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Cabozantinib in Men With Castration-Resistant Prostate Cancer

This study has been terminated.
(Closed 2017 for low accrual. Last data for primary outcome on 02Feb2015.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT01703065
First Posted: October 10, 2012
Last Update Posted: December 5, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
Prostate Cancer Foundation
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Celestia Higano, University of Washington
October 5, 2012
October 10, 2012
December 5, 2017
June 18, 2013
February 2, 2015   (Final data collection date for primary outcome measure)
Change in urinary N-telopeptide (uNTX) [ Time Frame: Baseline and 6 weeks ]
To be assessed pre and during treatment
Change in urinary N-telopeptide (uNTX) [ Time Frame: Baseline and 6 weeks ]
Will be analyzed after log-transformation.
Complete list of historical versions of study NCT01703065 on ClinicalTrials.gov Archive Site
  • Changes in dynamic histomorphometry of bone biopsy samples [ Time Frame: Baseline and at 6 weeks ]
    Assessment of samples from bone biopsies
  • Changes in serum markers of bone metabolism [ Time Frame: Baseline, 6 weeks and 12 weeks ]
    Markers of bone metabolism in blood include bone specific alkaline phosphatase, alkaline phosphatase, LDH.
  • Changes in biomarker expression in bone biopsy samples [ Time Frame: Baseline and at 6 weeks ]
    To include MET, AKT, FASN and VEGFR2 expression and phosphorylation status (activation) in osteoblasts/osteoclasts and prostate cancer cells. Will also include changes in markers of apoptosis, proliferation, and angiogenesis.
  • Changes in miRNA expression in the serial blood samples [ Time Frame: Baseline and at 6 weeks ]
    To be assessed pre and during treatment
  • Toxicity assessed using CTCAE version 4.0 [ Time Frame: Up to 4 weeks post-treatment ]
    Toxicity will be described by grade and frequency.
  • Progression-free survival [ Time Frame: Up to 4 weeks post-treatment ]
    Kaplan-Meier methods will be used to report progression-free survival.
  • Time to progression [ Time Frame: From date of registration to date of progressive disease, assessed up to 4 weeks post-treatment ]
    Kaplan-Meier methods will be used to report time to progression.
  • Objective response [ Time Frame: Up to 4 weeks post-treatment ]
    Proportions and 95% binomial confidence intervals will be reported for objective response.
  • PSA response [ Time Frame: Up to 4 weeks post-treatment ]
    Proportions and 95% binomial confidence intervals will be reported for PSA response.
  • Duration of response [ Time Frame: Up to 4 weeks post-treatment ]
    Mean and the corresponding standard deviation will be used to describe the duration of response among responders.
  • Changes in dynamic histomorphometry of involved and uninvolved bone [ Time Frame: Baseline and 12 weeks ]
    Logistic models will be used.
  • Changes in bone and serum markers of bone metabolism [ Time Frame: Baseline and 6 weeks ]
    Will be explored using a linear mixed model to determine if there is a difference in these markers over time between patients with progressive disease and those without.
  • Changes in MET, AKT, FASN and VEGFR expression and phosphorylation status (activation) in osteoblasts or osteoclasts and prostate cancer cells from bone biopsy specimens [ Time Frame: Baseline and 6 weeks ]
    Will be explored using a linear mixed model to determine if there is a difference in these markers over time between patients with progressive disease and those without.
Not Provided
Not Provided
 
Cabozantinib in Men With Castration-Resistant Prostate Cancer
A Pilot Study of the Effects of Cabozantinib (XL184) on Bone Turnover and the Microenvironment in Men With Non-Metastatic and Metastatic Castration-Resistant Prostate Cancer
This pilot clinical trial studies cabozantinib in treating men with castration-resistant prostate cancer. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Primary Outcome Measure:

  1. Change in urinary N-telopeptide (uNTX)

    Secondary Outcome Measures:

  2. Changes in dynamic histomorphometry of bone biopsy samples
  3. Changes in serum markers of bone metabolism. Markers of bone metabolism in blood include bone specific alkaline phosphatase, alkaline phosphatase, LDH.
  4. Changes in biomarker expression in bone biopsy samples. To include MET, AKT, FASN and VEGFR2 expression and phosphorylation status (activation) in osteoblasts/osteoclasts and prostate cancer cells. Will also include changes in markers of apoptosis, proliferation, and angiogenesis.
  5. Changes in miRNA expression in the serial blood samples

