A Phase Ib Study of the Akt Inhibitor GDC-0068 with Docetaxel or mFOLFOX6 in Patients with Advanced Solid Tumors

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Saura C,1 Jones S,2 Mateo J,3 Hollebecque A,4 Cleary J,5 Roda D,6 Zhu J,7 Musib L,7 Patel P,7 Cervantes A,6 Isakoff SJ,8 Soria JC,4 Molife LR,3 Tabernero J,1 Bendall JC2

1Vall d’Hebron University Hospital, Barcelona, Spain; 2Sarah Cannon Research Institute, Nashville, TN; 3The Royal Marsden/Institute of Cancer Research, Sutton, United Kingdom; 4Institut Gustave Roussy, Villejuif, France; 5Dana-Farber Cancer Institute, Boston, MA; 6INCLIVA, University of Valencia, Valencia, Spain; 7Genentech, Inc, South San Francisco, CA; 8Massachusetts General Hospital Cancer Center, Boston, MABACKGROUND

• Akt activity is frequently elevated in cancer via multiple mechanisms, including loss of function of the PTEN tumor suppressor gene or mutations/amplifications of the PIK3CA or Akt genes1

• Akt pathway activation is associated with poor prognosis and may lead to chemoresistance2

• GDC-0068 inhibits all 3 isoforms of Akt (IC50 5-30 nM), with high selectivity over other kinases, including > 100-fold selectivity over the closely related protein kinase A3

• In vitro, GDC-0068 shows synergistic anti-tumor activity when combined with cytotoxic agents, including docetaxel, 5-fluorouracil, and platinum chemotherapy4 (Figure 1)

• In an ongoing Phase Ia study, GDC-0068 has been well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21 days on/7 days off); pharmacodynamic down-regulation of Akt signaling in tumors has been observed at doses ≥ 100 mg (Figure 2)

Figure 1. Enhanced Activity Seen When GDC-0068 is Combined with Chemotherapeutic Agents.

Figure 2. Pharmacodynamic Effects Achieved at Clinical GDC-0068 Doses ≥ 100 mg.

In Vitro Multiple Cancer Cell Lines

Ant

agon

ism

Syn

ergy

Add

itive

0.00.20.40.60.81.01.21.41.61.8

Gemcitabine

Platinum agents

5-FU

Doxorubicin

Temozo

lomide

Docetaxe

l

Com

bina

tion

Inde

x

0 5 10 15 20 25 30

0.2

0.4

0.6

0.8

1.0

95% Quantile of Sampled Curves

AUC (uM.hr)

pGS

K3b

Rat

io

+

+

++

++

+

+++

++

+

++

+

+ +

+++

++

+

+

+

++

+

+

+

++++

+

+

++

++

+

+++++

+

+

EC80 achieved at daily dose of 400 mg

Median+ Observed

100 200 400mg mg mg

GDC-0068 combines well with several classes of chemotherapy agents in vitro.

Data from ongoing Phase Ia study: GDC-0068 AUC (Days 1 and 15) vs. percent inhibition of pGSK3β. Blue shaded area represents 95% confidence interval of fit.

OBJECTIVESPrimary Objectives: • Evaluate safety and tolerability, and estimate the MTD of increasing oral doses of GDC-0068

in combination with docetaxel or mFOLFOX6Secondary Objectives: • Evaluate the pharmacokinetics (PK) of GDC-0068 and chemotherapy agents when combined

Exploratory Objectives: • Evaluate preliminary clinical activity per mRECIST, in relation to PI3K/Akt pathway alterations

METHODSStudy Design • Open-label, multi-center, Phase Ib dose-escalation combination study using a 3+3 design • Key Eligibility Criteria: metastatic cancer refractory to standard therapy; patients with known

diabetes mellitus requiring insulin were excluded

Figure 3. Dosing Schedule.

Cycle 1Day 1 21

DLT assessment (Cycle 1 Days 1 to 21)

GDC-0068

Docetaxel(75 mg/m2)

Arm A: Docetaxel + GDC-0068 Arm B: mFOLFOX6 + GDC-0068

Day 1

DLT assessment (Cycle 1 Day 1 to Cycle 2 Day 14)

GDC-0068

mFOLFOX6

Cycle 1 Cycle 2

14

• GDC-0068 Schedule: - Arm A: oral daily x 14 days on / 7 days off (dosed on days 2-15 of each cycle) - Arm B: oral daily x 7 days on / 7 days off (dosed on days 1-7 of each cycle)

• Tumor Assessments by CT: Arm A - every 2 cycles, Arm B - every 4 cycles • GDC-0068 Doses tested: 100 mg, 200 mg, 400 mg, 600 mg • ≥ 3 patients were enrolled in most cohorts to collect additional combination safety data • Expansion (n=6 for each arm) at MTD

RESULTSPatients Table 1. Demographic and Baseline Characteristics, Data cutoff May 7, 2012.

No. (%) of Patients Arm A (n=24)

Arm B (n=23)

Total (N=47)

Age (yr), median (range) 62 (28–75) 58 (33–73) 60 (28–75) Sex, male 19 (79) 15 (65) 34 (72) Race, white 21 (88) 21 (91) 42 (89) ECOG Score 0 11 (46) 9 (39) 20 (43)No. prior systemic therapies, median (range) 4 (0–12) 3 (0–11) 4 (0–12)Prior taxane 15 (63) 5 (22) 20 (43)Prior platinum agents 20 (83) 17 (74) 37 (79)Prior 5-FU 12 (50) 13 (57) 25 (54)

ECOG = Eastern Cooperative Oncology Group; 5-FU = fluorouracil.

Figure 4. Time on Study: Arm A (GDC-0068 + Docetaxel) and Arm B (GDC-0068 + mFOLFOX6).

Discontinued due to progressive diseaseDiscontinued due to AE/other, unrelated to GDC-0068a

Continuing

0 8 16 24 32 40

Weeks on Study

GDC-0068600 mg

GDC-0068400 mg

GDC-0068200 mg

GDC-0068100 mg10101 NSCLC

10102 bladder10103 esophageal10201 esophageal10202 bladder10203 gastric10204 nonspecified lung10301 breast10303 urothelial10304 NSCLC10305 head and neck10306 bladder10307 esophageal10308 gastro-oesophageal10402 NSCLC10403 pancreatic10404 breast10405 NSCLC10406 unknown metastatic10407 breast10408 nonspecified lung30101 breast30102 cervical30103 esophageal

PR

PR

PR

PR

Arm A

50101 appendiceal50102 cholangiocarcinoma50103 colorectal50104 unknown primary50105 colorectal50106 cervical50201 colorectal50202 sertoli leydig cell50203 liver/biliary50204 pancreatic50205 colorectal50207 unknown primary50208 mesothelioma50209 esophageal50210 cervical50301 colorectal50302 colorectal50303 colorectal50304 esophageal50305 colorectal50306 anal50401 esophageal50402 colorectal

0 8 16 24 32 40 Weeks on Study

GDC-0068600 mg

GDC-0068400 mg

GDC-0068200 mg

GDC-0068100 mg

Discontinued due to progressive diseaseDiscontinued due to AE/otheraContinuing

Discontinued due to GDC-0068-related AE

PRPR

PR

Arm B

aIncludes clinical deterioration, withdrawal of consent, and loss to follow-up.NSCLC = non-small cell lung cancer.

Safety

Table 2. Grade ≥ 2 AEs Related to GDC-0068: Arm A (GDC-0068 + Docetaxel). GDC-0068 Doses are Shown.

Event Term, n (%) 100 mg (n=3)

200 mg (n=4)

400 mg (n=7)

600 mg (n=10)

All Subjects (N=24)

Any AE 1 (33) 2 (50) 4 (57) 3 (30) 10 (42)Nausea 0 0 3 (43) 1 (10) 4 (17)Fatigue 1 (33) 1 (25) 1 (14) 1 (10) 4 (17)Diarrhea 0 1 (25) 2 (29) 0 3 (13)Vomiting 0 0 2 (29) 0 2 (8)GERD/dyspepsia 1 (33) 0 1 (14) 0 2 (8)Anemia 0 0 1 (14) 0 1 (4)Hematemesis 0 0 1 (14) 0 1 (4)Hypophosphatemia 0 0 1 (14) 0 1 (4)Leukopenia 0 0 1 (14) 0 1 (4)Mucosal inflammation 0 0 0 1 (10) 1 (4)Rash 0 0 0 1 (10) 1 (4)

Table 3. Grade ≥ 2 AEs Related to GDC-0068: Arm B (GDC-0068 + mFOLFOX6). GDC-0068 Doses are Shown.

Event Term, n (%) 100 mg (n=6)

200 mg (n=9)

400 mg (n=6)

600 mg (n=2)

All Subjects (N=23)

Any AE 3 (50) 4 (44) 2 (33) 0 9 (39)Nausea 1 (17) 2 (22) 1 (17) 0 4 (17)Diarrhea 0 2 (22) 1 (17) 0 3 (13)Fatigue 0 3 (33) 0 0 3 (13)Neurotoxicity 1 (17) 0 0 0 1 (4)Thrombocytopenia 1 (17) 0 0 0 1 (4)Vomiting 1 (17) 0 0 0 1 (4)

• Safety data was available for 47 patients (24 patients in Arm A and 23 patients in Arm B) • All GDC-0068-related AEs were Grade 1 or 2, except Grade 3 diarrhea (n=1), leukopenia

(n=1), and hypophosphatemia (n=1) in Arm A, and Grade 3 thrombocytopenia (n=1) in Arm B • There were no Grade 4 drug-related AEs, and there were no DLTs

Pharmacokinetics

Figure 5. GDC-0068 Plasma Concentration-Time Profile in Arm A (Docetaxel) and Arm B (mFOLFOX6).

Arm A

Time (hours)0 4 8 12 16 20 24G

DC

-006

8 C

once

ntra

tion

(ng/

mL)

10

100

1000

Arm B

Time (hours)0 4 8 12 16 20 24G

DC

-006

8 C

once

ntra

tion

(ng/

mL)

1

10

100

1000Combo 600 mg (n=9) AUC0-24 = 2950 ± 1220 ng/ml*hrSingle Agent (n=8) AUC0-24 = 3130 ± 1110 ng/ml*hr

Combo 400 mg (n=5) AUC0-24 = 2400 ± 765 ng/ml*hrSingle Agent (n=8) AUC0-24 = 1850 ± 309 ng/ml*hr

• PK parameters for GDC-0068 were consistent with single agent Phase I studies • GDC-0068 exposure in the docetaxel and mFOLFOX6 treated arms were comparable to the

Phase Ia single agent data • No alteration in docetaxel, 5-FU or oxaliplatin PK were seen as compared with published

literature (data not shown) Clinical Activity • Multiple patients in each arm have experienced tumor reductions per RECIST and decreases

in tumor markers (Table 4, and Figures 4, 5, and 6) • Clinical activity observed in several patients having tumor PI3K/Akt pathway alterations

Table 4. Further Details on Patients Experiencing a Partial Response.a

Patient ID

Tumor Type Prior Therapy

PI3K/Akt Pathway

Alterations

Best RECIST Reduction

(%)

Tumor Marker Changes

Docetaxel (Arm A)

10101 NSCLC

• Adjuvant: Etoposide + Cisplatin • 1L: Carboplatin + Paclitaxel +

Avastin • 2L: Erlotinib + Pazopanib • 3L: Pemetrexed

unknown -32 -

10403 pancreatic • 1L: Gemcitabine • 2L: mFOLFOX6

unknown -33 -

10404 breast

• Adjuvant Doxorubicin + Cyclophosphamide + Paclitaxel

• Brain RT • 1L:Capecitabine

E17K Akt1 -40

Time Point

CA15-3 (U/mL)

Screen 75

Wk 3 51

Wk 6 36

30103 esophageal • 1L: Docetaxel + Carboplatin + 5-FU - -42 -

mFOLFOX6 (Arm B)

50105 CRC • 1L: mFOLFOX6 • 2L: Cetuximab + Irinotecan • 3L: Panitumumab

PTEN loss -50

Time Point

CEA (ng/mL)

Screen 422

Wk 4 395

Wk 6 108

Wk 8 37

Wk 10 22

50106 cervical • Adjuvant: Cisplatin + RT • 1L: Carboplatin + Paclitaxel

E545K PIK3CA -40

Time Point

CA125 (U/mL)

Screen 1612

Wk 2 1391

Wk 6 902

Wk 8 684

50209 esophageal • Neoadjuvant: Carboplatin + Paclitaxel HER2+ -38 -

aContains data from investigator communication. NSCLC = non-small cell lung cancer; CRC = colorectal cancer.

Figure 6. Examples of Patients Experiencing Partial Response. See Table 4 for Patient Information.

Patient 10404Breast cancerAkt1 E17K

Screening Week 6 (40% decrease)

Patient 50105Colorectal cancerPTEN loss

Screening Week 12 (50% decrease)

Patient 50106Cervical cancerE545K PIK3CA

Screening Week 8 (40% decrease)Screening Week 8

22 mm13 mm

Patient 50209Esophageal cancerHER2 positive

Screening Week 8 (38% decrease)

3.0 cm 1.9 cm

CONCLUSIONS • GDC-0068, when combined with docetaxel or mFOLFOX6, was safe and well-tolerated up to

the single agent MTD dose (600 mg) • No DLTs were observed during dose escalations in each arm; 1/47 patients discontinued due

to GDC-0068-related AEs • No PK interactions were observed between GDC-0068 and docetaxel or mFOLFOX6 • Both combinations show evidence of clinical benefit, including patients with PI3K/Akt pathway

alterations and with prior treatment with taxanes (Arm A) and platinum agents (Arm B) • Enrollment and evaluation in dose expansion cohorts is ongoing

REFERENCES1. Manning BD, Cantley LC. Cell 2007; 129:126174.2. Clark AS, West K, Streicher S, et al. Mol Cancer Ther 2002; 1:70717.3. Lin K, Wu WI, Ballerd J, et al. Signal 2012; 5:223.4. Wallin JJ, Guan J, Prior WW, et al. Sci Transl Med 2010; 2:48.

ACKNOWLEDGMENTS • We thank the patients who participated in the study and their families • We thank the Genentech/Array GDC-0068 Akt team • Genentech provided support for this poster

American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, June 1–5, 2012