Clinical Trials /

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

NCT04289779

Description:

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.

Related Conditions:
  • Bladder Urothelial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of CAbozantinib in Combination With AtezolizumaB for Muscle-Invasive BladdEr Cancer (ABATE)
  • Official Title: A Phase 2 Study of CAbozantinib in Combination With AtezolizumaB as NeoAdjuvant Treatment for Muscle-Invasive BladdEr Cancer (ABATE)

Clinical Trial IDs

  • ORG STUDY ID: HCRN GU18-343
  • NCT ID: NCT04289779

Conditions

  • Bladder Cancer

Interventions

DrugSynonymsArms
CabozantinibcabometyxTreatment Arm
AtezolizumabTecentriqTreatment Arm

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Treatment ArmExperimentalCabozantinib 40 mg orally daily x 9 weeks plus Atezolizumab 1200 mg every 3 weeks x 3 doses
  • Cabozantinib
  • Atezolizumab

Eligibility Criteria

        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 (TURBT sample obtained within 60 days prior to registration) is
             required, if available. If archival tissue is not available a biopsy is not required,
             and the subject may still be eligible.

          -  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.

          -  Recovery to baseline or ≤ Grade 1 CTCAE v5 from toxicities related to any prior
             treatment.

          -  Must have a life expectancy of at least 12 weeks at registration.

          -  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) ≤ 1.5 × ULN (Applies only to subjects not receiving
                  therapeutic anticoagulation; subjects receiving therapeutic anticoagulation
                  should be on a stable dose)

          -  Negative HIV test at screening; NOTE: patients with a positive HIV test at screening
             are eligible provided they are stable on anti-retroviral therapy, have a CD4 count
             ≥200/µL, and have an undetectable viral load.

          -  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 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.

          -  Females of childbearing potential must have a negative 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

          -  Females of childbearing potential and males must be willing to abstain from
             heterosexual activity or to use 2 forms of effective methods of contraception from the
             time of informed consent 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.

          -  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.

          -  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.

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
             obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active
             pneumonitis on screening chest imaging.

          -  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 stroke or TIA within 3 months of enrollment.

               -  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.

               -  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.

          -  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:

               -  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

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

          -  Cardiovascular disorders:

             --- Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg
             systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.

          -  Gastrointestinal (GI) disorders including those associated with a high risk of
             perforation or fistula formation:

               -  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.

          -  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 first dose.

          -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
             manifestation.

          -  Lesions invading or encasing any major blood vessels.

          -  Other clinically significant disorders that would preclude safe study participation.

               -  Serious non-healing wound/ulcer/bone fracture.

               -  Uncompensated/symptomatic hypothyroidism.

               -  Moderate to severe hepatic impairment (Child-Pugh B or C).

                    -  Major surgery (eg, GI surgery) within 8 weeks before C1D1. Complete wound
                       healing from major surgery must have occurred 1 month before first dose and
                       from minor surgery (eg, simple excision, tooth extraction) at least 10 days
                       before first dose. Subjects with clinically relevant ongoing complications
                       from prior surgery are not eligible.

                    -  For subjects with known QTcF of > 500 ms, corrected QT interval calculated
                       by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within
                       28 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.

                    -  Evidence of bleeding diathesis or significant coagulopathy (in the absence
                       of therapeutic anticoagulation).

                    -  Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct
                       thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).
                       Allowed anticoagulants are the following:

          -  Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.

          -  Low-dose low molecular weight heparins (LMWH) are permitted. NOTE: The use of
             full-dose oral or parenteral anticoagulants is permitted as long as the INR or aPTT is
             within therapeutic limits (according to the medical standard of the institution) and
             the subject has been on a stable dose of anticoagulants for at least two weeks at the
             time of study enrollment. Prophylactic use of anticoagulants is allowed.

          -  Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known
             brain metastases who are on a stable dose of LMWH for at least 6 weeks before first
             dose of study treatment, and who have had no clinically significant hemorrhagic
             complications from the anticoagulation regimen or the tumor.

               -  Uncontrolled gross hematuria associated with clots per investigator's discretion.

               -  Inability to swallow pills
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic Response Rate
Time Frame:12 months
Safety Issue:
Description:Estimate the pathologic response (PaR) rate to neoadjuvant cabozantinib and atezolizumab in subjects with muscle-invasive urothelial cancer of the bladder. Pathologic response rate (PaR) is defined as the absence of residual muscle-invasive cancer in the surgical specimen (pathologic downstaging to ≤ pT1pN0), which includes pT0, pT1, pTa, and pTis

Secondary Outcome Measures

Measure:Frequency and Severity of Adverse Events
Time Frame:12 months
Safety Issue:
Description:Assess the frequency and severity of adverse events per CTCAE v5
Measure:Pathologic complete response rate
Time Frame:12 months
Safety Issue:
Description:Estimate the pathologic complete response (pCR) rate to neoadjuvant cabozantinib and atezolizumab in subjects with muscle-invasive urothelial cancer of the bladder. pCR rate is defined as the proportion of patients whose pathological staging was T0N0M0 as assessed per local institutional pathology review using specimens obtained via cystectomy following the neoadjuvant treatment.
Measure:Event Free Survival
Time Frame:12 months
Safety Issue:
Description:EFS is defined as the time from registration to the first recurrence of disease after cystectomy, the time of first documented progression in patients who are precluded from cystectomy, or the time of death due to any cause, whichever occurs first.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Deepak Kilari

Trial Keywords

  • muscle invasive

Last Updated

June 15, 2020