| Eligibility |
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.
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