Annual Meeting Proceedings Part 1 - American Society of Clinical ...

178s Developmental Therapeutics—Experimental Therapeutics
3020 Poster Discussion Session (Board #12), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase I, single-institution, open-label, dose escalation trial with an
expansion cohort evaluating the safety and tolerability of AZD6244 and
IMC-A12 in subjects with advanced solid malignancies. Presenting Author:
Shabina Roohi Ahmed, The Johns Hopkins University School of Medicine,
Baltimore, MD
Background: Significant crosstalk exists between the PI3K and Raf/MEK/
ERK pathways and treatment of select cell lines with a MEK inhibitor and
an IGF1-R inhibitor has been shown to cause greater inhibition of growth
than either agent alone. IMC-A12 (I) is a recombinant human monoclonal
antibody directed IGFI-R; it blocks interaction between IGF-1R and its
ligands, IGF-I and -II. AZD6244 (A) is a highly selective, non-competitive
MEK ½ inhibitor. Methods: The study is a phase I, dose-escalation with a
standard 3�3 design. Eligible patients had advanced solid tumor, good
end organ function and performance status with exclusion for poorly
controlled diabetes or growth hormone abnormalities. Part 1: open label,
dose escalation. Pts were treated with A at 50 mg BID, then 75 mg BID; I at
12mg/kg q2wk held constant. DLTs were defined as grade (G) 3 or 4
toxicities during cycle 1. Part 2: expansion cohort of 15 pts for correlative
endpoints and PK studies; serial tumor biopsies will be evaluated for
changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS.
Mutational analysis of RAS and RAF will be done to correlate with PD
endpoints and disease response. Results: Part 1: 16 patients accrued with
6 treated at DL1 and 10 treated at DL2. Multiple tumor types were
represented, including 4 colon, 2 thyroid, 2 pancreatic, and 1 breast. At 75
mg of A, there was 1 DLT of visual changes. G3 AEs included nausea/
vomiting (n�2, 12%), visual changes/retinopathy (n�2, 12%), MRSA skin
infection (n�1, 6%), (n�1, 6%), hyperglycemia (n�1, 6%), and stroke
(n�1, 6%). Other common AEs included acneform rash (n�10, 63%),
nausea/vomiting (n�6, 37%), anorexia (n�4, 25%), and diarrhea (n�3,
19%). Of 10 evaluable patients in Part 1, 1 had a partial response and 4
patients had stable disease (40%). Sustained responses of 10 and 14
months were seen in the DTC patients. 3 patients are currently enrolled in
the expansion cohort. The RP2D is 50 mg of A, due to the visual changes
seen with 75 mg, and 12mg/kg of I. Conclusions: A at 50 mg QD combines
safely with I 12mg/kg. An expansion cohort is underway to determine if this
combination warrants further investigation.
3022 Poster Discussion Session (Board #14), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human
study of the oral class I PI3K inhibitor CH5132799, in patients with
advanced solid tumors. Presenting Author: Aurelius Gabriel Omlin, Section
of Medicine, The Institute of Cancer Research, Sutton, United Kingdom,
and Drug Development Unit, The Royal Marsden NHS Foundation Trust,
Sutton, United Kingdom
Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising
target in cancer. CH5132799 is a novel PI3K inhibitor, selectively
inhibiting class I PI3Ks (�, �, � and �) with no inhibition of class II and III
or mTOR, and with potent antitumor activity in preclinical studies (Tanaka
et al, Clin Cancer Res; 17; 3272-81, 2011). First-in-human study
objectives were determination of maximum tolerated dose (MTD), safety/
tolerability, PK/PD and clinical activity (RECIST). Methods: A3�3 dose
escalation design was used. The initial dosing schedule of
CH5132799(schedule A) was once a day (QD). Due to a relatively short
half-life, a twice a day (BID) schedule (schedule B) was introduced. PK
profiles were studied over 72 hours. PD analyses included quantification of
various phosphoproteins in platelet rich plasma (PRP). Tumor assessments
were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans
at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of
solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors
were breast, oesophageal, colorectal and ovarian). The starting doses were
2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A)
and 72 mg (B). The most frequently reported drug-related AEs were Grade
1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3
elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID.
MTD has not yet been determined. The preliminary mean �SD Cmax and
AUC at 96 mg QD were 202�129 ng/ml and 1407�935 ng·hr/ml
respectively, which is consistent with an efficacious exposure based on
preclinical models. Some patients achieved the expected exposure at over
32 mg. From single dose of 48mg there was a reduction of phosphorylation
of AKT in PRP after treatment, consistent with pathway modulation. A
patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48
mg BID showed �50% decrease in SUV on a PET scan at C1D8 and a 75%
decrease in CA-125 at C2D1. 5 pts exhibited SD (�8 weeks). Conclusions:
CH5132799 is well tolerated either QD �96 mg or BID �48 mg.
