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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

NCT02208375

Description:

The goal of this clinical research study is to learn about and compare the highest tolerable doses and combinations of the drugs Lynparza™ (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. This is an investigational study. Olaparib is commercially available and FDA approved for the treatment of certain types of ovarian cancer. Its use in this study is investigational. AZD2014 and AZD5363 are not FDA approved or commercially available. They are currently being used for research purposes only. The use of the study drugs in combination is investigational. The study doctor can explain how the study drugs are designed to work. Up to 150 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Breast Carcinoma
  • Endometrial Carcinoma
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: 2013-0784
  • SECONDARY ID: NCI-2014-01973
  • SECONDARY ID: SP50CA083639
  • NCT ID: NCT02208375

Conditions

  • Breast Cancer
  • Malignant Female Reproductive System Neoplasm

Interventions

DrugSynonymsArms
OlaparibOlaparib + AZD2014 (continuous dosing)
AZD2014Olaparib + AZD2014 (continuous dosing)
AZD5363Olaparib + AZD5363 (intermittent dosing)

Purpose

The goal of this clinical research study is to learn about and compare the highest tolerable doses and combinations of the drugs Lynparza™ (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.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study and agree, you will be enrolled in
      a study group based on when you join the study. Up to 3 groups of 30 participants will be
      enrolled in the Dose Escalation part of the study, and up to 60 participants will be enrolled
      in the Dose Expansion part.

      If you are in a Dose Escalation group, you will be assigned to a combination dose level of
      one of the following:

        -  Olaparib and AZD2014 both taken every day,

        -  Olaparib taken every day and AZD2014 taken for 2 days on and 5 days off

      If you are in the first group above, you will begin taking olaparib alone on Week -1 (the
      week before Week 1) on Days -3, -2, -1. Then you will take AZD2014 alone on Days 1-4 of Week
      1. You will start taking olaparib again on Day 5 of Week 1 with AZD2014 every day for the
      rest of Cycle 1. For Cycle 2 and every cycle after that, you will continue to take both
      olaparib and AZD2014 together every day.

      If you are in the second group above, you will begin taking olaparib alone on Week -1 on Days
      -5, -4, and -3. Then you will take AZD2014 alone on Days 1 and 2 of Week 1. You will start
      taking olaparib again on Day 3 of Week 1 and continue every day for the rest of Cycle 1. For
      Cycle 2 and every cycle after that, you will take olaparib every day. You will add AZD2014 to
      your dosing schedule starting Week 2 Day 8, on a 2 days on/5 days off schedule.

      Up to 5 combination dose levels will be tested in the Dose Escalation groups. Up to 3
      participants will be enrolled at each dose level. The first group of participants will
      receive the lowest dose level. Each new group may receive a higher dose of the study drugs
      than the group before it, if no intolerable side effects were seen. This will continue until
      the highest tolerable dose of the study drug combinations is found.

      If you are in the Dose Expansion group, you will receive either the combination of
      olaparib/AZD2014 or olaparib/AZD5363 at the highest dose combination and schedule that was
      tolerated in the escalation groups.

      Study Drug Administration:

      You should not take olaparib 2 hours before or within 2 hours after eating. The olaparib
      tablets should be swallowed whole with 8 ounces (1 cup) of water. You should not chew, crush,
      dissolve, or divide the tablets.

      If you take AZD5363 or AZD2014, you should fast (have nothing to eat or drink except for
      water) at least 2 hours before your dose and then again 2 hours after your dose. You should
      take these doses at about the same time each morning and evening.

      You should avoid sugary or fatty food before taking a dose of study drugs. The study drugs
      can be taken in any order.

      If you vomit shortly after the olaparib tablets are swallowed, the dose should only be
      replaced if all of the intact tablets can be seen and counted. If you miss a scheduled dose,
      you should take the dose up to 2 hours after that scheduled time. If more than 2 hours have
      passed after the scheduled time, the missed dose should not to be taken and you should wait
      until the next scheduled time.

      Study Visits:

      Each study cycle is 4 weeks. The following tests and procedures will be performed:

      Each Week during Cycle 1:

        -  You will have a physical exam. If the study doctor thinks it is needed, you will also
           have a pelvic exam.

        -  Blood (about 1-2 teaspoons) will be drawn for routine tests.

        -  If you have ovarian, primary peritoneal, or fallopian tube cancer, blood (about 1-2
           teaspoons) will be drawn to check the CA-125 level.

        -  You will have an EKG.

        -  One (1) time during Weeks 1 and 2 only, blood (about ½ teaspoon) will be drawn about 2-4
           hours after your study drug dose to test your blood sugar level.

      If you are in the Dose Expansion group, after Cycle 1 (4 weeks after starting the study
      drugs), you will have an image-guided biopsy of the tumor for biomarker testing.

      Every 4 weeks:

        -  You will have a physical exam.

