Clinical trial NCT03840200: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Breast Cancer
Prostate Cancer
Ovarian Cancer
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2019-02-15
Enrollment: 51
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Percentage of Participants With Adverse Events
timeFrame: From Baseline up until 90 days after the last dose of study drug (up to 2 years)
measure: Dose Escalation: Percentage of Participants With Dose-Limiting Toxicities (DLTs) That Determine the Maximum-Tolerated Dose (MTD) of the Ipatasertib and Rucaparib Combination
timeFrame: Day -7 to Day 28 of Cycle 1 (1 cycle = 28 days) (up to 35 days)
measure: Percentage of Participants With Prostate-Specific Antigen Response (PSAR)
timeFrame: From Baseline up to 1.5 years
Secondary outcomes:
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)
timeFrame: 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)
measure: Duration of Objective Response in Participants With Measurable Disease at Baseline, as Assessed by Investigator Based on RECIST v1.1
timeFrame: 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)
measure: Radiographic Progression Free Survival (rPFS), as Assessed by Prostate Cancer Working Group 3 Criteria (PCWG3)
timeFrame: 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)
measure: Overall Survival (OS) in All Participants
timeFrame: From Baseline to death from any cause, assessed up to 2 years
measure: Plasma Concentration of Ipatasertib
timeFrame: 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)
measure: Plasma Concentration of Ipatasertib's Metabolite (G-037720)
timeFrame: 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)
measure: Plasma Concentration of Rucaparib
timeFrame: Cycle 1 Day 15 and Cycle 2 Day 1 and 15: Predose (1 cycle = 28 days)
Other outcomes:
Locations:
city: San Marcos
country: United States
facility: California Cancer Associates for Research & Excellence, Inc.
state: California
city: East Brunswick
country: United States
facility: Regional Cancer Care Associates LLC, Central Jersey Division
state: New Jersey
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Dallas
country: United States
facility: Mary Crowley Medical Research Center; Oncology
state: Texas
city: Darlinghurst
country: Australia
facility: Kinghorn Cancer Centre; St Vincents Hospital
state: New South Wales
city: Macquarie Park
country: Australia
facility: Macquarie University Hospital
state: New South Wales
city: Malvern
country: Australia
facility: Cabrini Hospital Malvern
state: Victoria
city: Roma
country: Italy
facility: Istituto Nazionale Tumori Regina Elena IRCCS
state: Lazio
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori; S. C. Oncologia Medica 2
state: Lombardia
city: Terni
country: Italy
facility: Azienda Ospedaliera Santa Maria di Terni
state: Umbria
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS
state: Veneto
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Pamplona
country: Spain
facility: Clínica Universidad de Navarra
state: Navarra
city: Barcelona
country: Spain
facility: Vall d?Hebron Institute of Oncology (VHIO), Barcelona
city: Malaga
country: Spain
facility: Hospital Universitario Virgen de la Victoria
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical Trials
role: STUDY_DIRECTOR
References: