Clinical Trials /

Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss

NCT03131908

Description:

The goal of this clinical research study is to learn if GSK2636771 given in combination with pembrolizumab can help to control the disease in patients with refractory (has not responded to treatment) metastatic melanoma. The safety of this drug combination will also be studied. This is an investigational study. Pembrolizumab is FDA approved and commercially available and FDA approved for the treatment of several types of cancer, including melanoma. GSK2636771 is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work. Up to 41 participants will be enrolled in this study. All will take part at MD Anderson.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss
  • Official Title: Phase I/II Study of the Selective PI3K-Beta Inhibitor GSK2636771 in Combination With Pembrolizumab in Patients With Metastatic Melanoma and PTEN Loss

Clinical Trial IDs

  • ORG STUDY ID: 2016-0774
  • NCT ID: NCT03131908

Conditions

  • Melanoma and Other Malignant Neoplasms of Skin
  • Metastatic Melanoma

Interventions

DrugSynonymsArms
GSK2636771GSK2636771 + Pembrolizumab
PembrolizumabKeytruda, MK-3475, SCH-900475GSK2636771 + Pembrolizumab

Purpose

The goal of this clinical research study is to learn if GSK2636771 given in combination with pembrolizumab can help to control the disease in patients with refractory (has not responded to treatment) metastatic melanoma. The safety of this drug combination will also be studied. This is an investigational study. Pembrolizumab is FDA approved and commercially available and FDA approved for the treatment of several types of cancer, including melanoma. GSK2636771 is not FDA approved or commercially available. It is currently being used for research purposes only. The study doctor can explain how the study drugs are designed to work. Up to 41 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 study
      group based on when you join this study. Up to 3 groups of 3-6 participants will be enrolled
      in Phase 1 of the study, and up to 35 participants will be enrolled in Phase 2.

      If you have metastatic cancer, you may be enrolled in Phase 1 of this study. If you have
      metastatic melanoma, you may be enrolled in Phase 1 or Phase 2 of this study.

      If you are enrolled in Phase 1, the dose of GSK2636771 in combination with pembrolizumab you
      receive will depend on when you join this study. The first group of participants will receive
      the lowest dose level of GSK2636771. Each new group will receive a higher dose of GSK2636771
      than the group before it, if no intolerable side effects were seen. This will continue until
      the highest tolerable dose of GSK2636771 is found.

      If you are enrolled in Phase 2, you will receive GSK2636771 at the highest dose that was
      tolerated in Phase 1.

      All participants will receive the same dose level of pembrolizumab.

      Study Drug Administration:

      Every study cycle is 21 days.

        -  You will take GSK2636771 by mouth every day for 21 days.

        -  You will receive pembrolizumab by vein for 30 minutes one (1) time on Day 1 of every
           cycle.

      You should receive the study drugs at least 1 hour before or 2 hours after eating.

      Length of Study:

      You may receive the study drugs for up to 2 years. If the doctor thinks it is in your best
      interest, you may continue to receive either GSK2636771 or pembrolizumab for 1 more year. 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 Follow-Up Visits.

      Study Visits:

      On Day 1 of Cycles 1, 3, 5, and 7:

        -  You will have a physical exam.

        -  You will have an EKG. If the doctor thinks it is needed, you will also have an ECHO and
           MUGA scan.

        -  Blood (about 3 teaspoons) and urine will be collected for routine tests.

        -  Blood (about 2 tablespoons) will be drawn for pharmacokinetic (PK) testing before the
           dose, at 30 minutes, 1, 2, 3, 4, 6, and 24 hours after the dose. (Cycle 1 only). PK
           testing measures the amount of study drug in the body at different time points.

        -  Blood (about 2 tablespoons) will be drawn for immune function testing (Cycles 3 & 5
           only).

        -  You will have a PET/CT scan or MRI to check the status of the disease (Cycle 5 only and
           then every 12 weeks after that).

        -  If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
           pregnancy test.

      On Day 1 of Cycles 2, 4, 6, 8 and beyond:

        -  You will have a physical exam.

