mTORC1/2 Inhibitor AZD2014 or the Oral AKT Inhibitor AZD5363 for Recurrent Endometrial and Ovarian

NCT02208375 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: 2013-0784NCI-2014-01973P50CA083639
• Study Type: interventional
• Target: 159
• Locations: 1 country
• Sites: 1

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.

Conditions

High Grade Ovarian Serous Adenocarcinoma; BRCA1 Mutation Carrier; BRCA2 Mutation Carrier; Endometrial Adenocarcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Stage III Uterine Corpus Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Stage IV Uterine Corpus Cancer AJCC v7; Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (1)

• Maximum tolerated dose

  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.

  Up to 28 days

Secondary Outcomes (5)

• Toxicity profile, including dose-limiting toxicities

  Up to 4 weeks post-treatment

• Response rate

  Up to 4 weeks post-treatment

• Progression-free survival (PFS)

  At 6 months from study treatment

• Response duration

  Up to 4 weeks post-treatment

• Cmax for Olaparib

  Days -1, 4, and 8

Other Outcomes (2)

• Changes in protein expression

  Baseline and within 4 weeks post-treatment

• Cmax for AZD2014

  Days -1, 4, and 8

Study Arms (3)

Arm I (olaparib, vistusertib)

EXPERIMENTAL

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).

Other: Laboratory Biomarker Analysis; Drug: Olaparib; Other: Pharmacological Study; Drug: Vistusertib

Arm II (olaparib, vistusertib)

EXPERIMENTAL

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).

Other: Laboratory Biomarker Analysis; Drug: Olaparib; Drug: Vistusertib

Arm III (olaparib, capivasertib)

EXPERIMENTAL

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).

Drug: Capivasertib; Other: Laboratory Biomarker Analysis; Drug: Olaparib

Interventions

Capivasertib DRUG

Given PO

Also known as: AZD5363

Arm III (olaparib, capivasertib)

Laboratory Biomarker Analysis OTHER

Correlative studies

Arm I (olaparib, vistusertib); Arm II (olaparib, vistusertib); Arm III (olaparib, capivasertib)

Olaparib DRUG

Given PO

Also known as: AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281

Arm I (olaparib, vistusertib); Arm II (olaparib, vistusertib); Arm III (olaparib, capivasertib)

Pharmacological Study OTHER

Correlative studies

Arm I (olaparib, vistusertib)

Vistusertib DRUG

Given PO

Also known as: AZD 2014, AZD-2014, AZD2014

Arm I (olaparib, vistusertib); Arm II (olaparib, vistusertib)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• Presence of \< 4% blasts on hematologic studies (measured within 28 days prior to entry/randomization)
• Total bilirubin =\< 1.5 x institutional upper limit of normal (ULN) (measured within 28 days prior to entry/randomization)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =\< 2.5 x upper limit of normal unless the liver is involved with tumor, in that case, ALT/AST must be =\< 5 x ULN (measured within 28 days prior to entry/randomization)
• Creatinine clearance \> 50 mL/min (assessed by Cockcroft Gault estimation) (measured within 28 days prior to entry/randomization)
• Patients must be able to swallow and tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of AZD2014, AZD5363, or olaparib (e.g. uncontrolled nausea, vomiting, or diarrhea; malabsorption syndrome; ulcerative disease)

You may not qualify if:

• 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
• Patients who have received any hemopoietic growth factors (e.g., filgrastim \[G-CSF\], sargramostim \[GM-CSF\]) within 2 weeks prior to study start
• Patients receiving certain medications and/or substances that are prohibited within stated wash-out periods
• Patients with known hypersensitivity to olaparib, AZD5363, AZD2014 or any of their excipients; patients with a history of hypersensitivity to drugs with a similar chemical structure or class to olaparib, AZD5363, or AZD2014
• Patients who have experienced intolerable adverse events per treating investigator due to other PARP inhibitors, mTOR inhibitors, PI3 kinase inhibitors, or AKT inhibitors
• Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: a) coronary artery bypass graft; b) angioplasty; c) vascular stent; d) myocardial infarction; e) angina pectoris; f) congestive heart failure New York Heart Association grade \>= 2; g) ventricular arrhythmias requiring continuous therapy; h) supraventricular arrhythmias including atrial fibrillation, which are uncontrolled; i) hemorrhagic or thrombotic stroke, including transient ischemic attacks or any other central nervous system bleeding

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (1)

• Sun C, Fang Y, Labrie M, Li X, Mills GB. Systems approach to rational combination therapy: PARP inhibitors. Biochem Soc Trans. 2020 Jun 30;48(3):1101-1108. doi: 10.1042/BST20191092.

  PMID: 32379297 DERIVED

Related Links

• University of Texas MD Anderson Cancer Center Website

MeSH Terms

Conditions

Breast Neoplasms; Fallopian Tube Neoplasms; Ovarian Neoplasms; Triple Negative Breast Neoplasms

Interventions

capivasertib; olaparib; vistusertib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Fallopian Tube Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Endocrine System Diseases; Gonadal Disorders

Study Officials

• Shannon N Westin

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2014
• First Posted: August 5, 2014
• Study Start: November 11, 2014
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): June 30, 2026
• Last Updated: December 31, 2025

Record last verified: 2025-12

Locations

US (1)