| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Castrate-Resistant Prostate Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Prostate cancer is the development of cancer in the prostate, a gland in the male reproductive system |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
• To evaluate To evaluate the efficacy in the intent to treat (ITT) population
• To evaluate the efficacy in patients with PTEN-loss tumors by immunohistochemistry (IHC)
|
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the clinical benefit in the ITT population, and in patients with PTEN-loss tumors by IHC
• To evaluate the efficacy in patients with Phosphatase and tensin homolog (PTEN)-loss tumors by next-generation sequencing
• To evaluate the safety in the ITT population and in patients with PTEN-loss tumors by IHC
• To characterize ipatasertib and abiraterone pharmacokinetics
• To characterize ipatasertib exposure and abiraterone exposure in relation to efficacy and safety
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Aged >= 18 years
- Eastern Cooperative Oncology Group performance status of 0 or 1
- Adequate hematologic and organ function test results within 28 days before the first study treatment
- Life expectancy of at least 6 months
- Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined in the protocol
- For enrollment into the China extension cohort, residence in the People's Republic of China
Disease-Specific Inclusion Criteria:
- Histologically confirmed prostate adenocarcinoma without neuroendocrine differentiation or small-cell features
- Consent to provide a formalin-fixed, paraffin-embedded tissue block or a minimum of 15 freshly cut unstained tumor slides from the most recently collected, available tumor tissue accompanied by an associated pathology report
- A valid PTEN IHC result
- Metastatic disease documented prior to randomization by clear evidence of bone lesions by bone scan and/or measurable soft tissue disease by computed tomography (CT) and/ or magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors, Version 1.1(RECIST v1.1)
- Asymptomatic or mildly symptomatic form of prostate cancer
- Progressive disease before initiating study treatment, defined using at least one of the following criteria:
. Two rising prostate-specific antigen (PSA) levels measured >= 1 week apart with second result >= 1 ng/mL according to Prostate Cancer Working Group 3 (PCWG3) criteria (Patients who have received an anti-androgen therapy must have PSA progression after withdrawal [>= 4 weeks since last flutamide or >= 6 weeks since last treatment of bicalutamide or nilutamide])
. Radiographic evidence of disease progression in soft tissue according to RECIST v1.1 and/or bone scan according to PCWG3 criteria
- Ongoing androgen deprivation with gonadotropin-releasing hormone analog or bilateral orchiectomy, with serum testosterone <= 50 ng/dL (<= 2.0 nmol/L) within 28 days before randomization |
|
| E.4 | Principal exclusion criteria |
-Inability or unwillingness to swallow whole pills
-History of malabsorption syndrome/other condition that would interfere with enteral absorption
-Clinically significant history of liver disease consistent with Child-Pugh Class B or C including cirrhosis, current alcohol abuse or current known active infection with hepatitis B or B virus
.Patients positive for anti-HBc are eligible only if test results are negative for HBsAg and polymerase chain reaction is negative for HBV DNA
.Patients positive for HCV serology are eligible only if testing for HCV RNA is negative
-Need of more than 10 mg/day of prednisone or equivalent dose of other anti-inflammatory corticosteroids as a current systemic corticosteroid therapy to treat a chronic disease
-Active infection requiring intravenous antibiotics within 14 days before Day1 Cycle 1 (D1 C1)
-History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias
-History of another malignancy within 5 years prior to randomization except for either adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma in situ, adequately treated non-muscle-invasive urothelial carcinoma of bladder or other malignancies where patient has undergone potentially curative therapy with no evidence of disease and are deemed by treating physician to have a recurrence rate of <5% at 5 years
-Any other diseases, physical examination finding or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that may affect interpretation of results or renders patients at high risk from treatment complications
Disease-Specific Exclusion Criteria
-Pathologic findings consistent with small-cell or neuroendocrine carcinoma of the prostate
