Study of CAbozantinib in Combination With AtezolizumaB for Muscle-Invasive BladdEr Cancer (ABATE)

  • STATUS
    Recruiting
  • End date
    May 17, 2024
  • participants needed
    42
  • sponsor
    Deepak Kilari
Updated on 7 October 2022
radical cystectomy
cancer
white blood cell count
carcinoma
gilbert's syndrome
metastasis
neutrophil count
g-csf
aptt
bladder cancer
invasive bladder cancer
transitional cell carcinoma
transurethral resection
atezolizumab
bladder tumor

Summary

This is an open-label phase II study assessing the activity of cabozantinib combined with atezolizumab in patients with resectable muscle-invasive urothelial carcinoma who are ineligible for cisplatin-based therapy or decline cisplatin-based therapy. Each cycle equals 21 days. The dose of atezolizumab is 1200 mg IV flat dose every 3 weeks (Day 1) plus cabozantinib 40 mg orally daily (Day 1 through Day 21). Patients will receive three cycles of treatment prior to cystectomy unless they discontinue treatment for unacceptable toxicity or progressive disease by RECIST v1.1 or withdraw consent.

Details
Condition Bladder Cancer
Treatment Cabozantinib, Atezolizumab, Cystectomy
Clinical Study IdentifierNCT04289779
SponsorDeepak Kilari
Last Modified on7 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately
Age ≥18 years at the time of consent
ECOG Performance Status of ≤ 2 within 28 days prior to registration
Histological or cytologically confirmed muscle-invasive urothelial carcinoma of the bladder. Urothelial carcinoma invading into the prostatic stroma with no histologic muscle-invasion is allowed
Archival tissue is required, if available. The tissue should be identified at screening and shipped after registration, prior to Cycle 3 Day 1. If archival tissue is not available a repeat biopsy is not required, and the subject may still be eligible. Archival tissue should have been obtained within 60 days prior to registration
Urothelial carcinoma should be the predominant component (≥ 50%). NOTE: Any neuroendocrine differentiation is not permitted
Clinical stage T2-T4aN0/xM0 disease
No clinical or radiographic evidence for locally advanced or metastatic disease
Medically appropriate candidate for radical cystectomy as assessed by surgeon
Patients must have a contraindication to cisplatin or decline cisplatin based neoadjuvant chemotherapy. Absolute or relative contraindication to cisplatin, defined as one or more of the following within 28 days prior to registration (Grading per CTCAE v5)
Creatinine clearance < 60 mL/min (Cockcroft-Gault formula will be used to calculate creatinine clearance)
Grade ≥ 2 hearing loss
Grade ≥ 2 neuropathy
No radiation therapy < 4 weeks of registration. NOTE: prior radiation therapy to the
bladder is not allowed
Must have a life expectancy of at least 12 weeks at registration
Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior treatment
Demonstrate adequate organ function as defined in the table below. All screening labs to be obtained within 28 days prior to registration
White blood cell count ≥ 2500/mm3 (≥2.5 GI/L)
Absolute Neutrophil Count (ANC) ≥ 1500/mm3 (≥1.5 GI/L) without G-CSF
Platelet Count (Plt) ≥ 100,000/mm3 (≥100 GI/L) without transfusion
Hemoglobin (Hgb) ≥ 9 g/dL (may be transfused)
Calculated creatinine clearance ≥ 30 to ≤ 60 mL/min
Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
Bilirubin ≤ 1.5 × upper limit of normal (ULN); Documented Gilbert's syndrome ≤ 3 x ULN
Albumin ≥ 2.8 g/dl
Aspartate aminotransferase (AST) ≤ 2.5 × ULN
Alanine aminotransferase (ALT) ≤ 2.5 × ULN
Alkaline Phosphatase ≤ 2.5 x ULN
International Normalized Ratio (INR) or Prothrombin Time (PT); Activated Partial Thromboplastin Time (aPTT) ≤ 1.3 × ULN (Applies only to subjects not receiving therapeutic anticoagulation; subjects receiving therapeutic anticoagulation should be on a stable dose)
Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening. The HBV DNA test will be performed only for patients who have a positive total HBcAb test
Negative HIV test at screening; NOTE: patients with a positive HIV test at screening
Negative total hepatitis C core antibody (HCcAb) test at screening, or positive total HCcAb test followed by a negative hepatitis C virus (HCV) DNA test at screening. The HCV DNA test will be performed only for patients who have a positive total HCcAb test
are eligible provided they are stable on anti-retroviral therapy, have a CD4
Females of childbearing potential must have a negative urine or serum pregnancy test within 30 days prior to registration. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
count ≥200/µL, and have an undetectable viral load
Females of childbearing potential and males must be willing to abstain from heterosexual intercourse or to use 2 forms of effective methods of contraception from the time of informed consent (females) or initiation of treatment (males) until 5 months (150 days) after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method. Males should not donate sperm and women should not breastfeed or store breast milk for the timeframe outlined above
As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study

