Skip to main content

Restorative Microbiota Therapy in Combination with Durvalumab with or without Chemotherapy for the Treatment of Stage IIIB-IV Non-small Cell Lung Cancer

Trial Status: Approved

This phase II trial studies the effect, safety and tolerability of restorative microbiota therapy (RMT) in combination with durvalumab with or without chemotherapy in treating patients with stage IIIB-IV non-small cell lung cancer. RMT is prepared by extracting healthy bacteria from the stool of healthy human donors while rigorously testing samples for harmful bacteria and viruses before processing. The extract is then made into capsules which is taken by mouth. RMT may make immunotherapy more effective. Durvalumab is a type of anti-cancer therapy called immunotherapy that uses the patient’s own immune system to attack tumor cells. Chemotherapy drugs, such as cisplatin, pemetrexed, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving RMT may make durvalumab treatment with or without chemotherapy more effective in controlling stage IIIB-IV non-small cell lung cancer.

Inclusion Criteria

  • Histologically or cytologically confirmed adenocarcinoma of the lung that is unresectable stage IIIB/C or stage IV, does not have an EGFR sensitizing (activating) mutation or ALK or ROS1 translocation
  • Measurable disease based on RECIST 1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Body weight of > 30 kg
  • Prior chemotherapy or immunotherapy as adjuvant therapy for lung cancer is permitted as long as it has been > 6 months from last dose at the time of enrollment. Local treatment of isolated lesions, excluding target lesions, for palliative intent is acceptable (e.g. by local surgery or radiotherapy). Prior systemic therapy for advanced/metastatic non-small cell lung cancer (NSCLC) makes the patient ineligible for this study
  • Patients with treated brain metastasis are eligible as long as they have stable symptoms, are more than 2 weeks from completion of therapy, and do not require more than 10 mg of daily prednisone or equivalent
  • Tumor sample requirements * Mandatory provision of an unstained, archived tumor tissue sample in a quantity sufficient to allow for biomarker and genomic analysis. A minimum of 10 unstained slides should be available for evaluation. * Known PD-L1 tumor cell (TC) expression status assayed by Ventana SP263. Patients who have known PDL-1 as assayed by PharmDx 22C3 assay may be eligible; however, available archival tissue will be used to assay with Ventana SP263 test
  • Evidence of post-menopausal status, or negative urine or serum pregnancy test for female pre-menopausal patients. Women will be considered postmenopausal if they have amenorrhea for 12 months without an alternative medical explanation. The following age-specific requirements apply: * Women < 50 years old would be considered postmenopausal if they have amenorrhea for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range * Women >= 50 years of age would be considered postmenopausal if they have amenorrhea for 12 months or more following cessation of all exogenous hormonal treatments, radiation-induced oophorectomy with last menses > 1 year ago, chemotherapy-induced menopause with > 1-year interval since last menses, or surgical sterilization (bilateral oophorectomy or hysterectomy)
  • Hemoglobin >= 9.0 g/dL (within 14 days of study enrollment)
  • Absolute neutrophil count >= 1,500/mcL (within 14 days of study enrollment)
  • Platelets >= 100,000/mcL (within 14 days of study enrollment)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days of study enrollment) - this will not apply to patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis or hepatic pathology), who will be allowed only in consultation with their physician
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN unless liver metastases are present, in which case it must be =< 5 x ULN (within 14 days of study enrollment)
  • 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 (within 14 days of study enrollment)
  • Expected life expectancy of at least 12 weeks in the opinion of the enrolling investigator
  • Women of childbearing potential and men with partners of child-bearing potential must agree to use of contraception for the time of screening to the duration of treatment and 3 months after the last dose of study drug
  • Provide voluntary written consent prior to the performance of any research related tests or procedures

