Dose Finding Study of CBM588 in Combination With Nivolumab/Ipilimumab in 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 is a single arm open-label phase 1 study evaluating the safety and efficacy of escalating doses of CBM588 in combination with nivolumab and ipilimumab. A standard 3+3 dose escalation schema will be used initially to assess the maximum tolerated dose (MTD) followed by a dose expansion of 10 patients at the MTD to further evaluate safety and efficacy.

Study Overview

• Status: Recruiting
• Conditions: Advanced or Metastatic Renal Cell Carcinoma
• Intervention / Treatment: Biological: CBM588 Capsules; Biological: Nivolumab; Biological: Ipilimumab

Detailed Description

This protocol is a phase I open-label, single institution, dose escalation study designed to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of CBM588 in combination with nivolumab and ipilimumab in patients with previously untreated advanced or metastatic renal cell carcinoma.

The dose escalation phase of the trial will be conducted using a standard 3+3 dose-escalation design to determine the MTD or RP2D. In addition to prespecified dose escalation levels of CBM588, which will be given twice a day continuously, all patients will receive standard of care treatment with nivolumab (3 mg/kg IV every 3 weeks for 4 cycles, followed by 480 IV every 4 weeks) and ipilimumab (1 mg/kg IV q3wks for 4 cycles. At each dose level 3-6 patients will be enrolled based on the decision rule of 3+3 dose-escalation design. Initially, 3 patients are enrolled into the starting dose cohort. If no dose limiting toxicity (DLT) is observed in any of these subjects, the trial proceeds to enroll subjects into the next higher dose cohort. If one subject develops a dose limiting toxicity (DLT) at a specific dose, an additional three subjects are enrolled into that same dose cohort. Development of DLTs in more than 1 of 6 subjects in a specific dose cohort suggests that the MTD has been exceeded, and no further dose escalation is pursued.

Once the MTD is determined, a dose expansion phase will be conducted by enrolling 10 additional patients at the MTD to further evaluate that dose for safety and clinical efficacy endpoints.

• Study Type: Interventional
• Enrollment (Estimated): 28
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Alexander Chehrazi-Raffle, M.D.; Phone Number: (626) 256-4772; Email: achehraziraffle@coh.org
• Study Contact Backup: Name: Sumanta K. Pal, M.D.; Phone Number: (626) 256-4673; Email: spal@coh.org

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Principal Investigator: Alexander Chehrazi-Raffle, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Informed Consent and Willingness to Participate

1. Documented informed consent of the participant and/or legally authorized representative.
2. Agreement to allow the use of archival tissue from diagnostic tumor biopsies Age Criteria, Performance status
3. ECOG ≤ 2
4. Age ≥ 18 years Nature of Illness and Illness Related Criteria
5. Histologically confirmed renal cell carcinoma with clear cell renal cell carcinoma component or sarcomatoid component.
6. Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) renal cell carcinoma with intermediate- or poor-risk disease by IMDC criteria

7. No prior systemic therapy for RCC with the following exception:

   i. One prior adjuvant or neoadjuvant therapy for completely resectable RCC if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.

8. Measurable disease by RECIST 1.1
9. Fully recovered from the acute toxic effects (except alopecia) to ≤ Grade 1 to prior anti-cancer therapy Clinical Laboratory and Organ Function Criteria
10. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.
11. White blood cell count ≥ 2500/µL.
12. Platelets ≥ 100,000/µL without transfusion.
13. Hemoglobin ≥ 8 g/dL
14. 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.
15. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN).
16. Serum albumin ≥ 2.8 g/dl.
17. (PT)/INR or partial thromboplastin time (PTT) test < 1.3 x the laboratory ULN
18. Serum calculated creatinine clearance ≥ 50mL/min using the Cockcroft-Gault equation: i. Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72) ii. Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85 Contraception
19. 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.
20. 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 and concomitant therapies and supplements

1. Prior treatment with ipilimumab and/or nivolumab
2. Current use, or intent to use, probiotics, yogurt, or bacterial fortified foods during the period of treatment. Other illnesses or conditions
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent
4. Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitis requiring treatment with systemic steroids
5. 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.
6. Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
7. 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.

8. 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.

9. Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

10. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: i. 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. ii. 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. iii. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan. iv. Malabsorption syndrome. v. Uncompensated/symptomatic hypothyroidism. vi. Moderate to severe hepatic impairment (Child-Pugh B or C). vii. Requirement for hemodialysis or peritoneal dialysis. viii. History of solid organ or allogenic stem cell transplant ix. Other clinically significant disorders that would preclude safe study participation: 1). Any active, known, or suspected autoimmune disease will be excluded, with the following exceptions:

    1. Type 1 diabetes mellitus.
    2. Hypothyroidism only requiring hormone replacement.
    3. Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment.
    4. Conditions not expected to recur in the absence of an external trigger.
11. Pregnant or lactating females.
12. Inability to swallow tablets/capsules or unwillingness or inability to receive IV administration.

13. 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.

14. 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.
15. 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.
16. Exclusion of subjects whose baseline pulse oximetry is less than 92% on room air
17. 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. Noncompliance
18. 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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CBM588 Capsules; This will be a dose escalation study of CBM588 oral capsules at two potencies in combination with nivolumab and ipilimumab dual immune checkpoint therapy: 1x Capsule containing 4.0E+8 CFU/capsule; and 10x Capsule containing 4.0E+9 CFU/capsule. The dose escalation will begin with one 1x Capsule administered twice a day followed by three 1x Capsules b.i.d., and then one 10x Capsule b.i.d. until disease progression or dose limiting toxicity occurs.

Biological: CBM588 Capsules; CBM588 Capsule is a live biotherapeutic product (LBP) containing Clostridium butyricum MIYAIRI 588, a single strain of butyric acid producing bacteria, in a HPMC capsule. CBM588 Capsules are administered orally at different dosage levels twice a day until disease progression or dose limiting toxicity occurs.; Other Names: CBM588, Clostridium butyricum MIYAIRI 588, Live Biotherapeutic Product (LBP); Biological: Nivolumab; Nivolumab is an immunotherapy containing a fully human monoclonal antibody that blocks programmed cell death protein 1 (PD-1), a protein receptor that functions as an immune checkpoint and downregulates immune responses. Nivolumab will be administered at a dose of 3 mg/kg intravenously prior to administration of ipilimumab for the first 4 cycles (every 3 weeks) followed by dosing at 480 mg every 4 weeks.; Other Names: Opdivo, MDX-1106/ONO-4538; Biological: Ipilimumab; Ipilimumab is an immunotherapy containing a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte associated protein 4 CTLA-4, a protein receptor that functions as an immune checkpoint and downregulates immune responses. Ipilimumab will be administered after nivolumab administration, at a dose of 1 mg/kg intravenously for only the first 4 cycles (every 3 weeks), then it will be discontinued.; Other Names: Yervoy, MDX010

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To determine the number of participants with treatment-related dose limiting toxicity (DLT) of CBM588 at each dose level in combination with nivolumab/ipilimumab.	The number of participants with treatment-related adverse events at each dose level will be determined according to NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. At the end of DLT period, the Cohort Review Committee will review all available safety data for cohorts containing at least 3 subjects and dose escalation to the next cohort may proceed if 0 out of 3 subjects or ≤ 1 out of 6 subjects experience(s) a DLT. The maximal tolerated dose (MTD) estimate is the highest dose of CBM588 in combination with nivolumab/ipilimumab associated with the occurrence of DLTs in no more than 1 out of 6 of the patients.	28 days
To determine the number of participants with treatment-related adverse events of CBM588 given concurrently with nivolumab/ipilimumab as assessed by CTCAE v5.0.	Safety evaluation will be based on all patients that received at least one dose of the drug and will include AEs, SAEs, and changes from baseline in laboratory evaluations, vital signs, and physical examinations. Summaries will be provided overall and by dose group. The number and percentage of subjects reporting treatment-emergent AEs (TEAE) will be summarized overall and by the worst CTCAE grade, with a breakdown by dose.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	PFS is defined as the duration of time from start of treatment to time of progressive disease (as defined below) or death, whichever occurs first. Evaluation of Target Lesions: Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.	12 weeks
Best overall response rate (ORR)	Patients are re-evaluated for response every 12 weeks. Response and progression will be evaluated in this study using the new international criteria proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.	12 weeks
Effects on microbiome - Shannon diversity index	Change in stool microbial diversity: the Shannon index will be computed from metagenomic sequence data of stool samples collected at baseline and at week 12 for a comparison of microbial diversity at these two timepoints.	12 weeks
Effects on microbiome - Genera and species abundance	Changes in abundancies of gut microbiome species: whole metagenome sequencing and analysis will be conducted to provide detailed taxonomic composition of the stool microbiome at baseline and 12 weeks post-therapy. Genera and species that increase or decrease in abundance will be compared.	12 weeks
Effects on microbiome - Metabolic pathways	Changes in microbiome metabolic pathways will be analyzed using metagenomic sequence data from stool samples collected at baseline and week 12. Pathways that increase or decrease will be compared.	12 weeks
Effects on microbiome - Short chain fatty acid levels	Changes in serum butyrate levels and other short chain fatty acids will be assessed graphically across serial timepoints of blood collection to ascertain trends.	12 weeks
Effects on systemic immunomodulation - T regulatory cells and myeloid-derived suppressor cells	The proportion of circulating T regulatory cells (Tregs) and myeloid-derived suppressor cells (MDSCs) will be compared across serial timepoints of blood collection to ascertain trends.	12 weeks
Effects on systemic immunomodulation - Cytokine/chemokine levels	Comparison of IL-6, IL-8 and other cytokines/chemokines will be assessed graphically across serial timepoints of blood collection to ascertain any trends.	12 weeks

Collaborators and Investigators

• Sponsor: Osel, Inc.
• Collaborators: City of Hope Comprehensive Cancer Center; Miyarisan Pharmaceutical Co., Ltd.
• Investigators: Principal Investigator: Alexander Chehrazi-Raffle, M.D., City of Hope Medical Center

Publications and helpful links

General Publications

• 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.
• Tomita Y, Ikeda T, Sakata S, Saruwatari K, Sato R, Iyama S, Jodai T, Akaike K, Ishizuka S, Saeki S, Sakagami T. Association of Probiotic Clostridium butyricum Therapy with Survival and Response to Immune Checkpoint Blockade in Patients with Lung Cancer. Cancer Immunol Res. 2020 Oct;8(10):1236-1242. doi: 10.1158/2326-6066.CIR-20-0051. Epub 2020 Jul 14.
• Tomita Y, Goto Y, Sakata S, Imamura K, Minemura A, Oka K, Hayashi A, Jodai T, Akaike K, Anai M, Hamada S, Iyama S, Saruwatari K, Saeki S, Takahashi M, Ikeda T, Sakagami T. Clostridium butyricum therapy restores the decreased efficacy of immune checkpoint blockade in lung cancer patients receiving proton pump inhibitors. Oncoimmunology. 2022 May 27;11(1):2081010. doi: 10.1080/2162402X.2022.2081010. eCollection 2022.
• Tomita Y, Sakata S, Imamura K, Iyama S, Jodai T, Saruwatari K, Hamada S, Akaike K, Anai M, Fukusima K, Takaki A, Tsukamoto H, Goto Y, Motozono C, Sugata K, Satou Y, Ueno T, Ikeda T, Sakagami T. Association of Clostridium butyricum Therapy Using the Live Bacterial Product CBM588 with the Survival of Patients with Lung Cancer Receiving Chemoimmunotherapy Combinations. Cancers (Basel). 2023 Dec 21;16(1):47. doi: 10.3390/cancers16010047.
• Paz Del Socorro T, Oka K, Boulard O, Takahashi M, Poulin LF, Hayashi A, Chamaillard M. The biotherapeutic Clostridium butyricum MIYAIRI 588 strain potentiates enterotropism of Rorgammat+Treg and PD-1 blockade efficacy. Gut Microbes. 2024 Jan-Dec;16(1):2315631. doi: 10.1080/19490976.2024.2315631. Epub 2024 Feb 22.

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: April 29, 2024
• First Submitted That Met QC Criteria: May 9, 2024
• First Posted (Estimated): May 15, 2024

Study Record Updates

• Last Update Posted (Estimated): May 15, 2024
• Last Update Submitted That Met QC Criteria: May 9, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: Nivolumab; Ipilimumab; Gut Microbiome; Renal Cell Carcinoma; Phase 1 Clinical Trial; Immune Checkpoint Inhibitor; Live Biotherapeutic Product; Advanced Kidney Cancer; CBM588 Capsules; Clostridium butyricum MIYAIRI 588; Dose Escalation Trial
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Carcinoma, Renal Cell; Carcinoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab; Ipilimumab
• Other Study ID Numbers: 23554 (Other Identifier: City of Hope Comprehensive Cancer Center)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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