Clinical Trials /

Safety, Pharmacokinetics and Efficacy of GDC-0084 in Newly-diagnosed Glioblastoma Multiforme

NCT03522298

Description:

This protocol has a 2-part design: The phase 2a study component is an open-label, multicenter, phase 2a dose-escalation and expansion study to assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of GDC-0084 in patients with newly-diagnosed glioblastoma multiforme (GBM) with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (TMZ). The phase 2a study is fully detailed in this submission. The phase 2b study component comprises an evaluation of clinical activity of GDC-0084 compared to TMZ in as adjuvant therapy following surgical resection and initial chemoradiation with TMZ and will be initiated following the determination of RP2D in the phase 2a study (Part 1). The phase 2b component will be will be further detailed in an amendment to this submission.

Related Conditions:
  • Glioblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Safety, Pharmacokinetics and Efficacy of GDC-0084 in Newly-diagnosed Glioblastoma Multiforme
  • Official Title: A Phase 2 Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of the PI3K/mTOR Inhibitor GDC-0084 Administered to Patients With Glioblastoma Multiforme Characterized by Unmethylated O6-methylguanine-methyltransferase Promoter Status Following Surgical Resection and Standard Concomitant Chemoradiation Therapy With Temozolomide

Clinical Trial IDs

  • ORG STUDY ID: NVGN-0084-201
  • NCT ID: NCT03522298

Conditions

  • Glioblastoma, Adult

Interventions

DrugSynonymsArms
GDC-0084Dose Escalation and Expansion Cohorts

Purpose

This protocol has a 2-part design: The phase 2a study component is an open-label, multicenter, phase 2a dose-escalation and expansion study to assess the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of GDC-0084 in patients with newly-diagnosed glioblastoma multiforme (GBM) with unmethylated MGMT promoter status as adjuvant therapy following surgical resection and initial chemoradiation with temozolomide (TMZ). The phase 2a study is fully detailed in this submission. The phase 2b study component comprises an evaluation of clinical activity of GDC-0084 compared to TMZ in as adjuvant therapy following surgical resection and initial chemoradiation with TMZ and will be initiated following the determination of RP2D in the phase 2a study (Part 1). The phase 2b component will be will be further detailed in an amendment to this submission.

Detailed Description

      Phase 2a study - Stage 1 Dose-Escalation and Maximum Tolerated Dose The dose-escalation
      portion of the study (Stage 1) will use a standard "3 + 3" design to determine the MTDs for
      QD and intermittent dosing schedules.

      The MTDs for QD and intermittent dosing of GDC-0084 will be determined in 3 steps: QD (Step
      1), QOD (Step 2) and daily dosing for 3 consecutive days of the week (3 days on/4 days off)
      (Step 3). All 3 steps will follow the same dose-escalation rules as described below. Each
      step and each dose cohort within each step will consist of newly recruited patients with all
      patients receiving the dose to which they are originally assigned.

      Approximately 6 - 12 patients with newly diagnosed GBM will be enrolled in Step 1; the number
      of patients recruited to assess the intermittent dosing MTDs in each of Step 2 and Step 3 is
      assumed to be approximately the same (6 - 12 patients). However, numbers may vary for all 3
      steps, depending on the outcome of the dose-escalation of each step.

      Step 1 The MTD for QD dosing will be determined. The initial dose level for QD dosing will be
      60 mg (Dose Level 0). This dose is based on the phase 1 findings outlined in the rationale in
      the protocol, adding 1 dose level to test for a potential MTD increase. When the MTD for QD
      dosing has been determined, Step 2 and 3 will be initiated in parallel.

      Step 2/3 Once the MTD for QD has been determined, the QD MTD will be used as the initial dose
      level for the assessment of the QOD MTD in Step 2 and as the initial dose level for the
      assessment of the intermittent 3 days on/4 days off MTD in Step 3.

      Dose-escalation will occur in Stage 1:

        -  The initial dose (Dose Level 0) for QD MTD determination in Step 1 will be 60 mg. Dose
           levels will increase in 15 mg steps;

        -  The dose-escalation portion of the study (Stage 1) will use a standard "3 + 3" design to
           assess the safety, tolerability, and PK of GDC-0084 administered orally in 28-day
           cycles;

      Decisions regarding dose-escalation and selection will be made by a Cohort Review Committee
      (CRC).

      All AEs, including DLTs, will be reported, with severity assessed according to National
      Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

      After determination of the MTD, patients continue to receive their protocol-assigned dose
      levels of GDC-0084 until progression of their disease or an unacceptable toxicity, whichever
      occurs first.

      Phase 2a study - Stage 2 Expansion stage (2) of the study will be a three-arm, randomized,
      open-label expansion study to further characterize the safety, tolerability and PK of
      GDC-0084 as well as to provide a preliminary assessment of single-agent activity of GDC-0084
      in patients with GBM and to compare intermittent dosing MTDs vs. QD MTD in regard to safety
      and clinical activity. Approximately 30 patients will be enrolled in the expansion cohort in
      3 treatment arms (10 per am), according to the defined study eligibility criteria.

      Stage 2 of the study will be initiated with recruitment of new patients as soon as the MTD
      for intermittent dosing schedules has been determined (Stage 1, Step 3).

      Patients enrolled in Stage 2 may continue the study at the dose allocated until disease
      progression or unacceptable toxicity.
    

