Advanced Castration-resistant Prostate Cancer MedDRA version: 19.0 Level: PT Classification code 10036909 Term: Prostate cancer metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 19.0 Level: PT Classification code 10036920 Term: Prostate cancer stage IV System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 19.0 Level: PT Classification code 10060862 Term: Pro
Conditions
Interventions
Product Name: Onapristone
Product Code: AR-18
Pharmaceutical Form: Modified-release tablet
INN or Proposed INN: ONAPRISTONE
CAS Number: 96346-61-1
Concentration unit: mg milligram(s)
Concentration typ
Sponsors
Arno Therapeutics Inc
Eligibility
Sex/Gender
Male
Inclusion criteria
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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 15
Exclusion criteria
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 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 with
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: •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.;Secondary Objective: • 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);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). ;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] | — |
Secondary
| Measure | Time frame |
|---|---|
| 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);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. | — |
Countries
United Kingdom
Contacts
Public ContactChief Medical Officer
Arno Therapeutics Inc
Outcome results
None listed