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

Conditions:Brain Cancer
Therapuetic Areas:Oncology
Age Range:18 - Any
Start Date:May 15, 2018
End Date:December 30, 2020
Contact:Jeremy Simpson, PhD
Phone:+612 9472 4101

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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

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.

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

Decisions regarding dose-escalation and selection will be made by a Cohort Review Committee

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.

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;
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