Clinical Trials /

Cabozantinib and Abiraterone With Checkpoint Inhibitor Immunotherapy in Metastatic Hormone Sensitive Prostate Cancer (CABIOS Trial)

NCT04477512

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib and Abiraterone With Checkpoint Inhibitor Immunotherapy in Metastatic Hormone Sensitive Prostate Cancer (CABIOS Trial)
  • Official Title: A Phase 1b Clinical Trial of Cabozantinib and Abiraterone With Checkpoint Inhibitor Immunotherapy in Metastatic Hormone Sensitive Prostate Cancer (CABIOS Trial)

Clinical Trial IDs

  • ORG STUDY ID: 202009082
  • NCT ID: NCT04477512

Conditions

  • Metastatic Hormone Refractory Prostate Cancer

Interventions

DrugSynonymsArms
CabozantinibExpansion: Cabozantinib+Abiraterone acetate +Nivolumab
NivolumabExpansion: Cabozantinib+Abiraterone acetate +Nivolumab
Abiraterone acetateExpansion: Cabozantinib+Abiraterone acetate +Nivolumab
PrednisoneExpansion: Cabozantinib+Abiraterone acetate +Nivolumab

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
Level 1: Cabozantinib+Abiraterone acetate +NivolumabExperimental-Abiraterone acetate is an oral medication given at a dose of 1000 mg daily. Prednisone is an oral medication given at a dose of 5 mg daily. Nivolumab is given intravenously over 30 minutes on Day 1 of each 28-day cycle at a dose of 480 mg. Cabozantinib is an oral drug given daily; dosing will be 20 mg.
  • Cabozantinib
  • Nivolumab
  • Abiraterone acetate
  • Prednisone
Level 2: Cabozantinib+Abiraterone acetate +NivolumabExperimental-Abiraterone acetate is an oral medication given at a dose of 1000 mg daily. Prednisone is an oral medication given at a dose of 5 mg daily. Nivolumab is given intravenously over 30 minutes on Day 1 of each 28-day cycle at a dose of 480 mg. Cabozantinib is an oral drug given daily; dosing will be 40 mg.
  • Cabozantinib
  • Nivolumab
  • Abiraterone acetate
  • Prednisone
Expansion: Cabozantinib+Abiraterone acetate +NivolumabExperimental-Abiraterone acetate is an oral medication given at a dose of 1000 mg daily. Prednisone is an oral medication given at a dose of 5 mg daily. Nivolumab is given intravenously over 30 minutes on Day 1 of each 28-day cycle at a dose of 480 mg. Cabozantinib is an oral drug given daily; dosing will be dependent on recommended dose found in first part of study
  • Cabozantinib
  • Nivolumab
  • Abiraterone acetate
  • Prednisone

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed metastatic hormone-sensitive prostate
             cancer. May have relapsed metastatic disease after initial primary therapy or de novo
             metastatic disease.

          -  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 metastatic hormone-sensitive
             prostate cancer 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 (must be complete ≥14 days
             prior to enrollment) or any other radiation therapy (must be complete ≥28 days prior
             to enrollment) 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
                  factor support

               -  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
                  Cockcroft-Gault

               -  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
                  treatment)

          -  Castrate testosterone levels with serum testosterone ≤ 50 ng/mL at time of study drug
             start, with ongoing ADT throughout the study unless prior bilateral orchiectomy.

          -  Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG)

          -  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.

        Exclusion Criteria:

          -  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,
             apalutamide, darolutamide).

          -  Prior exposure to CYP17 inhibitors (e.g. abiraterone)

          -  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
             study treatment.

          -  Prior treatment with checkpoint inhibitor or other immunotherapy (e.g., anti-PD-1,
             anti-PD-L1, anti-CTLA4).

          -  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 Crohns 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
             criterion:

               -  Patients with vitiligo or alopecia

               -  Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
                  hormone replacement

               -  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
             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 events, or thromboembolic event (e.g., deep venous
                       thrombosis, pulmonary embolism) within six months before the first dose of
                       study treatment.

