Phase 1-2 Study of Onapristone in Patients With Advanced Castration-resistant Prostate Cancer

NCT02049190 | Unknown Phase 1 DMC

• 1 other identifier: ARN-AR18-CT-102
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Prostate Cancer; Metastatic Prostate Cancer; Androgen-independent Prostate Cancer; Recurrent Prostate Cancer

Keywords

Advanced Prostate Cancer; Castration-resistant Prostate Cancer; Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; onapristone

Outcome Measures

Primary Outcomes (2)

• 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

  Baseline to 57 days post-first dose

• Response to onapristone or the combination of onapristone and abiraterone

  * 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).

  Baseline to 30 Days after last dose

Secondary Outcomes (2)

• Safety and tolerability of extended-release onapristone tablets BID

  Baseline to 30 Days after last dose

• PK of onapristone, mono-demethylated onapristone and other metabolites in plasma and urine

  Baseline to 30 Days after last dose

Study Arms (8)

onapristone 10 mg BID

EXPERIMENTAL

onapristone 10 mg BID extended-release tablets

Drug: onapristone

onapristone 20 mg BID

EXPERIMENTAL

onapristone 20 mg BID extended-release tablets

Drug: onapristone

onapristone 30 mg BID

EXPERIMENTAL

onapristone 30 mg BID extended-release tablets

Drug: onapristone

onapristone 40 mg BID

EXPERIMENTAL

onapristone 40 mg BID extended-release tablets

Drug: onapristone

onapristone 50 mg BID

EXPERIMENTAL

onapristone 50 mg BID extended-release

Drug: onapristone

onapristone 30 mg BID + abiraterone 1000 mg

EXPERIMENTAL

Expansion cohort: onapristone 30 mg BID + abiraterone 1000 mg

Drug: onapristone; Drug: abiraterone

onapristone 50 mg BID + abiraterone 1000 mg

EXPERIMENTAL

Expansion cohort: onapristone 50 mg BID + abiraterone 1000 mg

Drug: onapristone; Drug: abiraterone

Expansion cohort: onapristone 50 mg BID

EXPERIMENTAL

Expansion cohort: onapristone 50 mg BID

Drug: onapristone

Interventions

onapristone DRUG

Also known as: ZK 98299

Expansion cohort: onapristone 50 mg BID; onapristone 10 mg BID; onapristone 20 mg BID; onapristone 30 mg BID; onapristone 30 mg BID + abiraterone 1000 mg; onapristone 40 mg BID; onapristone 50 mg BID; onapristone 50 mg BID + abiraterone 1000 mg

abiraterone DRUG

Also known as: Zytiga

onapristone 30 mg BID + abiraterone 1000 mg; onapristone 50 mg BID + abiraterone 1000 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male patients, 18 years of age or greater;
• Histologically confirmed adenocarcinoma of the prostate (without neuroendocrine differentiation or small cell features);
• 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;
• Metastatic or recurrent inoperable disease after previous surgery, radiation therapy, and/or chemotherapy;
• 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;
• 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;
• 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;
• The PSA value at screening and baseline should be ≥ 2 µg/L (2 ng/mL);
• 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;
• 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;
• Serum testosterone level \< 1.7 nmol/L (50 ng/dL);
• Patients receiving bisphosphonate therapy must have been on stable doses for at least 4 weeks;

You may not qualify if:

• Serum creatinine \>1.5 ULN;
• On ECG a QTc(F) interval \>480 msec or any clinically significant cardiac rhythm abnormalities;
• Liver function tests documented within the screening period and/or at baseline:
• Total bilirubin \> ULN (except in patients diagnosed with Gilbert's disease);
• Alkaline phosphatase \> 2.5 x UNL, unless test for alkaline phosphatase isoenzymes is elevated only for bone isoenzyme;
• ALT/AST \> UNL or \> 2.5 x UNL in case of liver metastases;
• 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;
• Serum albumin \< 25 g/L (2.5 g/dL);
• Known positive virology/serology for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B (surface antigen), or hepatitis C (testing not required);
• 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;
• Patients with any other prior malignancy are not allowed except for:
• Adequately treated basal cell or squamous cell skin cancer;
• Adequately treated Stage I or II cancer from which the patient is currently in complete remission;
• Other cancer from which the patient has been disease-free for 2 years;
• 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;

Sponsors & Collaborators

• Arno Therapeutics: lead

Study Sites (1)

Inst of Cancer Research & Royal Marsden NHS Foundation Trust

Sutton Surrey, SH2 5NG, United Kingdom

RECRUITING

MeSH Terms

Conditions

Prostatic Neoplasms; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases

Interventions

onapristone; abiraterone; Abiraterone Acetate

Condition Hierarchy (Ancestors)

Genital Diseases; Urogenital Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications

Intervention Hierarchy (Ancestors)

Androstenes; Androstanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Central Study Contacts

Alice S Bexon, MD

CONTACT

1-617-417-7300; alice.bexon@bexonclinical.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 28, 2014
• First Posted: January 30, 2014
• Study Start: February 1, 2014
• Primary Completion: July 1, 2017
• Study Completion: December 1, 2017
• Last Updated: June 24, 2015

Record last verified: 2015-06

Locations

GB (1)