Clinical Trials /

Selumetinib and Olaparib in Solid Tumors

NCT03162627

Description:

This study has 2 phases: Phase 1 (dose escalation) and Phase 2 (dose expansion). The goal of Phase 1 of this clinical research study is to find the highest tolerable dose combination of selumetinib and olaparib that can be given to patients who have solid tumors that are advanced or recurrent (has returned after treatment). The goal of Phase 2 is to learn if the highest tolerable dose combination found in Phase 1 can help to control advanced or recurrent solid tumors. The safety of the study drug combination will also be studied in both parts. This is an investigational study. Selumetinib is not FDA approved or commercially available. It is currently being used for research purposes only. Olaparib is FDA approved and commercially available for the treatment of ovarian cancer that has a certain type of genetic mutation (change). It is considered investigational to use selumetinib in combination with olaparib to treat advanced or recurrent cancer. The study doctor can explain how the study drugs are designed to work. Up to 90 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Selumetinib and Olaparib in Solid Tumors
  • Official Title: Evaluation of the Combination of Selumetinib and Olaparib in Endometrial, Ovarian and Other Solid Tumors With Ras Pathway Alterations, and Ovarian Tumors With PARP Resistance

Clinical Trial IDs

  • ORG STUDY ID: 2016-1129
  • SECONDARY ID: NCI-2018-01205
  • NCT ID: NCT03162627

Conditions

  • Malignant Neoplasm of Breast
  • Malignant Neoplasms of Digestive Organs
  • Malignant Neoplasms of Female Genital Organs
  • Malignant Neoplasms of Male Genital Organs
  • Malignant Neoplasms of Thyroid and Other Endocrine Glands

Interventions

DrugSynonymsArms
SelumetinibAZD6244Selumetinib + Olaparib
OlaparibLynparzaSelumetinib + Olaparib

Purpose

This study has 2 phases: Phase 1 (dose escalation) and Phase 2 (dose expansion). The goal of Phase 1 of this clinical research study is to find the highest tolerable dose combination of selumetinib and olaparib that can be given to patients who have solid tumors that are advanced or recurrent (has returned after treatment). The goal of Phase 2 is to learn if the highest tolerable dose combination found in Phase 1 can help to control advanced or recurrent solid tumors. The safety of the study drug combination will also be studied in both parts. This is an investigational study. Selumetinib is not FDA approved or commercially available. It is currently being used for research purposes only. Olaparib is FDA approved and commercially available for the treatment of ovarian cancer that has a certain type of genetic mutation (change). It is considered investigational to use selumetinib in combination with olaparib to treat advanced or recurrent cancer. The study doctor can explain how the study drugs are designed to work. Up to 90 participants will be enrolled in this study. All will take part at MD Anderson.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be assigned to a phase
      depending on when you join the study. Up to 30 participants will be enrolled in Phase 1, and
      up to 60 participants will be enrolled in Phase 2.

      If you are enrolled in Phase 1, the dose of the study drugs you receive will depend on when
      you join this study. Up to 3 dose level combinations of selumetinib and olaparib will be
      tested. The first group of participants will receive the lowest dose level of each study
      drugs. Each new group will receive a higher dose of either selumetinib or olaparib study
      drugs than the group before it, if no intolerable side effects were seen. This will continue
      until the highest tolerable dose combination of the study drugs is found.

      If you are enrolled in Phase 2, you will receive the highest study drug combination that was
      tolerated in Phase 1.

      Study Drug Administration:

      Each study cycle is 28 days.

      You will take both selumetinib and olaparib by mouth 2 times each day, about 12 hours apart
      (1 dose in the morning, 1 dose in the evening). You should fast (have nothing to eat or drink
      except water) for at least 2 hours before and 1 hour after your dose. If you vomit or miss a
      dose, you should not retake the dose. Wait and take your next scheduled dose.

      Depending on the dose level of selumetinib you are receiving, you may only take the study
      drug on Days 1-5 of each week. The study doctor will tell you how often you should take
      selumetinib.

      You will be given a study drug diary to record when you take each dose. The study staff will
      show you how to fill it out.

      You will wait to take your morning dose of study drugs at the clinic on certain days. The
      study staff will remind you before each of these clinic visits.

      Length of Treatment:

      You may continue to 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 receive the study drugs if the disease gets
      worse, if intolerable side effects occur, or if you are unable to follow study directions.

      Your active participation on the study will be over after the 30-day follow-up visit;
      however, you will be contacted by phone every 3 months to check on you and the status of the
      disease.

