Cabozantinib and Androgen Ablation in Patients With Androgen-Dependent Metastatic Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Intervention: Cabozantinib; Androgen Ablation Therapy
Intervention description: Starting dose of 60 mg by mouth every day of a 21 day cycle.; Androgen ablation therapy, either by means of luteinizing hormone-releasing hormone super-agonist (of any formulation), LHRH antagonist, or surgical castration given upon decision of study doctor.
Intervention MeSH terms: Androgens
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 62.0
Sex: Male
Healthy volunteers: No
Keywords: Prostate Cancer; Metastatic Prostate Cancer; Prostate adenocarcinoma; Androgen-Dependent Prostate Cancer; Cabozantinib; XL 184; Androgen Ablation

Summary:

      The goal of this clinical research study is learn if adding cabozantinib (also known as
      XL184) to hormonal therapy can help to control prostate cancer. The safety of this drug will
      also be studied.

      Cabozantinib is designed to block certain proteins in your blood that cause cancer cells to
      grow. This may cause cancer cells to die.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Histologic proof of prostate adenocarcinoma

          2. Newly diagnosed Androgen-Dependent Prostate Cancer. Patients already on ADT are
             eligible as long as the time from initiation of LHRH analog or antagonist is not
             greater than 3 months.

          3. Metastatic disease on bone scan and/or involvement of soft tissues (lymph nodes and/or
             viscera) by CT scan, PET/CT, or MRI

          4. PSA > 1 ng/ml, unless anaplastic features are present (according to eligibility 10)

          5. Life expectancy from a co-morbid illness > 3 years

          6. Eastern Cooperative Oncology Group (ECOG) performance status </= 2

          7. Patients must have adequate organ function as defined by: Absolute Neutrophil Count
             (ANC) >/= 1,500/ul (unless due to bone marrow infiltration by tumor in which case ANC
             >/=500/ml are allowed) Hemoglobin (Hgb) >/= 9 gm/dL (unless due to bone marrow
             infiltration by tumor in which case Hgb>8 gm/dL); Total bilirubin </= 1.5times the
             upper limit of normal (ULN). For patients with known Gilbert's disease, total
             bilirubin should be </= 3mg/dL; platelet count >/= 100,000/mm^3 (unless due to bone
             marrow infiltration by tumor in which case >/=50,000/ml are allowed); Alanine
             aminotransferase (ALT) and aspartate aminotransferase (AST) </= 3.0 x ULN if no liver
             involvement, or </= 5 x ULN with liver involvement; Lipase < 2 x the upper limit of
             normal; Urine protein/creatinine ratio (UPCR) </= 1; Serum phosphorus >/= lower limits
             of normal (LLN); estimated creatinine clearance of >/=40 ml/min.

          8. Prior ADT is allowed if it was an adjunct to definite local therapy, was given for
             </=1 year and was completed at least 12 months before initiating therapy for
             metastatic disease.

          9. Prior therapy with other tyrosine kinase inhibitors (TKI) inhibitors or any other type
             of investigational agent is allowed if it was an adjunct to definitive local therapy,
             was given for </=6 months, and was completed at least 12 months before initiating
             therapy for metastatic disease.

         10. Patients with "anaplastic" features are eligible for this trial as defined by at least
             one of the following: a) Any of the following metastatic presentations: exclusive
             visceral metastases, radiographically predominant lytic bone metastases identified by
             plain X-ray or CT scan, bulky (>5 cm in longest dimension) lymphadenopathy or
             high-grade (gleason >8) tumor mass in the prostate/pelvis.; b) Low PSA (</= 10 ng/ml)
             at initial presentation (prior to androgen ablation or at symptomatic progression in
             the castrate-setting) plus high volume (>/=20) bone metastases.; c) Elevated serum LDH
             (>/= 2 x ULN) or elevated serum CEA (>/= 2 x ULN) in the absence of other etiologies.;
             d) Short interval (</= 180 days) to castrate-resistant progression following
             initiation of hormonal therapy.

         11. Sexually active fertile subjects, and their partners, must agree to use medically
             accepted methods of contraception (eg, 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 drug(s).

        Exclusion Criteria:

          1. Biological agents (antibodies, immune modulators, cytokines, or vaccines) or
             radionuclide treatment within 6 weeks of the first dose of study treatment.

          2. Radiation therapy within 2 weeks prior to initiation of study treatment.

          3. Symptomatic or uncontrolled brain metastasis or epidural disease requiring current
             treatment including steroids and anti-convulsant.

          4. The subject has had another diagnosis of malignancy requiring systemic treatment
             within the last two years, unless non-melanoma skin cancer, or superficial bladder
             cancer.

          5. The subject has uncontrolled or significant intercurrent illness including, but not
             limited to, the following conditions: Chronically uncontrolled hypertension, defined
             conventionally as consistent and repeated systolic pressures above 140 mmHg or
             diastolic pressures above 90 mmHg despite anti-hypertensive therapy. This may be
             better established with home BP readings than with clinic visit results. There is no
             criterion related to a specific BP result required for eligibility, nor are acute BP
             elevations that are related to iatrogenic causes, acute pain, or other transient
             reversible causes considered to be an exclusion criteria. The intent is to exclude
             patients with chronically uncontrolled hypertension that might be further exacerbated
             by Cabozantinib.

          6. Continued from # 5) Other cardiovascular disorders such as symptomatic congestive
             heart failure (CHF), unstable angina pectoris, clinically-significant cardiac
             arrhythmias, history of stroke (including transient ischemic attack [TIA], or other
             ischemic event) within 6 months of study treatment, myocardial infarction within 6
             months of study treatment, history of thromboembolic event requiring therapeutic
             anticoagulation within 6 months of study treatment or main portal vein or vena cava
             thrombosis or occlusion. ;Gastrointestinal (GI) disorders particularly those
             associated with a high risk of perforation or fistula formation including: Any of the
             following at the time of screening; a) intra-abdominal tumor/metastases invading GI
             mucosa b) active peptic ulcer disease, c) inflammatory bowel disease (including
             ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic
             cholangitis or appendicitis

          7. Continued from # 6) Any of the following within 6 months before the first dose of
             study treatment: a) history of abdominal fistula b) gastrointestinal perforation c)
             bowel obstruction or gastric outlet obstruction; d) intra-abdominal abscess. Note:
             Complete resolution of an intra-abdominal abscess must be confirmed prior to
             initiating treatment with cabozantinib even if the abscess occurred more that 6 months
             ago. GI surgery (particularly when associated with delayed or incomplete healing)
             within 28 days. Note: Complete healing following abdominal surgery must be confirmed
             prior to initiating treatment with cabozantinib even if surgery occurred more that 28
             days ago. Other disorders associated with a high risk of fistula formation including
             PEG tube placement within 3 months before the first dose of study therapy or
             concurrent evidence of intraluminal tumor involving the trachea and esophagus.

          8. The subject is unable to swallow capsules tablets

          9. The subject has a previously-identified allergy or hypersensitivity to components of
             the study treatment formulation.

         10. Oral corticosteroids >/= 7.5mg/day prednisone (or prednisone equivalents).

         11. Prior treatment with cabozantinib.

         12. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
             >500 ms within 28 days before randomization.