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

3105 General Poster Session (Board #20G), Mon, 8:00 AM-12:00 PM
A phase Ib trial of FOLFIRINOX plus saridegib, an oral hedgehog (Hh)
inhibitor, in pts with advanced pancreatic cancer (PDAC). Presenting
Author: Andrew H. Ko, University of California, San Francisco Comprehensive
Cancer Center, San Francisco, CA
Background: FOLFIRINOX has emerged as the optimal 1st-line treatment
option for pts with advanced PDAC and good performance status; whether it
can serve as the backbone upon which to add targeted agents in clinical
trial design remains uncertain. The goal of this multicenter phase Ib study
is to evaluate FOLFIRINOX in combination with saridegib, a novel oral
agent that inhibits the Hh signaling pathway. In preclinical models of
PDAC, saridegib increases chemotherapy delivery by depleting peritumoral
stroma and increasing vascularity. Methods: Pts with previously untreated
metastatic or locally advanced PDAC and ECOG PS 0-1 were eligible.
Treatment consists of once-daily saridegib with concurrent administration
of biweekly FOLFIRINOX (omitting the 5-FU bolus). A 3�3 dose escalation
design was used (see dose levels below). Prophylactic WBC growth factor
support is mandated. DLT definitions include ALT/AST �10x ULN, grade 4
plts or ANC �5 d, or grade 3-4 nonheme toxicity. CT scans are obtained
every 4 cycles. Limited PK analyses are performed. Results: Seven pts have
been enrolled at the first 2 dose levels. Grade 1-2 AEs include GI (N/V/D),
dehydration, fatigue, and LFT abnormalities. There was one DLT (grade 3
ALT elevation) at DL2. Other serious toxicities seen include grade 3 nausea
(DL1) and grade 3 diarrhea (DL2). Tumor shrinkage has been observed in
all 4 pts at DL1, ranging from 17-54%, with 2 unconfirmed PRs. Final MTD
determination and updated safety and efficacy data will be presented at the
meeting. Conclusions: A modified FOLFIRINOX regimen can be safely
administered in combination with novel agents in clinical trials of PDAC.
While saridegib was not beneficial when added to gemcitabine in a separate
randomized phase II study, early evidence of significant responses on the
current trial suggests that a more intensive chemotherapy platform may
represent a preferable strategy in PDAC trial design.
Dose level
5-FU bolus
(mg/m2)
5-FU infusion
(mg/m2 x 46 hrs)
LV
(mg/m2) Oxaliplatin Irinotecan
(mg/m2) (mg/m2)
IPI-926
(mg/day)
-1 -- 1600 400 50 120 130
1* -- 1920 400 65 150 130
2 -- 2400 400 85 180 130
3 -- 2400 400 85 180 160
*Starting dose level.
3107^ General Poster Session (Board #21A), Mon, 8:00 AM-12:00 PM
First-in-human phase I dose-escalation study of the oral selective C-met
inhibitor EMD 1204831 in patients with advanced solid tumors. Presenting
Author: Hesham M. Amin, Department of Hematopathology, University
of Texas M. D. Anderson Cancer Center, Houston, TX
Background: The cell surface receptor tyrosine kinase c-Met and its ligand,
the hepatocyte growth factor, are implicated in tumor cell migration,
invasion, survival, and proliferation. EMD 1204831 is a novel potent and
highly selective reversible, ATP-competitive small molecule c-Met inhibitor.
Methods: This is a phase I, first-in-human clinical trial with escalating
doses of EMD 1204831 (NCT01110083). The primary objective was to
determine the maximum tolerated dose (MTD). Secondary objectives
included evaluation of safety, pharmacokinetics (PK), pharmacodynamics
(Pd), and preliminary anti-tumor activity. Eligible patients had advanced
solid tumors not amenable to standard therapies. Following a classical 3�3
dose-escalation scheme, successive cohorts of patients were treated with
twice daily (BID) oral EMD 1204831 in 21-day cycles. Pd markers were
evaluated in paired tumor biopsies (phospho-c-Met). Results: Until 31
December 2011, 30 patients were enrolled and treated. The dose was
escalated in successive cohorts starting from 50 mg BID up to 1400 mg
BID. After first (single) administration, median Cmax and AUC0–12 values
increased with dose. At higher doses, a decrease in exposure of EMD
1204831 was noted after multiple dosing, potentially caused by autoinduction
of the compound’s metabolism. Further dose escalation was discontinued,
and no further patients were enrolled. One dose-limiting toxicity (DLT)
of grade (G) 3 pancreatitis, considered as a serious adverse event (AE), was
observed at 400 mg BID. No other DLTs or treatment-related serious AEs
were observed. The remaining treatment-related AEs of G2 or higher
included G3 and G2 lipase elevation (n�1 for each grade), G2 upper
abdominal pain (n�2), G2 gastroesophageal reflux disease (n�2), and G2
constipation (n�1). Twenty-five patients (83%) had no drug-related
toxicity greater than G1. Of 29 patients evaluable for anti-tumor activity, 3
had stable disease lasting for at least 4 months. Conclusions: Due to
potential autoinduction of the compound’s metabolism, dose escalation
was discontinued before an MTD was reached. Final safety, PK, and clinical
tumor response results will be presented.
Developmental Therapeutics—Experimental Therapeutics
199s
3106 General Poster Session (Board #20H), Mon, 8:00 AM-12:00 PM
NRAS mutations in patients with advanced cancers treated with targetbased
therapies in early-phase clinical trials. Presenting Author: Vinu
Madhusudanannair, Department of Investigational Cancer Therapeutics
(Phase I Program), University of Texas M. D. Anderson Cancer Center,
Houston, TX
Background: NRAS mutations in cancers increase MAPK signaling. It is
plausible that NRAS mutations may be associated with sensitivity to drugs
targeting the MAPK pathway. Methods: Tumors from 689 patients with
advanced cancers referred to the Clinical Center for Targeted Therapy
(phase I program) were screened in a CLIA-certified laboratory for NRAS
mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN
aberrations. Whenever possible, patients with NRAS mutations were
treated with agents targeting the RAF-MEK pathway. Results: Of the 689
patients, 58 (8%) had NRAS mutations. NRAS mutations were most
prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial
(2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and
colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the
tested head and neck squamous cell cancers (n � 44); sarcomas (n � 41)
and breast cancers (n � 25). None (0/62, 0%) of the patients tested for
KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%)
tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58
patients with NRAS mutations, 14 (24%) were enrolled in trials that
included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and
1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage
�10% from baseline. In comparison, only 22/187 (12%) patients with
wild-type/unknown NRAS, KRAS and BRAF treated on the same trials
demonstrated tumor shrinkage �10% (p�0.086). Conclusions: NRAS
mutations are diagnosed in variety of advanced cancers. Patients with
NRAS mutations demonstrated a trend to better antitumor activity with
MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF
mutations. Further studies are warranted to delineate the role of NRAS
mutations in patients treated with MEK axis inhibitors.
3108 General Poster Session (Board #21B), Mon, 8:00 AM-12:00 PM
Phase I trials of PS-341 (bortezomib, B) in combination with topotecan (T)
in advanced solid tumors: A potential pharmacokinetic (PK) interaction.
Presenting Author: Robert Morgan, City of Hope, Duarte, CA
Background: Preclinical data has demonstrated that B when combined with
camptothecins enhances apoptotic effects which may be independent of
NF-�B status and dependent on the sequence of exposure to the proteasome
inhibitor. Other data suggests PK interactions of B with some
chemotherapeutic agents. It is hypothesized that B will act synergistically
with T and enhance the apoptotic effects of T. Conflicting data exists
regarding schedule dependent synergistic cytotoxicity of the combination.
This study examined both sequences of administration and determined the
PK of each sequence. Methods: A standard 3 � 3 schedule was used in both
sequences (S). The dose of B was fixed with escalating doses of T. S1: B 1.3
mg/m2 on days 1, 4, 8, and 11.T2to3.5mg/m2 on days 1 and 8 was given
6 h before B. S2: B 1.3 mg/m2 on days 1, 4, 8, 11 followed by T2to3
mg/m2 given 6 h after B. Cycle length was q28 days. PK sampling for both
sequences was performed. Results: 54 pts (S1: 27, S2: 27) received a
median of 2 cycles (range 1-7) of therapy. Pts were heavily pre-treated. For
S1, the maximum tolerated dose (MTD) of B and T were 1.3 and 3 mg/m2 respectively. For S2, the MTD of B and T were 1.3 and 2.5 mg/m2 respectively. Dose-limiting toxicities (2 pt in each sequence) were gr 3
thrombocytopenia in S1, and gr 4 thrombocytopenia in S2. Stable disease
was seen in 6/27 pts in S1, and 6/27 in S2. PK results for S2 show no
significant difference between the day 1 and day 8 PKs. However, the mean
AUC (454�150 mg/Lxhr) and Cmax (123�51 mg/L) at the MTD of 2.5
mg/m2 reached on this trial is similar to those reported with single agent
doses of 4 mg/m2 given over 30 minutes weekly x 3. As a result, the
estimated topotecan clearance (11.3�5 L/hr) when given following bortezomib
is approximately one half of the reported clearance for the single
agent. (Curtis et al, J Clin Pharmacol, 50:268, 2010). Conclusions: The
tolerability and toxicity of both sequences was similar. MTD differs with S2
having a lower tolerated dose of T. PK results suggest a possible drug-drug
interaction with decreased clearance of T with S2. PK results for S1 are
pending. Supported by CCSG CA62505.
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