A Phase Ib Study of the Oral PARP Inhibitor Olaparib With the Oral mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial, Triple Negative Breast, and Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
Overview
- Phase
- Phase 1
- Status
- Active, not recruiting
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 159
- Locations
- 1
- Primary Endpoint
- Maximum tolerated dose
Overview
Brief Summary
This phase Ib/II trial studies the side effects and best dose of olaparib and vistusertib (AZD2014) or olaparib and capivasertib (AZD5363) when given together in treating patients with endometrial, triple negative breast cancer, ovarian, primary peritoneal, or fallopian tube cancer that has come back (recurrent). Olaparib, vistusertib, and capivasertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:
I. To determine the maximally tolerated dose (MTD) and recommended phase II dose (RP2D) of the combinations of AZD2014 + olaparib and confirmation of recommended phase 2 dose (RP2D) for the AZD5363 + olaparib combination in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or recurrent breast cancer, BRCA mutant ovarian cancer.
SECONDARY OBJECTIVES:
I. To determine the tolerability of the RP2D of AZD2014 + olaparib and AZD5363 + olaparib.
II. To determine the safety and observed toxicities of the combination of AZD2014 + olaparib and AZD5363 + olaparib in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer.
III. To estimate the activity of these drug combinations at all dose levels in each patient cohort by objective response rate and proportion of patients surviving progression free (PFS) at 6 months.
IV. To determine response duration of these combinations at all dose levels. V. To determine the pharmacokinetics (PK) of each agent alone and in combination to assess the presence of any drug interaction between the two co-administered agents.
EXPLORATORY TRANSLATIONAL OBJECTIVES:
I. To determine if response to therapy is associated with molecular profile of the tumor (including, but not limited to, molecular aberrations in the phosphoinositide-3-kinase [PI3K]- v-akt murine thymoma viral oncogene homolog [AKT]- mechanistic target of rapamycin [mTOR] pathway or defects in homologous recombination) before treatment.
II. To examine associations with early changes in functional proteomic biomarkers in tumor biopsies before and after treatment and tumor response in patients with recurrent endometrial, recurrent triple negative breast, recurrent high-grade serous ovarian, or BRCA mutant ovarian cancer treated with the investigational agents.
III. To determine the molecular profile of unusual responders (significant regression of disease or progression of disease).
IV. To provide data to investigate the relationship between plasma concentrations/exposure and changes in safety and efficacy outputs to facilitate population analysis by sponsor.
OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 3 treatment arms.
ARM I (CONTINUOUS AZD2014 DOSING): Patients receive olaparib orally (PO) twice daily (BID) on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).
ARM II (INTERMITTENT AZD2014 DOSING): Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1).
ARM III (INTERMITTENT AZD5363 DOSING): Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1).
In all arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 4 weeks.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- Female
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Any histologically confirmed locally advanced recurrent endometrial adenocarcinoma (except for carcinosarcoma), recurrent high-grade serous ovarian/primary peritoneal/fallopian tube carcinoma, or deleterious BRCA mutant recurrent ovarian/primary peritoneal/fallopian tube cancer for whom no curative option is available will be eligible; any patient proven to have metastatic triple negative breast cancer, defined from standard pathologic assays as negative for estrogen receptor (ER) and progesterone receptor (PR) (\< 10% tumor staining) will be eligible
- •Patients may have unlimited prior chemotherapeutic regimens for management of recurrent locally advanced endometrial carcinoma, recurrent ovarian carcinoma, or metastatic triple negative breast cancer; treatment as frontline therapy for metastatic disease is acceptable; patients who have received prior PARP inhibitors, MTOR inhibitors, and/or AKT inhibitors are allowed to participate; patients may have progressed on prior PARP inhibitor, MTOR inhibitor, or AKT inhibitor but they may not have discontinued drug for toxicity
- •With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than Common Terminology Criteria for Adverse Events (CTCAE) (version 4.0) grade 1 at the time of starting study treatment
- •Patients should have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; if no measurable disease is present, patients should have assessable disease such as pleural effusion, ascites, with cancer antigen 125 (CA125) Gynecological Cancer Intergroup (GCIG) criteria
- •Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Women of child-bearing potential and their partners must agree to use contraception (hormonal or barrier method of birth control; abstinence) from study entry until 30 days after last dose of study drug; male partners should be instructed to use contraception during the study period; women of child-bearing potential (intact uterus) should have a negative serum pregnancy test; if a woman becomes pregnant or suspects she is pregnant while on study, she should tell her treating physician immediately; female patients must have evidence of non-child-bearing potential by fulfilling 1 of the following at screening: a) post-menopausal defined as \> 50 years old and amenorrheic for \>= 12 consecutive months following cessation of all exogenous hormonal treatments; b) documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation
- •Women must not breast-feed while taking the study medications
- •Absolute neutrophil count \>= 1,500/mcL (measured within 28 days prior to entry/randomization)
- •Hemoglobin \>= 10 gm/dL (measured within 28 days prior to entry/randomization)
- •Platelets \>= 100,000/mcL (measured within 28 days prior to entry/randomization)
Exclusion Criteria
- •Patients receiving any other investigational agents or any additional anti-cancer agents
- •Patients who have endometrial carcinosarcoma; patients with ovarian cancer who have histology other than high-grade serous in the absence of a deleterious BRCA mutation; if the patient has a deleterious BRCA mutation, any histology will be accepted
- •Patients who have recurrences that are amenable to potentially curative treatment with radiation therapy or surgery
- •Patients who have a history of other malignancies except for basal cell or squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free for at least five years; patients may have dual primaries of endometrial, ovarian or breast cancer
- •Patients who have a history of myelodysplastic syndrome
- •Patients who have symptomatic, uncontrolled spinal cord compression and/or brain metastases; a scan to confirm absence of brain metastasis is not required; patients can receive a stable dose of corticosteroids (except those prohibited per protocol) before/during study if these were started at least 28 days prior to entry
- •Patients who have had prior chemotherapy, biological therapy, radiation therapy, androgens, thalidomide, immunotherapy, other anticancer agents, and any investigational agents within 28 days of starting study treatment (not including palliative radiotherapy at focal sites), or corticosteroids that are prohibited per protocol within 14 days of starting study treatment
- •Patients who have had major surgery within 28 days prior to entry into the study or be recovering from any effects of surgery; patients who have had minor surgery within 2 weeks prior to entry into the study
- •Patients who have a resting electrocardiogram (ECG) with a Fridericia corrected QT (QTcF) interval of \>= 470 msec at 2 or more time points within a 24 hour period or a family history of long QT syndrome
- •Patients who have required a blood transfusion within 28 days prior to study start
Arms & Interventions
Arm I (olaparib, vistusertib)
CONTINUOUS AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).
Intervention: Laboratory Biomarker Analysis (Other)
Arm I (olaparib, vistusertib)
CONTINUOUS AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).
Intervention: Olaparib (Drug)
Arm I (olaparib, vistusertib)
CONTINUOUS AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).
Intervention: Pharmacological Study (Other)
Arm I (olaparib, vistusertib)
CONTINUOUS AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 5-28 of course 1 and alone on days -3 to -1 of week -1) and vistusertib PO BID on days 1-28 (alone on days 1-4 of week 1).
Intervention: Vistusertib (Drug)
Arm II (olaparib, vistusertib)
INTERMITTENT AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib 4 PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1).
Intervention: Laboratory Biomarker Analysis (Other)
Arm II (olaparib, vistusertib)
INTERMITTENT AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib 4 PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1).
Intervention: Olaparib (Drug)
Arm II (olaparib, vistusertib)
INTERMITTENT AZD2014 DOSING: Patients receive olaparib PO BID on days 1-28 (days 3-28 on course 1 and alone on days -5 to -3 of week -1) and vistusertib 4 PO BID for 2 days on and 5 days off (alone on days 1-2 of week 1).
Intervention: Vistusertib (Drug)
Arm III (olaparib, capivasertib)
INTERMITTENT AZD5363 DOSING: Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1).
Intervention: Capivasertib (Drug)
Arm III (olaparib, capivasertib)
INTERMITTENT AZD5363 DOSING: Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1).
Intervention: Laboratory Biomarker Analysis (Other)
Arm III (olaparib, capivasertib)
INTERMITTENT AZD5363 DOSING: Patients receive olaparib PO BID on days 1-28 (on days 5-28 of course 1 and alone on days -3 to -1 of week -1) and capivasertib PO BID for 4 days on and 3 days off (alone on days 1-4 of week 1).
Intervention: Olaparib (Drug)
Outcomes
Primary Outcomes
Maximum tolerated dose
Time Frame: Up to 28 days
Will be defined as the highest dose for which the posterior probability of toxicity is closest to 30%. The posterior probability of dose limiting toxicity (DLT) for each dose level and 90% credible interval for the probability of DLT at each dose level will be reported.
Secondary Outcomes
- Toxicity profile, including dose-limiting toxicities(Up to 4 weeks post-treatment)
- Response rate(Up to 4 weeks post-treatment)
- Response duration(Up to 4 weeks post-treatment)
- Cmax for Olaparib(Days -1, 4, and 8)
- Progression-free survival (PFS)(At 6 months from study treatment)