This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects
of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has
spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body
(metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes
needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a
toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and
delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be
safe and effective in treating locally advanced or metastatic urothelial cancer.
PRIMARY OBJECTIVES:
I. To determine the recommended phase II dose (RP2D) of cabozantinib s-malate (cabozantinib)
and enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 of a 28-day cycle based on safety and
tolerability. (Phase I dose escalation) II. To evaluate the ongoing safety and tolerability
of cabozantinib and enfortumab vedotin in a dose expansion cohort. (Phase Ib dose expansion)
SECONDARY OBJECTIVES:
I. Obtain preliminary evidence of anti-tumor activity of the combination of cabozantinib and
enfortumab vedotin by assessing the objective response rate (ORR) using Response Evaluation
Criteria in Solid Tumors (RECIST) version (v)1.1.
II. Progression-free survival (PFS). III. Overall survival (OS). IV. Disease control rate by
RECIST v1.1.
EXPLORATORY OBJECTIVES:
I. To assess the pharmacokinetic (PK) profile of cabozantinib during treatment with
enfortumab vedotin.
II. To evaluate the effect of the combination on selected biomarkers in the tumor
microenvironment, systemic circulation and gut microbiome and their relationship with
efficacy of the combination.
III. To evaluate quality of life, frailty and sarcopenia before, during and at the time of
treatment completion.
OUTLINE: This is dose-escalation study of cabozantinib.
Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and enfortumab vedotin
intravenously (IV) on days 1, 8, and 15. Cycles repeat every 28 days in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 days and then every 12
weeks.
Inclusion Criteria:
- Histologically-documented urothelial carcinoma (squamous differentiation or mixed cell
types allowed if urothelial carcinoma is present)
- Metastatic disease or unresectable locally-advanced disease
- Must have received prior treatment with a checkpoint inhibitor (CPI). A CPI is defined
as a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1)
inhibitor alone or with any other combination
- Must either have prior treatment with platinum-containing chemotherapy or be
ineligible at time of enrollment
- Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
(CTCAE) v5.0 from toxicities related to any prior treatments, unless AE(s) are
clinically nonsignificant and/or stable on supportive therapy
- Tumor tissue samples must be available for submission prior to initiation of study
treatment or patient must be willing to undergo repeat tumor biopsy
- Must have measurable disease according to Response Evaluation Criteria in Solid Tumors
(RECIST) (Version 1.1)
- An Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2
- Must be >= 18 years of age
- Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulating
factor support (within 28 days before first dose of study treatment)
- White blood cell count >= 2500/uL (within 28 days before first dose of study
treatment)
- Platelets >= 100,000/uL without transfusion (within 28 days before first dose of study
treatment)
- Hemoglobin >= 9 g/dL (within 28 days before first dose of study treatment)
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented
bone metastases (within 28 days before first dose of study treatment)
- Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 x ULN) (within
28 days before first dose of study treatment)
- Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time
(PTT) test < 1.3 x the laboratory ULN unless participant is receiving anticoagulant
therapy as long as PT or activated partial thromboplastin time (aPTT) is within
therapeutic range of intended use of anticoagulants (within 28 days before first dose
of study treatment)
- Calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault
equation (within 28 days before first dose of study treatment)
- Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)
urine protein =< 1 g (within 28 days before first dose of study treatment)
- Capable of understanding and complying with the protocol requirements and must have
signed the informed consent document
- Sexually active fertile subjects and their partners must agree to use medically
accepted methods of contraception (e.g., barrier methods, including male condom,
female condom, or diaphragm with spermicidal gel) during the course of the study and
for 4 months after the last dose of study treatment
- Female subjects of childbearing potential must not be pregnant at screening. Female
subjects are considered to be of childbearing potential unless one of the following
criteria are met: documented permanent sterilization (hysterectomy, bilateral
salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined
as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other
biological or physiological causes. In addition, females < 55 years-of-age must have a
serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note:
Documentation may include review of medical records, medical examinations, or medical
history interview by study site
Exclusion Criteria:
- Prior treatment with cabozantinib
- Prior enrollment in an enfortumab vedotin study or prior treatment with other
monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs)
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment
- Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
(including investigational) within 2 weeks before first dose of study treatment
- Radiation therapy within 2 weeks before first dose of study treatment. Systemic
treatment with radionuclides within 6 weeks before first dose of study treatment
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
first dose of study treatment after major surgery (e.g., removal or biopsy of brain
metastasis). Subjects must have complete wound healing from major surgery or minor
surgery before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
treatment
- 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
- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:
- Cardiovascular disorders:
- Congestive heart failure New York Heart Association Class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
treatment.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism) within 6 months before first dose of study
treatment
- Subjects with a diagnosis of incidental, subsegmental pulmonary
embolism (PE) or deep venous thrombosis (DVT) within 6 months are
allowed if stable, asymptomatic, and treated with a stable dose of
permitted anticoagulation for at least 1 week before first dose of
study 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 (e.g., 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 of study treatment.
- Note: Complete healing of an intra-abdominal abscess must be confirmed
before first dose of study treatment
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5
ml) of red blood, or other history of significant bleeding (e.g., pulmonary
hemorrhage) within 12 weeks before first dose of study treatment
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation
- Lesions invading or encasing any major blood vessels
- Ongoing sensory or motor neuropathy grade >= 2
- 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).
- Uncontrolled diabetes mellitus defined as a hemoglobin A1C >= 8%
- Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
within 10 days before first dose of study treatment. Subjects must have complete wound
healing from major surgery or minor surgery before first dose of study treatment.
Subjects with clinically relevant ongoing complications from prior surgery are not
eligible
- 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
- Pregnant or lactating females
- Inability to swallow tablets
- Previously identified allergy or hypersensitivity to components of the study treatment
formulations
- Any other active malignancy at time of first dose of study treatment or diagnosis of
another malignancy within 3 years prior to first dose of study treatment that requires
active treatment, except for locally curable cancers that have been apparently cured,
such as basal or squamous cell skin cancer, superficial bladder cancer, or prostate,
cervix, or breast