Trial Arms

NameTypeDescriptionInterventions
Dose Escalation and Expansion CohortsExperimentalThis is an open-label study. Patients in Stage 1 will be enrolled and sequentially assigned to a dose cohort. The initial cohort will receive an oral dose of 60 mg GDC-0084 QD (4 x 15 mg capsules). Patients of future dose cohorts will receive GDC-0084 at increasing levels with 15 mg steps until a dose-limiting toxicity occurs (DLT) occurs. The dose level where <1/3 of the patients exhibit a DLT will be determined the Maximum Tolerated Dose (MTD). Dose escalation will occur for three separate dose schedules including QD, every other day (QOD) and 3 times a week on consecutive days (3 days on/4 days off), i.e. an MTD will be established for three different dose schedules. In stage 2, the expansion phase, patients will receive doses of oral GDC-0084 at the MTD established for each of the three dosing schedules until disease progression or an unacceptable toxicity, whichever occurs first. Patients will be randomized in a 1:1:1 ratio to one of the three dose schedules.
  • GDC-0084

Eligibility Criteria

        Inclusion Criteria:

        Patients must meet all the following inclusion criteria to be eligible for enrollment into
        the study:

          1. Age ≥ 18 years;

          2. Life expectancy > 12 weeks;

          3. Present with histologically confirmed intracranial (supratentorial) unmethylated MGMT
             promotor status GBM (WHO Grade lV astrocytoma) with a MGMT status that has been
             confirmed by validated PCR or validated alternate genomic analysis;

          4. Have undergone maximal surgical resection of their tumor and within 6 weeks of surgery
             received initial treatment with XRT/TMZ which consisted of XRT by external beam to a
             partial brain field in daily fractions of 2.0 Gray (Gy), to a planned total dose to
             the tumor of 60.0 Gy, in conjunction with TMZ oral QD 75 mg/m2 in accordance with the
             Stupp regimen;

          5. Must have measurable disease, according to RANO criteria for inclusion in the
             expansion cohort. Patients with non-measurable disease can be included in the
             dose-escalation cohorts;

          6. KPS ≥ 70;

          7. Cranial magnetic resonance imaging (MRI) must have been performed within 7 days prior
             to or on the day of the Randomization/Week 1 Visit;

          8. Stable or decreasing corticosteroid dose within 7 days prior to the first dose;

          9. Adequate bone marrow/hematological function within 7 days prior to Day 1;

         10. Adequate liver and renal function within 14 days prior to Day 1;

         11. International normalized ratio (INR) or prothrombin time (PT) (secs) and activated
             partial thromboplastin time (aPTT) within 7 days prior to randomization:

         12. Patients must be willing to forego other drug therapy against the tumor while enrolled
             in the study.

        Exclusion Criteria:

          1. Previous radiotherapy to the brain or cytotoxic drug therapy (including Gliadel®
             wafers) in addition to the required postoperative radiation plus TMZ, non-cytotoxic
             drug therapy, or experimental drug therapy directed against the brain tumor prior to
             this regimen, will be excluded. Patients may have received or be receiving
             corticosteroids, analgesics, and other drugs to treat symptoms or prevent
             complications but the dose must be stable at treatment start. NOTE: 5 aminolevulinic
             acid-mediated photodynamic therapy administered prior to surgery to aid in optimal
             surgical resection is not considered a chemotherapy agent;

          2. Any prior or anticipated concomitant treatment involving a medical device (such as
             Optune®) applying tumor treating fields (TTF);

          3. QT interval time of ≥ 470 msec;

          4. Undetermined/indeterminate MGMT status;

          5. Diabetic patients; prediabetic patients treated with metformin;

          6. Use of any CYP3A4 inducing or inhibiting agents;

          7. Significant medical illnesses;

          8. Women who are pregnant or who are lactating;

          9. Diagnosed with infratentorial GBM, a tumor outside of brain or gliomatosis cerebri;

         10. Evidence of recent hemorrhage on postoperative MRI of the brain;

         11. Any previous malignancy; except for adequately controlled limited basal cell carcinoma
             of the skin, squamous carcinoma of the skin or carcinoma in situ of the cervix, or one
             which has been absent for ≥3 years;
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLTs)
Time Frame:12 months
Safety Issue:
Description:The recommended Phase 2 dose and schedule. DLTs according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03.

Secondary Outcome Measures

Measure:Incidence of treatment-emergent adverse events (TEAEs)
Time Frame:24 months
Safety Issue:
Description:TEAEs defined as any AE occurring or worsening on/after the first study drug dose and within 28 days after the last dose date. AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA).
Measure:Incidence of serious adverse events (SAEs)
Time Frame:24 months
Safety Issue:
Description:AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA).
Measure:Incidence of treatment-emergent Grade 3/4 clinical laboratory abnormalities.
Time Frame:24 months
Safety Issue:
Description:Clinical laboratory values will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03, for applicable tests.
Measure:Change in electrocardiogram (ECG) parameter QTc.
Time Frame:24 months
Safety Issue:
Description:The number and percentage of patients with an increase of QTc to a value ≥ 500 msec or a change from baseline of at least 60 msec will be presented overall and by visit.
Measure:Change in left ventricular ejection fraction (LVEF).
Time Frame:24 months
Safety Issue:
Description:The number and percentage of patients with a drop in LVEF to a value of ≤ 45% from baseline will be presented overall and by visit.
Measure:Progression-free survival interval using RANO Criteria.
Time Frame:24 months
Safety Issue:
Description:
Measure:Overall survival using RANO Criteria.
Time Frame:24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Kazia Therapeutics Limited

Trial Keywords

  • newly diagnosed
  • unmethylated O6 methylguanine-methyltransferase (MGMT) promoter status

Last Updated

September 11, 2018