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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified September 2014 by M.D. Anderson Cancer Center
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT02208375
First received: August 4, 2014
Last updated: September 8, 2014
Last verified: September 2014
  Purpose

The goal of this clinical research study is to learn about and compare the highest tolerable doses and combinations of the drugs olaparib, AZD2014, and AZD5363 that can be given to patients with recurrent endometrial, triple negative breast, ovarian, primary peritoneal, or fallopian tube cancer. The safety of these drugs and drug combinations will also be studied.


Condition Intervention Phase
Breast Cancer
Malignant Female Reproductive System Neoplasm
Drug: Olaparib
Drug: AZD2014
Drug: AZD5363
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • Maximum tolerated dose (MTD) of AZD2014 with Olaparib and AZD5363 with Olaparib [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    MTD defined by dose limiting toxicities (DLTs) that occur during the first 4 weeks of therapy and are related to the study medications. MTD defined as the highest dose for which the posterior probability of toxicity is closest to 30%.


Secondary Outcome Measures:
  • Response of AZD2014 with Olaparib and AZD5363 with Olaparib [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    Participants evaluated for response to therapy every two cycles (8 weeks). Participants undergo baseline imaging followed by repeat imaging every 8 weeks. Response and progression evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST).


Other Outcome Measures:
  • Biomarker Response [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
    Image-guided biopsy of the tumor for biomarker testing performed after Cycle 1 (4 weeks). Response tabulated by presence/absence of selected biomarkers (aberrations in PI3K/AKT/mTOR and HR defect pathway), and Fisher's exact test used to assess whether any of these biomarkers are related to response. Descriptive statistics and graphical methods used to compare pre-treatment to post-treatment changes in biomarker expression for each treatment overall and stratified by response and dose.


Estimated Enrollment: 150
Study Start Date: October 2014
Estimated Primary Completion Date: October 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Olaparib + AZD2014 (continuous dosing)

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -3.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Dose Escalation Starting Dose of AZD2014: 25 mg by mouth twice a day starting on Day 1.

Dose Expansion Starting Dose of AZD2014: MTD from Dose Escalation Phase. During the expansion phase, both drugs started simultaneously

Drug: Olaparib

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Drug: AZD2014

Dose Escalation Starting Dose of AZD2014: 25 mg by mouth twice a day for Olaparib + AZD2014 (continuous dosing) group, and 125 mg by mouth twice a day for Olaparib + AZD2014 (intermittent dosing) group.

Dose Expansion Starting Dose of AZD2014: MTD from Dose Escalation Phase.

Experimental: Olaparib + AZD2014 (intermittent dosing)

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -5.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Dose Escalation Starting Dose of AZD2014: 125 mg by mouth twice a day starting on Day 1 for 2 Days, then 5 Days off.

Dose Expansion Starting Dose of AZD2014: MTD from Dose Escalation Phase. During the expansion phase, both drugs started simultaneously

Drug: Olaparib

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Drug: AZD2014

Dose Escalation Starting Dose of AZD2014: 25 mg by mouth twice a day for Olaparib + AZD2014 (continuous dosing) group, and 125 mg by mouth twice a day for Olaparib + AZD2014 (intermittent dosing) group.

Dose Expansion Starting Dose of AZD2014: MTD from Dose Escalation Phase.

Experimental: Olaparib + AZD5363 (intermittent dosing)

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -3.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Dose Escalation Starting Dose of AZD5363: 320 mg by mouth twice a day starting on Day 1 for 4 days, then 3 days off.

Dose Expansion Starting Dose of AZD5363: MTD from Dose Escalation Phase. During the expansion phase, both drugs started simultaneously.

Drug: Olaparib

Dose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day.

Dose Expansion Starting Dose of Olaparib: MTD from Dose Escalation Phase.

Drug: AZD5363

Dose Escalation Starting Dose of AZD5363: 320 mg by mouth twice a day.

Dose Expansion Starting Dose of AZD5363: MTD from Dose Escalation Phase.


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  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Any histologically confirmed recurrent endometrial adenocarcinoma (except for carcinosarcoma), recurrent triple negative breast cancer, 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.
  2. Patients may have unlimited prior chemotherapeutic regimens for management of recurrent endometrial carcinoma, triple negative breast, or ovarian carcinoma. 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.
  3. With the exception of alopecia, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.0) Grade 1 at the time of starting study treatment.
  4. Patients should have measurable disease as defined by RECIST 1.1. If no measurable disease is present, patients should have assessable disease such as pleural effusion, ascites, with CA125 GCIG criteria.
  5. Patients must have an ECOG performance status of 0 or 1.
  6. Effects of AZD2014, AZD5363, and olaparib on the developing human fetus are unknown. 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.
  7. It is unknown if AZD2014, AZD5363, or olaparib are expressed in human breast milk. For this reason, women must not breast-feed while taking the study medications.
  8. Patients must have normal organ and marrow function (measured within 28 days prior to entry/ randomization) as defined below: a) Absolute neutrophil count >/= 1,500/mcL; b) Hemoglobin >/= 10gm/dL; c) Platelets >/= 100,000/mcL; d) Presence of < 4% blasts on hematologic studies; e) Total Bilirubin </= 1.5 x institutional upper limit of normal (ULN); f) AST/ALT </= 2.5x upper limit of normal unless the liver is involved with tumor, in that case, ALT/AST must be </= 5x ULN; g) Creatinine clearance > 50 mL/min (assessed by Cockcroft Gault estimation)
  9. Patients with type II diabetes mellitus that is well controlled by dietary measures alone and have an 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.
  10. 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).
  11. Participants' life expectancy must be > 4 months
  12. Patients must be able to understand and willing to sign an informed consent.
  13. Patients must be at least 18 years of age.
  14. FOR EXPANSION PHASE ONLY: For the expansion phase, patients must have measurable disease accessible for biopsy.

Exclusion Criteria:

  1. Patients receiving any other investigational agents or any additional anti-cancer agents.
  2. 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.
  3. Patients who have recurrences that are amenable to potentially curative treatment with radiation therapy or surgery.
  4. 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.
  5. Patients who have a history of myelodysplastic syndrome.
  6. 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.
  7. 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.
  8. 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.
  9. Patients who have a resting ECG with a QTc interval of >/= 470 msec at 2 or more time points within a 24 hour period or a family history of long QT syndrome.
  10. Patients who have required a blood transfusion within 28 days prior to study start.
  11. Patients who have received any hemopoietic growth factors (e.g., G-CSF, GM-CSF) within 2 weeks prior to study start.
  12. Patients receiving certain medications and/or substances that are prohibited within stated wash-out periods. Reference and use of the appendix with the list of agents that can be updated and is more inclusive will be used for determining eligibility.
  13. Participants receiving any medications or substances that are known to cause QT prolongation, or have factors that increase the risk of QTc prolongation or risk of arrhythmic events (such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age).
  14. 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.
  15. Patients who have experienced intolerable adverse events per treating Investigator due to other PARP inhibitors, mTOR inhibitors, PI3 kinase inhibitors, or AKT inhibitors.
  16. 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
  17. Patients who have abnormal echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) at baseline (left ventricular ejection fraction [LVEF] <55%. Appropriate correction to be used if a MUGA is performed.
  18. Patients with Torsades de Pointes within 12 months of study entry.
  19. Patients with uncontrolled hypotension (systolic blood pressure < 90mmHg and/or diastolic blood pressure < 50mmHg).
  20. Patients with proteinuria (3+ on dipstick analysis or >500mg/24 hours).
  21. Patients with Diabetes Type I or uncontrolled Type II (HbA1c >8 % assessed locally) as judged by the Investigator.
  22. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases (eg, 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.
  23. 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.
  24. FOR EXPANSION PHASE ONLY: Lack of accessible tumor for biopsy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02208375

Contacts
Contact: Shannon Westin, MD 713-794-4314

Locations
United States, Texas
University of Texas MD Anderson Cancer Center Not yet recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
AstraZeneca
Investigators
Principal Investigator: Shannon Westin, MD M.D. Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02208375     History of Changes
Other Study ID Numbers: 2013-0784
Study First Received: August 4, 2014
Last Updated: September 8, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by M.D. Anderson Cancer Center:
Breast Cancer
Malignant Female Reproductive System Neoplasm
Recurrent endometrial cancer
Triple negative breast cancer
Ovarian cancer
Primary peritoneal cancer
Fallopian tube cancer
Recurrent endometrial adenocarcinoma
Olaparib
AZD2014
AZD5363

Additional relevant MeSH terms:
Neoplasms
Breast Neoplasms
Genital Neoplasms, Female
Neoplasms by Site
Breast Diseases
Skin Diseases
Urogenital Neoplasms

ClinicalTrials.gov processed this record on September 22, 2014