Fecal Microbial Transplantation Non-Small Cell Lung Cancer and Melanoma

Phase II Trial of Fecal Microbial Transplantation in Patients With Advanced Non-Small Cell Lung Cancer and Melanoma Treated With Immune Checkpoint Inhibitors.

The aim of this study is to assess the anti-tumor activity of FMT administered in combination with ICI therapy.

Immune-checkpoint inhibitors (ICI) now represent the backbone therapy for patients with advanced or unresectable non-small cell lung cancer (NSCLC) and melanoma. With the use of anti-PD-1 (Pembrolizumab), overall survival (OS) is now 45% at two years for patients with metastatic NSCLC with a PD-L1 expression level above 50%. The OS for patients with metastatic melanoma is now 52% at five years with combination therapy of anti-CLTA-4 (Ipilimumab) and anti-PD-1 (Nivolumab).

However, only a minority of patients obtain durable responses and current biomarkers are unable to consistently and accurately predict response to ICI. Addressing these unmet needs, the gut microbiome has emerged as a potential biomarker of response to ICI. Modulating the gut microbiome to improve response to ICI is an active area of study. One way to modify the gut microbiome composition is through fecal microbial transplantation (FMT) and pre-clinical studies showed improved effectiveness of ICI when mice received FMT from lung cancer patients responding to ICI. Recently, 2 phase I clinical studies published in Science consolidated these findings, and demonstrated the safety of FMT in patients with melanoma treated with ICI.

Building on phase I studies showing that FMT is safe in patients with cancer receiving ICI, and compelling data demonstrating the potential of FMT to reverse ICI resistance, there is a strong rationale to further study the role of FMT in improving ICI efficacy in patients with melanoma and NSCLC treated with ICI in the first-line setting in a phase II study.

Our primary objective is to assess the impact of FMT on ICI response and survival. Other goals of this trial are to study the changes in the patient's gut microbiome composition and tumor microenvironment contexture following the combination treatment of ICI and FMT. Efficacy of FMT in terms of response rate and overall survival in patients with metastatic melanoma and uveal melanoma will be studies as part of an exploratory endpoint.

Inclusion Criteria:

1. Signed, informed consent;
2. Patients must be able to understand the infectious and non-infectious risks associated with FMT administration;
3. Must understand that data regarding the long-term safety risks of FMT administration are lacking;
4. Age 18 years or older;
5. Confirmed histological diagnosis of either: unresectable or metastatic melanoma, unresectable or metastatic uveal melanoma, or unresectable or metastatic non-small cell lung cancer (NSCLC);
6. Stage IV or unresectable disease;
7. No prior anti-PD1 treatment;
8. For patients with newly diagnosed metastatic melanoma who relapsed after adjuvant immunotherapy, patients can be included in this study if they relapsed >6 months after their last dose of immunotherapy given in the adjuvant setting;
9. For patients with NSCLC, tumor PD-L1 expression level 50%
10. Evaluable disease as per iRECIST;
11. ECOG performance status of 0-2;
12. Ability to ingest capsules;
13. 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 permitted);
14. Negative pregnancy test for women of child-bearing potential; and
15. Highly effective contraception for both male and female subjects throughout the study and for at least 60 days after last treatment administration if the risk of conception exists

Exclusion Criteria:

1. 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.

2. Current or recent [in the last 90 days] exposure to high dose oral or IV corticosteroids

   a. Patients who require intermittent use of bronchodilators or local steroid injections are not excluded from the study.

3. Has a diagnosis of immunodeficiency (e.g. HIV, transplantation) or receiving systemic steroid therapy (>10mg prednisone daily or equivalent) or any other form of immunosuppressive therapy one year prior to trial treatment.

4. Presence of a chronic debilitating intestinal disease (e.g. Malabsorption, colonic tumor)

   a. Use of probiotics during FMT. Probiotics must be discontinued a minimum of 24 hours before FMT administration and patients are not permitted to take probiotics during the course of immunotherapy treatment.

5. Use of antibiotics within 2 weeks of enrollment in the study.

6. Presence of absolute contra-indications to FMT administration

   1. Toxic megacolon
   2. Severe dietary allergies (e.g. shellfish, nuts, seafood)
   3. Active inflammatory bowel disease

7. Expected to require any other form of systemic or localized anti-neoplastic therapy while on study.

8. 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 two years.

   a. NOTE: This time requirement 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.

9. Active untreated central nervous system (CNS) metastases and/or leptomeningeal involvement (leptomeningeal enhancement on MRI/CT imaging and/or positive CSF cytology).

10. Has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents.

    a. Patients with vitiligo, type I diabetes, resolved childhood asthma/atopy are exceptions to this exclusion criteria.

11. A history of (non-infectious) pneumonitis that required steroids or current pneumonitis.

12. Has serious concomitant illnesses, such as: impaired cardiovascular function of clinically significant cardiovascular disease (uncontrolled congestive heart failure requiring treatment (NYHA grade > 2), uncontrolled hypertension, acute myocardial cardiac ischemia or unstable angina < 6 months prior to study entry, and severe cardiac arrhythmia), active systemic infections, and active inflammatory bowel disorders.

    a. This includes HIV or AIDS-related illness, or active HBV and HCV.

13. Has an active infection requiring systemic therapy.

14. Patient has received a live vaccine within 4 weeks prior to the first dose of treatment

    a. 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.

15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.