Dose-escalation continues and updated safety/efficacy/PK/PD data will be
presented.
3021 Poster Discussion Session (Board #13), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase Ib study of the Akt inhibitor GDC-0068 with docetaxel (D) or
mFOLFOX-6 (F) in patients (pts) with advanced solid tumors. Presenting
Author: Cristina Saura, Medical Oncology Department, Vall d’Hebron
University Hospital, Barcelona, Spain
Background: Activation of the Akt pathway is observed in multiple tumors
and may contribute to chemoresistance. GDC-0068 is an ATP-competitive
small molecule inhibitor of all three isoforms of Akt; in a phase Ia study, it
was well tolerated with maximum tolerated dose (MTD) of 600 mg daily (21
days on/7days off) and pharmacodynamic down-regulation of Akt signaling
in tumors at doses �100 mg. In vitro, GDC-0068 shows synergism with
cytotoxic agents. This phase Ib study defines the dose limiting toxicities
(DLT), MTD, safety and pharmacokinetics (PK) of GDC0068 in combination
with D and F. Methods: Using a 3�3 designeligible patients (pt) with
advanced/metastatic solid tumors were treated with either D, 75 mg/m2 day
1 and GDC-0068 daily on days 2-15 of a 21 day cycle (Arm A); or F, bolus
5FU 400mg/m2 , leucovorin 400 mg/m2 , oxaliplatin 85 mg/m2 all day 1,
and infusional 5FU 2400mg/m2 for 46 hours and GDC-0068 daily on days
1-7 of a 14 day cycle (Arm B). PK sampling was performed in Cycles 1 and
2. Results: 23 pts have enrolled; Arm A (GDC-0068, mg): 100 (n�3), 200
(n�4), and 400 (n�5); Arm B:100 (n�6) and 200 (n�5). Median prior
therapies � 3. GDC-0068-related adverse events in � 10% of pts were
diarrhea, nausea, vomiting, fatigue, and decreased appetite. All GDC-0068related
AEs were grade 1 or 2, except one grade 4 neutropenia in Arm A. No
DLTs have been reported to date. Preliminary data show no alteration in the
PK of GDC-0068, D or F compared to phase Ia or historical data. Two
heavily pretreated pts with cervical and PTEN-loss colon cancers treated in
Arm B demonstrated both RECIST partial response and tumor marker
decrease by first CT evaluation. Conclusions: The combination of GDC-
0068 with D or F is well-tolerated and shows early signs of anti-tumor
activity. Dose-escalations continue.
3023 Poster Discussion Session (Board #15), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A five-arm, open-label, phase I/lb study to assess safety and tolerability of
the oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination
with chemotherapy or erlotinib in patients with advanced solid tumors.
Presenting Author: Carlos Becerra, Internal Medicine, Sammons Cancer
Center, Dallas, TX
Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated
single-agent clinical activity. In vitro studies of trametinib plus docetaxel
(doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth
inhibition of lung cancer cell lines with and without RAS/RAF mutations.
Trametinib�doc significantly increased apoptosis compared with either
agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label
study to evaluate the safety and tolerability of trametinib plus doc, erl, pem,
pem�carboplatin (pem�carbo), or nab-paclitaxel (nab-pac)
(NCT01192165). Part I is dose escalation in patients (pts) with advanced
solid tumors; part II is dose expansion in pts with lung and pancreatic
cancers. A 3�3 dose-escalation design was used to determine the
maximum tolerated dose (MTD) and the recommended phase II regimen
(RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined
during the first treatment cycle (21 days). Trametinib was started at
0.5 mg/day; chemotherapy was given at full recommended doses. Erl was
escalated from 50 mg/day. Pharmacokinetic (PK) samples were collected
pre-, and 1, 2, 3 and 6 hours post-dose. Results: As of January 2012, 80 pts
have been enrolled across all arms except trametinib�nab-pac. Preliminary
exposure results of trametinib�doc, erl, or pem suggest no PK
drug-drug interaction. The predominant DLT for trametinib�doc without
growth factors (MTD � 0.5 mg�60 mg/m2 ) was neutropenia. When
administered with growth factors, trametinib�doc has been given up to 1.5
mg�75 mg/m2 with no DLTs. The predominant DLTs for trametinib�erl
(MTD � 1 mg�100 mg) were diarrhea and mucositis and for
trametinib�pem (MTD � 1.5 mg�500 mg/m2 ) were mucositis and febrile
neutropenia. The MTD for trametinib�pem�carbo has not yet been
determined. To date there are 5 PRs in the trametinib�doc group and 2
PRs in the trametinib�pem group. An NSCLC expansion cohort for
trametinib�pem is enrolling. Conclusions: Trametinib�doc and
trametinib�pem have shown acceptable tolerability and initial evidence of
clinical activity.
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