      Study Visits:

      On Days 1 and 15 of Cycle 1:

        -  You will have a physical exam

        -  Blood (about 3 tablespoons) will be drawn for routine and PD testing.

        -  If you are in Phase 1, part of this sample on Day 1 will be used for pharmacokinetic
           (PK) testing. PK testing measures the amount of study drug in the body at different time
           points.

        -  If you are in Phase 2, part of this sample will be used for tumor marker testing.

        -  You will have an EKG.

        -  On Day 15, if you are in Phase 2, you will have a tumor biopsy for PD testing, including
           genetic testing.

      On Day 8 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 3 tablespoons) will be drawn for routine and PD tests. If you are in Phase
           2, part of this sample will be used for tumor marker testing.

        -  You will have an EKG.

      On Day 22 of Cycle 1:

        -  You will have a physical exam.

        -  Blood (about 3 tablespoons) will be drawn for routine and PD tests. If you are in Phase
           2 and have endometrial or ovarian cancer, part of this blood will be used for tumor
           marker testing.

      On Day 1 of Cycle 2:

        -  You will have a physical exam.

        -  You will have an eye exam.

        -  Blood (about 3 tablespoons) will be drawn for routine and PD tests.

        -  If you are in Phase 1, part of this blood will be used for PK testing.

        -  If you are in Phase 2, part of this blood will be used for tumor marker testing.

      On Day 26 of Cycle 2, you will have an MRI or a CT scan.

      On Day 1 of Cycles 3 and beyond:

        -  You will have a physical exam

        -  Blood (about 3 tablespoons) will be drawn for routine and PD tests. If you are in Phase
           2, part of this blood will be used for tumor marker testing.

      Starting on Day 1 of Cycle 4 and every 3 cycles after that, you will have an ECHO.

      During Cycles 4 and 6 and then every 3 cycles after that (Cycles 9, 12, 15, and so on), you
      will have MRI or a CT scan.

      At any time the study doctor thinks it is needed, you may have some or all of these tests
      repeated to check on your health.

      End-of-Treatment Visit:

      Within 7 days after your last dose of study drugs:

        -  You will have a physical exam.

        -  Blood (about 3 tablespoons) will be drawn for routine and PD tests.

        -  If it has been more than 28 days since the last scan, you will have an MRI or CT scan.

      Follow-Up:

      About 30 days after your last study drug dose:

        -  You will have a physical exam.

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

      You may be called by a member of the study staff every 3 months to ask how you are doing and
      if you have had any side effects. This call should last about 5-10 minutes.
    

Trial Arms

NameTypeDescriptionInterventions
Selumetinib + OlaparibExperimentalDose Escalation Phase: Participants take both Selumetinib and Olaparib by mouth 2 times each day, about 12 hours apart at the Starting Dose Level. Treatment cycle is 28 days. When maximum tolerated dose reached, Dose Expansion Phase begins.
  • Selumetinib
  • Olaparib
Ovarian Cancer with RPAExperimentalDose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.
  • Selumetinib
  • Olaparib
Endometrial Cancer with RPAExperimentalDose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.
  • Selumetinib
  • Olaparib
Ovarian Cancer-Progression-prior PARP TreatmentExperimentalDose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.
  • Selumetinib
  • Olaparib
Solid Tumors that Harbor Somatic RPAExperimentalDose Expansion Phase: Selumetinib + Olaparib taken at the maximum tolerated dose from Dose Escalation Phase.
  • Selumetinib
  • Olaparib

Eligibility Criteria

        Inclusion Criteria:

          1. Written informed consent obtained from the subject prior to performing any
             protocol-related procedures, including screening evaluations.

          2. Age >/= 18 years at time of study entry

          3. Patients with advanced cancer that is refractory to standard therapy, or that has
             either relapsed after standard therapy or has no standard therapy that increases
             survival by at least three months.

          4. Patients may have unlimited prior chemotherapy treatments.

          5. For dose escalation phase, patients may have evaluable or measurable disease. For
             ovarian cancer, if no measurable disease is present, patients should have assessable
             disease such as pleural effusion, ascites, with CA-125 GCIG criteria.

          6. For dose expansion phase, patients must have at least one site of measurable disease
             as defined by RECIST criteria (Version 1.1).

          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          8. All prior treatment-related toxicities must be Common Terminology Criteria for Adverse
             Events (CTCAE) (Version 4.03) </= Grade 1 at the time of screening (except alopecia).

