Phase III Double Blinded Trial of Immune-Based Therapy With a Live Biotherapeutic MO-03 or Placebo for Frontline Therapy of Advanced Clear Cell Renal Cell Carcinoma [BioFront Trial]

Official Summary

This phase III trial compares the effect of adding live biotherapy, MO-03, to standard of care (SOC) immunotherapy, including ipilimumab, nivolumab, axitinib, pembrolizumab, cabozantinib, and lenvatinib, to SOC immunotherapy alone in treating patients with clear cell renal cell cancer that may have spread from where it first started (primary site) to nearby tissue, lymph nodes, or distant parts of the body (advanced) or that has spread from where it first started to other places in the body (metastatic). Studies have shown that gut health (the gut microbiome) may impact the effectiveness of immunotherapy. The microbiome includes all of the bacteria and organisms naturally found in the digestive tract. MO-03, a type of biotherapy, contains material from living organisms that may help keep the digestive tract healthy and may help to increase the effect of immunotherapy. Immunotherapy with monoclonal antibodies, such as ipilimumab, nivolumab, pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Axitinib, cabozantinib, and lenvatinib are a type of angiogenesis inhibitor and tyrosine kinase inhibitor (TKI) that block certain proteins which may help keep tumor cells from growing and may also help prevent the growth of new blood vessels that tumors need to grow. Adding MO-03 to SOC immunotherapy may be more effective than SOC immunotherapy alone in treating patients with advanced or metastatic clear cell renal cell cancer.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: DOUBLE
• Enrollment: 718 participants

Study Arms

• Arm 1 (MO-03, SOC immunotherapy) (EXPERIMENTAL)
  See Detailed Description
• Arm 2 (placebo, SOC immunotherapy) (PLACEBO_COMPARATOR)
  See Detailed Description

Interventions

• DRUG: Axitinib — Given PO
• PROCEDURE: Biospecimen Collection — Undergo blood sample collection
• PROCEDURE: Bone Scan — Undergo bone scan
• DRUG: Cabozantinib — Given PO
• DRUG: Clostridium butyricum CBM 588 Probiotic Strain — Given PO

Primary Outcomes

• Progression-free survival (PFS) (From date of randomization to date of first documentation of progression, or death due to any cause, assessed up to 5 years)

Secondary Outcomes

• Incidence of adverse events (AEs) (Safety run-in) (During the first 12 weeks (2 cycles [cycle length =42 days]))
• Overall survival (From date of randomization to date of death due to any cause, assessed up to 5 years)
• PFS rates between the study arms (At 12 and 24 months)
• Incidence of AEs between study arms (Up to 90 days after last dose of study treatment)

Eligibility Criteria

Inclusion Criteria:

* Participants must have histologically confirmed renal cell carcinoma (RCC) with clear cell component that is advanced (not amenable to curative surgery or radiation therapy) or metastatic RCC at the time of registration on study
* Participants must have measurable/evaluable disease by RECIST 1.1 criteria. Participants with only bone metastases or only pleural effusions are considered evaluable disease and are eligible
* Participants with new or progressive brain metastases (active brain metastases) or leptomeningeal disease must not require immediate central nervous system (CNS) specific treatment at the time of study registration or anticipated treatment during the first cycle of therapy
* Participants must not be currently enrolled or plan to participate in treatment studies while enrolled on this study
* Participants must not plan to take any over the counter probiotic supplements at time of study registration and while on protocol treatment

  * NOTE: Vitamin and electrolyte or mineral supplements are permitted
* Participants must not have had prior systemic therapy for advanced or metastatic RCC or any treatment with immune based combination therapy

  * NOTE: Participants can have prior neo/adjuvant treatment with an anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 antibody or other therapies for any current or prior malignancy if \> 12 months prior to registration
* Participants must not be receiving steroid replacement therapy for adrenal insufficiency greater than 50 mg daily of hydrocortisone or prednisone equivalent dose at the time of registration
* Participants must not require the use of systemic corticosteroids \> 10 mg/day of prednisone or its equivalent for any reason other than replacement therapy for adrenal insufficiency
* Participants must not have received any systemic antibiotics within 7 days prior to registration

  * NOTE: Uncontrolled infections must be completely resolved
* Participants must be ≥ 18 years old at the time of registration
* Participants must have a Zubrod performance status 0-2 within 28 days of registration
* Participants must be able to safely receive at least one of the standard of care regimens, per the current Food and Drug Administration (FDA)-approved package inserts, treating investigator's discretion, and institutional guidelines

  * NOTE: Participants with favorable risk as defined by the International Metastatic RCC Database Consortium (IMDC) must plan to receive one of the TKI+ immunotherapy treatment combinations. They are not able to receive regimen 1 (ipilimumab + nivolumab) for this study
* Participants must be able to swallow and retain oral medications and have no known gastrointestinal disorders likely to interfere with absorption of oral medications
* Participants must have serum creatinine ≤ 2 x ULN (upper limit of normal). This specimen must have been drawn and processed within 28 days prior to registration
* Hemoglobin ≥ 8 g/dL (within 28 days prior to registration)
* Leukocytes ≥ 3 x 10\^3/uL (within 28 days prior to registration)
* Absolute neutrophil count ≥ 1.5 x 10\^3/uL (within 28 days prior to registration)
* Platelets ≥ 100 x 10\^3/uL (within 28 days prior to registration)
* Total bilirubin ≤ institutional upper limit of normal (ULN) unless history of Gilbert's disease (within 28 days prior to registration) Participants with history of Gilbert's disease must have total bilirubin ≤ 5 x institutional ULN
* Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3 x institutional ULN (\< 5 x institutional ULN if liver metastases are present) (within 28 days prior to registration)
* Participants must have alkaline phosphate measured as a part of the liver function assessment within 28 days prior to registration
* Participants must have albumin corrected calcium measured within 28 days prior to registration
* Participants with a history human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load on the most recent test results obtained within 6 months prior to registration
* Participants with a history of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration
* Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration
* Participants must not have uncontrolled blood pressure and hypertension within 28 days prior to registration
* Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
* Participants must not have

Study Officials

• Pedro Barata — PRINCIPAL_INVESTIGATOR
  SWOG Cancer Research Network

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