Poster
#ACTR-51,
SNO Meeting, Nov 2018 ClinicalTrials.gov identifier: NCT03522298 Phase 2 study
to evaluate the safety, pharmacokinetics and clinical activity of PI3K/mTOR inhibitor
GDC-0084
given to glioblastoma (GBM) patients with unmethylated
O6-methylguanine-methyltransferase
promoter status v Patrick Y. Wen,1 Timothy Cloughesy2, John de Groot3, James D. Battiste4, James Garner5, Jeremy Simpson5, Alan Olivero6 and Elizabeth R. Gerstner7. 1Center
for Neuro-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 2Department of Neurology, Ronald Reagan UCLA Medical Center University of California, Los Angeles, CA; 3Department of Neuro-Oncology, Division of Cancer Medicine,
The University of Texas MD Anderson Cancer Center, Houston, TX; 4Stephenson Cancer Center, University of Oklahoma, Oklahoma City, OK; 5Kazia Therapeutics Limited, Sydney, Australia; 6Genentech Inc., South San Francisco, CA; 7Department of Neurology,
Massachusetts General Hospital, Boston, MA. BACKGROUND Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancer with survival rates of
3-4
months left untreated, and
12-15
months with treatment. Standard of care therapy, i.e. debulking surgery + chemoradiation therapy with temozolomide (XRT/TMZ), show a ~65% failure rate1.
GDC-0084
is a
potent, oral, selective small molecule inhibitor of class I phosphoinositide
3-kinase
and mammalian target of rapamycin (PI3K/mTOR) that crosses the blood brain barrier (BBB)2,3.
GDC-0084
has shown efficacy in GBM models driven by activation of the PI3K pathway, which is upregulated in ~85% of GBM cases per the Cancer Genome Atlas4. Phase I study (NCT01547546) investigated
GDC-0084
given once-daily as an oral (PO) dose in 47 patients with recurrent high-grade gliomas: Maximum tolerated dose (MTD) was 45 mg once daily.
GDC-0084
was rapidly
absorbed and demonstrated linear- and dose-proportional increases in exposure and 7/8 patients receiving the 45mg dose had drug exposure consistent with anti-tumor activity in
pre-clinical
models Adverse
events (AE) were consistent with established Class I PI3K/mTOR inhibitor class-effects (Table 1). Fluorodeoxyglucose-positron emission tomography
(FDG-PET)
scans suggested that
GDC-0084
crossed the BBB with a uniform distribution throughout the brain. Of the patients who underwent
FDG-PET
imaging, 7/27 (26%) had metabolic partial response5. Table 1.
Key adverse events in patients exposed to 45 mg
GDC-0084
(n=8). Preferred Hyperglycemia Stomatitis/ Diarrhea Nausea/ Rash Fatigue Term mucositis vomiting 2 (25%) 4 (50%) 1 (12%) 2 (25%) 5 (63%) 5 (62%)—1
(12%) — Grade 3 AE Figure 1. Response of patients by dose cohort and exposure to
GDC-0084
shows a trend towards stablizing disease at the 45 mg dose. CR – Complete response; PD—Progressive
disease; SD—Stable disease OBJECTIVES The current phase IIa study (NCT03522298) is investigating the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK) and clinical activity of
GDC-0084
in patients with newly diagnosed GBM with unmethylated
O6-methylguanine-methyltransferase
(MGMT) promoter status as adjuvant therapy following surgical
resection and initial chemoradiation with TMZ. METHODS This open-label, multicentre, 2 year study recruiting patients with newly diagnosed GBM from
6-8
sites in the US has 2 stages: Stage 1 (dose escalation)
and Stage 2 (expansion cohort) (Figure 2). Subject eligibility Male and female patients
³
18 years. Histologically confirmed diagnosis of GBM (World Health Organization [WHO] Grade IV astrocytoma) with
unmethylated MGMT promoter status. Undergone surgical resection of tumor(s) and initial treatment with XRT/TMZ (or XRT only if indicated). Figure 2. Study design for Stage 1 and Stage 2 of the study protocol. Stage 1: Dose Escalation Standard
“3+3” design: to determine the MTD for QD dosing schedule, and safety, tolerability and PK of
GCD-0084.
~12 patients (range:
6-24)
Stage 2: Expansion Cohort
Two-arm,
open-label, expansion design to: characterize safety, tolerability and PK of
GDC-0084.
assess single agent activity of
GDC-0084.
explore effect of fed vs. fasting state on PK of
GDC-0084.