          9. Life expectancy of >/= 16 weeks.

         10. Adequate normal organ and marrow function as defined by: Hemoglobin >/= 10.0 g/dL with
             no blood transfusion within 28 days of starting treatment; White blood cells (WBC) >3
             x 10^9/L; Absolute neutrophil count (ANC) >/= 1.5 x 10^9/L (> 1500 per mm^3); Platelet
             count >/= 100 x 10^9/L (>100,000 per mm^3); Serum bilirubin </= 1.5 x institutional
             upper limit of normal (ULN); AST (SGOT) and ALT (SGPT) </= 2.5 x ULN unless liver
             metastases are present, in which case it must be </= 5x ULN; Serum creatinine CL>50
             mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
             collection for determination of creatinine clearance--Creatinine CL
             (ml/min)=[Weight(kg)*(140-Age)*(0.85 for females or 1 for males)/[72*serum creatinine
             (mg/dL)].

         11. Subject is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

         12. Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential: negative urine or serum pregnancy test within 7 days of study treatment.
             Postmenopausal is defined as: amenorrheic for 1 year or more following cessation of
             exogenous hormonal treatments; luteinizing hormone (LH) and follicle stimulating
             hormone (FSH) levels in the postmenopausal range for women under 50; radiation-induced
             oophorectomy with last menses > 1 year ago; chemotherapy-induced menopause with > 1
             year interval since last menses; OR surgical sterilization (bilateral oophorectomy or
             hysterectomy).

         13. Female patients of childbearing potential must use two highly effective forms of
             contraception.

         14. Male patients must use a condom during treatment and for 3 months after the last dose
             of olaparib when having sexual intercourse with a pregnant woman or with a woman of
             childbearing potential. Female partners of male patients should also use a highly
             effective form of contraception if they are of childbearing potential.

         15. Additional criteria for escalation cohorts: A) Patients must have RPA (including KRAS,
             NRAS, NF1, HRAS, and BRAF); B) Prior treatment with MEK inhibitors and/or PARP
             inhibitors is allowed.

         16. Additional criteria for expansion cohorts: A) Patients must have
             histologically-confirmed advanced or recurrent ovarian cancer with RPA or that had
             progression during prior PARP inhibitor treatment, endometrial cancer with RPA, or
             other solid tumor types with RPA; B) Measurable and biopsy-accessible disease; C)
             Patient must be willing to undergo biopsy procedure; D) Prior treatment with PARP
             inhibitors is allowed.

        Exclusion Criteria:

          1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
             staff and/or staff at the study site).

          2. Previous enrollment in the present study.

          3. Participation in another clinical study with an investigational product during the 4
             weeks prior to therapy initiation.

          4. Recent major surgery within 4 weeks prior to starting study treatment. Minor surgery
             within 2 weeks of starting study treatment. Patients must be recovered from effects of
             surgery.

          5. Patients receiving any systemic chemotherapy or radiotherapy (except for palliative
             reasons) within 3 weeks prior to study treatment initiation.

          6. Concomitant use of known strong (e.g., phenobarbital, enzalutamide, phenytoin,
             rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or
             moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil). The required washout
             period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3
             weeks for other agents.

          7. Concomitant use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin,
             clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir,
             saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g.,
             ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout
             period prior to starting olaparib is 2 weeks.

          8. Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal
             therapy (Hormone replacement therapy is acceptable), radiotherapy (except for
             palliative), biological therapy or other novel agent) or live virus and live bacterial
             vaccines while the patient is receiving study medication. Strong or Moderate CYP3A
             inhibitors and inducers should not be taken with study treatment; however, if no other
             suitable alternative concomitant medication is available, dose reductions may be
             allowed under careful monitoring.

          9. Known severe hypersensitivity to selumetinib or olaparib, their comparators, or
             combination medications or any excipient of these medicinal products, or history of
             allergic reactions attributed to compounds of similar chemical or biologic composition
             to selumetinib or olaparib, or their comparator.

         10. History of another primary malignancy except for: A) Malignancy treated with curative
             intent and with no known active disease >/= 3 years before the first dose of study
             drug and of low potential risk for recurrence; B) Adequately treated non-melanoma skin
             cancer or lentigo maligna without evidence of disease; C) Adequately treated carcinoma
             in situ without evidence of disease, e.g. cervical cancer in situ; D) Synchronous
             endometrial and ovarian cancer is allowed, provided the endometrial cancer is presumed
             Stage IA/B grade 1/2.

         11. Any unresolved toxicity (>/= CTCAE grade 2) from previous anti-cancer therapy,
             excluding alopecia.

         12. Known or suspected brain metastases or spinal cord compression, unless the condition
             has been asymptomatic, has been treated with surgery and/or radiation, and has been
             stable without requiring corticosteroids nor anticonvulsant medications for at least 4
             weeks prior to the first dose of study medication. Patients with history of brain
             metastases should undergo brain imaging within 4 weeks of therapy initiation and at
             each restaging.

         13. Known myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of
             MDS/AML.

         14. Female subjects who are pregnant/breast-feeding or who are of reproductive potential
             and not employing acceptable methods of birth control.

         15. Cardiac conditions as follows: Uncontrolled hypertension (BP >/= 150/95 mmHg despite
             medical therapy); Acute coronary syndrome within 6 months prior to starting treatment;
             Uncontrolled Angina - Canadian Cardiovascular Society grade II-IV despite medical
             therapy; Symptomatic heart failure NYHA Class II-IV, prior or current cardiomyopathy,
             or severe valvular heart disease; Prior or current cardiomyopathy including but not
             limited to the following: known hypertrophic cardiomyopathy or known arrhythmogenic
             right ventricular cardiomyopathy; Previous moderate or severe impairment of left
             ventricular systolic function (LVEF <45% on echocardiography or equivalent on MUGA)
             even if full recovery has occurred; Severe valvular heart disease;

         16. (Continued from previous) Baseline LVEF below the LLN measured by ECHO or
             institution's LLN for MUGA; Atrial fibrillation with a ventricular rate >100 bpm on
             ECG at rest; QTcF >470ms on two or more timepoints or other factors that increase the
             risk of QT prolongation such as family history of long QT syndrome.

         17. Ophthalmological conditions as follows: Current or past history of retinal pigment
             epithelial detachment (RPED)/central serous retinopathy (CSR) or retinal vein
             occlusion; or Intraocular pressure (IOP) > 21 mmHg or uncontrolled glaucoma
             (irrespective of IOP)

         18. Any evidence of a severe or uncontrolled systemic disease (e.g. unstable or
             uncompensated respiratory, cardiac, hepatic, or renal disease, active infection
             (including hepatitis B, hepatitis C, human immunodeficiency virus [HIV]), active
             bleeding diatheses or renal transplant.

         19. Previous allogenic bone marrow transplant or double umbilical cord blood
             transplantation.

         20. Whole blood transfusion in the last 120 days prior to entry to the study.

         21. Patient is confirmed to have actively symptomatic pneumonitis.

         22. Extensive bilateral lung disease on high-resolution computed tomography (HRCT) scan.

         23. Patients unable to swallow orally administered medication and patients with
             gastrointestinal disorders likely to interfere with absorption of the study
             medication.

         24. Immunocompromised patients, e.g. patients known to be serologically positive for HIV.
             Patients do NOT need to be tested for HIV in order to enroll on study.

         25. Evidence of any other significant clinical disorder or laboratory finding that, in the
             opinion of the investigator, would interfere with evaluation of study treatment or
             interpretation of patient safety or study results.

         26. For the expansion cohorts only: Prior treatment with any MEK inhibitor is not allowed
             in the expansion cohorts.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose (MTD) for Combination of Selumetinib and Olaparib in Participants with Advanced or Recurrent Solid Tumors
Time Frame:28 days
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. Grading of DLTs follow the guidelines provided in the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Secondary Outcome Measures

Measure:Determination of Drug Concentration in Selumetinib and Olaparib
Time Frame:Day 1,8, and 15 of Cycle 1, and Day 1 of Cycle 2.
Safety Issue:
Description:Samples for determination of drug concentration in selumetinib and olaparib analyzed using an appropriate bioanalytical method.
Measure:Comparison of Baseline Expression Values with Differing Treatment Responses of Selumetinib and Olaparib
Time Frame:Day 1,8,15,22 of Cycle 1, Day 1 of Cycle 2.,Day 1 of Cycle 3, and 7 days after last dose of study drugs.
Safety Issue:
Description:Two sample t-test with a 2-sided significance level of 0.05 used to compare baseline expression values with differing treatment responses.
Measure:Anti-Tumor Activity Evaluation by RECIST v1.1
Time Frame:4 months
Safety Issue:
Description:

Details

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

Trial Keywords

  • Malignant neoplasm of breast
  • Malignant neoplasms of digestive organs
  • Malignant neoplasms of female genital organs
  • Malignant neoplasms of male genital organs
  • Malignant neoplasms of thyroid and other endocrine glands
  • Solid tumors
  • Ras Pathway Alterations
  • Ovarian Tumors with PARP Resistance
  • Selumetinib
  • AZD6244
  • Olaparib
  • Lynparza

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