MC# 19-26 - 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

  • Agent(s): Ipatasertib and Rucaparib
  • Disease Type(s): Prostate, Ovarian, Breast
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): AKT, PARP-1, PARP-2, PARP-3, PI3K

Mechanism of Action

Ipatasertib targets and binds to the adenosine triphosphate (ATP)-binding pocket of the 3 activated isoforms of AKT, potentially inhibiting downstream signaling.

Rucaparib is a small molecule inhibitor of PARP1, PARP2 and PARP3.

Purpose

In this study, the sponsor and investigators want to learn:

  • How much of Ipatasertib and Rucaparib when given in combination can be given with an acceptable level of side effects
  • About the safety and tolerability of Ipatasertib and Rucaparib when given in combination
  • How proteins that indicate the status of your disease are affected with use of Ipatasertib and Rucaparib when given in combination
  • How much Ipatasertib and Rucaparib when given in combination are absorbed into the blood and how fast they are removed
  • If research tests can be used in the future to predict who will benefit from Ipatasertib when given with Rucaparib
Inclusion Criteria
  • Signed Informed Consent Form
  • Age ≥ 18 years at time of signing Informed Consent Form
  • Ability to comply with the study protocol, in the investigator's judgment
  • 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).
    • ANC ≥1500 cells/µL (1.5 x 109/L) without granulocyte-colony stimulating factor support
    • Platelet count ≥100.0 x 109/L
    • Hemoglobin ≥9 g/dL (or 5.6 mmol/L)
  • Chemistry panel assessments
    • AST and ALT ≤ 1.5 x ULN; if liver metastases, ≤ 2.5 x ULN
    • Bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if hyperbilirubinemia is due to Gilbert’s syndrome)
    • Serum albumin ≥ 3.0 g/dL
    • Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min
    • Fasting glucose ≤ 150 mg/dL and hemoglobin A1c (HbA1c) ≤ 7.5%
  • Resolved or stabilized toxicities resulting from previous therapy to Grade 1 (except for alopecia and neuropathy)
    • An ongoing, Grade 2, non-hematologic toxicity related to the most recent treatment regimen may be permitted with approval from the Medical Monitor

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):
    • High-grade (2 or 3) serous or endometrioid or clear cell epithelial ovarian, fallopian tube, or primary peritoneal cancer (PPC).  If the tumor is of mixed histology, > 50% of the primary tumor must be confirmed to be high-grade serous, endometrioid, or clear cell.
    • Must have received at least one prior platinum-based therapy and may have platinum-sensitive disease (i.e., documented radiologic disease progression ≥ 6 months following the last dose of the platinum treatment administered) or platinum-resistant disease
    • Have a CA-125 level that is > 2 x ULN
    • Must have measurable disease by RECIST v1.1
  • For patients with breast cancer (Part 1 only): must be HER2-(ER/progesterone positive or negative)
    • ER/progesterone-positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic)
    • ER/progesterone-negative/HER2- (TNBC) patients must have received at least one prior line of chemotherapy for metastatic breast cancer
    • Must not have received more than two prior lines of chemotherapy for metastatic breast cancer
    • Must have measurable disease by RECIST v1.1
  • For patients with prostate cancer:
    • Adenocarcinoma of the prostate without small cell or neuroendocrine features
    • Surgical or medical castration with testosterone < 50 ng/dL (1.7 nM)
    • 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
    • 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
    • Must have received at least one prior line of second-generation androgen receptor targeted therapy (e.g., abiraterone, enzalutamide, apalutamide)
    • 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.
    • If the specimen is either insufficient or unavailable, the patient may still be eligible if the patient is willing to consent to and undergo an additional pretreatment core or excisional biopsy of the non-target lesion (if it is assessable and the biopsy can be safely obtained).  In general, a minimum of three core biopsies for NGS testing are required.
  • For women of childbearing potential: be abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating eggs, as defined below:
    • Women must be abstinent or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for at least 28 days after the final dose of ipatasertib or 6 months after the last dose of rucaparib, whichever occurs later.  Women must refrain from donating eggs during this same period.
    • A woman is considered to be of childbearing potential if she is post menarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).  The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
    • Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, and established proper use of progesterone-only injectable or implantable contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices
    • Hormonal contraceptive methods must be supplemented by a barrier method plus spermicide
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient
    • Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception
  • For men: be abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm, as defined below:
    • With female partners of childbearing potential, men must be abstinent or use a condom plus an additional contraceptive method that together result in a failure rate of < 1% per year during the treatment period and for 28 days after the last dose of ipatasertib or for 6 months after last dose of rucaparib whichever occurs later.  Men must refrain from donating sperm during this same period.
    • With pregnant female partners, men must be abstinent or use a condom during the treatment period and for 28 days after the last dose of ipatasertib or rucaparib to avoid exposing the embryo
    • Examples of contraceptive methods with a failure rate of < 1% per year, when used consistently and correctly, include combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, bilateral tubal occlusion, male sterilization, intrauterine hormone releasing system, and sexual abstinence
    • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
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
    • Women of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of study drug
  • 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
    • Patients with asymptomatic previously treated CNS metastases are eligible provided they have been clinically stable for at least 4 weeks
    • Patients with leptomeningeal carcinomatosis will be excluded
  • Uncontrolled tumor-related pain
    • Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization.  Patients should be recovered (e.g., to Grade 1 or resolved)from the effects of radiation prior to study enrollment.  There is no required minimum recovery period beyond the 7 days required for radiation therapy.
    • Asymptomatic metastatic lesions whose further growth would likely cause functional deficits or intractable pain (e.g., epidural metastasis that is not presently associated with spinal cord compression) should be considered for loco-regional therapy if appropriate prior to randomization
  • Non-study-related minor surgical procedures  5 days or major (invasive) surgical procedure  14 days prior to first dose of study treatment
    • Patient must be sufficiently recovered from surgery and stable, and wound healing must have occurred
  • Patients with active hepatitis C virus (HCV)
    • Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA
  • 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
    • If a patient has a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test, a quantitative HBV DNA test must be performed
    • Patients receiving anti-viral therapy for HBV are not eligible
  • 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, including the following:
    • History of stroke or transient ischemic attack within 6 months prior to enrollment
    • History of myocardial infarction within 6 months prior to first dose of study drug
    • New York Heart Association Class III or IV cardiac disease
    • Unstable arrhythmias or unstable angina
  • 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
    • However, patients who are on a stable dose of oral diabetes medication ≥ 4 weeks prior to initiation of study treatment may be eligible for enrollment.  Patients must meet the laboratory eligibility criteria for fasting blood glucose and HbA1C as outlined in the inclusion criteria.
  • 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

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03840200

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Re: MC# 19-26