Cabozantinib Plus Docetaxel and Prednisone for Advanced Prostate Cancer

NCT01683994 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 12020412-C-0204
• Study Type: interventional
• Target: 49
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Cabozantinib is a drug that slows the growth of blood vessels that feed tumors. It is approved for medullary thyroid cancer. However, studies have shown that prostate tumors respond to it. Docetaxel and prednisone are standard treatments for advanced prostate cancer. Researchers want to see if adding cabozantinib to these two drugs can be a safe and effective treatment for this type of cancer. Objectives: \- To test the safety and effectiveness of cabozantinib with standard treatments for advanced prostate cancer. Eligibility: \- Individuals at least 18 years of age who have advanced prostate cancer that has not responded to standard treatments. Design:

• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will also be performed.
• Participants will receive the cancer drugs over 21-day cycles of treatment. They will take docetaxel and cabozantinib on day 1 of each cycle. Each docetaxel infusion will take about 1 hour. They will also take prednisone by mouth twice each day.
• Treatment will be monitored with frequent blood tests and imaging studies.
• Participants will continue to take the study drugs for as long as their cancer does not worsen and side effects are not too severe.

Conditions

Prostatic Neoplasms

Keywords

Angiogenesis Inhibitors; Small Molecules; Tyrosine Kinase Inhibitor

Outcome Measures

Primary Outcomes (2)

• Progression Free Survival (PFS) of Cabozantinib + Docetaxel + Prednisone Compared to Docetaxel + Prednisone Alone

  PFS is the time interval from start of treatment to documented evidence of disease progression or death. Disease progression was assessed by the Response Criteria in Solid Tumors (RECIST) and is defined as at least a 20% increase in the sum of the diameters of target lesions as referenced by the smallest sum on study. Appearance of one or more new lesions on bone scan and/or two consecutive rising prostatic-specific antigen values above the baseline at a minimum of one week intervals. A normal PSA value is 4.0 ng/ml and lower.

  From start date of treatment until the date of first documented progression, date of death from any cause and up to 40 months, whichever occurred first.

• Maximum Tolerated Dose (MTD)

  MTD is defined as the dose level at which no more than 1 of 6 patients experiences a dose limiting toxicity (DLT) at the level below that which had two instances of DLT. A DLT are defined as adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0) occurring during the first two cycles of therapy and related to the study medications (attributions: possible, probable, and definite) while fulfilling one of the following criteria: Any Grade 3 or greater non-hematologic toxicity except asymptomatic grade 3 hypertension, hypomagnesemia, hyponatremia, hypophosphatemia, hypocalcemia, and asymptomatic grade 4 uric acid. A treatment delay of \> 2 weeks due to an adverse event (delays due to dental procedures are not included). Grade 4 neutropenia (absolute neutrophil count \<500/µL lasting \> 5 days. Febrile neutropenia. Grade 3 thrombocytopenia lasting for 7 days or more or thrombocytopenia \< 50K/µL requiring platelet transfusion for bleeding.

  First two cycles of treatment (each cycle is 21 days), approximately 42 days.

Secondary Outcomes (1)

• Number of Participants With Serious and Non-serious Adverse Events Assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0)

  Adverse events were assessed from the date treatment consent signed to date off study, approximately 45 months and 14 days for Arm A; 43 months and 14 days for Arm B; 9 months and 11 days for DL1; 27 months and 1 day for DL2; & 11 months & 25 days for DL3

Other Outcomes (2)

• Number of Participants With a Dose Limiting Toxicities (DLTs)

  First two cycles of treatment (each cycle is 21 days), approximately 42 days.

