The goal of this study is to determine the recommended phase 2 dose of the multi-drug
combination of abiraterone, cabozantinib, and nivolumab in conjunction with ongoing androgen
deprivation therapy in previously untreated metastatic hormone-sensitive prostate cancer
patients. The investigators hypothesize that the combination of cabozantinib and abiraterone
acetate/prednisone in conjunction with nivolumab will have an acceptable safety profile and
will be feasible to administer in patients with hormone-sensitive metastatic prostate cancer.
- Histologically or cytologically confirmed metastatic hormone-sensitive prostate
cancer. May have relapsed metastatic disease after initial primary therapy or de novo
- Must have evidence of metastatic disease on CT or MRI of the chest, abdomen, and
pelvis, or technetium bone scan. May have any type or location of metastases (bone,
lymph node, visceral).
- May have been on androgen deprivation therapy (ADT) for ≤ 12 weeks prior to study
enrollment (GnRHR agonist such as leuprolide, goserelin, triptorelin, buserelin,
histrelin; GnRHR antagonists such as degarelix). Prior ADT for localized prostate
cancer is allowed.
- Prior palliative radiation therapy for bone metastasis within 2 weeks or any other
radiation therapy within 4 weeks before first dose of study treatment is allowed.
Prior definitive radiation therapy for localized prostate cancer is allowed.
- If the patient has undergone bilateral orchiectomy, it must have occurred no more than
12 weeks before study enrollment.
- Recovery to baseline or ≤ grade 1 from toxicities related to any prior treatments,
unless AEs are clinically nonsignificant and/or stable on supportive therapy.
- At least 18 years of age.
- ECOG performance status ≤ 1
- Normal bone marrow and organ function as defined below:
- Absolute neutrophil count ≥ 1,500 K/cumm without granulocyte colony-stimulating
- White blood cell count ≥ 2,500 K/cumm
- Platelets ≥ 100,000 K/cumm without transfusion
- Hemoglobin ≥ 9.0 g/DL
- Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease ≤ 3.0 x IULN)
- AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x
IULN with documented bone metastases
- Serum creatinine ≤ 2.0 x IULN or calculated creatinine clearance ≥ 30 mL/min by
- Serum albumin ≥ 2.8 g/dL
- Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
- PT/INR or PTT < 1.3 x IULN (within seven days before the first dose of study
- Castrate testosterone levels with serum testosterone ≤ 50 ng/mL at time of study drug
start, with ongoing ADT throughout the study.
- Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG
within 28 days before the first dose of study treatment).
- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of the legally authorized representative, if applicable).
- Heterosexually active male patients (along with their female partners) are required to
use two forms of acceptable contraception, including one barrier method, during
participation in the study and for 5 months following the last day of study treatment.
If a female partner of a male patient becomes pregnant during therapy or within 5
months after the last day of study treatment, the investigator must be notified in
order to facilitate outcome follow-up.
- Any evidence of castrate resistant prostate cancer, as defined by defined by disease
progression despite androgen depletion therapy (ADT), either by continuous rise in
serum PSA levels as measured over at least 2 consecutive values, or the clinical or
radiographic progression of disease, as assessed by the investigator.
- Prior exposure to second-generation androgen receptor inhibitors (e.g., enzalutamide,
- No chronic concomitant treatment with strong cytochrome P450 (CYP) 3A4 inducers or
inhibitors. If patients are on such agents and these can be safely discontinued, may
not have received a strong CYP3A4 inducer/inhibitor within 5 half-lives.
- Prior systemic chemotherapy for prostate cancer (either for localized or metastatic
disease). Patients may have received androgen deprivation therapy (ADT) for < 12 weeks
prior to start of study drug; no other cytotoxic, biologic, or other systemic
anticancer therapy (including investigational) within 4 weeks before first dose of
- Prior treatment with checkpoint inhibitor or other immunotherapy (e.g., anti-PD-1,
- 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.
- Inability to swallow pills.
- Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, etc.]). The following are exceptions to this
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only
after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- Presence of a condition requiring systemic treatment with either corticosteroids (> 10
mg daily prednisone equivalent) or other immunosuppressive medications within 14
calendar days of start of study treatment. Inhaled or topical steroids and adrenal
replacement steroid doses < 10 mg daily prednisone equivalent are permitted in the
absence of active autoimmune disease.
- 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 carcinoma
in situ of the prostate, cervix, or breast.
- Currently receiving any other investigational agents.
- 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 cardioprotection (per applicable local
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 one week before the first
dose of study treatment without clinically significant hemorrhagic complications
from the anticoagulation regimen or the tumor.
- Patients with 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.
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to cabozantinib, nivolumab, or abiraterone or other agents used
in the study.
- Uncontrolled, significant intercurrent illness including, but not limited to, the
- 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
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic events, or thromboembolic event (e.g., deep venous
thrombosis, pulmonary embolism) within six months before the first dose of
- Subjects with a diagnosis of incidental, subsegmental PE or DVT within
six months are allowed if stable, asymptomatic, and treated with
anticoagulation for at least 1 week before the first dose of study
- 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
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
abscess within six months before the first dose.
Note: Complete healing of an intra-abdominal abscess must be confirmed before the 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 the 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).
- Active hepatitis B or C; active HIV.
- History of organ allograft.
- Major surgery (e.g., GI surgery removal or biopsy of brain metastasis)
within eight weeks before the first dose of study treatment. Complete wound
healing from major surgery must have occurred one month before the first
dose and from minor surgery (e.g., simple excision, tooth extraction) at
least ten days before the first dose. Patients with clinically relevant
ongoing complications from prior surgery are not eligible.