| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced Castration-resistant Prostate Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036909 |
| E.1.2 | Term | Prostate cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036920 |
| E.1.2 | Term | Prostate cancer stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10036911 |
| E.1.2 | Term | Prostate cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10036910 |
| E.1.2 | Term | Prostate cancer NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066489 |
| E.1.2 | Term | Progression of prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10062904 |
| E.1.2 | Term | Hormone-refractory prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
•In Stage 1, determine the recommended phase 2 dose (RP2D) of a single agent extended-release tablet formulation of oral onapristone for future clinical development in men with prostate cancer.
• In Stage 2, determine the recommended phase 2 dose of onapristone in combination with abiraterone.
•In Stage 2, determine the response rate of onapristone monotherapy in abiraterone/enzalutamide resistant mCRPC and onapristone-abiraterone combination therapy at the RP2D in abiraterone-resistant mCRPC. |
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| E.2.2 | Secondary objectives of the trial |
• Determine the safety profile of extended-release oral onapristone tablets administered on a chronic BID schedule in this population.
•Study the PK of chronic twice-daily dosing of the extended-release onapristone tablet formulation.
•Evaluate for exposure differences for onapristone or abiraterone indicative of a drug interaction during onapristone-abiraterone combination therapy (Stage 2 only) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male patients, 18 years of age or greater;
2. Histologically confirmed adenocarcinoma of the prostate (without neuroendocrine differentiation or small cell features).
3.In stage 2, for the abiraterone combination arm patients’ disease should have progressed on abiraterone and for the monotherapy arm patients’ disease should have progressed on previous abiraterone or enzalutamide.
4.For Stage 2 only:
a. for patients recruited to the abiraterone-onapristone combination arm, if biopsy is feasible (non-bone lesions are preferred), it should be performed while the patient is on abiraterone
b. for additional patients who are being recruited as T878A positive for the combination arm, the T878A mutation must be confirmed on plasma testing or tumor tissue
c. for patients in the monotherapy arm, if biopsy is feasible (non-bone lesions are preferred), it should be performed within 6-weeks prior to starting study treatment
d. if biopsy is not feasible the PI must have initiated the request for archival tissue for central analysis;
5. Metastatic or recurrent inoperable disease after previous surgery, radiation therapy, and/or chemotherapy;
6. For patients in Stage 1 and for patients in Stage 2 who will receive combination therapy with onapristone
and abiraterone: no more than one prior chemotherapy regimens for CRPC ( single agent docetaxel rechallenge will be regarded as one line of chemotherapy); for patients in Stage 2 who will receive onapristone monotherapy: no prior chemotherapy is allowed;
7. Disease that has progressed by PSA or radiologically on abiraterone or enzalutamide. Disease progression for study entry is defined as one or both of:
•PSA progression defined by a minimum of two rising PSA levels with an interval of ≥1 week between each determination and a value ≥ 2 µg/L (2 ng/mL);
•Radiological progression per RECIST 1.1;
8. For patients recruited to the abiraterone-onapristone combination arm, progression on abiraterone as their last line of treatment is required with discontinuation up to 8 weeks prior to date of consent and treatment with continuous abiraterone for a minimum of 12 weeks.; patients recruited to the monotherapy arm may initiate study treatment immediately upon discontinuation of abiraterone or enzalutamide;
9.The PSA value at screening and baseline should be ≥ 2 μg/L (2 ng/mL);
10. For onapristone monotherapy, corticosteroid discontinuation >4 weeks or >2 weeks with normal adrenal function confirmed by an ACTH stimulation test. For the combination onapristone – abiraterone arm, prednisolone 5mg BID and no other steroid regimen allowed for 2 weeks prior to treatment initiation;
11. Ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue or orchiectomy (i.e., surgical or medical castration);
•For patients who have not had an orchiectomy, there must be a plan to maintain effective GnRH-analogue therapy for the duration of the trial;
12. Serum testosterone level < 1.7 nmol/L (50 ng/dL);
13. Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks;
14. ECOG performance status 0-2;
15. Life expectancy ≥ 3 months;
16. Willing and able to sign written informed consent per ICH-GCP, the local regulatory requirements, and local data protection laws prior to study-specific screening procedures. |
|
| E.4 | Principal exclusion criteria |
1. Serum creatinine >1.5 ULN;
2. On ECG a QTc(F) interval >480 msec or any clinically significant cardiac rhythm abnormalities;
3. Liver function tests documented within the screening period and/or at baseline:
a.Total bilirubin > ULN (except in patients diagnosed with Gilbert’s disease);
b. Alkaline phosphatase > 2.5 x UNL, unless test for alkaline phosphatase isoenzymes is elevated only for bone isoenzyme;
c. ALT/AST > UNL or > 2.5 x UNL in case of liver metastases;
d. Grade ≥ 2 AST, ALT or bilirubin elevation on prior abiraterone treatment (for Stage 2 combination arm only)
4. Absolute neutrophil count < 1,500/µL, platelet count < 100,000/µL, and hemoglobin < 5.6 mmol/L (9 g/dL) and no growth factors or blood transfusions within 7 days of these values;
