Safety, Pharmacokinetic and Proof-of-Concept Study of ARN-509 (Apalutamide) in Castration-Resistant Prostate Cancer (CRPC)

Aragon Pharmaceuticals

Status and phase: Completed; Phase 2; Phase 1

Conditions: Prostate Cancer

Treatments: Drug: ARN-509 (Phase 2); Drug: ARN-509 (Phase 1)

Study type: Interventional

Funder types: Industry

Identifiers

NCT01171898

ARN-509-001 (Other Identifier)

CR103304

Details and patient eligibility

About

The purpose of this study is to assess the safety and activity of ARN-509 in men with advanced castration resistant prostate cancer. Patients will first be enrolled into Phase 1 of the study to identify a tolerable dose for the Phase 2 portion of the study. In the Phase 2, 3 different cohorts of patients will be enrolled to evaluate the safety and activity of ARN-509.

Enrollment: 127 patients

Sex: Male

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

NON-METASTATIC CRPC

Inclusion Criteria

1. Histologically or cytologically proven prostate cancer with high risk for development of metastases, defined as either a PSA value >=8 ng/mL within the last 3 months or PSA Doubling Time <=10 months
2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. A life expectancy of at least 3 months

Exclusion Criteria

1. Distant metastases, including CNS and vertebral or meningeal involvement
2. Prior treatment with MDV3100
3. Prior treatment with abiraterone
4. Prior treatment with ketoconazole
5. Concurrent treatment with medications known to have seizure potential
6. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
7. QTc > 450 msec
8. History of seizure or condition that may predispose to seizure
9. Evidence of severe or uncontrolled systemic disease or HIV infection

METASTATIC CRPC, TREATMENT-NAIVE

Inclusion Criteria

1. Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression
2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. A life expectancy of at least 3 months

Exclusion Criteria

1. History of, or current metastases in the brain or untreated spinal cord compression
2. Prior treatment with MDV3100
3. Prior treatment with abiraterone
4. Prior treatment with ketoconazole
5. Concurrent treatment with medications known to have seizure potential
6. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
7. QTc > 450 msec
8. History of seizure or condition that may predispose to seizure
9. Evidence of severe or uncontrolled systemic disease or HIV infection

METASTATIC CRPC, CHEMOTHERAPY-NAIVE, POST-ABIRATERONE

Inclusion Criteria

1. Histologically or cytologically proven prostate cancer with progressive disease based on either PSA or radiographic progression
2. Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH) analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration)
3. Castrate levels of serum testosterone of less than or equal to 50 ng/dL
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
5. A life expectancy of at least 3 months
6. Patients must have received a minimum of 6 months of abiraterone treatment prior to disease progression

Exclusion Criteria

1. History of, or current metastases in the brain or untreated spinal cord compression
2. Prior treatment with MDV3100
3. Prior treatment with ketoconazole
4. Concurrent treatment with medications known to have seizure potential
5. Concurrent treatment with corticosteroids. If they are already on steroids, patients will be allowed to enroll on the study but will need to taper off as soon as possible.
6. QTc > 450 msec
7. History of seizure or condition that may predispose to seizure
8. Evidence of severe or uncontrolled systemic disease or HIV infection

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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127 participants in 4 patient groups

Dose Escalation Cohort (Phase 1)

Experimental group

Description:

ARN-509 will be administered at a starting dose of 30 milligram per day (mg/day), with escalations to 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, 390 mg, and 480 mg daily. Once Recommended Phase 2 Dose (RP2D) has been selected, Phase 1 participants being treated at the lower dose levels will be allowed to escalate to the RP2D level at the discretion of the primary investigator.

Treatment:

Drug: ARN-509 (Phase 1)

Non-metastatic CRPC (Phase 2)

Experimental group

Description:

Participants with non-metastatic, treatment-naive Castration-Resistant Prostate Cancer (CRPC) with rapidly rising Prostate Specific Antigen (PSA) will be enrolled. ARN-509 will be administered at Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D), determined in Phase 1.

Treatment:

Drug: ARN-509 (Phase 2)

Treatment-naive metastatic CRPC (Phase 2)

Experimental group

Description:

Participants with treatment-naive metastatic CRPC will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.

Treatment:

Drug: ARN-509 (Phase 2)

Post-abiraterone metastatic CRPC (Phase 2)

Experimental group

Description:

Participants with metastatic CRPC that are chemotherapy-naive, but have been previously treated with abiraterone will be enrolled. ARN-509 will be administered at MTD and/or RP2D, determined in Phase 1.

Treatment:

Drug: ARN-509 (Phase 2)