Phase 1-2 Study of Onapristone in Patients With Advanced Castration-resistant Prostate Cancer
Phase 1-2 Study of Onapristone in Patients With Advanced Castration-resistant Prostate Cancer
This is an open-label, randomized, parallel group two-stage phase 1-2 study with an
 escalation and an expansion component. This study will evaluate an extended-release (ER)
 formulation of onapristone in patients with prostate cancer in which Progesterone Receptor
 (PR) may be contributing to tumor progression. A companion diagnostic to select patients
 whose prostate cancer expresses the activated form of the PR (APR) is under development and
 will be implemented in this study; it may be used to further enrich the selection of the
 population based upon ongoing review of the results. Patients will be treated until
 occurrence of an intolerable safety issue, treatment failure, if patient elects to withdraw,
 or for non-compliance with either protocol-specified evaluations or onapristone treatment. An
 additional cohort of patients will be included at the recommended phase 2 dose to gain
 additional understanding of the onapristone safety profile and potential anti-cancer
 activity.
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, a mandatory biopsy is required with confirmed PR or APR in ≥1% tumor
 cells. For patients recruited to the abiraterone-onapristone combination arm, the
 biopsy must be performed on abiraterone administered as the most recent treatment and
 after a minimum of 2 weeks continuous treatment. For other patients, the biopsy must
 be taken at progression on or after abiraterone or enzalutamide or before screening
 with no anti-cancer treatment taken in the intervening period and a maximum of six (6)
 months prior to study start. If archival tissue is also available this should be
 provided for comparison purposes; a paired biopsy at day 8-28 is optional;

 4. Metastatic or recurrent inoperable disease after previous surgery, radiation therapy,
 and/or chemotherapy;

 5. 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 regimen
 for CRPC (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;

 6. 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.

 -  Radiological progression per RECIST 1.1;

 7. For patients recruited to the abiraterone-onapristone combination arm, progression on
 abiraterone as their last line of treatment is required after a prior response to
 abiraterone;

 8. The PSA value at screening and baseline should be ≥ 2 µg/L (2 ng/mL);

 9. 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;

 10. 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;

 11. Serum testosterone level < 1.7 nmol/L (50 ng/dL);

 12. Patients receiving bisphosphonate therapy must have been on stable doses for at least
 4 weeks;

 13. Evaluable disease per RECIST 1.1 [Eisenhauer 2009] or Prostate Cancer Clinical Trials
 Working Group 2 (PCWG2) [Scher 2008];

 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.

 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:

 1. Total bilirubin > ULN (except in patients diagnosed with Gilbert's disease);

 2. Alkaline phosphatase > 2.5 x UNL, unless test for alkaline phosphatase isoenzymes
 is elevated only for bone isoenzyme;

 3. ALT/AST > UNL or > 2.5 x UNL in case of liver metastases;

 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:

 1. Adequately treated basal cell or squamous cell skin cancer;

 2. Adequately treated Stage I or II cancer from which the patient is currently in
 complete remission;

 3. 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 (see
 Appendix 4);

 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:

 1. Ketoconazole or bicalutamide within 6 weeks;

 2. Systemic hormone therapy, chemotherapy, targeted therapies, antibodies within 4
 weeks excluding abiraterone in the abiraterone-onapristone combination arm;

 3. Fractionated radiotherapy within 3 weeks;

 4. Single fraction of radiotherapy within 2 weeks;

 5. Radionuclide therapy within 8 weeks;

 6. Brachytherapy Pd-103 implant within the last 3 months;

 7. 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 1 month 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.