• Number of Participants Achieving Prostatic-Specific Antigen (PSA) Decline of 30% or 50% From Baseline

  up to 38 months

Study Arms (3)

combination of cabozantinib, docetaxel and prednisone

EXPERIMENTAL

combination of cabozantinib, docetaxel and prednisone

Drug: Cabozantinib; Drug: Docetaxel; Drug: Prednisone

PII/ Arm 1-docetaxel + prednisone only

ACTIVE COMPARATOR

docetaxel + prednisone only

Drug: Docetaxel; Drug: Prednisone

PII/Arm 2 -docetaxel+ prednisone + cabozantinib

ACTIVE COMPARATOR

docetaxel+ prednisone + cabozantinib

Drug: Cabozantinib; Drug: Docetaxel; Drug: Prednisone

Interventions

Cabozantinib DRUG

Assigned dose given daily during each 21 day cycle. Treatment may continue until disease progression or intolerable toxicity.

Also known as: Cometriq

PII/Arm 2 -docetaxel+ prednisone + cabozantinib; combination of cabozantinib, docetaxel and prednisone

Docetaxel DRUG

75mg/m\^2 intravenous (IV) over approximately 60 minutes on cycle 1 day 1 and repeated every 21 days until disease progression or intolerable toxicity.

Also known as: Taxotere

PII/ Arm 1-docetaxel + prednisone only; PII/Arm 2 -docetaxel+ prednisone + cabozantinib; combination of cabozantinib, docetaxel and prednisone

Prednisone DRUG

5 mg by mouth (PO) twice a day during each 21 day cycle until disease progression or intolerable toxicity.

Also known as: Deltasone

PII/ Arm 1-docetaxel + prednisone only; PII/Arm 2 -docetaxel+ prednisone + cabozantinib; combination of cabozantinib, docetaxel and prednisone

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must have metastatic, progressive, castrate resistant prostate cancer (CRPC). There must be radiographic evidence of disease after primary treatment with surgery or radiotherapy that has continued to progress radiographically or biochemically (rising PSA levels on successive measurements) despite adequate androgen-deprivation therapy, which is defined as having undergone bilateral surgical castration or continued treatment on GnRH agonists or antagonists.
• Progression must be evidenced and documented by any of the following parameters:
• Two consecutively rising PSA values, above the baseline, at a minimum of 1- week intervals
• Appearance of one or more new lesions on bone scan
• Progressive measurable disease by RECIST 1.1
• The use of androgen receptor inhibitors is not required prior to study entry. For those patients receiving an anti-androgen agent (flutamide, bicalutamide, or nilutamide), for at least 6 consecutive months immediately prior to study entry, and are entering the trial due to a rise in PSA, they must demonstrate a continued rise in PSA within 4 weeks after stopping flutamide and within 6 weeks after stopping bicalutamide or nilutamide. Flutamide, nilutamide and bicalutamide disease progression requirements only apply to patients who have been on these drugs for at least the prior 6 months.
• Histopathological confirmation of prostate cancer by the Laboratory of Pathology of the National Cancer Institute (NCI) Pathology Department of the Walter Reed National Military Medical Center or YALE is required prior to entering this study. Patients whose pathology specimens are no longer available may be enrolled if the patient has a clinical course that is consistent with prostate cancer and available documentation from an outside pathology laboratory of the diagnosis. All efforts should be made to have the material forwarded to the research team for use in correlative studies in cases where original tissue blocks or archival biopsy material is available.
• Patients must have metastatic disease, defined as at least one lesion on bone scan or at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam.
• Patients must have a performance status of 0 to 2 according to the ECOG criteria.
• Patients must have adequate bone marrow, hepatic, and renal function with:
• Hemoglobin greater than or equal to 9 grams per deciliter
• Leukocytes greater than or equal to 3000 per microliters
• ANC greater than or equal to 1500 per microliters, without CSF support
• Platelets greater than or equal to 100,000 per microliters
• AST (SGOT) less than or equal to 2.5 times upper limit of normal (ULN)

You may not qualify if:

• The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment
• The subject is unable to swallow tablets
• The subject has tumor invading (or there is concern for invasion of) major blood vessel
• The subject has active brain metastases or epidural disease Subjects with brain metastases previously treated with whole brain radiation or radiosurgery or subjects with epidural disease previously treated with radiation or surgery who are asymptomatic and do not require steroid treatment for at least 2 weeks before starting study treatment are eligible. Neurosurgical resection of brain metastases or brain biopsy is permitted if completed at least 3 months before starting study treatment. Baseline brain scans are not required to confirm eligibility.
• The subject requires concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel). Low dose aspirin (less than or equal to 81 milligrams per day), low-dose warfarin (less than or equal to1 milligrams per day), and prophylactic low molecular weight heparin (LMWH) are permitted.
• The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) greater than 500 milliseconds within 28 days before initiation of protocol therapy. Note: if initial QTcF is found to be greater than 500 milliseconds, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is less than or equal to 500 milliseconds, the subject meets eligibility in this regard.
• Patients with contraindication to steroid use
• Prior treatment with cabozantinib
• The patient has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or nitrosoureas or mitomycin within 6 weeks before the first dose of study treatment.
• The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal therapy (including investigational kinase inhibitors or hormones) within 14 days or five half-lives of the compound or active metabolites, whichever is longer, before the first dose of study treatment with the exception of patients receiving prior abiraterone or ketoconazole. For patients receiving prior abiraterone or ketoconazole, they must discontinue the medication within 5 half lives of the compound before the first dose of study treatment in order to participate in this study. Note: Subjects with prostate cancer currently receiving LHRH or GnRH agonists must be maintained on these agents.
• The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
• The subject has received radiation therapy:
• to the thoracic cavity or gastrointestinal tract within 3 months before the first dose of study treatment
• to bone or brain metastasis within 14 days before the first dose of study treatment
• to any other site(s) within 28 days before the first dose of study treatment

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, Eisenberger MA, Higano C, Bubley GJ, Dreicer R, Petrylak D, Kantoff P, Basch E, Kelly WK, Figg WD, Small EJ, Beer TM, Wilding G, Martin A, Hussain M; Prostate Cancer Clinical Trials Working Group. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26(7):1148-59. doi: 10.1200/JCO.2007.12.4487.

  PMID: 18309951 BACKGROUND

• Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010 Sep-Oct;60(5):277-300. doi: 10.3322/caac.20073. Epub 2010 Jul 7.

  PMID: 20610543 BACKGROUND

• Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, Burch PA, Berry D, Moinpour C, Kohli M, Benson MC, Small EJ, Raghavan D, Crawford ED. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004 Oct 7;351(15):1513-20. doi: 10.1056/NEJMoa041318.

  PMID: 15470214 BACKGROUND

• A phase I and randomized phase II study of cabozantinib plus docetaxel and prednisone (C+DP) versus docetaxel and prednisone (DP) alone in metastatic castrate-resistant prostate cancer (mCRPC). Munjid Al Harthy, Ravi Amrit Madan, Fatima Karzai, Daniel Peter Petrylak, Joseph W. Kim, Philip M. Arlen, Marc Robert Theoret, Jenn Marte, Marijo Bilusic, Anna Couvillon, Guinevere Chun, Helen Owens, Amy Hankin, Lisa M. Cordes, William Douglas Figg, James L. Gulley, and William L. Dahut Journal of Clinical Oncology 2019 37:7_suppl, 173-173

  RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Prostatic Neoplasms

Interventions

cabozantinib; Docetaxel; Prednisone

Condition Hierarchy (Ancestors)

Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Dr. William Dahut
• Organization: National Cancer Institute

william_dahut@nih.gov

240-760-6070

Study Officials

• William L Dahut, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: September 8, 2012
• First Posted: September 12, 2012
• Study Start: September 7, 2012
• Primary Completion: July 1, 2018
• Study Completion: January 16, 2019
• Last Updated: November 8, 2019
• Results First Posted: November 8, 2019

Record last verified: 2019-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)