~20 patients (2 parallel groups of 10 patients) Treatment Following screening, patients treated with
GDC-0084
at doses described in Figure 3 depending on study Stage. Patients in Stage 1/2 who discontinue treatment followed every 6 wk until determination of disease progression. Subsequent anti-cancer therapy
and survival
follow-up
(FU) collected every 12 wks until death. Figure 3. Treatment of patients with
GDC-0084.
Screening Stage 1 Stage 2 PERIOD XRT/TMZ or Cohort 1:
GDC-
GDC-0084
PO TREATMENT Debulking XRT/ TMZ XRT 2 Gy/d (5 0084 60 mg PO QD QD at RP2D surgery determined d/wk for 6 wks (4x15 mg) in
28-d
total 60 Gy). cycles*. from Stage 1 dosing in
28-d
Concomitant Cohort
2-x:
GDC-
cycles until TMZ 75 0084 PO increasing disease mg/m2/d PO at 15 mg progression or from first to last increments in
28-d
unacceptable day of cycles (until disease toxicity* radiotherapy. progression or
unacceptable toxicity)* * On day 1 of each cycle Recovery from side (i.e. cycle 1, 2, 3 onwards) effects before Adjudicated by blinded central review committee entering Stage 1 N=3 per Cohort Randomized: SAMPLE N=10—fed N=10—fasted
Dose-escalation rules for Stage 1: If no patients experience a dose limiting toxicity (DLT; defined a priori in protocol) within assessment period (d
1-28),
escalation will proceed to the next higher dose in 3
newly-recruited patients. If 1 patient experiences DLT, Cohort expanded (max. 6) until a 2nd patient experiences a DLT MTD 1 dose level below. If
³
2 patients experience a DLT at dose level 0 MTD 45 mg.
KEY STUDY ASSESSMENTS CYCLE 1CYCLE 2CYCLE 3 onwards SCRWk
1EveryEveryEveryEOT/Post-EoT
(-28
d)D 1D 14 Wks8 Wks8 WksFU startFU KPSXXXXX MRIXXX
FDG-PET
scanX ECGXXXXX LVEFXX aPTT / PT / INRXXXXX Pregnancy TestXXXXX PK SamplingXX Hematol/ChemistryXXXXX AEsXXXXXX Disease statusX SCR: screening; EOT: end of treatment STUDY ENDPOINTS Primary safety endpoint:
Dose limiting toxicities (DLT). Key secondary safety endpoints: Treatment-emergent adverse events (TEAEs), Grade
3-5
TEAEs, serious adverse events (SAEs), fatal AEs, TEAEs leading to drug discontinuation or
study withdrawal. Treatment-emergent Grade 3/4 clinical laboratory abnormalities. Change/shift in clinical laboratory, vital signs, and electrocardiogram (ECG) parameters. Change in corticosteroid use. Change in left ventricular ejection fraction
(LVEF). Change in Karnovsky Performance Status (KPS). Secondary clinical benefit endpoints: Progression free survival (PFS) from first dose (in Stage 1) or randomization (Stage 2) to disease progression (RANO criteria) or death. Overall survival
(OS) from first dose (in Stage 1) or from randomization (Stage 2) to death. Time to progression (TTP) from first dose (Stage 1) or randomization (Stage 2) to disease progression. Exploratory endpoints will include PK parameters,
FDG-PET
uptake in tumor and normal brain tissue, and disease control rate. SUMMARY Results for this phase IIa study will be available end of 2019. A future phase IIb study is planned to evaluate clinical activity of
GDC-0084
at the RP2D vs TMZ as adjuvant therapy following surgical resection/chemoradiation in 224 patients. REFERENCES 1. Hegi ME et al. N Engl J Med 2005; 352:
997-1003.
2. Heffron TP et al. ACS Med Chem Lett. 2016; 7(4):
351-356.
3. Salphati L et al. Drug Metab Dispos. 2016; 44(12): 1881-1889. 4. Brennan CW et al. Cell 2013;
155(2):
462-477.
5. Wen PY et al. Data presented at American Society for Clinical Oncology (ASCO) Annual Meeting, June
3-7,
2016, Chicago IL. ACKNOWLEDGEMENTS The
authors would like to thank the patients and their families for participating in the study. This study is funded by Kazia Therapeutics Ltd, Australia