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A Study Evaluating the Safety, Pharmacokinetics and Efficacy of Ipatasertib Administered in Combination With Rucaparib in Participants With Advanced Breast, Ovarian Cancer, and Prostate Cancer.

NCT03840200

Description:

This is a study in participants with advanced breast, ovarian, or prostate cancer to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of ipatasertib in combination with rucaparib. The study consists of two parts: a Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer and a Dose-Expansion Phase (Part 2) in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).

Related Conditions:
  • Breast Carcinoma
  • Fallopian Tube Clear Cell Adenocarcinoma
  • Fallopian Tube Endometrioid Adenocarcinoma
  • High Grade Fallopian Tube Serous Adenocarcinoma
  • High Grade Ovarian Serous Adenocarcinoma
  • Malignant Ovarian Clear Cell Tumor
  • Ovarian Endometrioid Tumor
  • Primary Peritoneal Carcinoma
  • Primary Peritoneal Serous Adenocarcinoma
  • Prostate Adenocarcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study Evaluating the Safety, Pharmacokinetics and Efficacy of Ipatasertib Administered in Combination With Rucaparib in Participants With Advanced Breast, Ovarian Cancer, and Prostate Cancer.
  • Official Title: A Phase Ib, Open-Label, Multicenter Study Evaluating the Safety and Efficacy of Ipatasertib in Combination With Rucaparib in Patients With Advanced Breast, Ovarian, or Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: BO40933
  • NCT ID: NCT03840200

Conditions

  • Breast Cancer
  • Prostate Cancer
  • Ovarian Cancer

Interventions

DrugSynonymsArms
Part 1, Dose Level 1 and Dose Level 2a: IpatasertibRO5532961, GDC-0068Ipatasertib + Rucaparib
Part 1, Dose level 2b and dose level 3: IpatasertibRO5532961, GDC-0068Ipatasertib + Rucaparib
Part 1, Dose Level 1 and Dose Level 2b: RucaparibCO-338Ipatasertib + Rucaparib
Part 1, Dose Level 2a and Dose Level 3: RucaparibCO-338Ipatasertib + Rucaparib

Purpose

This is a study in participants with advanced breast, ovarian, or prostate cancer to investigate the dose, safety, pharmacokinetics, and preliminary efficacy of ipatasertib in combination with rucaparib. The study consists of two parts: a Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer and a Dose-Expansion Phase (Part 2) in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).

Detailed Description

      There are two parts in the study. A Dose-Escalation Phase (Part 1) in participants with
      previously treated advanced breast cancer, ovarian cancer, or prostate cancer. There will be
      a 7-day run-in period with ipatasertib alone prior to Cycle 1, Day 1. After the completion of
      the ipatasertib run-in period, participants will begin Cycle 1, Day 1 of the ipatasertib and
      rucaparib combination treatment. Each cycle has 28 days. Participants will be split into 4
      cohorts: Dose Level 1 group - 300 mg ipatasertib once daily (QD) + 400 mg rucaparib twice
      daily (BID), Dose Level 2a: 300 mg ipatasertib QD + 600 mg rucaparib BID, Dose Level 2b: 400
      mg ipatasertib QD + 400 mg rucaparib BID, Dose Level 3: 400 mg ipatasertib QD + 600 mg
      rucaparib BID

      A Dose-Expansion Phase (Part 2) - The recommended dose identified in Part 1 (highest dose
      level of ipatasertib and rucaparib with an acceptable safety profile and less than one-third
      of participants experience a dose limiting toxicity) will be evaluated in participants with
      advanced prostate cancer who have had at least one line of prior therapy with
      second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide,
      apalutamide).
    

Trial Arms

NameTypeDescriptionInterventions
Ipatasertib + RucaparibExperimentalA Dose-Escalation Phase (Part 1) in participants with previously treated advanced breast cancer, ovarian cancer, or prostate cancer. There will be a 7-day run-in period with ipatasertib alone prior to Cycle 1, Day 1. After the completion of the ipatasertib run-in period, participants will begin Cycle 1, Day 1 of the ipatasertib and rucaparib combination treatment. Each cycle has 28 days. Participants will be split into 4 cohorts: Dose Level 1 group - 300 mg ipatasertib once daily (QD) + 400 mg rucaparib twice daily (BID), Dose Level 2a: 300 mg ipatasertib QD + 600 mg rucaparib BID, Dose Level 2b: 400 mg ipatasertib QD + 400 mg rucaparib BID, Dose Level 3: 400 mg ipatasertib QD + 600 mg rucaparib BID
  • Part 1, Dose Level 1 and Dose Level 2a: Ipatasertib
  • Part 1, Dose level 2b and dose level 3: Ipatasertib
  • Part 1, Dose Level 1 and Dose Level 2b: Rucaparib
  • Part 1, Dose Level 2a and Dose Level 3: Rucaparib
Part 2: Ipatasertib + RucaparibExperimentalA Dose-Expansion Phase (Part 2) - The recommended dose identified in Part 1 (highest dose level of ipatasertib and rucaparib with an acceptable safety profile and less than one-third of participants experience a dose limiting toxicity) will be evaluated in participants with advanced prostate cancer who have had at least one line of prior therapy with second-generation androgen-receptor (AR)-targeted agents (e.g., abiraterone, enzalutamide, apalutamide).
  • Part 1, Dose Level 1 and Dose Level 2a: Ipatasertib
  • Part 1, Dose level 2b and dose level 3: Ipatasertib
  • Part 1, Dose Level 1 and Dose Level 2b: Rucaparib
  • Part 1, Dose Level 2a and Dose Level 3: Rucaparib

Eligibility Criteria

        Inclusion Criteria:

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

          -  A life expectancy of at least 3 months

          -  Ability to swallow oral study drug

          -  Have adequate organ and marrow function as confirmed by the laboratory values listed
             below, obtained within 28 days prior to the first dose of study treatment:

          -  Bone marrow function assessments (without transfusion within 28 days prior to receipt
             of study treatment):

               1. ANC >= 1500 cells/uL (1.5 x 10^9/L) without granulocyte-colony stimulating factor
                  support

               2. Platelet count >= 100.0 x 10^9/L

               3. Hemoglobin >= 9 g/dL (or 5.6 mmol/L)

          -  Chemistry panel assessments:

               1. AST and ALT <= 1.5 x upper limit of normal (ULN); if liver metastases, <= 2.5 x
                  ULN

               2. Bilirubin <= 1.5 x ULN (<= 3 x ULN if hyperbilirubinemia is due to Gilbert's
                  syndrome)

               3. Serum albumin >= 3.0 g/dL

               4. Serum creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min

               5. Fasting glucose <= 150 mg/dL and hemoglobin A1c <= 7.5%

          -  Resolved or stabilized toxicities resulting from previous therapy to Grade 1 (except
             for alopecia and neuropathy).

        Cancer-Related Inclusion Criteria

          -  Have a histologically confirmed diagnosis of ovarian (Part 1 only), breast (Part 1
             only) or prostate cancer (Part 1 and Part 2)

          -  Disease must be either metastatic or locally advanced disease that cannot be treated
             with curative intent

          -  For patients with ovarian cancer (Part 1 only):

               1. High-grade (2 or 3) serous or endometrioid or clear cell epithelial ovarian,
                  fallopian tube, or primary peritoneal cancer (PPC)

               2. Must have received at least one prior platinum-based therapy and may have
                  platinumsensitive disease (i.e., documented radiologic disease progression >= 6
                  months following the last dose of the platinum treatment administered) or
                  platinum-resistant disease

               3. Have a CA-125 level that is > 2 x ULN

               4. Must have measurable disease by RECIST v1.1

          -  For patients with breast cancer (Part 1 only): must be human epidermal growth factor
             receptor 2 negative (HER2-) (estrogen receptor [ER]/progesterone positive or
             negative):

               1. ER/progesterone-positive patients must have received and progressed on at least
                  one endocrine therapy (adjuvant or metastatic)

               2. ER/progesterone-negative/HER2- (triple-negative breast cancer [TNBC]) patients
                  must have received at least one prior line of chemotherapy for metastatic breast
                  cancer

               3. Must not have received more than two prior lines of chemotherapy for metastatic
                  breast cancer

               4. Must have measurable disease by RECIST v1.1

        For patients with prostate cancer:

          1. Adenocarcinoma of the prostate without small cell or neuroendocrine features

          2. Surgical or medical castration with testosterone < 50 ng/dL (1.7 nM)

          3. Patients treated with luteinizing hormone-releasing hormone analogs must have
             initiated therapy at least 4 weeks prior to the first dose of study treatment and
             continue throughout the study treatment

          4. Progression of prostate cancer either via PSA progression (two rising PSA levels
             measured >= 1 week apart, with second result >= 1 ng/mL) or radiographic progression
             with or without PSA progression

          5. Must have received at least one prior line of second-generation androgen receptor
             targeted therapy (e.g., abiraterone, enzalutamide, apalutamide)

          6. Patients with prostate cancer must have either measurable disease by RECIST v1.1 or
             bone lesions by bone scan, or both.

               -  Submission of a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or a
                  minimum of 12 freshly cut, unstained, serial tumor slides from the most recently
                  collected tumor tissue for central molecular analysis (retrospective NGS testing
                  for HR and PI3K-AKT pathway status and for other protocol-mandated secondary and
                  exploratory assessments). Cytologic or fine needle aspirate samples are not
                  acceptable. Tumor tissue from bone metastases is not acceptable.