                         -  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
                            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 six months before the first dose.

        Note: Complete healing of an intra-abdominal abscess must be confirmed before the first
        dose.

          -  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
             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).

                    -  Active hepatitis B or C; active HIV. Patients with well-controlled HIV or
                       hepatitis B or C, or who have had curative treatment for hepatitis C, may be
                       considered if they meet all other criteria and after discussion with the PI
                       and drug manufacturers (BMS and Exelixis) using the following criteria for
                       guidance: https://www.fda.gov/media/121319/download

                    -  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 with the exception of the baseline
                       biopsy, which must have occurred no less than 6 days prior to the first
                       dose). Patients with clinically relevant ongoing complications from prior
                       surgery are not eligible.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Frequency of dose-limiting toxicities (DLTs)
Time Frame:Completion of 1st cycle of treatment for patients in dose level 1 & dose level 2 (estimated to be 11 months)
Safety Issue:
Description:Hematologic DLT in 1st cycle possibly/probably/definitely related to treatment: Grade 4 neutropenia >5 days duration; Febrile neutropenia with temperature >38.5°C; Grade 4 anemia requires transfusion on more than 2 occasions in 7 days; Grade 3 thrombocytopenia with hemorrhage or grade 4 thrombocytopenia Non-hematologic DLT possibly/probably/definitely related grade 3/grade 4 toxicity in 1st cycle except:Grade 3/4 nausea/vomiting/diarrhea that returns to Grade 1 prior to cycle 2 or lasting <72 hours without therapy; Grade 3 triglycerides will be DLT if patients have grade 3 despite lipid-lowering therapy; Grade 3 rash will be DLT for patients who received 2 weeks of supportive care with no improvement; Grade 3 colitis lasting ≤7 days; grade 3 hypokalemia unless patient has for 72 hours despite replacement therapy or who is symptomatic regardless of duration Death not due underlying disease or extraneous cause; Hy's law criteria event; delay in cycle 2 due to toxicity by >14 days

Secondary Outcome Measures

Measure:PSA response rate
Time Frame:Through end of treatment (estimated to be 24 months)
Safety Issue:
Description:-PSA response rate will be defined as the proportion of subjects who have PSA response as defined by at least 50% decline in PSA level from baseline measured twice at least 3 weeks apart. Based on the PCWG3 criteria, a favorable effect on PSA may be delayed for ≥ 12 weeks. Therefore, early rises in PSA before 12 weeks will not be considered when determining PSA response.
Measure:Overall response rate (ORR)
Time Frame:Through end of treatment (estimated to be 24 months)
Safety Issue:
Description:-The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria.
Measure:Overall survival (OS)
Time Frame:From start of treatment through 1 year of follow-up (estimated to be 36 months)
Safety Issue:
Description:-Defined as time of enrollment to time of death from any cause
Measure:Progression-free survival (PFS)
Time Frame:From start of treatment through 1 year of follow-up (estimated to be 36 months)
Safety Issue:
Description:Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of first PCWG3 defined progression or death, the event that occurs first. Patients who have not experienced either event at the time of analysis will be censored at the date of their last progression assessment. For rising PSA after an initial decline from baseline, the PSA is recorded from the start of therapy to first PSA increase that is ≥ 25% and ≥ 2ng/mL above the nadir, which is confirmed by a second value 4 or more weeks later, confirming a rising trend. If there is no initial decline from baseline, PSA progression is defined as ≥ 25% increase and ≥ 2 ng/mL increase from baseline beyond 12 weeks.
Measure:Disease specific survival (DSS)
Time Frame:From start of treatment through 1 year of follow-up (estimated to be 36 months)
Safety Issue:
Description:-Defined as time of enrollment to time of prostate-cancer related death
Measure:Incidence of adverse events as measured per CTCAE v 5.0
Time Frame:From time of consent through 100 days after last dose of nivolumab (estimated to be 28 months)
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

March 9, 2021