Clinical Trials /

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

NCT02049190

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Unknown status

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase 1-2 Study of Onapristone in Patients With Advanced Castration-resistant Prostate Cancer
  • Official Title: A Phase 1-2 Study of Onapristone in Patients With Advanced Castration-resistant Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: ARN-AR18-CT-102
  • NCT ID: NCT02049190

Conditions

  • Prostate Cancer
  • Metastatic Prostate Cancer
  • Androgen-independent Prostate Cancer
  • Recurrent Prostate Cancer

Interventions

DrugSynonymsArms
onapristoneZK 98299onapristone 10 mg BID
abirateroneZytigaonapristone 30 mg BID + abiraterone 1000 mg

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
onapristone 10 mg BIDExperimentalonapristone 10 mg BID extended-release tablets
  • onapristone
onapristone 20 mg BIDExperimentalonapristone 20 mg BID extended-release tablets
  • onapristone
onapristone 30 mg BIDExperimentalonapristone 30 mg BID extended-release tablets
  • onapristone
onapristone 40 mg BIDExperimentalonapristone 40 mg BID extended-release tablets
  • onapristone
onapristone 50 mg BIDExperimentalonapristone 50 mg BID extended-release
  • onapristone
onapristone 30 mg BID + abiraterone 1000 mgExperimentalExpansion cohort: onapristone 30 mg BID + abiraterone 1000 mg
  • onapristone
  • abiraterone
onapristone 50 mg BID + abiraterone 1000 mgExperimentalExpansion cohort: onapristone 50 mg BID + abiraterone 1000 mg
  • onapristone
  • abiraterone
Expansion cohort: onapristone 50 mg BIDExperimentalExpansion cohort: onapristone 50 mg BID
  • onapristone

Eligibility 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, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Time Frame:Baseline to 57 days post-first dose
Safety Issue:
Description: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).

Secondary Outcome Measures

Measure:Safety and tolerability of extended-release onapristone tablets BID
Time Frame:Baseline to 30 Days after last dose
Safety Issue:
Description:Safety will be assessed by physical exam, vital signs, monitoring of adverse events, changes in ECG, and changes in PSA and other clinical laboratory values.
Measure:PK of onapristone, mono-demethylated onapristone and other metabolites in plasma and urine
Time Frame:Baseline to 30 Days after last dose
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Unknown status
Lead Sponsor:Arno Therapeutics

Trial 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

Last Updated