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) from baseline to after 6 weeks of treatment with cabozantinib in men with non-metastatic CRPC.

   Secondary Outcome Measures:

2. Changes in serum markers of bone metabolism from baseline to after 6 weeks of treatment with cabozantinib. Markers of bone metabolism in blood include bone specific alkaline phosphatase, alkaline phosphatase, LDH.

3. 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.

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.

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.