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

184s Developmental Therapeutics—Experimental Therapeutics
3044 General Poster Session (Board #13B), Mon, 8:00 AM-12:00 PM
SORAVE: Phase I study for the treatment of relapsed solid tumors with the
combination of sorafenib and everolimus. Presenting Author: Lucia Nogova,
Lung Cancer Group Cologne, Center for Integrated Oncology, University
Hospital Cologne, Cologne, Germany
Background: Dual inhibition of signaling pathways interfering with angiogenesis
and cell proliferation may increase anti-tumor efficacy. We evaluated
the combination of the VEGFR inhibitor sorafenib (S) and the mTOR
inhibitor everolimus (E) and used FDG-PET to assess pharmacodynamic
(PD) activity of E. Methods: Patients with relapsed solid tumors were treated
with escalating doses of E 2.5-10.0mg/d p.o. in a 14 days monotherapy run
in phase followed by combination therapy with a fixed dose of S 400mg bid
from day 15. The primary aim was to define a safe and feasible combination
treatment regimen for a subsequent phase II trial. DLT was defined as any
drug related toxicity of CTC IV° or toxicity requiring hospitalization or
interruption of therapy for more than 2 weeks within the first 29 days of
treatment. Pharmacokinetic (PK) analyses were performed on day 5, 14
and 29 combined with explorative PD assessment of E by FDG-PET on days
1, 5 and 14 of treatment. Results: Nineteen patients were treated with the
combination of E and S. The DLT was not reached according to protocol
definition. However, at a dose level of E 10mg/d p.o. the following adverse
events (AE) occurred in the non-DLT interval: Pneumonia III°, treatment
delay due to leucopoenia/thrombopenia III° and sudden cardiac death
probably due to arrhythmia. Based on these observations, the dose level of
7.5mg/day E p.o. in combination with 400mg S bid was defined as the
MTD. The steady state of E alone was reached after 5 days of treatment and
did not change until day 14. However, on day 29 everolimus plasma
concentrations (AUC and Cmax) showed a significant 30 % reduction when
co-administered with S. A metabolic response of the hottest lesion in PET
on day 5 defined as � 80% of baseline was seen in 4 of 15 evaluable
patients. Median PFS and OS were 4.2 and 5.4 months, respectively. A
patient with neuroendocrine carcinoma reached the longest PFS of 16.6
months. Conclusions: Treatment of patients with relapsed solid tumors with
a combination of E 7.5mg/day and 400mg S bid is safe and feasible. The
extension phase for confirmation of safety data, further PK and PD
modeling and preliminary exploration of efficacy in KRAS mutant cancer
patients will be performed at this dose level.
3046 General Poster Session (Board #13D), Mon, 8:00 AM-12:00 PM
A dose-escalation phase I study of oral pan-CDK inhibitor BAY 1000394 in
patients with advanced solid tumors: Dose escalation with an intermittent
28 days on/14 days off schedule. Presenting Author: Juneko E. Grilley-
Olson, University of North Carolina at Chapel Hill, Chapel Hill, NC
Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting
CDKs 1, 2, 4, 7, and 9 in the low nanomolar range. A phase I dose
escalation multicenter study was initiated to determine the maximum
tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics
(PD) in patients (pts) with advanced solid tumors. Methods: BAY was
administered twice daily as an oral solution on a 28 days on / 14 days off
schedule (cycle length 42 days, 3�3 design). PK was evaluated on cycle 1
day 1, 2, and 15. Response rate was assessed according to RECIST 1.1.
Results: Ten pts were treated at doses of 0.6 (4 pts) and 1.0 (6 pts) mg per
day. Tumor types included 3 non-small cell lung, 2 colorectal, 2 melanoma
and 3 others. CTCAEv4 grade 1/2 drug related adverse events (AEs)
occurring in more than 3 patients were nausea (5 pts), hot flashes (4),
vomiting, diarrhea, dyspepsia, and fatigue (3). The median interval
between start of treatment and occurrence of hot flashes was 23 days.
Drug-related grade 3 AEs were hyponatremia (2 pts) and edema, lymphopenia,
myalgia, fatigue, and hypokalemia in 1 pt each. Hyponatremia in one
and hypokalemia in another patient were dose limiting toxicities in cohort
2. Enrollment has been stopped. BAY PK was dose proportional and T1/2 was 13 hours; major metabolite levels were low. One pt with metastatic
malignant melanoma pretreated with interferon, talimogene laherparepvec,
and ipilimumab (best prior response: progressive disease) achieved stable
disease (SD) lasting for 5 months. Three pts had SD lasting for 2.5 - 3
months (thyroid, colorectal, squamous esophageal). Conclusions: BAY
administered for 28 days on / 14 days off demonstrated a limited
tolerability. This is in contrast to the ongoing 3 days on / 4 days off trial
which is currently at a dose level of 20 mg per day. Hot flashes were an
infrequent AE in the other dosing schedule but occurred in 4 of the 10 pts
presented here. The long interval between start of treatment and occurrence
of hot flashes suggests that the 28 days of continuous treatment
contributed to the lower tolerability observed in this trial. The 3 days on / 4
days off schedule will be used in the further clinical development of BAY.
3045 General Poster Session (Board #13C), Mon, 8:00 AM-12:00 PM
Phase I dose-escalation study of AZD7762 alone and in combination with
gemcitabine in Japanese patients with advanced solid tumors. Presenting
Author: Takashi Seto, National Kyushu Cancer Center, Fukuoka, Japan
Background: AZD7762, a potent Chk1/Chk2 inhibitor, has been shown to
enhance the antitumor activity of gemcitabine in xenograft models (Zabludoff
SD et al. Mol Cancer Ther 2008;7:2955–66). Methods: This open-label
dose-escalation study evaluated the safety, pharmacokinetics (PK), and
preliminary efficacy (RECIST) of AZD7762 alone and in combination with
gemcitabine in Japanese patients (pts) with advanced solid tumors
(NCT00937664). Pts received AZD7762 iv alone on days 1 and 8 of a
14-day cycle (Cycle 0), followed by AZD7762 plus gemcitabine 1000
mg/m2 on days 1 and 8 of 21-day cycles, in sequential ascending AZD7762
dose cohorts. Results: 20 pts (mean age 60 years) received AZD7762 at
doses of 6 (n�3), 9 (3), 21 (6), and 30 mg (8). The most common primary
tumor site was lung (n�14). All pts had received �1 prior chemotherapy
and 18 had metastatic disease. Dose-limiting toxicities (DLTs) occurred in
two of six evaluable pts (both 30 mg cohort): one, grade 3 (CTCAE, v3.0)
elevated troponin T (Cycle 0; AZD7762 monotherapy); one, neutropenia,
thrombocytopenia, and elevated AST and ALT (Cycle 1; combination
therapy). Thus, the 30 mg dose was regarded as non-tolerable. DLTs
resolved following treatment discontinuation. The most frequently reported
adverse events (AEs) in Cycle 0 (AZD7762 monotherapy) were bradycardia
(50%), hypertension (25%) and fatigue (15%). Overall, the most common
AEs were bradycardia (55%), neutropenia (45%), and hypertension,
fatigue, and rash (30% each). AEs grade �3 were reported in 11 pts, the
most common being neutropenia (45%) and leukopenia (25%). No pt died
due to an AE. AZD7762 exposure (Cmax, AUC) increased in an approximately
linear manner. Gemcitabine did not appear to affect AZD7762 PK.
Arithmetic mean t½ and geometric mean CL of AZD7762 across the dose
groups were 16.1–19.4 h and 22.0–32.7 L/h, respectively during the
monotherapy cycle, and 15.6–18.3 h and 21.1–24.4 L/h, respectively in
combination with gemcitabine. There were no objective responses; five pts
(all lung cancer) had stable disease. Conclusions: The maximum tolerated
dose of AZD7762 in combinationwith gemcitabine 1000 mg/m2 was
determined as 21 mg in Japanese pts.
3047 General Poster Session (Board #13E), Mon, 8:00 AM-12:00 PM
Clinical and correlative science results in a phase II study of UCN-01 in
combination with irinotecan in recurrent triple-negative breast cancer
(TNBC). Presenting Author: Cynthia X. Ma, Washington University School
of Medicine, St. Louis, MO
Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing
“mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan
(I) combined with UCN-01, a nonselective Chk1 inhibitor, showed
promising activity in TNBC in our phase I study. The primary objective of
the phase II trial was to determine the efficacy and toxicity. Correlatives
included assessing tumor molecular subtype, TP53, PTEN and pathways
targeted by UCN-01. Methods: Pts with measurable, metastatic (met)
TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial
peripheral blood mononuclear cells (PBMC) and optional tumor biopsies
were collected. Results: Twenty five pts were enrolled. All had prior A and T.
The median no. of prior regimens for met disease was 3 (range 1-4).
Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia.
Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a
clinical benefit rate (CR�PR�SD�6 mos) of 3/25 (12%), 95% CI (3,
31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6
was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC
24h post UCN-01, but close to baseline by d8. Immunostain of cleaved
caspase 3 (CC3), pHistone H3 (pHH3), �H2AX, and pS6 were done on
serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6
was reduced 24h post UCN-01. Results for other markers were variable.
One case with TP53 deletion showed an induction of CC3, with an increase
in pHH3 and �H2AX, suggesting abrogation of cell cycle arrest and
enhanced DNA damage. Among 15 with sufficient specimen for analysis,
most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2)
by PAM50, low in PTEN level (11) and carried mutations in TP53 (8).
Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95%
CI: 2.9, - ) mos in wild type populations (p�0.004). Conclusions: This
regimen had limited activity in TNBC. Despite the long half-life, drug
activity is not detectable by d8 based on PBMC analysis. Our data indicates
that future trials in TNBC should consider p53 status.
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