        -  Blood (about 1½ teaspoon) and urine will be collected for routine tests.

        -  Blood (about 1 teaspoon) will be drawn for PK testing before the dose. (Cycle 2 only)

        -  If the doctor thinks it is needed, you will have an ECHO and MUGA scan.

        -  If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
           pregnancy test.

      On Day 1 of Cycles 2, 3, and 5, and every 12 weeks after that, you will be asked to have a
      core biopsy. Only 1 of these will be required, and the others will be optional. Though it is
      preferred that this be performed at Cycle 2, you and your doctor will choose which of these
      biopsies will be the required one.

      Every 12 weeks after Cycle 5, blood (about 2½ tablespoons) will be drawn for immune system
      testing.

      End of Study Dosing Visit:

      After you stop receiving the study drugs:

        -  You will have a physical exam.

        -  If the doctor thinks it is needed, you will have an ECHO and MUGA scan.

        -  Blood (about 1 teaspoon) and urine will be collected for routine tests.

        -  If the disease got worse while you are on study, you may have a core biopsy.

        -  If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
           pregnancy test.

      Follow-Up Period:

      Up to 30 days after the End-of-Study Dosing Visit and every 6 weeks:

        -  You will have a physical exam.

        -  Blood (about 2 tablespoons) and urine will be collected for routine tests.

        -  If the doctor thinks it is needed, you will have an ECHO and MUGA scan.

        -  If you can become pregnant, blood (about ½ teaspoon) or urine will be collected for a
           pregnancy test.

      One (1) time every 12 weeks:

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

        -  You will be called by a member of the study staff to check your health. These calls
           should last about 5 minutes each time.

      Treatment Beyond Progression:

      If the disease appears to be getting worse or the tumors appear to be getting larger, you may
      still be able to receive the study drug if you and your doctor decide it is in your best
      interest. Sometimes the disease appears to get worse but the study drug is actually working.

      However, there are risks of continuing to receive the study drug because the disease may
      actually be getting worse. You are still at risk for side effects due to the study drug. This
      could also delay starting other treatments. The disease may get worse to the point that you
      are no longer able to receive other treatments.

      If you choose to receive the study drug after the disease gets worse, you will continue to
      have study visits. The study doctor will discuss this option with you.

      Alcohol and Activity Restriction:

      On days when you have multiple PK blood draws, you should not have alcohol for at least 24
      hours before your dose of study drug.

      You should not exercise for 48 hours before each PK and/or routine testing blood draw.
    

Trial Arms

NameTypeDescriptionInterventions
GSK2636771 + PembrolizumabExperimentalPhase I: Participants receive the lowest dose level of GSK2636771. Each new group receives a higher dose of GSK2636771 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of GSK2636771 is found. Participants receive the same dose level of Pembrolizumab. Phase II: Participants receive GSK2636771 at the highest dose that was tolerated in Phase 1. Participants receive the same dose level of Pembrolizumab.
  • GSK2636771
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Be willing and able to provide written informed consent for the trial.

          2. Be >/= 18 years of age on day of signing informed consent.

          3. Evidence of PTEN loss in tumors by IHC or molecular analysis.

          4. Have measurable disease based on RECIST 1.1.

          5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
             Performance Scale.

          6. Patients who have unresectable Stage III through stage IV metastatic cancer who have
             not achieved complete or partial response after 6 months of therapy or who have
             progressed on PD-L1 or PD-1 directed therapy including combinations. The Phase II
             portion eligibility will be restricted to patients with metastatic melanoma.

          7. In Phase I, Patients are allowed to have more than three prior systemic therapeutic
             regimens. Patients enrolled to Phase II, can have no more than three prior systemic
             therapeutic regimen for unresectable stage III or stage IV metastatic cancer. This
             includes chemotherapy, biologic therapy, biochemotherapy, or investigational
             treatment. This does not include any therapies given in the adjuvant setting.

          8. Have a life expectancy of at least 12 weeks.

          9. Have not received any chemotherapeutic, biological, investigational agent, radiation
             therapy, or used an investigational device within 28 days of study drug
             administration.

         10. Able to swallow and retain orally administered medication.

         11. On the dose expansion and Phase II portions of the study, patients must be willing to
             provide tissue from a newly obtained core or excisional biopsy of a tumor lesion
             before and at least one time point while on therapy. Correlative biopsies will be
             optional in the Phase I portion of the study. Newly-obtained is defined as a specimen
             obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1 without
             intervening systemic therapy.

         12. Within 10 days of treatment initiation, the subject must demonstrate adequate organ
             function defined as follows: Absolute neutrophil count must be >/= 1500 per microliter
             (uL). Platelets must be >/=100,000 per uL. Hemoglobin must be >/= 9 grams per
             deciliter or >/= 5.6 millimoles per liter without transfusion or EPO dependency within
             7 days of assessment. Serum creatinine must be </= 1.0 times the upper limit of normal
             (ULN) OR measured or calculated creatinine clearance per institutional standard
             (Glomerular Filtration Rate (GFR) can also be used in place of creatinine or CrCl)
             must be >/= 60 milliliters per minute OR proteinuria by urine dipstick must be </= 1+.
             Aspartate aminotransferase (AST) AND alanine aminotransferase (ALT) must be </= 2.5
             times the ULN OR each must be </= 5 times the ULN for subjects with liver metastases.
             Alkaline phosphatase (ALP) must be </= 2 times the ULN. Serum

         13. Cont#12 total bilirubin must be </= 2.0 milligrams per deciliter except in patients
             with Gilbert's disease. Direct bilirubin must be </= the upper limit of normal for
             subjects with total bilirubin levels > 1.5 times the upper limit of normal. Albumin
             must be >/= 2.5 grams per deciliter. Left ventricular ejection fraction (LVEF) must be
             >/= 50% by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan. International
             Normalized Ratio (INR) must be </= 1.5 times the upper limit of normal unless the
             subject is receiving anticoagulant therapy as long as prothrombin time(PT) or partial
             thromboplastin time(PTT) is within therapeutic range of intended use of
             anticoagulants.Activated partial thromboplastin time(aPTT) must be </= 1.5 times the
             upper limit of normal unless the subject is receiving anticoagulant therapy as long as
             PT or PTT is within therapeutic range of intended use of anticoagulants. Serum
             phosphate must be within normal limit. Serum calcium must be within normal limit

         14. Female subject of childbearing potential should have a negative urine or serum
             pregnancy within 72 hours prior to receiving the first dose of study medication. If
             the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
             will be required.

         15. Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 4 months after the last dose of
             study medication. Note: Abstinence is acceptable if this is the usual lifestyle and
             preferred contraception for the subject.

         16. Male subjects with a female partner of childbearing potential must agree to use
             acceptable methods of contraception from the time of Screening until 3 months after
             the last dose of study treatments.

        Exclusion Criteria:

          1. Patients are excluded if they have a history of or active autoimmune disease, as
             follows: Patients with a history of inflammatory bowel disease are excluded from this
             study as are patients with a history of symptomatic disease (e.g., rheumatoid
             arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus,
             autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Patients with motor
             neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and
             Myasthenia Gravis) are excluded. Patients with a history of autoimmune thyroiditis are
             eligible if their current thyroid disorder is treated and stable with replacement or
             other medical therapy.

          2. Has active infections or serious general medical conditions (such as active myocardial
             infarction (MI), cerebrovascular accident (CVA), or respiratory failure).

          3. Any unresolved > Grade 1 toxicity (per CTCAE 4.0) from previous anti-cancer therapy or
             previously administered agent at the time of enrollment, except for alopecia, Grade 2
             anemia (if hemoglobin is >9 grams per deciliter (g/dL)) Note: If the subject received
             major surgery, they must have recovered adequately from the toxicity and/or
             complications from the intervention prior to starting therapy.

          4. Presence of any clinically significant gastrointestinal (GI) abnormality or other
             condition(s) that may alter absorption such as malabsorption syndrome or major
             resection of the stomach or substantial portion of the small intestine.

          5. Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra
             abdominal abscess within 28 days prior to enrollment

          6. Previous major surgery within 28 days prior to enrollment.

          7. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
             respiratory, hepatic, renal or cardiac disease).

          8. Has a QTc >450 milliseconds (msec) or QTc >480 msec for subjects with bundle branch
             block (BBB) NOTES: The QTc is the QT interval corrected for heart rate by Bazett's
             formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or
             manually over-read. The specific formula that will be used to determine eligibility
             and discontinuation for an individual subject should be determined prior to initiation
             of the study. In other words, several different formulae cannot be used to calculate
             the QTc for an individual subject and then the lowest QTc value used to include or
             discontinue the subject from the trial. For purposes of data analysis QTcF will be
             used.

          9. History or evidence of cardiovascular risk including any of the following: -
             Clinically significant electrocardiogram (ECG) abnormalities including second degree
             (Type II) or third degree atrioventricular block - History of myocardial infarction,
             acute coronary syndromes (including unstable angina), coronary angioplasty, stenting,
             or bypass grafting within the past 6 months prior to enrollment - Class III or IV
             heart failure as defined by the New York Heart Association (NYHA) functional
             classification system - Left ventricular ejection fraction (LVEF) below 50% - Known
             cardiac metastases.

         10. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >/= 150
             millimeters of mercury (mmHg) or diastolic blood pressure [DBP] of >100 mmHg based on
             a mean of three measurements at approximately 2-minute intervals) NOTE: Initiation or
             adjustment of antihypertensive medication(s) is permitted if done thirty or more days
             prior to enrollment.

         11. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome,
             Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)

         12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment. NOTE: Replacement dose steroids (equivalent to 10 mg prednisone) are
             allowed.

         13. Has a known history of active TB (Bacillus Tuberculosis).

         14. Hypersensitivity to Pembrolizumab or GSK2636771 or excipients.

         15. Has a known prior or additional malignancy that is progressing or requires active
             treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
             carcinoma of the skin that has undergone potentially curative therapy or in situ
             cervical cancer.

         16. Has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. Subjects with previously treated brain metastases may participate provided
             they are stable (without evidence of progression by imaging for at least two weeks
             prior to the first dose of trial treatment and any neurologic symptoms have returned
             to baseline), have no evidence of new or enlarging brain metastases, and are not using
             steroids for at least 7 days prior to trial treatment. This exception does not include
             carcinomatous meningitis which is excluded regardless of clinical stability.

         17. Has a history of (non-infectious) pneumonitis that required steroids or current
             pneumonitis.

         18. Has a history or current evidence of any condition, therapy, or laboratory abnormality
             that might confound the results of the trial, interfere with the subject's
             participation for the full duration of the trial, or is not in the best interest of
             the subject to participate, in the opinion of the treating investigator.

         19. Has known psychiatric or substance abuse disorders that in the opinion of the
             registering physician or PI would interfere with cooperation with the requirements of
             the trial.

         20. Has a known history or positive test for Human Immunodeficiency Virus (HIV) (HIV 1/2
             antibodies). Testing at the time of Screening is not required.

         21. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
             result at time of Screening or any history of hepatitis.

         22. Has received a live vaccine within 30 days of planned start of study therapy.

         23. Current use of or anticipated requirement during the study of any prohibited
             medication(s). Note: Seasonal influenza vaccines for injection are generally
             inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g.,
             Flu-Mist®) are live attenuated vaccines, and are not allowed.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum-Tolerated Dose (MTD) of GSK2636771 in Combination with Pembrolizumab in Participants with Metastatic Melanoma and PTEN Loss
Time Frame:3 weeks
Safety Issue:
Description:Maximum-tolerated dose defined as the highest dose where ≤ 1 out of 6 participants experiences dose limiting toxicities (DLTs).

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:2 years
Safety Issue:
Description:Overall survival (OS) defined from treatment start date to date of death for any cause.

Details

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

Trial Keywords

  • Melanoma and other malignant neoplasms of skin
  • Metastatic Melanoma
  • GSK2633771
  • Pembrolizumab
  • Keytruda
  • MK-3475
  • SCH-900475

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