               -  For men and women of child bearing potential: agreement to remain abstinent or
                  use protocol defined contraceptive measures during the treatment period and for
                  at least 28 days after the last dose of ipatasertib,or 6 months after the last
                  dose of rucaparib, whichever occurs later

        Exclusion Criteria:

          -  Pregnant or breastfeeding, or intending to become pregnant during the study or within
             28 days after the final dose of ipatasertib or 6 months after the final dose of
             rucaparib

          -  Prior treatment with a PARP inhibitor, AKT inhibitor, or PI3K inhibitor

          -  Treatment with investigational therapy within 14 days prior to initiation of study
             drug

          -  Symptomatic and/or untreated CNS metastases

          -  Uncontrolled tumor-related pain

          -  Non-study-related minor surgical procedures <= 5 days or major (invasive) surgical
             procedure <=14 days prior to first dose of study treatment

          -  Patients with active hepatitis C virus (HCV)

          -  Hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive
             hepatitis B surface antigen (HBsAg) test or a positive quantitative HBV DNA test

          -  Known HIV infection

          -  Illicit drug or alcohol abuse within 12 months prior to screening, in the
             investigator's judgment

          -  Malabsorption syndrome or other condition that would interfere with enteral absorption

          -  Serious infection requiring antibiotics within 14 days of first dose of study
             treatment

          -  Any serious medical condition or abnormality in clinical laboratory tests that, in the
             investigator's judgment, precludes the patient's safe participation in and completion
             of the study

          -  Need for chronic corticosteroid therapy of >= 10 mg of prednisone per day or an
             equivalent dose of other anti-inflammatory corticosteroids or immunosuppressants for a
             chronic disease

          -  History of another malignancy within 5 years prior to randomization, except for either
             adequately treated non-melanomatous carcinoma of the skin, adequately treated melanoma
             in situ, adequately treated non-muscle-invasive urothelial carcinoma of the bladder
             (Tis, Ta, and low-grade T1 tumors), or other malignancies where the patient has
             undergone potentially curative therapy with no evidence of disease and are deemed by
             the treating physician to have a recurrence rate of < 5% at 5 years.

          -  History of clinically significant cardiovascular dysfunction

          -  Presence of any other condition that may have increased the risk associated with study
             participation or may have interfered with the interpretation of study results, and, in
             the opinion of the investigator, would have made the patient inappropriate for entry
             into the study

        Ipatasertib-Specific Exclusion Criteria:

          -  Type 1 or Type 2 diabetes mellitus requiring insulin at study entry

          -  History of inflammatory bowel disease (e.g., Crohn disease and ulcerative colitis),
             active bowel inflammation (e.g., diverticulitis)

          -  Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 4 weeks or five
             elimination half-live of the inhibitors, whichever is longer, prior to initiation of
             study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Participants with Adverse Events
Time Frame:Baseline up to approximately 3 years
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Percentage of Participants with Objective Response, as Assessed by Investigator Based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1)
Time Frame:At end of Cycle 2, 4, 6 and every 3 cycles thereafter up to progression (1 cycle = 28 days; baseline up to approximately 3 years)
Safety Issue:
Description:
Measure:Duration of Objective Response in Participants with Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1
Time Frame:At end of Cycle 2, 4, 6 and every 3 cycles thereafter up to progression (1 cycle = 28 days; baseline up to approximately 3 years)
Safety Issue:
Description:
Measure:Radiographic Progression Free Survival, as Assessed by Prostate Cancer Working Group 3 Criteria
Time Frame:At end of Cycle 2, 4, 6 and every 3 cycles thereafter up to radiographic progression (1 cycle = 28 days; baseline up to approximately 3 years)
Safety Issue:
Description:
Measure:Overall Survival in All Participants
Time Frame:Baseline up to disease progression or death due to any cause whichever occurs first (up to approximately 3 years)
Safety Issue:
Description:
Measure:Plasma Concentration of Ipatasertib
Time Frame:Day -7, 1, 15 of Cycle 1, Day 1, 15 of Cycle 2 (1 cyce = 28 days)
Safety Issue:
Description:
Measure:Plasma Concentration of Ipatasertib's Metabolite, G-037720
Time Frame:Day -7, 1, 15 of Cycle 1, Day 1, 15 of Cycle 2 (1 cycle = 28 days)
Safety Issue:
Description:
Measure:Plasma Concentration of Rucaparib
Time Frame:Day -7, 1, 15 of Cycle 1, Day 1, 15 of Cycle 2 (1 cycle = 28 days)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Hoffmann-La Roche

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