CBM588, Nivolumab, and Ipilimumab in Treating Patients With Stage IV or Advanced Kidney Cancer

NCT ID: NCT03829111

Last Updated: 2024-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-05-14
• Study Completion Date: 2023-12-13

Brief Summary

This phase I trial studies how well CBM588 works when given together with nivolumab and ipilimumab in treating patients with kidney cancer that is stage IV or has spread to other places in the body (advanced). CBM588 is a probiotic that may help to increase the effect of immunotherapy. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving CBM588, nivolumab, and ipilimumab may work better in treating patients with kidney cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the effect of clostridium butyricum CBM 588 probiotic strain (CBM588) (in combination with nivolumab/ipilimumab) on the gut microbiome in patients with metastatic renal cell carcinoma (mRCC).

SECONDARY OBJECTIVES:

I. To evaluate the effect of CBM588 on the clinical efficacy of the nivolumab/ipilimumab combination.

II. To assess the effect of CBM588 on systemic immunomodulation of the nivolumab/ipilimumab combination in patients with mRCC.

III. To assess the effect of CBM588 on toxicities such as diarrhea and nausea using Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 criteria with the nivolumab/ipilimumab combination in patients with mRCC.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive clostridium butyricum CBM 588 probiotic strain orally (PO) twice daily (BID), nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, treatment with clostridium butyricum CBM 588 probiotic strain and nivolumab repeats every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and periodically thereafter.

Conditions

Advanced Renal Cell Carcinoma; Clear Cell Renal Cell Carcinoma; Metastatic Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v8; Stage IV Renal Cell Cancer AJCC v8; Unresectable Renal Cell Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm I (nivolumab, ipilimumab)

Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, patients receive nivolumab IV over 30 minutes on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: ACTIVE_COMPARATOR

Ipilimumab

Intervention Type: BIOLOGICAL

Given IV

Nivolumab

Intervention Type: BIOLOGICAL

Given IV

Arm II (CBM588, nivolumab, ipilimumab)

Patients receive clostridium butyricum CBM 588 probiotic strain PO BID, nivolumab IV over 30 minutes on day 1, and ipilimumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Beginning in cycle 5, treatment with clostridium butyricum CBM 588 probiotic strain and nivolumab repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Group Type: EXPERIMENTAL

Clostridium butyricum CBM 588 Probiotic Strain

Intervention Type: DRUG

Given PO

Ipilimumab

Intervention Type: BIOLOGICAL

Given IV

Nivolumab

Intervention Type: BIOLOGICAL

Given IV

Interventions

Clostridium butyricum CBM 588 Probiotic Strain

Given PO

Intervention Type: DRUG

Ipilimumab

Given IV

Intervention Type: BIOLOGICAL

Nivolumab

Given IV

Intervention Type: BIOLOGICAL

Other Intervention Names

C. butyricum CBM 588 Probiotic Strain; C. butyricum MIYAIRI Strain; C. butyricum Strain MIYAIRI 588; CBM 588; CBM588; Clostridium butyricum MIYAIRI 588; Clostridium butyricum MIYAIRI 588 Probiotic Strain; MIYAIRI 588; MIYAIRI 588 Strain of C. butyricum; Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody; BMS-734016; MDX-010; MDX-CTLA4; Yervoy; BMS-936558; MDX-1106; NIVO; ONO-4538; Opdivo

Eligibility Criteria

Inclusion Criteria

• Be willing and able to provide informed consent for the trial
• Histological confirmation of RCC with a clear-cell component
• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) RCC
• Intermediate or poor risk disease by International Metastatic RCC Database Consortium (IMDC) classification
• No prior systemic therapy for RCC with the following exception:

• One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets PD-1 or PD-L1 and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Any ethnicity or race
• Calculated creatinine clearance >= 30 milliliters per minute (mL/min) per the Cockcroft and Gault formula or serum creatinine < 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN if liver metastases are present)
• Total bilirubin < 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin up to 3.0 mg/dL)
• White blood cells (WBC) > 2,000/mm^3
• Neutrophils > 1,500/mm^3
• Platelets > 100,000/mm^3

Exclusion Criteria

• Presence of untreated brain metastases. Patients with treated brain metastases must be stable for 4 weeks after completion of treatment and have documented stability on pre-study imaging. Patients must have no clinical symptoms from brain metastases and have no requirement for systemic corticosteroids amounting to > 10 mg/day of prednisone or its equivalent for at least 2 weeks prior to first dose of study drug. Patients with known leptomeningeal metastases are excluded, even if treated

• Not recovered to =< grade 1 toxicities related to any prior therapy before administration of study drug
• Favorable risk disease by IMDC classification
• Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
• Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll
• Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitis requiring treatment with systemic steroids
• Baseline pulse oximetry less than 92% "on room air"
• Current use, or intent to use, probiotics, yogurt or bacterial fortified foods during the period of treatment
• Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease
• Uncontrolled adrenal insufficiency
• 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
• Not recovered to =< grade 1 toxicities related to any prior therapy before administration of study drug
• Women who are pregnant or breastfeeding
• 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
• White blood cells (WBC) < 2,000/mm^3
• Neutrophils < 1,500/mm^3
• Platelets < 100,000/mm^3
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 x upper limit of normal (ULN) (> 5 x ULN if liver metastases are present)
• Total bilirubin > 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin 3.0 mg/dL)
• Calculated creatinine clearance < 30 millimeters per minute (mL/min) per the Cockcroft and Gault formula or serum creatinine > 1.5 x upper limit of normal (ULN)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

City of Hope Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Sumanta K Pal

Role: PRINCIPAL_INVESTIGATOR

City of Hope Medical Center

Locations

City of Hope Medical Center

Duarte, California, United States

Countries

United States

References

Villemin C, Six A, Neville BA, Lawley TD, Robinson MJ, Bakdash G. The heightened importance of the microbiome in cancer immunotherapy. Trends Immunol. 2023 Jan;44(1):44-59. doi: 10.1016/j.it.2022.11.002. Epub 2022 Dec 1.

Reference Type: DERIVED

PMID: 36464584 (View on PubMed)

Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, Frankel P, Cui Y, Mira V, Llamas M, Hsu J, Zengin Z, Salgia N, Salgia S, Malhotra J, Chawla N, Chehrazi-Raffle A, Muddasani R, Gillece J, Reining L, Trent J, Takahashi M, Oka K, Higashi S, Kortylewski M, Highlander SK, Pal SK. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022 Apr;28(4):704-712. doi: 10.1038/s41591-022-01694-6. Epub 2022 Feb 28.

Reference Type: DERIVED

PMID: 35228755 (View on PubMed)

Other Identifiers

NCI-2019-00248

Identifier Type: REGISTRY

Identifier Source: secondary_id

18523

Identifier Type: OTHER

Identifier Source: secondary_id

P30CA033572

Identifier Type: NIH

Identifier Source: secondary_id

View Link

18523

Identifier Type: -

Identifier Source: org_study_id