OUTLINE:

Patients receive cabozantinib orally (PO) once daily (QD) in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

Interventional
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Two separate patient population arms (metastatic CRPC and non-metastatic CRPC) but both populations are given the same interventional treatment and the same safety assessments.
Masking: None (Open Label)
Masking Description:
Treatment is open label and non-randomized. Split in to two patient populations - metastatic CRPC and non-metastatic CRPC.
Primary Purpose: Treatment
  • Adenocarcinoma of the Prostate
  • Castration-resistant Prostate Cancer
  • Recurrent Prostate Cancer
  • Stage III Prostate Cancer
  • Stage IV Prostate Cancer
Drug: Cabozantinib
Given orally once a day
Other Names:
  • BMS-907351
  • Cometriq
  • XL184
  • cabozantinib-s-malate
  • Experimental: Cabozantinib in metastatic CRPC
    Metastatic CRPC patients to receive cabozantinib PO QD in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Cabozantinib
  • Experimental: Cabozantinib in non-metastatic CRPC
    Non-Metastatic CRPC patients to receive cabozantinib PO QD in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Cabozantinib
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Terminated
9
September 18, 2015
February 2, 2015   (Final data collection date for primary outcome measure)

INCLUSION CRITERIA

  1. The subject has a proven histologic diagnosis of prostate adenocarcinoma, but may have undergone prior surgery and/or radiation.
  2. The subject must currently have castration resistant prostate cancer defined as 2 serial rising PSAs with a castrate level of testosterone (<50 ng/dL).
  3. A subject with non-metastatic CRPC may not have received prior chemotherapy unless in the neoadjuvant or adjuvant setting > 24 months ago and may not have received prior zoledronic acid or denosumab.
  4. A subject with metastatic CRPC must have bone metastases accessible for biopsy by CT guidance.
  5. The subject must be willing to undergo sequential biopsy of bone or bone metastases.
  6. Subjects must have discontinued additional hormonal (eg bicalutamide, abiraterone, estrogen) therapy prior to the first dose of cabozantinib. No antiandrogen withdrawal period is required.
  7. Subjects previously treated on another investigational agent must have a 2-week or more washout before starting cabozantinib, depending on the agent, toxicity profile, and half-life. However, such patients may begin tetracycline dosing after consent is signed.
  8. Subjects who are currently on GnRH agonists or antagonist therapy must continue androgen suppression.
  9. The subject is ≥18 years old on day of consent.
  10. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1.
  11. Organ and marrow function as follows:

    1. ANC ≥1500/mm3 without colony stimulating factor support.
    2. Platelets ≥100,000/mm3.
    3. Hemoglobin ≥9 g/dL.
    4. Total bilirubin ≤1.5 x the upper limit of normal (ULN). For subjects with known Gilbert's disease, bilirubin≤3.0 mg/dL.
    5. Serum albumin ≥2.8g/dL.
    6. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance >50 mL/min. The Cockcroft and Gault equation should be used: Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72).
    7. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x ULN.
    8. Lipase <2.0 × ULN and no radiologic or clinical evidence of pancreatitis.
    9. Serum testosterone level <50 ng/dL.
    10. Urine protein/creatinine (UPC) ratio ≤1.0 unless the patient has a neobladder.
    11. Serum phosphorus, magnesium, calcium and potassium ≥ lower limit of normal (LLN).
  12. The subject is capable of understanding and complying with the protocol requirements and has signed the informed consent document.
  13. Sexually active subjects and their partners must agree to use medically accepted barrier methods of contraception (eg, male or female condom) during the course of the study and for 4 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must agree to use both a barrier method and a second method of birth control during the course of the study.

