Restorative Microbiota Therapy in Combination with Durvalumab, Tremelimumab, and Chemotherapy for the Treatment of Stage IIIB-IV Non-small Cell Lung Cancer

Inclusion Criteria

• Diagnosis of locally advanced (stage III B or C) or metastatic (stage IV) non-small cell lung cancer with adenocarcinoma and squamous histology that is considered incurable with current standard treatment options in the opinion of the enrolling investigator as documented in the medical record
• Measurable disease based on RECIST 1.1
• No known targetable mutation for EGFR or ALK or ROS1 or BRAF or RET or NTRK or MET ex 14 mutation
• No prior anti-cancer systemic therapy directed at advanced/metastatic disease, with the exceptions of: * Prior treatment for early-stage cancer is permitted and/or localized treatment of isolated lesions for palliative intent is permitted as long as not a target lesion per RECIST * Current use of hormones for non-cancer related conditions such as insulin for diabetes and hormone replacement therapy
• Histological confirmation of current disease – must have a minimum of 10 unstained slides available (or able to obtain fresh tissue) for biomarker and genomic testing. The requirement for unstained slides may be waived in situations where biopsy is not safe or feasible after review by the principal investigator
• PD-L1 status is available (for statistical sub analysis)
• Treated brain metastasis are permitted as long as stable symptoms, at least 2 weeks from completion of therapy, and does not require more than 10 mg of daily prednisone or 2 mg of dexamethasone (or equivalent)
• Age 18 years of age or older at the time of signing the study consent
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Body weight of > 30 kg
• Hemoglobin >= 9.0 g/dL (within 14 days prior to the first RMT/placebo dose)
• Absolute neutrophil count >= 1,000/mcL (within 14 days prior to the first RMT/placebo dose)
• Platelets >= 100,000/mcL (within 14 days prior to the first RMT/placebo dose)
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to the first RMT/placebo dose) - this will not apply to patients with known history of Gilbert’s syndrome 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 prior to the first RMT/placebo dose)
• 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 prior to the first RMT/placebo dose)
• Women of childbearing potential and men with partners of child-bearing potential must agree to use effective contraception from the time of screening throughout the duration of treatment, 180 days after the last dose of durvalumab + tremelimumab, and 90 days after the last dose of durvalumab
• Participant must agree to not donate blood or blood products while receiving study treatment and for at least 90 days following the last infusion of tremelimumab and/or durvalumab
• Provides voluntary written consent prior to the performance of any research related activity and by doing so indicates an understanding and ability to comply with study related activities and follow-up

Exclusion Criteria

• Large cell, or NSCLC NOS (not otherwise specified) histology or mixed histology tumors
• Pregnant or breast feeding. Evidence of post-menopausal status, or negative urine or serum pregnancy test for pre-menopausal patients (performed within 1 week prior to the first dose of RMT/placebo). Women are considered postmenopausal if they have amenorrhea for 12 months without an alternative medical explanation
• Known dysphagia and/or difficulty with swallowing oral medications whole
• Known sensitivity to any component of therapeutic agents used in this study
• Prior adjuvant treatment within the previous 6 months with any of the following: * Another anti-PD-1 (i.e. nivolumab or pembrolizumab), or PD-L1 (durvalumab or atezolizumab) * An antibody * A small molecule targeting other immuno-regulatory receptors
• Receipt of any immunotherapy or investigational drug for any other reason within 4 weeks prior to the first dose of RMT/placebo
• Taking daily probiotics and unwilling to discontinue at least 4 weeks prior to first dose of RMT/placebo
• Current or prior use of immunosuppressive medication within 4 weeks prior to the first dose of RMT/placebo, with the exceptions of: * Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra articular injection) * Corticosteroids or systemic corticosteroids at physiological doses, which do not exceed 10 mg/day of prednisone, or an equivalent corticosteroid * Steroids as premedication for hypersensitivity reactions * Use for contrast allergies * Treatment of brain metastases
• Major surgery within 4 weeks prior to the 1st dose of RMT/placebo that could interfere with receiving the study related treatment
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Grave’s disease, rheumatoid arthritis, hypophysitis, uveitis, etc.]). Patient may be considered for study if the last documented “flare-up” was > 5 years ago, but only after consultation with the study principal investigator (PI). The following are exceptions to this criterion: * Vitiligo or alopecia * Hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Celiac disease controlled by diet alone
• History of primary immunodeficiency
• History of organ transplant that requires therapeutic immunosuppression
• Known untreated brain metastasis or known active leptomeningeal carcinomatosis
• Known human immunodeficiency virus (HIV) infection unless on standard anti-retroviral treatment for >= 6 months and have an absolute CD4 count > 500
• Known history of or active hepatitis B or C: * Active hepatitis B defined as: Patients with untreated chronic hepatitis B virus (HBV) or chronic HBV carriers whose HBV deoxyribonucleic acid (DNA) is >= 500 IU/mL are excluded * Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B patients (HBV DNA < 500 IU/mL) are eligible * Active hepatitis C virus (HCV) defined as: Patients with positive HCV antibody result and positive quantitative HCV ribonucleic acid (RNA) results are excluded * Patients with HCV who are on anti-viral suppressive therapy or cured hepatitis C patients (both defined as positive HCV antibody test and negative HCV ribonucleic acid test) are eligible
• Known history of active tuberculosis. Patients with prior history of latent tuberculosis (TB) could be included if they have been treated previously with isoniazid
• Uncontrolled intercurrent illness per investigator, including but not limited to, ongoing or active systematic infection, or serious chronic gastrointestinal conditions that would interfere with absorption or general gut health
• Myocardial infarction or stroke within 3 months prior to enrollment
• Symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, New York Heart Association (NYHA) class III or IV symptoms
• Active or prior history of (non-infectious) pneumonitis that required steroids for interstitial lung disease
• On chronic systemic antibiotic therapy (defined as antibiotics for >= 60 consecutive days within 12 weeks of 1st RMT/placebo dose). Note: Patients who receive systemic antibiotics for an acute infection between consent signing and start of RMT/placebo are eligible
• Receipt of live attenuated vaccination within 30 days of 1st RMT/placebo dose
• Current use of herbal and natural remedies with immune-modulating effects (unless agreed upon by the sponsor)
• History of another primary malignancy (excluding non-melanoma skin cancer) unless the patient has had no evidence of disease recurrence for at least 5 years since initiation of potentially curative treatment
• Psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the patient to give written informed consent