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.

NCT ID: NCT03840200

Last Updated: 2023-10-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-12
• Study Completion Date: 2022-01-04

Brief Summary

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).

Enrollment in Cohort 3 in dose escalation phase was not opened as one-third of Dose Limiting Toxicity (DLT) evaluable participants receiving the highest dose of rucaparib in Cohort 2a experienced a DLT.

Conditions

Breast Cancer; Prostate Cancer; Ovarian Cancer

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Dose escalation-Cohort 1

Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 milligrams (mg), orally, once daily (QD) for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 400 mg, orally twice daily (BID) in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib will be administered orally.

Rucaparib

Intervention Type: DRUG

Rucaparib will be administered orally.

Dose escalation-Cohort 2a

Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 300 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 300 mg, orally QD, and rucaparib, 600 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib will be administered orally.

Rucaparib

Intervention Type: DRUG

Rucaparib will be administered orally.

Dose escalation-Cohort 2b

Participants with advanced breast cancer, ovarian cancer, or prostate cancer will receive ipatasertib, 400 mg, orally, QD for 7 days in the run-in period. Participants will then receive ipatasertib, 400 mg, orally QD, and rucaparib, 400 mg, orally BID in each 28-day cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib will be administered orally.

Rucaparib

Intervention Type: DRUG

Rucaparib will be administered orally.

Dose escalation-Cohort 3

Participants with advanced breast cancer, ovarian cancer, or prostate cancer are planned to receive ipatasertib 400 mg orally QD for 7 days (run-in period prior to Cycle 1). Participants will then receive ipatasertib 400 mg orally QD and rucaparib 600 mg, orally BID in 28 days cycle until disease progression, unacceptable toxicity, death, or participant or investigator's decision to withdraw, whichever occurs first.

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib will be administered orally.

Rucaparib

Intervention Type: DRUG

Rucaparib will be administered orally.

Dose Expansion

The recommended dose (ipatasertib and rucaparib) identified in Part 1 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).

Group Type: EXPERIMENTAL

Ipatasertib

Intervention Type: DRUG

Ipatasertib will be administered orally.

Rucaparib

Intervention Type: DRUG

Rucaparib will be administered orally.

Interventions

Ipatasertib

Ipatasertib will be administered orally.

Intervention Type: DRUG

Rucaparib

Rucaparib will be administered orally.

Intervention Type: DRUG

Other Intervention Names

RO5532961, GDC-0068; CO-338

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).

• 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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Trials

Role: STUDY_DIRECTOR

Hoffmann-La Roche

Locations

California Cancer Associates for Research & Excellence, Inc.

San Marcos, California, United States

Regional Cancer Care Associates LLC, Central Jersey Division

East Brunswick, New Jersey, United States

Fox Chase Cancer Center

Philadelphia, Pennsylvania, United States

Mary Crowley Medical Research Center; Oncology

Dallas, Texas, United States

Kinghorn Cancer Centre; St Vincents Hospital

Darlinghurst, New South Wales, Australia

Macquarie University Hospital

Macquarie Park, New South Wales, Australia

Cabrini Hospital Malvern

Malvern, Victoria, Australia

Istituto Nazionale Tumori Regina Elena IRCCS

Rome, Lazio, Italy

Fondazione IRCCS Istituto Nazionale dei Tumori; S. C. Oncologia Medica 2

Milan, Lombardy, Italy

Azienda Ospedaliera Santa Maria di Terni

Terni, Umbria, Italy

Istituto Oncologico Veneto IRCCS

Padua, Veneto, Italy

Seoul National University Hospital

Seoul, , South Korea

Severance Hospital, Yonsei University

Seoul, , South Korea

Samsung Medical Center

Seoul, , South Korea

Clínica Universidad de Navarra

Pamplona, Navarre, Spain

Vall d?Hebron Institute of Oncology (VHIO), Barcelona

Barcelona, , Spain

Hospital Universitario Virgen de la Victoria

Málaga, , Spain

Countries

United States; Australia; Italy; South Korea; Spain

References

Pook D, Geynisman DM, Carles J, de Braud F, Joshua AM, Perez-Gracia JL, Llacer Perez C, Shin SJ, Fang B, Barve M, Maruzzo M, Bracarda S, Kim M, Kerloeguen Y, Gallo JD, Maund SL, Harris A, Huang KC, Poon V, Sutaria DS, Gurney H. A Phase Ib, Open-label Study Evaluating the Safety and Efficacy of Ipatasertib plus Rucaparib in Patients with Metastatic Castration-resistant Prostate Cancer. Clin Cancer Res. 2023 Sep 1;29(17):3292-3300. doi: 10.1158/1078-0432.CCR-22-2585.

Reference Type: DERIVED

PMID: 37339186 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

BO40933

Identifier Type: -

Identifier Source: org_study_id