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

  • End date
    Dec 10, 2024
  • participants needed
  • sponsor
    National Cancer Institute (NCI)
Updated on 24 October 2022


This phase III trial compares the effect of adding cabozantinib to avelumab versus avelumab alone in treating patients with urothelial cancer that has spread 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.



I. To evaluate the effect of cabozantinib S-malate (cabozantinib) in combination with avelumab on overall survival (OS) compared to avelumab alone in patients with metastatic urothelial cancer (mUC) who did not progress during first-line platinum-based chemotherapy therapy, i.e. patients who had complete response (CR), partial response (PR) or stable disease (SD) after completion of first line platinum-based chemotherapy.


I. To evaluate the effect of cabozantinib in combination with avelumab on progression-free survival (PFS) compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy.

II. To evaluate the safety and tolerability of cabozantinib in combination with avelumab in mUC compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy.

III. To evaluate activity of cabozantinib in combination with avelumab based on Response Evaluation Criteria in Solid Tumors (RECIST) compared to avelumab alone for maintenance treatment following initial first-line treatment in patients who had a CR, PR or SD upon completion of first-line platinum-based chemotherapy.

IV. Results of the primary analysis will be examined for consistency, while accounting for the stratification factors and/or covariates of baseline quality of life (QOL) and fatigue.

V. To evaluate the activity of cabozantinib in combination with avelumab compared to avelumab alone based on PD-L1 status of patients' tumors.


I. To compare quality-adjusted survival between patients randomized to receive cabozantinib and avelumab versus (vs.) avelumab alone using the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L).

II. To compare patient-reported fatigue as assessed by the Patient Reported Outcomes Measurement Information System (PROMIS)-Fatigue 4a from baseline through 12 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone.

III. To compare patient-reported global health status/quality of life as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-Core (C)30 from baseline through 12 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone.

IV. To compare scale scores of the EORTC QLQ-Bladder Cancer Muscle-Invasive (BLM)30 (urinary symptoms, urostomy problems, catheter problems, future perspectives, abdominal bloating and flatulence, body image, sexual function) at 3, 6, 12, 18, and 24 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone.

V. To compare scale scores of the EORTC QLQ-C30 (global health status/quality of life; physical, role, emotional, cognitive, and social function; symptoms) at 3, 6, 12, 18, and 24 months between patients randomized to receive cabozantinib and avelumab vs. avelumab alone.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive avelumab intravenously (IV) over 60 minutes on days 1 and 15 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive avelumab IV over 60 minutes on days 1 and 15 of each cycle and cabozantinib orally (PO) daily on days 1-28 of each cycle. Cycles repeat every 28 days for 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 30 days through 90 days, then every 3 months for 5 years.

Condition 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, Stage III Renal Pelvis Cancer AJCC v8, Stage III Ureter Cancer AJCC v8, Stage III Urethral Cancer AJCC v8, Stage IV Bladder Cancer AJCC v8, Stage IV Renal Pelvis and Ureter Cancer AJCC v8, Stage IV Renal Pelvis Cancer AJCC v8, Stage IV Ureter Cancer AJCC v8, Stage IV Urethral Cancer AJCC v8
Treatment questionnaire administration, quality-of-life assessment, Avelumab, Cabozantinib S-malate
Clinical Study IdentifierNCT05092958
SponsorNational Cancer Institute (NCI)
Last Modified on24 October 2022


Yes No Not Sure

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
Patients with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible
Absolute neutrophil count (ANC) >= 1,000/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 8 g/dL
Calculated (Calc.) creatinine clearance >= 30 mL/min using the Cockcroft-Gault equation: (140 - age) × weight (kg)/(serum creatinine [mg/dL] × 72)
Total serum bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x ULN (or =< 5 x ULN for patients with liver metastases or Gilbert's disease)
Urine protein creatinine (UPC) ratio =< 1 or 24-hour protein < 1 g

Exclusion Criteria

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 magnetic resonance imaging (MRI) scans for subjects with known brain metastases is required to confirm eligibility
Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
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 (e.g. 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) > 500 ms and confirmed by electrocardiogram (ECG) within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is =< 500 ms, the subject meets eligibility in this regard
Any history of congenital long QT syndrome
Stroke, transient ischemic attack (TIA), myocardial infarction, or other symptomatic ischemic event or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism (DVT/PE) within 6 months before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if asymptomatic and stable at screening and treated with low molecular weight heparin (LMWH) or the direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban for at least 1 week before randomization. Non-symptomatic white matter disease in the brain is acceptable
No significant gastrointestinal disorders, particularly those associated with a
high risk of perforation or fistula formation including unresolved active
peptic ulcer disease, cholecystitis, diverticulitis, symptomatic cholangitis
or appendicitis, or malabsorption syndrome within 28 days of randomization
No other clinically significant disorders such as
Any active infection requiring systemic treatment within 14 days before randomization. Subjects receiving oral (including prophylactic) antibiotics with no symptoms of infection at randomization are eligible
Serious non-healing wound/ulcer/bone fracture within 28 days before randomization
History of organ or allogeneic stem cell transplant
No persisting toxicity related to prior therapy grade > 2 constituting a safety
risk based on the investigator's judgment
No diagnosis of any other malignancy within 3 years prior to randomization, except for locally curable cancers that have been adequately treated such as basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, Gleason < 7 prostate cancer on surveillance without any plans for treatment intervention (e.g., surgery, radiation, or castration), or prostate cancer that has been adequately treated with prostatectomy or radiotherapy and currently with no evidence of disease or symptoms and no indication for treatment
No concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel)
Allowed anticoagulants are the following
Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
Physicians should consider whether any of the following may render the patient
inappropriate for this protocol
Psychiatric illness which would prevent the patient from giving informed consent
Uncontrolled medical conditions which, in the opinion of the treating physician, would make this protocol unreasonably hazardous for the patient
Patients who cannot swallow oral formulations of the agent(s)
In addition
Women and men of reproductive potential should agree to use an appropriate method of birth control throughout their participation in this study due to the teratogenic potential of the therapy utilized in this trial. Include as applicable: Appropriate methods of birth control include abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)
Patients with rheumatoid arthritis and other rheumatologic arthropathies, Sjogren's syndrome and psoriasis controlled with topical medication and or steroids equivalent to < 10 mg prednisone daily, not on immunosuppressive medications and patients with positive serology are eligible. Patients with vitiligo, endocrine deficiencies including hypo or hyper thyroid disease managed with replacement, diabetes type 1 are eligible
Sexually active subjects (men and women) must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the study and continue for 4 months after the last dose of study drugs, even if oral contraceptives are also used
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