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.

Breast Cancer Clinical Trial

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 Details — Status: Completed

Administrative data

• NCT number: NCT03840200
• Other study ID #: BO40933
• Status: Completed
• Phase: Phase 1
• Start date: June 12, 2019
• Est. completion date: January 4, 2022

Study information

• Verified date: October 2023
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: January 4, 2022
• Est. primary completion date: December 7, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Carcinoma, Ovarian Epithelial
• Ovarian Cancer
• Ovarian Neoplasms
• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Ipatasertib
Ipatasertib will be administered orally.
• Rucaparib
Rucaparib will be administered orally.

Locations

Country	Name	City	State
Australia	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
Italy	Fondazione IRCCS Istituto Nazionale dei Tumori; S. C. Oncologia Medica 2	Milano	Lombardia
Italy	Istituto Oncologico Veneto IRCCS	Padova	Veneto
Italy	Istituto Nazionale Tumori Regina Elena IRCCS	Roma	Lazio
Italy	Azienda Ospedaliera Santa Maria di Terni	Terni	Umbria
Korea, Republic of	Samsung Medical Center	Seoul
Korea, Republic of	Seoul National University Hospital	Seoul
Korea, Republic of	Severance Hospital, Yonsei University	Seoul
Spain	Vall d?Hebron Institute of Oncology (VHIO), Barcelona	Barcelona
Spain	Hospital Universitario Virgen de la Victoria	Malaga
Spain	Clínica Universidad de Navarra	Pamplona	Navarra
United States	Mary Crowley Medical Research Center; Oncology	Dallas	Texas
United States	Regional Cancer Care Associates LLC, Central Jersey Division	East Brunswick	New Jersey
United States	Fox Chase Cancer Center	Philadelphia	Pennsylvania
United States	California Cancer Associates for Research & Excellence, Inc.	San Marcos	California

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  Italy,  Korea, Republic of,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants With Adverse Events	An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product.	From Baseline up until 90 days after the last dose of study drug (up to 2 years)
Primary	Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination	A DLT was defined as adverse events related to study treatments occurring during the DLT reporting period, which included: any death related to study treatment; grade 4 neutropenia lasting for =7 days; grade =3 neutropenia complicated by fever =38°C or infection; grade 4 thrombocytopenia lasting for =7 days; grade =3 thrombocytopenia complicated by hemorrhage or that requires transfusion; study treatment-related grade =3 non-hematologic toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5 (NCI CTCAE, v5.0).	Day -7 to Day 28 of Cycle 1 (1 cycle = 28 days) (up to 35 days)
Primary	Percentage of Participants With Prostate-Specific Antigen Response (PSAR)	PSA response was defined as the percentage of participants with a reduction in the PSA level of 50% or more. PSA response analysis was based on central PSA measurement. The 95% CI was estimated using the Clopper-Pearson method.	From Baseline up to 1.5 years
Secondary	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)	Objective response rate (ORR), defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR) on two consecutive occasions =4 weeks apart, as determined by the investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1). A complete response was defined as the disappearance of all lesions. Pathological lymph nodes (whether target or non-target) must have a reduction in short axis to less than 10 millimeters (mm). A partial response was defined as =30% decrease in the sum of the diameter of target lesions, in the absence of CR persistence of one or more non-target lesions. The analysis is based on the subset of participants with measurable lesions as per RECIST criteria at baseline. ORR was calculated, and the 95% CI was estimated using the Clopper-Pearson method.	From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days)
Secondary	Duration of Objective Response in Participants With Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1	DOR was defined as the time from the first occurrence of a documented objective response until the time of documented disease progression or death from any cause during the study, whichever occurred first. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and an absolute increase of at least 5 mm, or the presence of new lesions. The duration of response was estimated by Kaplan-Meier. 95% CI for median was computed using the method of Brookmeyer and Crowley.	From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days)
Secondary	Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3)	rPFS was defined as the time from study treatment initiation to the first occurrence of documented disease progression, as assessed by the investigator with the use of the PCWG3 criteria (soft tissue: Progressive disease on computed tomography [CT] or MRI scans according to RECIST v1.1, and bone metastasis by bone scan according to the PCWG3 criteria) or death from any cause, whichever occurred first. Progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions compared to the smallest sum of diameters on-study and an absolute increase of at least 5 mm, or the presence of new lesions. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.	From Baseline up to 1.5 years (assessed at the end of Cycle 2,4,6, and every 3 cycles thereafter up to progression, 1 cycle= 28 days)
Secondary	Overall Survival (OS) in All Participants	OS was defined as the time from study treatment initiation to the time of death due to any cause. Kaplan-Meier method was used to estimate the median. 95% CI for median was computed using the method of Brookmeyer and Crowley.	From Baseline to death from any cause, assessed up to 2 years
Secondary	Plasma Concentration of Ipatasertib		Dose Escalation: Cycle 1: Day 1 and 15 (1, 2 ,3, 5 hours post-dose), Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose); Dose Expansion: Cycle 1: Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose) (1 cycle = 28 days)
Secondary	Plasma Concentration of Ipatasertib's Metabolite (G-037720)		Dose Escalation: Cycle 1: Day 1 and 15 (1, 2 ,3, 5 hours post-dose), Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose); Dose Expansion: Cycle 1: Day 15 (Predose) and Cycle 2: Day 1 and 15 (Predose) (1 cycle = 28 days)
Secondary	Plasma Concentration of Rucaparib		Cycle 1 Day 15 and Cycle 2 Day 1 and 15: Predose (1 cycle = 28 days)