MAIN-CAV: Phase III Randomized Trial of Maintenance Cabozantinib and Avelumab vs Maintenance Avelumab After First-Line Platinum-Based Chemotherapy in Patients With Metastatic Urothelial Cancer

Plain English Summary

Testing the Addition of the Anti-cancer Drug, Cabozantinib, to the Usual Immunotherapy Treatment, Avelumab, in Patients With Metastatic Urothelial Cancer, MAIN-CAV Study is a Phase 3 clinical trial sponsored by National Cancer Institute (NCI) studying Advanced Bladder Urothelial Carcinoma, Advanced Renal Pelvis Urothelial Carcinoma, Advanced Ureter Urothelial Carcinoma, Advanced Urethral Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage III Renal Pelvis and Ureter Cancer AJCC v8. This trial compares a new combination of drugs to a standard treatment for advanced urothelial cancer. It's for patients with metastatic urothelial cancer who have already received first-line chemotherapy. Participants will receive infusions of avelumab and oral cabozantinib, and will have regular scans and blood tests. There are other treatments available, such as chemotherapy and immunotherapy. The trial aims to enroll 654 participants.

Official Summary

This phase III trial compares the effect of adding cabozantinib to avelumab versus avelumab alone in treating patients with urothelial cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cabozantinib and avelumab together may further shrink the cancer or prevent it from returning/progressing.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible patients must have advanced or metastatic urothelial cancer and have completed first-line chemotherapy. Patients must be 18 years or older and in good general health. Women of childbearing potential must have a negative pregnancy test. Patients cannot have active autoimmune diseases or certain recent surgeries. This trial is studying Advanced Bladder Urothelial Carcinoma, Advanced Renal Pelvis Urothelial Carcinoma, Advanced Ureter Urothelial Carcinoma, Advanced Urethral Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage III Renal Pelvis and Ureter Cancer AJCC v8, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcome measures survival, which means it will tell us how long patients live after starting the treatment. The specific primary outcome measures are: Overall survival (OS) (Time from randomization until death due to any cause, assessed up to 5 years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill a treatment gap by testing a new combination that may improve survival and quality of life for patients with advanced urothelial cancer. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Advanced Bladder Urothelial Carcinoma, Advanced Renal Pelvis Urothelial Carcinoma, Advanced Ureter Urothelial Carcinoma, Advanced Urethral Urothelial Carcinoma, Metastatic Bladder Urothelial Carcinoma, Metastatic Renal Pelvis Urothelial Carcinoma, Metastatic Ureter Urothelial Carcinoma, Metastatic Urethral Urothelial Carcinoma, Stage III Bladder Cancer AJCC v8, Stage III Renal Pelvis and Ureter Cancer AJCC v8, where improved treatment options are needed.

Investor Insight

The market for urothelial cancer treatments is large, with many patients needing effective new options. This trial has a good chance of success. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage. The large enrollment target of 654 participants suggests significant investment in this program.

Is This Trial Right for Me?

Ask your doctor if you have any of the conditions listed in the trial, such as advanced bladder or kidney cancer. You will need to have regular scans and blood tests, and take a new medication daily. The trial is being conducted at 20 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 654 participants

Interventions

• DRUG: Avelumab — Given IV
• PROCEDURE: Biospecimen Collection — Undergo collection of blood and urine samples
• PROCEDURE: Bone Scan — Undergo bone scan
• DRUG: Cabozantinib S-malate — Given PO
• PROCEDURE: Computed Tomography — Undergo CT

Primary Outcomes

• Overall survival (OS) (Time from randomization until death due to any cause, assessed up to 5 years)

Secondary Outcomes

• Progression free survival (PFS) (Time from randomization until disease progression as assessed by the treating physician using Response Evaluation Criteria in Solid Tumors (RECIST) or death due to any cause, assessed up to 5 years)
• Tumor response (Up to 5 years)
• Incidence of adverse events (AE) (Up to 5 years)

Full Eligibility Criteria

Inclusion Criteria:

* Histologically or cytologically-confirmed diagnosis of advanced or metastatic urothelial cancer of the renal pelvis, ureter, bladder, or urethra (transitional cell and mixed transitional/non-transitional cell histologies except for small-cell histology), including N3 only disease prior to start of first-line platinum-based chemotherapy
* Prior first-line treatment must have consisted of 4-6 cycles of 1st-line therapy (platinum-based chemotherapy; gemcitabine-cisplatin, gemcitabine-carboplatin, methotrexate, vinblastine, doxorubicin and cisplatin \[MVAC\] or dose-dense \[dd\]MVAC)
* No more than 1 line of prior chemotherapy for metastatic or locally advanced disease (neoadjuvant or adjuvant chemotherapy will be allowed if given 12 or more months prior to registration)
* Tumor objective response of CR, PR, or SD upon completion of first line platinum-based chemotherapy by treating physician's assessment
* The last dose of first-line chemotherapy must have been received no less than 3 weeks, and no more than 10 weeks, prior to randomization in the present study
* No prior immunotherapy with IL-2, IFN-alpha, or an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or CTLA-4 antibody (including ipilimumab), or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
* Age \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects
* Women of childbearing potential must have a negative pregnancy test =\< 14 days prior to registration.

  * Women of childbearing potential include women who have experienced menarche and who have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or are not postmenopausal. Post menopause is defined as amenorrhea \>= 12 consecutive months. Note: women who have been amenorrheic for 12 or more months are still considered to be of childbearing potential if the amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression or any other reversible reason
* No use of immunosuppressive medication within 7 days prior to randomization except:

  * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection);
  * Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent;
  * Steroids as premedication for hypersensitivity reactions (e.g., computed tomography \[CT\] scan premedication)
* Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
* Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
* None of the following:

  * Active autoimmune disease that might deteriorate when receiving the anti PD-L1 agent, avelumab.
  * No known symptomatic central nervous system (CNS) metastases. Patients with previously diagnosed CNS metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to randomization, have discontinued corticosteroid treatment for at least 2 weeks, and are neurologically stable. Baseline brain imaging with contrast-enhanced CT or MRI scans for subjects with known brain metastases is required to confirm eligibility.
  * No major surgery within 4 weeks prior to randomization. Subjects must have complete wound healing from surgery before randomization. Subjects with clinically relevant ongoing complications from prior surgery are not eligible.
  * No palliative radiotherapy within 48 hours prior to patient randomization.
  * No hemoptysis of ≥ 0.5 teaspoon (2.5 mL) of red blood, clinically significant hematuria, hematemesis, coagulopathy, or other history of significant bleeding (eg. Pulmonary hemorrhage) within 3 months before randomization.
  * No known cavitating pulmonary lesion(s) or known endobronchial disease manifestation.
  * No administration of a live, attenuated vaccine within 30 days prior to randomization. The use of inactivated (killed) vaccines for the prevention of infectious disease is permitted. The use of COVID-19 vaccines is permitted.
  * No uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    * Cardiovascular disorders including:

      * Congestive heart failure (CHF): New York Heart Association (NYHA) class III (moderate) or class IV (severe) at the time of screening.
      * Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) \> 150 mm Hg systolic, or \> 90 mm Hg diastolic despite optimal antihypertensive treatment.
      * The patient has a known history of corrected QT interval calculated by the Fridericia formula (QTcF) \> 50

Trial Locations

• Mayo Clinic Hospital in Arizona, Phoenix, Arizona, United States
• Sutter Auburn Faith Hospital, Auburn, California, United States
• Alta Bates Summit Medical Center-Herrick Campus, Berkeley, California, United States
• Palo Alto Medical Foundation-Fremont, Fremont, California, United States
• Memorial Medical Center, Modesto, California, United States
• Palo Alto Medical Foundation-Camino Division, Mountain View, California, United States
• Palo Alto Medical Foundation Health Care, Palo Alto, California, United States
• Sutter Roseville Medical Center, Roseville, California, United States
• Sutter Medical Center Sacramento, Sacramento, California, United States
• University of California Davis Comprehensive Cancer Center, Sacramento, California, United States
• ...and 10 more locations

Frequently Asked Questions

Related Conditions

• Advanced Bladder Cancer
• Renal Pelvis Cancer
• Ureter Cancer
• Urethral Cancer
• Metastatic Urothelial Cancer
• Stage III Bladder Cancer
• Stage III Renal Pelvis and Ureter Cancer

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