-Any therapy including chemotherapy or biological therapy for treatment of castration-resistant prostate cancer. Previous treatment with flutamide, steroidal anti-androgens, androgens, estrogens, bicalutamide, nilutamide, or 5-α reductase inhibitor is permitted
-In setting of chemotherapy received for hormone-sensitive prostate cancer, treatment with chemotherapy initiated more than 6 months after time of first castration. Patients should not have progressed during/within 3 months after completion of chemotherapy-based treatment
-Use of opioid medication for cancer-related pain including codeine and dextropropoxyphene currently or any time within 4 weeks of D1 C1
-Prior treatment with abiraterone/other known potent CYP17 inhibitors or investigational agents that block androgen synthesis. Prior treatment with itraconazole and fluconazole is permitted
-Prior treatment with enzalutamide/other potent androgen-receptor blockers approved or experimental
-Prior treatment with flutamide, steroidal anti-androgens, androgens or estrogens treatment within 4 weeks of C1 D1
-Prior treatment with bicalutamide/nilutamide within 6 weeks of C1 D1
-Prior treatment with 5α reductase inhibitors within 4 weeks of C1 D1
-Prior treatment with systemic radiopharmaceuticals (except for imaging). Focal palliative radiation to treat cancer-related pain is permitted provided that last treatment with radiation is at least 14 days prior to C1 D1
-Prior treatment with approved or experimental therapeutic agents with known inhibition of PI3K pathway, including PI3K inhibitors, AKT inhibitors, and mTOR inhibitors
-Administration of investigational therapeutic agent within 28 days of C1 D1
-Known untreated or active central nervous system (CNS) metastases
-Patients with a history of treated CNS metastases are eligible provided they meet all of the following criteria:
.An evaluable or measurable disease according to inclusion criteria outside the CNS
.Radiographic demonstration of improvement upon completion of CNS-directed therapy and no evidence of interim progression between completion of CNS-directed therapy and screening radiographic study
.No history of intracranial hemorrhage or spinal cord hemorrhage
.Minimum of 2 weeks between completion of radiotherapy and D1 C1 and recovery from significant (Grade >= 3) acute toxicity, with no ongoing requirement for >= 10 mg/day of prednisone or equivalent dose of another corticosteroid
-Any chronic therapy or use of food supplement that is a strong CYP3A4/5 inhibitor or inducer, or sensitive CYP3A substrates with a narrow therapeutic window
Abiraterone-Specific Exclusion Criteria
-Uncontrolled hypertension
-History of pituitary or adrenal dysfunction
-Any ongoing cardiac arrhythmias (including atrial fibrillation) that require medical therapy
Ipatasertib-Specific Exclusion Criteria
-Type 1 or Type 2 diabetes mellitus requiring insulin at study entry
-History of inflammatory bowel disease and active bowel inflammation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 1) Investigator-assessed radiographic progression-free survival (rPFS), per PCWG3 criteria |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1) Overall survival
2) Time to pain progression
3) Time to initiation of cytotoxic chemotherapy for prostate cancer
4) Time to function deterioration per European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 physical function and role functioning
5) Time to PSA progression, per the PCWG3 criteria
6) Time to first opioid use
7) Time to symptomatic skeletal events
8) Objective response rate, per RECIST v1.1 and PCWG3 criteria in patients with measurable disease
9) PSA response rate
10) Investigator-assessed rPFS per PCWG3 criteria
11) Incidence, nature, and severity of adverse events
12) Plasma concentration of ipatasertib and abiraterone
13) Relationship between plasma concentration or PK parameters of ipatasertib and abiraterone, via safety and efficacy endpoints
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-11. Approximately 7 years
12-13. Cycle 1 Day 1, Cycle 1 Day 15, Cycle 3 Day 1, and Cycle 6 Day 1
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|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 97 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| China |
| Costa Rica |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| Thailand |
| United States |
| Russian Federation |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Ireland |
| Italy |
| Norway |
| Poland |
| Portugal |
| Slovenia |
| Spain |
| Sweden |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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