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Testing the Addition of the Anti-cancer Drug, Cabozantinib, to the Usual Immunotherapy Treatment, Avelumab, in Patients With Metastatic Urothelial Cancer, MAIN-CAV Study

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ClinicalTrials.gov Identifier: NCT05092958
Recruitment Status : Recruiting
First Posted : October 26, 2021
Last Update Posted : March 17, 2023
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief 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 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.

Condition or disease Intervention/treatment Phase
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 Drug: Avelumab Drug: Cabozantinib S-malate Other: Quality-of-Life Assessment Other: Questionnaire Administration Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 654 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : March 10, 2022
Estimated Primary Completion Date : December 10, 2024
Estimated Study Completion Date : December 10, 2024

Arm Intervention/treatment
Active Comparator: Arm A (avelumab)
Patients receive avelumab 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Experimental: Arm B (avelumab, cabozantinib)
Patients receive avelumab IV over 60 minutes on days 1 and 15 of each cycle and cabozantinib 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.
Drug: Avelumab
Given IV
Other Names:
  • Bavencio
  • MSB-0010718C
  • MSB0010718C

Drug: Cabozantinib S-malate
Given PO
Other Names:
  • BMS-907351
  • Cabometyx
  • Cometriq
  • XL-184
  • XL184

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Other: Questionnaire Administration
Ancillary studies

Primary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Time from randomization until death due to any cause, assessed up to 5 years ]
    Subgroup analyses will be done using a stratified Cox model that includes the treatment arm assignment as an explanatory variable and a separate model will be generated for each level for the subgroup of interest.

Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: 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 ]
    A stratified Cox model will be used to compare the outcomes between the two treatment groups. The subgroup analyses will be done using a stratified Cox model that includes the treatment arm assignment as an explanatory variable and a separate model will be generated for each level for the subgroup of interest.

  2. Tumor response [ Time Frame: Up to 5 years ]
    Will be defined as a complete response or partial response (PR) as measured with Immune-Modified RECIST. Will be compared between the arms using a Mantel-Haenszel test (that accounts for the randomization stratification factors) comparing the response rates between the two treatment arms. This analysis will only include patients who had a PR or stable disease (SD) response to first-line therapy. An additional analysis will be conducted using logistic regression analysis that includes treatment arm and any baseline variables that are imbalanced between the arms as explanatory variable.

  3. Incidence of adverse events (AE) [ Time Frame: Up to 5 years ]
    Will be assessed by Common Terminology Criteria for Adverse Events 5.0. Will be summarized with frequencies and relative frequencies. The maximum grade for an AE will be recorded for each patient by treatment arm. The number (percent) of patients that experience each observed adverse event will be summarized by treatment arm. In addition, the proportion of patients that experience a grade 3+, grade 4+, and grade 5 adverse event will be summarized as the number and percent of patients by treatment arm. The primary summary will be regardless of attribution. Will also do an analogous summary for the adverse events that were deemed at least possibly related to treatment.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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
  • 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:

  • Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent
  • 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
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05092958

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Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Shilpa Gupta Alliance for Clinical Trials in Oncology
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT05092958    
Other Study ID Numbers: NCI-2021-11166
NCI-2021-11166 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
A032001 ( Other Identifier: Alliance for Clinical Trials in Oncology )
A032001 ( Other Identifier: CTEP )
U10CA180821 ( U.S. NIH Grant/Contract )
First Posted: October 26, 2021    Key Record Dates
Last Update Posted: March 17, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Urethral Neoplasms
Ureteral Neoplasms
Pelvic Neoplasms
Kidney Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Urethral Diseases
Ureteral Diseases
Kidney Diseases
Antibodies, Monoclonal
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs