An Open-Label, Phase I, Dose-Finding Study of CBM588 in Combination With Nivolumab/Ipilimumab for Patients With Advanced Stage Renal Cell Carcinoma
An Open-Label, Phase I, Dose-Finding Study of CBM588 in Combination With Nivolumab/Ipilimumab for Patients With Advanced Stage Renal Cell Carcinoma
This phase I trial tests the safety, side effects, best dose, and effectiveness of CBM588 in combination with nivolumab and ipilimumab in treating patients with kidney cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). CBM588 is a live biotherapeutic that may help improve the effects of immunotherapy. Nivolumab and ipilimumab are monoclonal antibodies that may interfere with the ability of tumor cells to grow and spread by enhancing the ability of the body's immune cells to attack tumor cells. CBM588 in combination with nivolumab and ipilimumab may be safe, tolerable, and/or effective in treating patients with advanced stage kidney cancer.
PRIMARY OBJECTIVE:
I. To evaluate the safety and tolerability of nivolumab/ipilimumab with escalating doses of Clostridium butyricum MIYAIRI 588 capsules (CBM588) in patients with metastatic renal cell carcinoma.
SECONDARY OBJECTIVES:
I. To evaluate the effect of CBM588 on the clinical efficacy of nivolumab/ipilimumab.
II. To determine the effect of CBM588 (in combination with nivolumab/ipilimumab) in modulation of the gut microbiome in patients with metastatic renal cell carcinoma.
III. To assess the effect of CBM588 on the change of metabolic pathways with the nivolumab/ipilimumab combination in patients with metastatic renal cell carcinoma.
IV. To determine the effect of CBM588 on systemic immunomodulation.
OUTLINE: This is a dose-escalation study of CBM588 followed by a dose-expansion study.
Patients receive CBM588 capsules orally (PO) twice daily (BID) on days 1-21, nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 days for 4 cycles. Patients then receive CBM588 PO BID on days 1-28 and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo computed tomography (CT), bone scan and blood sample collection throughout the study. Patients may optionally undergo magnetic resonance imaging (MRI) on study.
After completion of study treatment, patients are followed up once a year.
Inclusion Criteria:
Documented informed consent of the participant and/or legally authorized representative
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
Eastern Cooperative Oncology Group (ECOG) ≤ 2
Age ≥ 18 years
Histologically confirmed renal cell carcinoma with clear cell renal cell carcinoma component or sarcomatoid component
Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) renal cell carcinoma with intermediate- or poor-risk disease by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria
No prior systemic therapy for renal cell carcinoma (RCC) with the following exception:
Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
Absolute neutrophil count (ANC) ≥ 1500/uL without granulocyte colony-stimulating factor support
White blood cell count ≥ 2500/uL
Platelets ≥ 100,000/uL without transfusion
Hemoglobin ≥ 8 g/dL
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN). ALP ≤ 5 x ULN with documented bone metastases
Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN)
Serum albumin ≥ 2.8 g/dl
Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN
Serum calculated creatinine clearance ≥ 50mL/min using the Cockcroft-Gault equation
Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 5 months after the last dose of nivolumab for women with childbearing potential, and 7 months after the last dose of nivolumab for men
Female subjects of childbearing potential must not be pregnant at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: documented permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes. In addition, females < 55 years-of-age must have a serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause).
Exclusion Criteria:
Prior treatment with ipilimumab and/or nivolumab
Current use, or intent to use, probiotics, yogurt, or bacterial fortified foods during the period of treatment
History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitis requiring treatment with systemic steroids
Known medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results
Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment
Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Subjects must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment
Administration of a live, attenuated vaccine within 30 days before first dose of study treatment
The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days before first dose of study treatment. Note: Inhaled, intranasal, intra-articular, or topical steroids are permitted. Adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent are permitted. Transient short-term use of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is also allowed
Active infection requiring systemic treatment. Acute or chronic hepatitis B or C infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness requiring systemic treatments, or known positive test for tuberculosis infection where there is clinical or radiographic evidence of active mycobacterial infection
History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan
Malabsorption syndrome
Uncompensated/symptomatic hypothyroidism
Moderate to severe hepatic impairment (Child-Pugh B or C)
Requirement for hemodialysis or peritoneal dialysis
History of solid organ or allogenic stem cell transplant
Other clinically significant disorders that would preclude safe study participation
Any active, known, or suspected autoimmune disease will be excluded, with the following exceptions:
Pregnant or lactating females
Inability to swallow tablets/capsules or unwillingness or inability to receive IV administration
Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded
Any other active malignancy at time of first dose of study treatment or diagnosis of another malignancy within 3 years prior to first dose of study treatment that requires active treatment, except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
Exclusion of subjects with a history of myocarditis or congestive heart failure (as defined by New York Heart Association Functional Classification III or IV), as well as unstable angina, serious uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction 6 months prior to study entry
Exclusion of subjects whose baseline pulse oximetry is less than 92% on room air
Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)