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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02208375
Recruitment Status : Active, not recruiting
First Posted : August 5, 2014
Last Update Posted : July 21, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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.

Condition or disease Intervention/treatment Phase
BRCA1 Mutation Carrier BRCA2 Mutation Carrier Endometrial Adenocarcinoma Estrogen Receptor Negative HER2/Neu Negative High Grade Ovarian Serous Adenocarcinoma 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 Drug: Capivasertib Other: Laboratory Biomarker Analysis Drug: Olaparib Other: Pharmacological Study Drug: Vistusertib Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 159 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : November 11, 2014
Estimated Primary Completion Date : November 30, 2021
Estimated Study Completion Date : November 30, 2021


Arm Intervention/treatment
Experimental: 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).
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Other: Pharmacological Study
Correlative studies

Drug: Vistusertib
Given PO
Other Names:
  • AZD 2014
  • AZD-2014
  • AZD2014

Experimental: 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).
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281

Drug: Vistusertib
Given PO
Other Names:
  • AZD 2014
  • AZD-2014
  • AZD2014

Experimental: 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).
Drug: Capivasertib
Given PO
Other Name: AZD5363

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281




Primary Outcome Measures :
  1. 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 Outcome Measures :
  1. Toxicity profile, including dose-limiting toxicities [ Time Frame: Up to 4 weeks post-treatment ]
    Descriptive statistics will be used to summarize the demographic and clinical characteristics of patients. Adverse events will be tabulated by grade, dose level, and overall.

  2. Response rate [ Time Frame: Up to 4 weeks post-treatment ]
    Will be measured using Response Evaluation Criteria in Solid Tumors 1.1 criteria. The proportion of patients with response with 95% exact binomial confidence intervals will be estimated. Response will be tabulated by presence/absence of selected biomarkers (aberrations in I3K/AKT/mTOR and HR defected pathway).

  3. Progression-free survival (PFS) [ Time Frame: At 6 months from study treatment ]
    PFS will be estimated with the Kaplan-Meier product limit estimator. Depending on distribution of marker aberration status, the relationship between these markers and PFS will be explored using the log-rank test.

  4. Response duration [ Time Frame: Up to 4 weeks post-treatment ]
    Descriptive statistics will be used to summarize response duration.

  5. Cmax for Olaparib [ Time Frame: Days -1, 4, and 8 ]
    For continuous and intermittent dosing, maximum plasma concentration will be measured,


Other Outcome Measures:
  1. Changes in protein expression [ Time Frame: Baseline and within 4 weeks post-treatment ]
    Descriptive statistics and graphical methods will be used to compare pre-treatment to post-treatment changes in biomarker expression for each treatment overall and stratified by response and dose. Mean changes from pre-treatment to post-treatment will be estimated with 95% confidence intervals. A paired t-test will also be used to test whether these changes are statistically significant, and a 2-sample t-test will be used to compare changes between selected doses and specific subgroups.

  2. Cmax for AZD2014 [ Time Frame: Days -1, 4, and 8 ]
    For continuous and intermittent dosing, maximum plasma concentration will be measured.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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)
  • 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 with type II diabetes mellitus that is well controlled by dietary measures alone and have a hemoglobin A1c (HgA1c) < 8% are eligible to participate; patients found to have a fasting glucose >= 7 mmol/L (>= 126 mg/dL) or glycosylated hemoglobin > 8% (64 mmol/mol) at screening should be assessed for appropriate management according to local policy; those in whom dietary measures alone provide good diabetic control will be eligible for inclusion; type I or II diabetes mellitus requiring either insulin or oral hypoglycemics for routine management will be excluded
  • 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)
  • Participants' life expectancy must be > 4 months
  • Patients must be able to understand and willing to sign an informed consent
  • FOR EXPANSION PHASE ONLY: For the expansion phase, patients must have measurable disease accessible for biopsy
  • FOR EXPANSION PHASE ONLY: For the expansion phase, patients must have archival specimens from the time of primary or recurrence diagnosis

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
  • 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
  • Patients who have abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] < 50%); appropriate correction to be used if a MUGA is performed
  • Patients with torsades de pointes within 12 months of study entry
  • Patients with uncontrolled hypotension (systolic blood pressure < 90 mmHg and/or diastolic blood pressure < 50 mmHg)
  • Patients with proteinuria (3+ on dipstick or 300 mg/dL on urine analysis or > 500 mg/dL/24 hours)
  • Patients with diabetes type I or uncontrolled type II (HbA1c > 8 % assessed locally) as judged by the investigator
  • As judged by the investigator, any evidence of severe or uncontrolled systemic diseases (e.g., severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled chronic renal diseases [glomerulonephritis, nephritic syndrome, Fanconi syndrome or renal tubular acidosis]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled hypertension (blood pressure >= 140/90), active bleeding diatheses or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus; screening for chronic conditions is not required
  • As judged by the investigator, the patient is unsuitable to participate in the study and the patient is unlikely to comply with study procedures, restrictions, and requirements
  • FOR EXPANSION PHASE ONLY: Lack of accessible tumor for biopsy
  • Lack of archival specimens from the time of primary or recurrence diagnosis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02208375


Locations
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United States, Texas
M D Anderson Cancer Center
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Shannon N Westin M.D. Anderson Cancer Center
Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02208375    
Other Study ID Numbers: 2013-0784
NCI-2014-01973 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2013-0784 ( Other Identifier: M D Anderson Cancer Center )
P30CA016672 ( U.S. NIH Grant/Contract )
P50CA083639 ( U.S. NIH Grant/Contract )
First Posted: August 5, 2014    Key Record Dates
Last Update Posted: July 21, 2020
Last Verified: July 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Adenocarcinoma
Breast Neoplasms
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents