Microbiota Transplant in Advanced Lung Cancer Treated With Immunotherapy

The gut microbiota can modulate the effectiveness of cancer therapies, especially immunotherapy. Manipulating the microbial populations in patients with advanced lung cancer through fecal microbiota transplantation from healthy individuals or from long-term survivors to advanced lung cancer will enhance the efficacy of immunotherapy.

Study Overview

• Status: Recruiting
• Conditions: Lung Cancer
• Intervention / Treatment: Dietary supplement: Microbiota Transplant plus anti PD1 therapy; Drug: anti PD1 therapy

Detailed Description

Lung cancer is a leading cause of mortality worldwide, and its treatment and prognosis are being revolutionized by immunotherapy. The gut microbiome has been shown able to modulate the antitumor efficacy of immunotherapeutic agents in pre-clinical models, demonstrating that patients can be stratified into responders and nonresponders to immunotherapy on the basis of their microbiota composition. Fecal microbiota transplants have demonstrated to improve the efficacy of immunotherapy in animal models. In this study, investigators will include 20 stage III/V non-small cell lung cancer naïve for PD/PD L-1 inhibitors that require treatment in monotherapy or combined with chemotherapy as consolidation strategy after concurrent chemotherapy and radiotherapy (stage III), upfront treatment (stage IV patients with PDL1 status > 50%) or as second line strategy for those patients with advanced disease who progressed to chemotherapy alone. The participants will be randomized to receive either fecal microbiota capsules from 3 donors selected based on the fecal abundance of bacterial taxa shown to correlate with a greater response to immunotherapy or not, in combination with the PDL/PDL1 agent. The primary outcome will be safety. The secondary outcomes will be treatment response (iRECIST criteria). Investigators will also examine engraftment of donor's microbiota on host microbiota using Illumina DNA shotgun sequencing, changes in the bacterial metabolism using metaproteomics, and in the plasma metabolite fingerprint by untargeted mass spectrometry in bacterial and plasma samples, and changes in peripheral immune cells subpopulations and antitumoral immunity. MORELIA could improve the prognosis of a lung cancer in a subset of patients with limited therapeutic options and inform on how to exploit host-microbiota interactions with tailored fecal microbiota transplantation to boost the clinical response to immunotherapy in advanced cancer.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Sergio Serrano-Villar, MD; Phone Number: 913368975; Email: serranovillar@gmail.com
• Study Contact Backup: Name: Pilar Garrido, MD; Phone Number: 913368263; Email: pilargarridol@gmail.com

Study Locations

• Spain
  • Madrid, Spain, 28034
    • Recruiting
    • Hospital Universitario Ramon y Cajal
    • Contact: Sergio Serrano-Villar, MD, PhD; Email: serranovillar@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Willing to sign the informed consent
2. Age >18 years.
3. Diagnosis of unresectable stage III non-small cell cancer histologically or citologically confirmed.
4. Eastern Cooperative Oncology Group (ECOG) Score ≤1
5. Disease able to be monitored using the RECIST v.1.1. criteria (lesions treated with radiotherapy can be defined as target lesions if the progression has been documented).
6. At least 3 weeks since the last treatment for cancer, including chemotherapy and radiotherapy when combined in stage III patients, and recovery ≤1 from any adverse event related with previous treatment for cancer, excluding sensorial neuropathy, anemia, asthenia, hair loss, all grade ≤2), according to the National Cancer Institute (CTCAE del NCI, v.5) definitions

7. Adequate bone marrow, renal, liver and metabolic parameters (evaluated at least 7 days prior the inclusion in the study:

   • Platelet count ≥100 x 109/l, hemoglobin ≥9 g/dl and absolute neutrophil count ≥1,000 x 109/l.
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 times the upper limit of normality, independently of the presence of liver metastases.
   • Alkaline phosphatase ≤ 2,5 times the upper limit of normality.
   • Total bilirubin ≤1,5 times the upper limit of normality o direct bilirubin below the upper level of normality.
   • INR<1,5, except if concomitant oral anticoagulation
   • Estimated glomerular filtration rate ≥30 ml/minute using the EPI equation
   • Albumin ≥3 g/dl without previous parenteral albumin treatment.
8. All men and women with childbearing potential must accept the use of highly efficacious contraceptive methods during the study.

Exclusion Criteria:

1. Active of untreated central nervous system (CNS) involvement. Treated CNS metastases must be radiologically stable (defined as the absence of CNS progression during at least 3 weeks from the first CNS imaging after radiotherapy to the CNS imaging prior the screening visit. Participants will not be included in the presence of any neurological sign or symptom secondary to CNS metastases or radiotherapy. Any treatment with steroids must have been completed at least 14 days before the first study intervention.
2. Prior use of immunotherapy of immunomodulatory treatment for non-small cell lung cancer, either in combination or in monotherapy, at any stage of the disease.
3. Radiotherapy in >35% the bone marrow.
4. Prior bone marrow or cell-stem transplant.
5. Treatment with immunoestimulatory agents, including interferons or interleukin-2 before 4 weeks or 5 drug half-lives (whichever longer) before the randomization.
6. Prior neoplasia, with the exception of skin basocelular carcinoma, superficial bladder carcinoma, squamous cell skin carcinoma, cervix high degree intrasquamous lesion. Those patients with prior neoplasia free of recurrence during at least 2 years are eligible.
7. Severe infections four weeks before the screening, including hospitalization due to any infection, bacteremia or severe pneumonia.
8. Rectal colonization by vancomycin resistant enterococci
9. Overt immunodeficiency, including systemic treatment with steroids at >10 mg of prednisone/day (or its equivalent) or other immunosuppressive agents during the 14 days before the first study intervention.
10. Moderates-severe mucositis , GI symptoms
11. Dysphagia, history of aspirative pneumonia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: anti PD1 therapy plus Microbiota Transplant; Active arm: Pooled fecal microbiota capsules of 1 donor selected based on their fecal abundance in Faecalibacterium prausnitzii, Bifidobacterium longum, Akkermansia muciniphila and Fusobacterium spp. after screening and metagenomic analysis of 10 donors with high-fiber diets (>30g/day). anti PD1 therapy every 2-3 weeks	Dietary supplement: Microbiota Transplant plus anti PD1 therapy; Pooled fecal microbiota capsules of 1 donor selected based on their fecal abundance in Faecalibacterium prausnitzii, Bifidobacterium longum, Akkermansia muciniphila and Fusobacterium spp. after screening and metagenomic analysis of 10 donors with high-fiber diets (>30g/day). anti PD1 therapy every 2-3 weeks; Other Names: anti PD1 therapy Pembrolizumab, Nivolizumab, Atezolizumab
Active Comparator: anti PD1 therapy; Control arm: no intervention before anti PD1 therapy	Drug: anti PD1 therapy; anti PD1 therapy every 2-3 weeks; Other Names: Pembrolizumab, Nivolizumab, Atezolizumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of safety	The safety variables (vital signs, physical examinations, symptoms, laboratory test results and the occurrence of adverse events) will be assessed at each visit. The incidence of adverse events will be categorized by severity and related to the time of occurrence. Changes in physical examinations, changes in laboratory test results (hematology, biochemistry and urinalysis tests) from screening period, and change of vital signs will be summarized and analyzed by the descriptive statistics. Adverse events will be defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. v5.0	27 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure of Efficacy	Immunotherapy Response Evaluation Criteria in Solid Tumors-iRECIST	27 weeks

Collaborators and Investigators

• Sponsor: Fundacion para la Investigacion Biomedica del Hospital Universitario Ramon y Cajal

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2021
• Primary Completion (Estimated): December 31, 2023
• Study Completion (Estimated): July 31, 2024

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: June 9, 2021
• First Posted (Actual): June 14, 2021

Study Record Updates

• Last Update Posted (Actual): May 31, 2023
• Last Update Submitted That Met QC Criteria: May 30, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Lung Cancer; Fecal Microbiota Transplantation; Microbiota; Immunotherapy; Metabolomics; Chemotherapy; Oncology; Immunosenescence; Metagenomics; Metaproteomics
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Antibodies, Monoclonal; Atezolizumab
• Other Study ID Numbers: MORELIA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No