Trial of Dasatinib (Sprycel®) in Subjects With Hormone-refractory Prostate Cancer

Metastatic prostate adenocarcinoma is initially dependent on exogenous androgens for survival
and growth; hence, androgen blockade is a key initial intervention for these patients.
Whether by orchiectomy or by biochemical blockade, androgen deprivation produces objective
regression of prostate cancer in >90% of patients for an average of 1.5-2yrs. Afterwards,
however, the remaining prostate cancer cells become independent of exogenous androgen and
resume their growth. At this stage the disease is referred to as hormone-refractory prostate
cancer (HRPC).

Treatment for HRPC remains unsatisfactory. Only two interventions have been proven through
randomized, prospective studies to confer a survival advantage. Docetaxel administered along
with prednisone or estramsutine increases overall survival by approximately 3 months,
compared with patients treated with mitoxantrone (1,2). In addition, a cell-based vaccine
(APC8015) has recently been shown to confer a similar survival advantage for patients with
HRPC (3). In 127 patients with HRPC randomized to receive the APC8015 vaccine or unactivated
autologous peripheral blood mononuclear cells, there was a 4.5-month increase in median
overall survival for the treated cohort (p = 0.01). Thus additional therapeutic tools are
needed.

Although the mechanisms whereby androgen-independence develops are not yet fully clarified
(7), it is known that malignant progression of prostate cancer involves upregulation of
autocrine growth factors and their receptors (8). The process of autocrine reprogramming
facilitates autonomous growth and metastasis of the tumor cells. For this reason many of the
major novel therapeutic approaches for prostate cancer, currently in clinical trials, are
directed against growth factor signaling pathways involving tyrosine kinase receptors and
their downstream signaling messengers. Among these, recent evidence suggests a centrol role
for the non-receptor tyrosine kinase c-src, in the development, growth, and metastasis of
many human cancers (9,10), including prostate carcinomas. Several SFKs are present in
prostate cancer cells, including c-src, yes, lck, and lyn (11). SFKs are thought to mediate
the signaling pathways of several growth factors and stressors, such as lysophosphatidic
acid, bombesin, androgens, and hypoxia (12-15). In prostate cancer cells that are
androgen-independent, activation of SFKs is constitutive, rather than ligand-regulated (16).
SFKs in turn regulate such diverse prostate cell pathways as VEGF production (15), and FAK
signaling (17). Among the response phenotypes mediated by SFKs include cell spreading and
attachment, migration and invasion. Genetic and pharmacologic inhibitors of SFKs have been
tested on prostate cancer cell lines. Thus two pyrrolopyrimidine c-src inhibitors were shown
to inhibit production of the protease MMP-9, as well as the functional ability of the cells
to invade Matrigel (18). These phenotypes occurred at inhibitor concentrations that did not
significantly affect cell proliferation. In contrast a peptide inhibitor of the lyn kinase
inhibited the proliferation of prostate cancer cell lines in culture, and reduced the growth
of DU145 xenografts in nude mice (19). Thus a spectrum of responses have been seen in
prostate cancer cells or tumors treated with SFK inhibitors, including inhibition of growth.

Inclusion Criteria:

- Must have biopsy-proven adenocarcinoma of the prostate

- Must have hormone-refractory prostate cancer, defined as an increasing PSA by >= 3
ng/ml from androgen-blockade nadir, or new measurable or evaluable lesion on imaging
studies, after treatment with orchiectomy, luteinizing hormone-releasing hormone
(LHRH) agonist, antiandrogen or diethylstilbestrol (DES)

- Subjects must have received at least one cycle of single-agent or combination
chemotherapy for hormone refractory prostate cancer (HRPC), last administered at least
4 weeks prior to the start of dasatinib

- Subjects may not have received more than one type (single agent or combination) of
chemotherapy regimen; subjects may include (but are not limited to) the following:
HRPC subjects who were treated with palliative chemotherapy and either failed to
respond, or responded for a period of time but now have worsening disease (i.e.
relapsed/refractory to chemotherapy); HRPC subjects who were treated with palliative
chemotherapy but stopped treatment because of toxicity (i.e. intolerant of
chemotherapy); HRPC subjects who have been treated with palliative chemotherapy with
response, whose chemotherapy has been interrupted, and who now have evidence of
progressive disease (i.e. potentially chemotherapy responsive but subject does not
desire to restart cytotoxic drugs)

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

- Life expectancy of at least 8 weeks, based on clinical judgment of the treating
physician

- Adequate hematologic, renal and liver function as evidenced by the following (subjects
may have lower hematologic parameters if the cytopenias are thought by the treating
physician to be secondary to marrow involvement by prostate cancer):

- white blood cell count (WBC) > 2.0 bil/L; grade 0-1

- absolute neutrophil count (ANC) > 1.0 bil/L; grade 0-1

- Platelets > 100 bil/L; grade 0-1

- Hemoglobin > 8.0gm/dL

- Creatinine < 1.5x upper limit of normal (ULN)

- Prothrombin time (PT), Partial Thromboplastin Time (PTT) < 1.2 x ULN; grade 0-1

- Total bilirubin < 2x ULN

- aspartate aminotransferase (AST), alanine aminotransferase (ALT) < 2.5x ULN

- Na, K, Mg, P, Ca >= lower limit of normal

- Elevated PSA level (at least 3 ng/mL), or measurable prostate cancer by CT or MRI
scans (PSA level must have shown two consecutive increases [at >= 14 day intervals]
since the previous nadir)

- Ability to take oral medication (dasatinib must be swallowed whole)

- Subjects of reproductive potential must agree to use an adequate method of
contraception throughout treatment and for at least 4 weeks after study drug is
stopped

- Signed informed consent documents including Health Insurance Portability and
Accountability Act (HIPAA) according to institutional guidelines

- Concomitant Medications: Patient agrees to discontinue St. Johns Wort while receiving
dasatinib therapy (in addition Patient agrees that IV bisphosphonates will be withheld
for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia)

Exclusion Criteria:

- Subjects should have had no chemotherapy within 4 weeks of the start of treatment with
dasatinib

- Prior localized radiotherapy for metastatic disease is permitted, provided the
treatment volume is less than25% of potential marrow space (the radiotherapy must have
been completed 6 weeks prior to enrollment)

- Systemic radiotherapy with samarium-153 must have been completed at least 2 months
prior to enrollment (subjects may not have received prior strontium-89 [Metastron]
therapy)

- At least 6 weeks have elapsed from the last dose of cytotoxic or targeted therapeutics
to the time of prescreening; if the subject has received a combination regimen of
standard chemotherapy plus an investigational agent, a 6 week washout period is
required

- Subjects may not have received treatment with any kinase inhibitor

- At least 2 months must have elapsed from time of dosing with vaccines to the time of
prescreening

- No malignancy, other than prostate cancer, that required radiotherapy or systemic
treatment within the past 5 years

- Subjects may not have any of the following: Clinical evidence of uncontrolled heart
failure, myocardial infarction, or angina within the previous 6 months; prolonged QT
interval Fridericia's (QTcF) > 450msec; history of unstable ventricular arrhythmias
(ventricular tachycardia, ventricular fibrillation, or torsades de pointes);
concomitant use of drugs known to cause torsades de pointes [quinidine, procainamide,
disopyramide, amiodarone, sotalol, ibutilide, dofetilide, erythromycins,
clarithromycin, chlorpromazine, haloperidol, mesoridazine,thioridazine, pimozide,
cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone,
halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine] (these agents must
have been discontinued at least 7 days prior to starting dasatinib); subjects with
hypokalemia or hypomagnesemia are excluded if the electrolyte anomaly cannot be
corrected

- Subjects may not be enrolled with any of the following: History of a significant
bleeding disorder unrelated to cancer, including diagnosed congenital bleeding
disorders (e.g., von Willebrand's disease), and diagnosed acquired bleeding disorder
within one year (e.g., acquired anti-factor VIII antibodies); GI bleeding from any
cause within 3 months; Concomitant use of anticoagulants, except for low-dose warfarin
(for prophylaxis to prevent catheter thrombosis) or heparin flushes (for IV lines), is
prohibited (Note that chronic use of aspirin is prohibited)

- Subjects must meet the following restrictions: Subjects may not have a concurrent
medical condition which may increase the risk of toxicity, including pleural or
pericardial effusion of any grade, or uncontrolled hypertension; Concomitant use of H2
blockers or proton pump inhibitors with dasatinib is not recommended (The use of
antacids should be considered in place of H2 blockers or proton pump inhibitors in
patients receiving dasatinib therapy); Patient must discontinue St. Johns Wort while
receiving dasatinib therapy; Subjects must not use intravenous bisphosphonates during
the first 8 weeks of dasatinib therapy due to risk of hypocalcemia; Subjects may not
be receiving any restricted cytochrome P450 3A4 (CYP3A4) inhibitors (If the
investigator feels that any of these agents should be given as uniquely useful for a
clear diagnosis, the situation should be discussed with the Principal Investigator,
and a clear monitoring program should be planned)

- Subjects may not have evidence of untreated intracranial metastases, or untreated
prostate cancer producing spinal cord compression