Cabozantinib in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)

  • End date
    May 31, 2025
  • participants needed
  • sponsor
    Weill Medical College of Cornell University
Updated on 21 April 2022


The purpose of this study is to determine what effects (good and bad) cabozantinib has in treatment of patients with metastatic castrate resistant prostate cancer (mCRPC).

The hypothesis for this trial is that cabozantinib has anti-tumor activity in a molecularly-selected group of patients with CRPC.


This is a single-arm, open-label Phase II multi-institutional trial in 30 patients that have been molecularly selected based on that their tumors possess alterations in molecular targets of cabozantinib. Patients will be treated be continuously until they develop radiographic progression or discontinue cabozantinib for toxicity. If 6 or more out of 12 subjects with particular mutation or gene amplification show progression prior to 6 months, accrual for the particular genomic alteration may close. In addition, a series of correlative studies will be performed including tissue biopsies in order to further define the mechanisms of cabozantinib anti-tumor action in prostate cancer and identify surrogate markers of response.

This research study is being done because additional effective treatments are needed for prostate cancer that has spread and is growing despite hormone suppression. Prior studies indicate that Cabozantinib may be effective in a subset of these participants, but that has not yet been determined.

About 30 subjects will take part in this study at 4 participating sites. We expect to enroll approximately 20 participants at Weill Cornell Medicine and approximately 3-5 subjects per participating site. All subjects participating in this study will be treated with Cabozantinib. All subjects will continue to take LHRH analogue therapy.

Once eligible participants will be enrolled on the trial for approximately approximately 12 months. At that point, subjects will switch to long-term follow up for two years after removal from the study or until death, whichever occurs first.

Study related procedures can be combined with routine Standard of Care (SOC) visits. These will include obtaining medical history, vitals, routine blood collection, radiographic imaging (CT, MRI and Bone scan), EKG and between 2 and 4 weeks after starting therapy, a tumor biopsy is required. This will be done with a needle by local sedation by an Interventional Radiologist.

Condition Prostate Cancer
Treatment Cabozantinib
Clinical Study IdentifierNCT04631744
SponsorWeill Medical College of Cornell University
Last Modified on21 April 2022


Yes No Not Sure

Inclusion Criteria

Age >18 years
Documented histological or cytological diagnosis of prostate carcinoma
Evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan)
Agree to undergo a biopsy of at least one metastatic site or primary prostate prior to beginning therapy. Adequate archival metastatic tissue can be used if available in lieu of a biopsy if done when patient had CRPC and within 3 months the start of treatment
Agree to undergo a biopsy of at least one metastatic site or primary prostate after 3 weeks weeks of therapy (biopsy must be between day 21 and day 24 of treatment). Rebiopsy of same pre-treatment biopsy soft tissue site is preferred
Serum testosterone level less than 50 ng/dl. Subjects without prior orchiectomy must be currently taking and willing to continue luteinizing hormone-releasing hormone (LHRH) analogue (agonist or antagonist) therapy until permanent discontinuation of study treatment
Previously received either abiraterone acetate and/or enzalutamide or similar AR pathway inhibitor
Previous docetaxel chemotherapy is allowed in hormone-sensitive setting and in castration-resistant disease if not within 12 months of enrolling
Documented progressive metastatic CRPC based on at least one of the following
PSA progression according to Prostate Cancer Working Group 3 (PCWG3) criteria
Objective radiographic progression, according to PCWG3 criteria
ECOG performance status of 0-1
Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless specified below or AE(s) are clinically nonsignificant and/or stable on supportive therapy
Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment
Absolute neutrophil count (ANC) ≥ 1500/mm3 (≥ 1.5 GI/L) without granulocyte colony-stimulating factor support
White blood cell count ≥ 2500/mm3 (≥ 2.5 GI/L)
Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without transfusion
Hemoglobin ≥ 9 g/dL (≥ 90 g/L)
Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3 x ULN)
Serum albumin ≥ 2.8 g/dl
Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault equation
If urine dipstick is positive, then: Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
Evidence of amplification or activating mutation of selected targets of cabozantinib
DNA sequencing of metastatic tumor biopsy specimen or cfDNA test
(including MET, KIT, RET, VEGFR-1, VEGFR-2, VEGFR-3, FLT3, AXL, TRKB, or TIE2)
RNA sequencing of metastatic tumor biopsy specimen
by at least one of the following
Commercial cell-free DNA assay
Overexpression by IHC on metastatic tumor biopsy specimen
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

Exclusion Criteria

Prior treatment with cabozantinib
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) except agents to maintain castrate status within 4 weeks before first dose of study treatment. Antiresportive bone agents are also allowed
Subject has received abiraterone acetate or enzalutamide within 2 weeks before enrollment
Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible
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 for neurological indications 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
The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
3 x the laboratory ULN within 7 days before the first dose of study
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
Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation
Serious non-healing wound/ulcer/bone fracture
Uncompensated/symptomatic hypothyroidism
Note: Complete healing of an intra-abdominal abscess must be confirmed before first
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
Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
Lesions invading or encasing any major blood vessels. Subjects with lesions
invading the intrahepatic vasculature, including portal vein, hepatic vein, and
hepatic artery, are eligible
Other clinically significant disorders that would preclude safe study
Molecular Eligibility
Moderate to severe hepatic impairment (Child-Pugh B or C)
Major surgery (e.g., GI surgery, removal or biopsy of brain metastasis) within 8 weeks
before first dose of study treatment. Complete wound healing from major surgery must
have occurred 1 month before first dose and from minor surgery (e.g. simple excision
tooth extraction) at least 10 days before first dose. 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 28 days before first dose of study treatment [add
reference for Fridericia formula]
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
Inability to swallow tablets
Previously identified allergy or hypersensitivity to components of the study treatment
Diagnosis of another malignancy within 2 years before first dose of study treatment
except for superficial skin cancers, or localized, low-grade tumors deemed cured and
not treated with systemic therapy
To be eligible, a patient's tumor must have evidence of gene amplification, an activating
mutation, or overexpression of one of the following genes: MET, KIT, RET, VEGFR-1, VEGFR-2
VEGFR-3, FLT3, AXL, TRKB, or TIE2. Eligibility can be met via the following diagnostic
DNA sequencing of a metastatic tumor biopsy specimen showing gene amplification or
activating mutation using a CLIA-certified assay. Tumor tissue samples must have been
collected within 6 months of enrollment
Protein overexpression in a metastatic tumor biopsy specimen determined by
immunohistochemistry (IHC) showing 2+ or 3+ protein expression using a CLIA-certified
assay.These include common in-house KIT and commercial reference labs for panTRK (e.g
NeoGenomics) and cMET (e.g. NeoGenomics, Caris, Mayo Clinic)
CLIA-certified commercial cell free DNA assay reporting gene amplification or
activating mutation within 3 months of enrollment
For the Guardant360 Liquid Biopsy amplification must be at least (++) or (+++)
for to meet eligibility
For the FoundationOneLiquid assay, amplification will be eligible. Reports that
have an "equivocal" or "subclonal" designation will not be eligible
Any non-CLIA certified assay such as RNA expression profiling of a metastatic tumor
biopsy specimen showing overexpression must be confirmed by a CLIA-certified assay
(i.e., immunohistochemistry showing 2+ or 3+ protein expression)
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