Clinical Trials /

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

NCT04631744

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC)
  • Official Title: Open Label Phase II Trial of Cabozantinib in Patients With Metastatic Castrate Resistant Prostate Cancer (mCRPC) and Known Amplifications or Activating Mutations in Gene Targets of Cabozantinib Who Have Received Prior Anti-Androgen Therapy

Clinical Trial IDs

  • ORG STUDY ID: 19-04020287
  • NCT ID: NCT04631744

Conditions

  • Prostate Cancer

Interventions

DrugSynonymsArms
CabozantinibCabozantinib Arm

Purpose

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.

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Cabozantinib ArmExperimental
  • Cabozantinib

Eligibility Criteria

        Inclusion Criteria

          1. Age >18 years.

          2. Documented histological or cytological diagnosis of prostate carcinoma.

          3. Evidence of metastatic PC on imaging (bone scan and/or CT/MRI scan)

          4. 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.

          5. 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). Re-
             biopsy of same pre-treatment biopsy soft tissue site is preferred.

          6. 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.

          7. Previously received either abiraterone acetate and/or enzalutamide or similar AR
             pathway inhibitor.

          8. Previous docetaxel chemotherapy is allowed in hormone-sensitive setting and in
             castration-resistant disease if not within 12 months of enrolling

          9. Documented progressive metastatic CRPC based on at least one of the following
             criteria:

               -  PSA progression according to Prostate Cancer Working Group 3 (PCWG3) criteria

               -  Objective radiographic progression, according to PCWG3 criteria

         10. ECOG performance status of 0-1

         11. 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.

         12. 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)

         13. Evidence of amplification or activating mutation of selected targets of cabozantinib
             (including MET, KIT, RET, VEGFR-1, VEGFR-2, VEGFR-3, FLT3, AXL, TRKB, or TIE2) by at
             least one of the following:

               -  DNA sequencing of metastatic tumor biopsy specimen or cfDNA test

               -  RNA sequencing of metastatic tumor biopsy specimen

               -  Commercial cell-free DNA assay

               -  Overexpression by IHC on metastatic tumor biopsy specimen

         14. 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

         15. Capable of understanding and complying with the protocol requirements and must have
             signed the informed consent document

        Exclusion Criteria

          1. Prior treatment with cabozantinib

          2. Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 2 weeks before first dose of study treatment.

          3. 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.

          4. Subject has received abiraterone acetate or enzalutamide within 2 weeks before
             enrollment.

          5. 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.

          6. 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.

          7. 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.

          8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥
             1.3 x the laboratory ULN within 7 days before the first dose of study treatment.

          9. 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.

               -  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.

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

               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
                  manifestation.

               -  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
                  participation.

                    -  Serious non-healing wound/ulcer/bone fracture.

                    -  Uncompensated/symptomatic hypothyroidism.

                    -  Moderate to severe hepatic impairment (Child-Pugh B or C).

         10. 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.

         11. 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.

         12. Inability to swallow tablets.

         13. Previously identified allergy or hypersensitivity to components of the study treatment
             formulations.

         14. 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.

        Molecular Eligibility

        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
        tests:

          1. 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.

          2. 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).

          3. 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.

          4. 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)
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in radiographically progression-free survival following treatment with Cabozantinib radiographically progression-free after 6 months
Time Frame:Will be assessed at 6 months
Safety Issue:
Description:Progression-free survival is defined as the time from randomization to minimum of radiographic progression or death, whichever occurs first. Radiographic response rate will be captured through radiographic scans such as MRI, CT and bone scans. Response evaluation criteria in solid tumors (RECIST) criteria with Prostate Cancer Working Group 3 (PCWG3) modifications.

Secondary Outcome Measures

Measure:Change in prostate specific antigen (PSA)
Time Frame:Will be collected at the time of visit 1 through end of study or 100 months
Safety Issue:
Description:PSA decline by with Prostate Cancer Working Group 3 (PCWG3) modifications
Measure:Change in adverse event rate response rate
Time Frame:Will be collected at the time of visit 1 through end of study or 100 months
Safety Issue:
Description:National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 is used to grade all adverse events
Measure:Change in overall survival (OS)
Time Frame:Will be collected at the time of visit 1 through end of study or 100 months
Safety Issue:
Description:Overall survival will be captured through in-clinic or telephone contact with subjects
Measure:Proportion of patients with circulating tumor cells (CTC) response
Time Frame:Will be collected at the time of visit 1 through end of study or 100 months
Safety Issue:
Description:CTCs will be analyzed through blood specimen collection via CellSearch methodology lab testing
Measure:Proportion of patients with a tumor response
Time Frame:Will be collected at the time of visit 1 through end of study or 100 months
Safety Issue:
Description:Modified response evaluation criteria in solid tumors (RECIST) criteria will be use to determine complete response (CR) or partial response (PR)

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Weill Medical College of Cornell University

Last Updated

November 17, 2020