
Sub-Investigator: Andreas Ullern, MD         
Principal Investigator: Jon Amund Kyte, MD Ph.D.         
Sponsors and Collaborators
Oslo University Hospital
Investigators
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Principal Investigator: Jon Amund Kyte, MD, Ph.D. Oslo University Hospital
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Responsible Party: Jon Amund Kyte, Principal Investigator, Oslo University Hospital
ClinicalTrials.gov Identifier: NCT05286294    
Other Study ID Numbers: MITRIC
First Posted: March 18, 2022    Key Record Dates
Last Update Posted: April 1, 2022
Last Verified: March 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jon Amund Kyte, Oslo University Hospital:
Fecal microbiotal transplant (FMT)
Immunotherapy
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Carcinoma, Renal Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Kidney Diseases
Urologic Diseases
Head and Neck Neoplasms