        -  Blood (about 2½ teaspoons) will be drawn for routine tests and to check the level of fat
           in your blood.

        -  After Cycle 1, if you have ovarian, primary peritoneal, or fallopian tube cancer, blood
           (about 1-2 teaspoons) will be drawn to check the CA-125 level.

      Every 8 weeks:

        -  Blood (about ½ teaspoon) will be drawn to test your blood sugar.

        -  You will have a CT scan or MRI to check the status of the disease.

      After Cycle 2, you will have an ECHO every 8 weeks and then again whenever the study doctor
      thinks it is needed.

      After 6 months, you will have a CT scan every 3 cycles to check the status of the disease.

      Pharmacokinetic Testing:

      Blood (about ½ teaspoon each time) will be drawn for pharmacokinetic (PK) testing. PK testing
      measures the amount of study drug in the body at different time points. The time points for
      these draws will depend upon which study group you are in:

        -  If you will take both olaparib and AZD2014 every day, you will have PK draws on Days -1,
           4, and 8.

        -  If you will take olaparib every day and AZD2014 for 2 days on and 5 days off, you will
           have PK draws on Days -3, 1, 8, and 9.

      Length of Study:

      You will receive the study drugs for as long as the study doctor thinks it is in your best
      interest. You will no longer be able to take the study drugs if the disease gets worse, if
      intolerable side effects occur, or if you are unable to follow study directions.

      Your participation on the study will be over after the end-of-study visit.

      End-of-Study Visit:

      Within 4 weeks after your last dose of study drugs, the following tests and procedures will
      be performed:

        -  You will have a physical exam.

        -  Blood (about 2½ teaspoons) will be drawn for routine tests and to check the level of fat
           in your blood and your blood sugar level.

        -  You will have an EKG and an ECHO.

        -  You will have a CT scan or MRI to check the status of the disease.

        -  If you have ovarian, primary peritoneal, or fallopian tube cancer, blood (about 1-2
           teaspoons) will be drawn to check the CA-125 level.

      This is an investigational study. Olaparib is commercially available and FDA approved for the
      treatment of certain types of ovarian cancer. Its use in this study is investigational.
      AZD2014 and AZD5363 are not FDA approved or commercially available. They are currently being
      used for research purposes only. The use of the study drugs in combination is
      investigational.

      The study doctor can explain how the study drugs are designed to work.

      Up to 150 participants will be enrolled in this study. All will take part at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Olaparib + AZD2014 (continuous dosing)ExperimentalDose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -3 for three days. 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
  • Olaparib
  • AZD2014
Olaparib + AZD2014 (intermittent dosing)ExperimentalDose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -5 for three days. 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
  • Olaparib
  • AZD2014
Olaparib + AZD5363 (intermittent dosing)ExperimentalDose Escalation Starting Dose of Olaparib: 100 mg by mouth twice a day starting on Day -3 or -5 for three days or 300 mg by mouth twice a day if in Group 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.
  • Olaparib
  • AZD5363

Eligibility Criteria

        Inclusion Criteria:

          1. 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 ER and PR (<10%
             tumor staining) will be eligible.

          2. 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.

          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.

         15. For the expansion phase, patients must have archival specimens from the time of
             primary or recurrence diagnosis.

        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 QTcF 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. 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.

         14. Patients who have experienced intolerable adverse events per treating Investigator due
             to other PARP inhibitors, mTOR inhibitors, PI3 kinase inhibitors, or AKT inhibitors.

         15. 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

         16. 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.

         17. Patients with Torsades de Pointes within 12 months of study entry.

         18. Patients with uncontrolled hypotension (systolic blood pressure < 90mmHg and/or
             diastolic blood pressure < 50mmHg).

         19. Patients with proteinuria (3+ on dipstick or 300 mg/dL on urine analysis or
             >500mg/dL/24 hours).

         20. Patients with Diabetes Type I or uncontrolled Type II (HbA1c >8 % assessed locally) as
             judged by the Investigator.

         21. 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.

         22. 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.

         23. FOR EXPANSION PHASE ONLY: Lack of accessible tumor for biopsy.

         24. Lack of archival specimens from the time of primary or recurrence diagnosis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of AZD2014 with Olaparib and AZD5363 with Olaparib
Time Frame:4 weeks
Safety Issue:
Description: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

Measure:Response of AZD2014 with Olaparib and AZD5363 with Olaparib
Time Frame:8 weeks
Safety Issue:
Description: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).

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Breast Cancer
  • Malignant Female Reproductive System Neoplasm
  • Recurrent endometrial cancer
  • Recurrent endometrial adenocarcinoma
  • Triple negative breast cancer
  • Ovarian cancer
  • Primary peritoneal cancer
  • Fallopian tube cancer
  • Olaparib
  • AZD2014
  • AZD5363

Last Updated

August 23, 2017