Exclusion Criteria

  • Dysphagia or inability to swallow medications
  • Squamous cell, large cell, or NSCLC NOS (not otherwise specified) histology or mixed tumors
  • Has untreated brain metastasis or active leptomeningeal carcinomatosis
  • Has a known sensitivity to any component of therapeutic agents used in this study
  • Receipt of any immunotherapy or investigational drug within 4 weeks prior to the first dose of study drug; and in the case of monoclonal antibodies 6 weeks prior to the first dose of study drug
  • Had prior treatment with any other anti-PD-1, or PD-L1, including durvalumab or an anti-PD-L2 agent or an antibody or a small molecule targeting other immuno-regulatory receptors except as adjuvant therapy for NSCLC so long as it has been greater than six months since the last treatment
  • Current or prior use of immunosuppressive medication within 28 days before the first dose of study drug, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
  • Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of study drug
  • Active or prior documented autoimmune disease within the past 2 years requiring systemic treatment (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Patients with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
  • Active documented inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) who require immunosuppression or patients who exceed 10 mg/day of prednisone, or an equivalent corticosteroid are excluded
  • History of primary immunodeficiency
  • History of organ transplant that requires therapeutic immunosuppression
  • Taking daily probiotics (patients with last probiotic > 4 weeks prior to first dose of RMT are eligible)
  • History of human immunodeficiency virus (HIV) (known HIV 1/2 antibodies positive) who are on anti-retroviral treatment for < 6 months and absolute CD4 count < 500 (patients with HIV not meeting these criteria are eligible)
  • Has known active hepatitis B or C. Active hepatitis B is defined as a known positive hepatitis B surface antigen (HBsAg), and positive hepatitis B virus quantification assay (patients with history of hepatitis B who have seroconversion i.e. hepatitis B core antibody positive and hepatitis B surface antibody positive are eligible). Active hepatitis C is defined by a known positive hepatitis C antibody (Hep C Ab) result and positive quantitative hepatitis C virus (HCV) ribonucleic acid (RNA) results (Patients with hepatitis C who are on anti-viral suppressive therapy and negative quantitative HCV RNA results are eligible)
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses
  • Myocardial infarction or stroke within 3 months prior to enrollment
  • History of systolic or diastolic heart failure with New York Heart Association (NYHA) class III or IV symptoms
  • Has active or prior history of (non-infectious) pneumonitis that required steroids or patients with interstitial lung disease
  • Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent
  • Known history of active tuberculosis. Patients with prior history of latent tuberculosis (TB) could be included if they have been treated previously with isoniazid
  • Patients who are on chronic systemic antibiotic therapy (antibiotics for >= 60 consecutive days within 12 weeks of enrollment). Patients who receive systemic antibiotics between enrollment and start of RMT are eligible
  • Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving RMT
  • History of another primary malignancy (excluding non-melanoma skin cancer) within 5 years prior to starting RMT, except if the patient has undergone potentially curative therapy with no evidence of disease recurrence for 5 years since initiation of that therapy
  • Any condition that, in the opinion of the investigator, would interfere with evaluation of the study drug or interpretation of patient safety or study results


University of Minnesota / Masonic Cancer Center
Contact: Manish Patel
Phone: 612-624-6940


I. To determine the objective response rate (ORR) in patients with restorative microbiota therapy (RMT) in combination with durvalumab or durvalumab + chemotherapy as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with untreated advanced or metastatic adenocarcinoma non-small cell lung cancer (NSCLC).

II. To evaluate the safety and tolerability of restorative microbiota therapy (RMT) in combination with durvalumab or durvalumab + chemotherapy.


I. To estimate the progression-free survival (PFS) using RECIST 1.1 and overall survival (OS) in each treatment arm.

II. To determine the duration of response (DOR) of treatment with RMT in each treatment arm per RECIST 1.1.

III. To determine rate of immune mediated adverse events (imAE) in each treatment arm.

IV. To estimate objective response rate (ORR) and progression free survival (PFS) using immune Response Evaluation Criteria in Solid Tumors (iRECIST).

V. To assess change in health-related quality of life (QoL) using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-30) and Lung Cancer Module (LC-13).


I. To determine the impact of chemotherapy on microbial diversity by comparing the microbiome composition of patients treated on Arm A and Arm B.

II. To determine the rate of microbial engraftment following RMT in each arm.

III. To determine the impact of baseline microbial diversity on ORR and PFS per RECIST 1.1.

IV. To compare the ORR as assessed by RECIST 1.1 in patients whose microbial diversity was restored by RMT versus not restored.

V. To determine the association of high and low tumor mutational burden (TMB) with ORR per RECIST 1.1 in the two arms.

VI. To evaluate the changes in systemic immune response markers from peripheral blood immunophenotyping following RMT in each arm.

VII. To determine the relationship between the baseline anti-tumor immune response markers in the tumor microenvironment (TME) and microbiome diversity.

VIII. To evaluate whether increased relative abundances of butyrate producing bacteria and microbial genes involved in butyrate metabolism at baseline is associated with diminished treatment response in patients receiving durvalumab or durvalumab + chemotherapy.

IX. To evaluate the pulmonary microbiome at baseline in relation to outcomes from bronchoscopy specimens.

OUTLINE: Patients are assigned to 1 of 2 arms.

ARM A (High PD-L1 Tumor Cell): Patients receive RMT orally (PO) weekly for 16 doses. Beginning week 2, patients also receive durvalumab intravenously (IV) over 1 hour every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.

ARM B (Low PD-L1 Tumor Cell): Patients receive RMT as in Arm A. Beginning week 2, patients also receive durvalumab IV over 1 hour, standard of care cisplatin IV over 30 minutes or carboplatin IV over 30 minutes, and pemetrexed IV over 30 minutes. Treatment with cisplatin or carboplatin repeats every 3 weeks for 4 cycles and treatment with durvalumab and pemetrexed repeats every 3 weeks up for to 2 years in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for a maximum of 3 years from 1st dose of durvalumab, or until study data collection ends whichever is the shortest.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Minnesota / Masonic Cancer Center

Principal Investigator
Manish Patel

  • Primary ID 2019LS010
  • Secondary IDs NCI-2020-07398
  • ID NCT04105270