EXCLUSION CRITERIA

  1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment.
  2. Prior treatment with cabozantinib and other met inhibitors.
  3. 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, or before the first dose of study treatment.
  4. The subject has received radiation therapy:

    1. to the thoracic cavity or gastrointestinal tract within 3 months of the first dose of study treatment.
    2. to bone or brain metastasis within 14 days of the first dose of study treatment.
    3. to any other site(s) within 28 days of the first dose of study treatment.
  5. The subject has received radionuclide treatment within 6 weeks of the first dose of study treatment.
  6. The subject has received any other type of investigational agent within 28 days before the first dose of study treatment.
  7. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs.
  8. The subject has a primary brain tumor.
  9. The subject has active brain metastases or epidural disease (Note: 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.)
  10. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial thromboplastin time (PTT) test results at screening ≥ 1.3 x the laboratory ULN.
  11. 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 (eg, clopidogrel). Low dose aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low molecular weight heparin (LMWH) are permitted.
  12. The subject requires chronic concomitant treatment of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John's Wort). Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.asp; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.
  13. The subject has experienced any of the following:

    1. clinically-significant gastrointestinal bleeding within 6 months before the first dose of study treatment.
    2. hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months before the first dose of study treatment.
    3. any other signs indicative of pulmonary hemorrhage within 3 months before the first dose of study treatment.
  14. The subject has radiographic evidence of cavitating pulmonary lesion(s).
  15. The subject has tumor in contact with, invading or encasing major blood vessels.
  16. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor within 28 days before the first dose of cabozantinib.
  17. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:

    a. Cardiovascular disorders including: i. Congestive heart failure (CHF): New York Heart Association (NYHA) Class III (moderate) or Class IV (severe) at the time of screening.

    ii. Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment within 7 days before the first dose of study treatment.

    iii. Any history of congenital long QT syndrome. iv. Any of the following within 6 months before the first dose of study treatment:

    • unstable angina pectoris
    • clinically-significant cardiac arrhythmias
    • stroke (including TIA, or other ischemic event)
    • myocardial infarction
    • thromboembolic event requiring therapeutic anticoagulation (Note: subjects with a venous filter (e.g. vena cava filter) are not eligible for this study) b. Gastrointestinal disorders particularly those associated with a high risk of perforation or fistula formation including: i. Any of the following within 28 days before the first dose of study treatment:
    • intra-abdominal tumor/metastases invading GI mucosa
    • active peptic ulcer disease
    • inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis
    • malabsorption syndrome ii. Any of the following within 6 months before the first dose of study treatment:
    • abdominal fistula
    • gastrointestinal perforation
    • bowel obstruction or gastric outlet obstruction
    • intra-abdominal abscess. Note: Complete resolution of an intraabdominal abscess must be confirmed prior to initiating treatment with cabozantinib even if the abscess occurred more that 6 months before the first dose of study treatment.

      c. Other disorders associated with a high risk of fistula formation including PEG tube placement within 3 months before the first dose of study therapy.

      d. Other clinically significant disorders such as: i. active infection requiring systemic treatment within 28 days before the first dose of study treatment ii. serious non-healing wound/ulcer/bone fracture within 28 days before the first dose of study treatment iii. history of organ transplant iv. concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days before the first dose of study treatment v. history of major surgery as follows:

    • Major surgery within 3 months of the first dose of cabozantinib if there were no wound healing complications or within 6 months of the first dose of cabozantinib if there were wound complications
    • Minor surgery within 1 months of the first dose of cabozantinib if there were no wound healing complications or within 3 months of the first dose of cabozantinib if there were wound complications In addition, complete wound healing from prior surgery must be confirmed at least 28 days before the first dose of cabozantinib irrespective of the time from surgery
  18. The subject is unable to swallow tablets.
  19. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms within 28 days before Day 1 of Cycle 1. Note: if initial QTcF is found to be > 500 ms, two additional EKGs separated by at least 3 minutes should be performed. If the average of these three consecutive results for QTcF is ≤500 ms, the subject meets eligibility in this regard.
  20. The subject has a previously identified allergy or hypersensitivity to components of the study treatment formulation.
  21. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.
  22. For disease specific studies: The subject has had evidence within 2 years of the start of study treatment of another malignancy which required systemic treatment.
  23. The subject has a known allergy to tetracycline.
Sexes Eligible for Study: Male
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT01703065
7819
NCI-2012-01898 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA015704 ( U.S. NIH Grant/Contract )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Plan to Share IPD: No
Plan Description: We do not plan to make individual participant data (IPD) available to other researchers.
Celestia Higano, University of Washington
University of Washington
  • Prostate Cancer Foundation
  • National Cancer Institute (NCI)
Principal Investigator: Celestia S Higano, MD Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
University of Washington
November 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP