Metastatic Castration Resistant Prostate Cancer
Conditions
Keywords
CRPC, PARP inhibitor, RAMP, homologous recombination, DNA repair, DNA defect, DNA anomaly, mCRPC, enzalutamide, abiraterone, Zytiga, Xtandi, ADT, AR, ARi
Brief summary
Assess the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Oral Rucaparib in Combination with Other Anticancer Agents in Patients with Metastatic Castration Resistant Prostate Cancer
Interventions
DRUGRucaparib
Oral rucaparib will be administered twice daily
DRUGEnzalutamide
Enzalutamide will be administered once daily. Enrollment into Arm A will be prioritized over Arm B until the objectives for Arm A have been achieved.
DRUGAbiraterone
Abiraterone will be administered once daily with prednisone
Sponsors
pharmaand GmbH
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Have signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved informed consent form prior to any study-specific evaluation * Be ≥18 yrs of age at the time the informed consent form is signed * Be either AR-directed therapy-naive or have received 1-2 lines of AR-directed therapy in the castration-resistant setting. * Adequate organ function * ECOG 0 or 1 * Have a histologically or cytologically confirmed adenocarcinoma or poorly differentiated carcinoma of the prostate that is metastatic * Be surgically or medically castrated, with serum testosterone levels of ≤ 50 ng/dL (1.73 nM) * Have disease progression after initiation of most recent therapy
Exclusion criteria
* Active second malignancy, with the exception of curatively treated non melanoma skin cancer, carcinoma in situ, or superficial bladder cancer * Have received greater than 2 previous lines of chemotherapy for mCRPC * Prior treatment with any PARP inhibitor * Symptomatic and/or untreated central nervous system metastases * Pre-existing duodenal stent and/or any gastrointestinal disorder or defect that would, in the opinion of the investigator, interfere with absorption of study drug * Spinal cord compression, symptomatic and/or untreated central nervous system (CNS) metastases or leptomeningeal disease. Patients with asymptomatic previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks * Any clinically significant cardiovascular disease * Taking any concomitant medications or herbs that could interfere or interact with the study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | 1 week rucaparib only run-in and 1 cycle (28 days) of combination treatment | Cmin of rucaparib and its metabolite. Rucaparib only run-in Cmin includes run-in D6, D7 and Cycle 1 D1. All of these samples were collected following rucaparib monotherapy. Rucaparib and other anticancer agent Combination Cmin includes Cycle 1 (D8, D15, and D22). |
| Incidence of Dose-Limiting Toxicities (DLTs) in Participants Taking Rucaparib in Combination With Other Anticancer Agents for mCRPC | First 2 cycles of rucaparib combination treatment (56 days) for Arm A | A DLT is defined according to criteria specified in the protocol and assessed by the investigator, based on toxicity grade (according to the NCI CTCAE v5.0), clinical significance, and possible relationship to the study drug combination. The toxicity cannot be a recognized adverse effect of enzalutamide, abiraterone or prednisone/prednisolone and/or attributable to mCRPC or mCRPC-related processes under investigation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | 2 years to complete | The ORR is defined as the proportion of patients with a documented and confirmed best overall response of complete response (CR) or partial response (PR) per mRECIST v1.1 as assessed by the investigator using local standardized radiological methods e.g. CT, MRI, etc. A complete response (CR) is defined as complete disappearance of all target and non-target lesions together with normalization of tumor biomarkers. A partial response (PR) represents at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum LD with non-progression of non-target lesions and no new lesions. Overall Response (OR) = CR + PR. A confirmed CR or PR is a response that is maintained and documented on a subsequent tumor assessment at least 4 weeks after initial response. PSA response per PCWG3 criteria is a confirmed PSA response (≥ 50% decrease from baseline) as reflected by local laboratory measurements. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Oral Rucaparib and Enzalutamide Rucaparib: Oral rucaparib will be administered twice daily
Enzalutamide: Enzalutamide will be administered once daily.
Enrollment into Arm A will be prioritized over Arm B until the objectives for Arm A have been achieved. | 8 |
| Arm B: Oral Rucaparib and Abiraterone Rucaparib: Oral rucaparib will be administered twice daily
Abiraterone: Abiraterone will be administered once daily with prednisone
Arm B was never opened | 0 |
| Total | 8 |
Baseline characteristics
| Characteristic | Arm B: Oral Rucaparib and Abiraterone | Total | Arm A: Oral Rucaparib and Enzalutamide |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 5 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 7 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 0 Participants | 8 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 0 |
| other Total, other adverse events | 8 / 8 | 0 / 0 |
| serious Total, serious adverse events | 2 / 8 | 0 / 0 |
Outcome results
Primary
Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC.
Cmin of rucaparib and its metabolite. Rucaparib only run-in Cmin includes run-in D6, D7 and Cycle 1 D1. All of these samples were collected following rucaparib monotherapy. Rucaparib and other anticancer agent Combination Cmin includes Cycle 1 (D8, D15, and D22).
Time frame: 1 week rucaparib only run-in and 1 cycle (28 days) of combination treatment
Population: Arm B was never open
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A: Oral Rucaparib and Enzalutamide | Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Cmin of rucaparib during 1-week rucaparib only run-in | 1345 ng/ml | Standard Deviation 529 |
| Arm A: Oral Rucaparib and Enzalutamide | Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Cmin of rucaparib metabolite M324 during 1-week rucaparib only run-in | 233 ng/ml | Standard Deviation 103 |
| Arm A: Oral Rucaparib and Enzalutamide | Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Cmin of rucaparib during 1st cycle of rucaparib enzalutamide combo treatment | 1558 ng/ml | Standard Deviation 510 |
| Arm A: Oral Rucaparib and Enzalutamide | Evaluate the PK of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Cmin of rucaparib metabolite M324 during 1st cycle of rucaparib enzalutamide combo treatment | 311 ng/ml | Standard Deviation 161 |
Primary
Incidence of Dose-Limiting Toxicities (DLTs) in Participants Taking Rucaparib in Combination With Other Anticancer Agents for mCRPC
A DLT is defined according to criteria specified in the protocol and assessed by the investigator, based on toxicity grade (according to the NCI CTCAE v5.0), clinical significance, and possible relationship to the study drug combination. The toxicity cannot be a recognized adverse effect of enzalutamide, abiraterone or prednisone/prednisolone and/or attributable to mCRPC or mCRPC-related processes under investigation.
Time frame: First 2 cycles of rucaparib combination treatment (56 days) for Arm A
Population: Number of participants deemed DLT-evaluable~Arm B was never opened
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Oral Rucaparib and Enzalutamide | Incidence of Dose-Limiting Toxicities (DLTs) in Participants Taking Rucaparib in Combination With Other Anticancer Agents for mCRPC | 0 Participants |
| Arm B: Oral Rucaparib and Abiraterone | Incidence of Dose-Limiting Toxicities (DLTs) in Participants Taking Rucaparib in Combination With Other Anticancer Agents for mCRPC | 0 Participants |
Secondary
Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC.
The ORR is defined as the proportion of patients with a documented and confirmed best overall response of complete response (CR) or partial response (PR) per mRECIST v1.1 as assessed by the investigator using local standardized radiological methods e.g. CT, MRI, etc. A complete response (CR) is defined as complete disappearance of all target and non-target lesions together with normalization of tumor biomarkers. A partial response (PR) represents at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum LD with non-progression of non-target lesions and no new lesions. Overall Response (OR) = CR + PR. A confirmed CR or PR is a response that is maintained and documented on a subsequent tumor assessment at least 4 weeks after initial response. PSA response per PCWG3 criteria is a confirmed PSA response (≥ 50% decrease from baseline) as reflected by local laboratory measurements.
Time frame: 2 years to complete
Population: Preliminary ORR could only be evaluated in patients with measurable target lesions at baseline. Only 1 patient had measurable disease at baseline that could be evaluated for a tumor response.~Arm B was never opened
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Oral Rucaparib and Enzalutamide | Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Patients with measurable disease at baseline and a confirmed response of CR or PR by RECISTv1.1 | 1 Participants |
| Arm A: Oral Rucaparib and Enzalutamide | Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Patients inevaluable for response by RECISTv1.1 | 7 Participants |
| Arm B: Oral Rucaparib and Abiraterone | Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Patients with measurable disease at baseline and a confirmed response of CR or PR by RECISTv1.1 | 0 Participants |
| Arm B: Oral Rucaparib and Abiraterone | Preliminary Overall Confirmed Response Rate (ORR) of Rucaparib in Combination With Other Anticancer Agents for mCRPC. | Patients inevaluable for response by RECISTv1.1 | 0 Participants |