Clinical trial NCT00953576
Conditions: Prostate Cancer
Keywords: castration resistant prostate cancer KHAD
Sponsor: Dana-Farber Cancer Institute
Start date: 2009-09-29; Completion date: 2013-04-11
Enrollment: 11 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this research study is to determine the safety of giving ketoconazole, hydrocortisone and dutasteride (KHAD) with lapatinib. Safety is primarily based on dose limiting toxicity (DLT) evaluation at various dose levels (DL). The investigators believe that there is evidence in castrate resistant prostate cancer (CRPC) that two growth factor receptors (EGFR and Her 2/Neu) are increased in prostate cancer (PCa) cells. Both these receptors are turned off by the drug lapatinib. By adding lapatinib, the investigators hope that signaling from the receptors will be turned off and therefore make the participant's cancer more responsive to KHAD treatment.

Detailed description:
The current study builds on investigators' KHAD experience by further targeting pathways that may still be enhancing AR activity despite reduced testosterone and DHT. Importantly, studies from several groups have shown that EGFR and Her2/Neu activation can enhance AR signaling and increase AR transcriptional activity in response to low levels of androgens. Evaluation in the clinic and lab has shown that there is increased expression of EGFR or Her2/Neu in CRPC. In addition to upregulation in EGFR and Her2/Neu protein expression, signaling through these receptors may be enhanced in some tumors by increases in growth factor levels or other mechanisms. Based on these results, the investigators suggest that EGFR and Her2/Neu contribute to enhancing AR transcriptional activity especially at low androgen levels. If this hypothesis is correct, then dual blockade of EGFR and Her2/Neu in CRPC should enhance the ability of KHAD to abrogate AR activity. Moreover, as androgens can protect PCa cells from cell death in response to EGFR/Her2/Neu/PI3 kinase pathway inhibition, we propose that KHAD plus lapatinib may be a particularly active combination therapy for CRPC.

Arms: arm 1: For the initial four weeks (1 cycle=28 days), participants receive KHAD treatment.

Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day

Participants start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: 250 mg orally 1x day

Participants are treated until unacceptable toxicity, disease progression or withdrawal. arm 2: For the initial four weeks (1 cycle=28 days), participants will receive KHAD treatment.

Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day

Participants will start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: 500 mg orally 1x day arm 3: For the initial four weeks (1 cycle=28 days), participants receive KHAD treatment.

Ketoconazole: 400 mg orally 3x day Hydrocortisone: 30 mg (a.m.) and 10 mg (p.m.) orally 2x day Dutasteride: 0.5 mg orally 1x day

Participants start KHLAD on day 29 or d1 of cycle 2/ week 5. Lapatinib: according to the established dose escalation schedule

Participants are treated until unacceptable toxicity, disease progression or withdrawal.
Interventions: intervention 1: ketoconazole intervention 2: hydrocortisone intervention 3: dutasteride intervention 4: lapatinib
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol documents: