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.
|Overal Status||Start Date||Phase||Study Type|
|Recruiting||May 21, 2020||Phase 2||Interventional|
Primary Outcome 1 - Measure: Pathologic Response Rate
Primary Outcome 1 - Time Frame: 12 months
- 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.
r/> - 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
- 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
- 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
- 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
- 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 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
- 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.
- 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
- 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
- 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
- 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
- Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic
- Conditions not expected to recur in the absence of an external trigger.
Cabozantinib -Specific Exclusion Criteria
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- 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
- 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
- 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
- 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
- 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 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
- 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.
- Evidence of bleeding diathesis or significant coagulopathy (in the absence of
- 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 aspirin for cardioprotection (per local applicable guidelines) is
- Low-dose low molecular weight heparins (LMWH) are permitted. Prophylactic use of
anticoagulants is allowed.
- 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.
- Uncontrolled gross hematuria associated with clots per investigator's discretion.
- Inability to swallow pills
Minimum Age: 18 Years
Maximum Age: N/A
Healthy Volunteers: No
Name: Deepak Kilari, MD
Role: Principal Investigator
Affiliation: Medical College of Wisconsin
Name: Deepak Kilari, MD
Phone: (414) 805-4600
|University of Rochester Medical Center
Rochester, New York 14642
|Vanderbilt-Ingram Cancer Center
Nashville, Tennessee 37232
|Froedtert and The Medical College of Wisconsin
Milwaukee, Wisconsin 53226