5. Serum albumin < 25 g/L (2.5 g/dL);
6. Known positive virology/serology for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B (surface antigen), or hepatitis C (testing not required);
7. Chronic inflammatory liver condition. History or clinical evidence of any liver or biliary pathology including cirrhosis, infectious disease, inflammatory conditions, steatosis, or cholangitis (including ascending cholangitis, primary sclerosing cholangitis, obstruction, perforation, fistula of biliary tract, spasm of sphincter of Oddi, biliary cyst or biliary atresia;
8. Patients with any other prior malignancy are not allowed except for:
a. Adequately treated basal cell or squamous cell skin cancer;
b. Adequately treated Stage I or II cancer from which the patient is currently in complete remission;
c. Other cancer from which the patient has been disease-free for 2 years;
9. For stage 1 only: Chronic adrenal failure or is receiving concurrent long-term corticosteroid therapy. Prior long-term corticosteroids must be stopped ≥4 weeks or >2 weeks if normal adrenal function is confirmed by an ACTH stimulation test prior to start of study drug;
10. History or clinical evidence of any surgical or medical condition which the investigator judges as likely to interfere with the results of the study or pose an additional risk in participating; e.g., active or clinically significant history of disease involving a major organ system—vascular, cardiac, uncontrolled hypertension, pulmonary, gastrointestinal, hematologic, neurologic, neoplastic, renal, endocrine or immunodeficiency, or clinically significant active psychiatric disorders;
11. Used any prescription medication during the prior 2 weeks that the investigator judges is likely to interfere with the study or to pose an additional risk to the patient in participating, specifically inhibitors or inducers of cytochrome P450 (CYP)3A4;
12. Received an investigational product or been treated with an investigational device within 30 days prior to first drug administration, or plans to start any other investigational product or device study within 30 days after last drug administration;
13. Received prior therapies within the following time period prior to receipt of first dose of study drug (Day 1, without withdrawal response and with no plans to initiate any of these during study:
a. Ketoconazole or bicalutamide within 6 weeks;
b. Systemic hormone therapy, chemotherapy, targeted therapies, antibodies within 4 weeks excluding abiraterone in abiraterone-onapristone combination arm;
c. Fractionated radiotherapy within 3 weeks;
d. Single fraction of radiotherapy within 2 weeks;
e. Radionuclide therapy within 8 weeks;
f. Brachytherapy Pd-103 implant within the last 3 months;
g. Brachytherapy I-125 implants within 12 months.
14. Concurrent use of herbal products that may decrease PSA levels (e.g., saw palmetto);
15. Residual toxicity of prior anticancer treatment > grade 1 except for alopecia;
16. Brain metastases, active epidural disease or spinal cord compression, unless treated at least 4 weeks before entry, and stable with steroid treatment for ≥1 week;
17. Paget’s disease of the bone;
18. Structurally unstable bone lesions suggesting impending fracture;
19. Patients with reproductive potential not employing adequate contraception during treatment and for 6 months after completing treatment;
20. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to swallow pills;
21. Mental incapacity or language barriers precluding adequate understanding, co-operation, and compliance with the study requirements;
22. Is, in the judgment of the investigator, unable or unwilling to comply with the requirements of the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Dose limiting toxicities related to onapristone or the combination of onapristone and abiraterone utilizing a day 57 safety cut off and based on CTCAE v4.
• Response to onapristone or the combination of onapristone and abiraterone will be defined by either of the following:
- Objective partial or complete response by RECIST 1.1, confirmed on a second CT scan at least 4 weeks apart
and / or
-PSA decline of ≥ 50% (according to the PCWG2).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety:
For the determination of dose limiting toxicities and therefore the RP2D, a 57-day cutoff will be used. However, all
AEs and SAEs(including abnormal laboratory test results) will be collected from the time of signing the informed consent until 30 days after the last onapristone dose.
Antitumor activity:
Tumor assessments per RECIST 1.1 [Eisenhauer 2009] (CT/MRI) and PCWG2 [Scher 2008] |
|
| E.5.2 | Secondary end point(s) |
• Safety and tolerability of extended-release onapristone tablets BID.
• PK of onapristone, mono-demethylated onapristone and other metabolites in plasma and urine (Stage 1 only).
• PK of onapristone and abiraterone after combination therapy (Stage 2 only) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
In stage 1, plasma concentrations of onapristone, and mono-demethylated onapristone (M1) on day 1 at hours 0 1, 2, 4 and 6 and days 8, 29 and 57 at hour 0.
Additionally, in Stage 1 and 2 if a grade 3-4 LFT elevation occurs, a PK sample will be drawn as soon as possible. This applies to the entire treatment period, even outside of the 8 week safety observation period.
In addition, urine will be analyzed for onapristone metabolites if grade 3-4 LFT elevation occurs.
In Stage 2, plasma concentrations of abiraterone on day -7 at H8 post-dose and for onapristone and abiraterone on day 1 at H8.
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| First in male administration |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
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