Exclusion Criteria

Prior treatment with cabozantinib
Active infection requiring systemic therapy
Active tuberculosis
Prior history of stem cell or solid organ transplantation
Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during the study or within 5 months after the last dose of study drug
Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study)
Treatment with any investigational drug within 30 days prior to registration
Known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or II cancer from which the patient is currently in complete remission, or other cancer for which the subject has been disease-free for at least five years. Patients with localized prostate cancer who are either being followed by an active surveillance program OR planning to undergo definitive treatment are also eligible
History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins. NOTE: Previously identified allergy or hypersensitivity to components of the study treatment formulations or history of severe infusion-related reactions to monoclonal antibodies are excluded. Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption are also excluded
Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the atezolizumab or cabozantinib formulation
Prior treatment with the following is prohibited unless otherwise specified
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies or systemic chemotherapy (prior intravesical induction immunotherapy for non-muscle invasive disease is allowed)
Any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment
Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy within 4 weeks before first dose of study treatment
Significant cardiovascular disease, such as
New York Heart Association Congestive Heart Failure Class II or greater
Myocardial infarction, unstable angina or unstable arrhythmias within 3 months of enrollment
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
History of stroke or TIA within 3 months of enrollment
obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of
Other clinically significant arterial vascular disease within 6 months of enrollment (e.g. aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis). Prior history of adequately treated venous thromboembolism > 7 days prior to C1D1 on stable dose of therapeutic anticoagulation is permitted
active pneumonitis on screening chest imaging
Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate
Atezolizumab-Specific Exclusion Criteria
Treatment with systemic immunostimulatory agents (including but not limited to IFNs, interleukin [IL]-2) within 6 weeks or five half-lives of the drug, whichever is shorter, prior to Cycle 1 Day 1
Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [anti-TNF] agents) within 2 weeks prior to Cycle 1 Day 1, or anticipated requirement for systemic immunosuppressive medications during the trial (Subjects who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled ).The use of inhaled corticosteroids, physiologic replacement doses of glucocorticoids (i.e., for adrenal insufficiency), and mineralocorticoids (e.g., fludrocortisone for adrenal insufficiency) is allowed. The use of prednisone 10 mg or equivalent dose of steroids is also allowed
Subjects with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible for this study
Graves' disease
Subjects with controlled Type I diabetes mellitus on a stable dose of insulin regimen may be eligible for this study
Subjects with a history of celiac disease may be eligible if controlled with diet
Cabozantinib -Specific Exclusion Criteria
Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment
History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with anti-phospholipid syndrome, granulomatosis with polyangiitis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis. Exceptions include
The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions
Conditions not expected to recur in the absence of an external trigger
\--Cardiovascular disorders
Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
History of additional risk factors for torsades de pointes (e.g., long QT syndrome)
The subject has evidence of tumor invading the GI tract, active peptic ulcer disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or common bile duct, or gastric outlet obstruction
Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before first dose. NOTE: Complete healing of an intra-abdominal abscess must be confirmed before first dose
Evidence of abdominal free air not explained by paracentesis or recent surgical procedure
Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation
Lesions invading or encasing any major blood vessels
Gastrointestinal (GI) disorders including those associated with a high risk of
Other clinically significant disorders that would preclude safe study participation
perforation or fistula formation
Serious non-healing wound/ulcer/bone fracture
Uncompensated/symptomatic hypothyroidism
Moderate to severe hepatic impairment (Child-Pugh B or C)
Hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or other history
of significant bleeding (eg, pulmonary hemorrhage) within 12 weeks before
Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
For subjects with known QTcF of > 500 ms, corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment. NOTE: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3 min must be performed within 30 min after the initial ECG, and the average of these three consecutive results for QTcF will be used to determine eligibility
first dose
Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted
Concomitant anticoagulation with coumarin agents (eg, warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (eg, clopidogrel). Allowed anticoagulants are the following
Low-dose low molecular weight heparins (LMWH) are permitted. Prophylactic use of anticoagulants is allowed
Uncontrolled gross hematuria associated with clots per investigator's discretion
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
Inability to swallow pills
Major surgery (eg, GI surgery) within 2 weeks before C1D1. Complete wound healing from
major surgery and from minor surgery (eg, simple excision, tooth extraction)
must have occurred prior to treatment. Subjects with clinically relevant
ongoing complications from prior surgery are not eligible
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