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

196s Developmental Therapeutics—Experimental Therapeutics
3092 General Poster Session (Board #19B), Mon, 8:00 AM-12:00 PM
BI 836845, a fully human IGF ligand neutralizing antibody, to improve the
efficacy of rapamycin by blocking rapamycin-induced AKT activation.
Presenting Author: Paul J. Adam, Boehringer Ingelheim RCV GmbH & Co.
KG, Vienna, Austria
Background: Analogs of rapamycin (rapalogs) targeting mammalian target
of rapamycin complex 1 (mTORC1) have shown clinical activity in several
cancers. Nonetheless, preclinical and clinical data suggest that there may
be intrinsic resistance to rapalogs through a feedback loop which activates
upstream signaling when mTORC1 is blocked. BI 836845 is a fully human
antibody, currently in phase I clinical trials, which potently neutralizes both
IGF-1 and IGF-2. We tested whether BI 836845 is able to improve the
efficacy of rapamycin by inhibiting upstream signaling in preclinical
models. Methods: Cancer cell lines were profiled in vitro and in vivo for
sensitivity to BI 836845 and rapamycin, alone or in combination. Mitogenic
signaling was examined by measuring levels of phosphorylated AKT
(pAKT) using Western blot analysis. IGF bioactivity was determined using a
cellular IGF-1R phosphorylation ELISA. Results: The combination of BI
836845 and rapamycin was more effective than either agent alone at
inhibiting the proliferation of Ewing’s sarcoma cells cultured in vitro as well
as in a nude mouse xenograft model in vivo. Analysis of cell signaling
upstream of mTOR demonstrated that treatment with rapamycin alone
resulted in elevated pAKT, indicating feedback loop activation. BI 836845
treatment alone or in combination with rapamycin inhibited AKT phosphorylation,
demonstrating that the rapamycin-induced increase in pAKT was
due to elevated IGF bioactivity. Consistent with this we demonstrated that
rapamycin increased IGF bioactivity in mice and that this could be
inhibited by BI 836845. We extended these studies to include other cancer
cell lines and profiled the correlation between improved efficacy of the
combination with BI 836845 inhibition of rapamycin-induced feedback. A
correlation has been observed for cancer cells derived from several
indications. Conclusions: Rapamycin treatment increases AKT activation
via elevated IGF ligand bioactivity. This effect can be inhibited by BI
836845, thus explaining the improved pre-clinical efficacy seen when both
agents are combined. These data provide a rationale for the clinical
combination of rapalogs and BI 836845.
3094 General Poster Session (Board #19D), Mon, 8:00 AM-12:00 PM
A phase I and pharmacokinetic study of multiple schedules of ganetespib
(STA-9090), a heat shock protein 90 inhibitor, in combination with
docetaxel for subjects with advanced solid tumor malignancies. Presenting
Author: John S. Kauh, Winship Cancer Institute, Emory University, Atlanta,
GA
Background: Ganetespib is a next-generation Hsp90 inhibitor unrelated to
the first-generation ansamycin class of Hsp90 inhibitors and has superior
activity to these agents in preclinical studies. Ganetespib is well tolerated
with promising antitumor activity. Based on synergy between ganetespib
(G) and docetaxel (D), a phase I study evaluating preclinical dosing models
was performed. Methods: Patients (pts) with advanced solid tumor malignancies
and ECOG performance status (PS) 0-2 were eligible. Sequential
cohorts of pts were treated (3�3 design) with increasing doses of D (day 1)
and G (days 1, 8) (A) Q 21 days. Following MTD determination, safety and
exploratory cohorts of D day 1 with G days 1, 15 (B); or G days 1, 4, 15 (C)
were completed. PK sampling was performed during schedule A. The
primary endpoint was determination of optimal doses and schedule of the
two agents for combination therapy. Results: Twenty-seven patients were
enrolled in schedules A (n�12), B (n�8), and C (n�7). Median age-64
(44-75); 11-M, 16-F; ECOG PS: 0 (n�5),1(n�21), 2 (n�1). Most pts had
NSCLC (n�9), others were head/neck (n�4), and SCLC (n�3). The defined
MTD was level 2 (D-75 mg/m2, G-150 mg/m2), as 2 of 4 pts at level 3
(D-75 mg/m2, G-200 mg/m2) had DLTs (febrile neutropenia and one g4
neutropenia of � 7 days), requiring expansion of level 2. The median
number of cycles received is 2 (1-11), with 3 pts in schedule C still on
study. Among 22 pts evaluable for response, 1 had a PR (head/neck), 12
had SD following 6 weeks evaluation, 10 pts for 12 weeks and 6 pts for 18
weeks. Common AEs included neutropenia, diarrhea, anemia, fatigue,
nausea, and febrile neutropenia. Prophylactic filgrastim/pegfilgrastim was
not used at any time. PK data indicates similar G exposure alone compared
to G administered prior to D. No accumulation was observed following
once-weekly dosing, consistent with studies of G alone. Conclusions: The
combination is well tolerated at the recommended doses of D 75 mg/m2
and G 150 mg/m2. Promising anti-cancer activity was noted, and a
randomized phase 2b/3 study with D day 1 and G days 1, 15 regimen is
ongoing in advanced NSCLC (NCT01348126).
3093 General Poster Session (Board #19C), Mon, 8:00 AM-12:00 PM
Phase I dose-finding and pharmacokinetic study of a combination of
elisidepsin (E) and erlotinib (T) in patients (pts) with advanced solid
tumors. Presenting Author: Sanjay Goel, Montefiore Einstein Cancer
Center, Bronx, NY
Background: E is a new marine compound that has shown synergism with T
in vitro even in T-resistant non-small-cell lung cancer (NSCLC) cell lines.
Based on these findings, a phase I clinical trial was undertaken to identify
the maximum tolerated dose (MTD) and recommended dose (RD) of E (3-h
iv, days 1, 8 and 15) followed by T (once daily) in 3-week cycles. Secondary
objectives were evaluation of safety and feasibility, PK and preliminary
efficacy results. Methods: Patients (pts) with advanced solid tumors with no
standard therapeutic option were recruited. Cohorts of 3-6 pts were
included at each dose level (DL), with escalating doses of E in increments
of 25-50% according to toxicities, and 2 different T doses (100 and 150
mg/day). Results: Thirty pts (median age, 57 years; 19 females) were
evaluable. Main tumor types included NSCLC, colorectal, melanoma, and
ovarian cancer. Six DLs were assessed. Starting DL was E 0.33 mg � T
100mg. One dose-limiting toxicity (DLT) out of 6 pts (grade 3 bilirubin
increase) was observed at DL3 (E 0.75 mg � T 150 mg). Another DLT (dose
omissions due to ALT increase) was found at DL6 (E 2.25 mg � T 100 mg).
Frequent toxicities were diarrhea (53%), nausea (23%), vomiting (33%),
rash (47%), pruritus (43%), dry skin (27%) and acneiform dermatitis
(17%). Grade 3/4 toxicities included diarrhea (2 pts), rash (2 pts) and
pruritus (1 pts). Main biochemical abnormalities were ALT (grade 3/4 in 4
pts) and total bilirubin increase (grade 3 in 2 pts). No severe hematological
abnormalities were observed. Most toxicities were related to T; therefore, T
dose was reduced to 100 mg/day. No PK interaction between E and T was
observed. No objective responses were reported. Six pts attained stable
disease �3 months (3 NSCLC; 1 ovarian cancer, 1 colorectal cancer, 1
invasive thymoma). Conclusions: E � T was a manageable combination;
however, the difficulty of combining E with the standard dose of T (150mg)
and the lack of activity made this combination unattractive for further
development in the current schedule. Possibly, other schedules may
demonstrate more efficacy.
3095 General Poster Session (Board #19E), Mon, 8:00 AM-12:00 PM
A phase I trial of the mTOR inhibitor temsirolimus (TEM) in combination
with capecitabine (CAP) in patients with advanced malignancies. Presenting
Author: Michael J. Pishvaian, Lombardi Comprehensive Cancer Center,
Georgetown University, Washington, DC
Background: The mammalian target of rapamycin (mTOR) signaling pathway
is critical for cell growth and proliferation. mTOR antagonists, such as
TEM, have proven anti-cancer efficacy. Pre-clinical models and early phase
clinical trials have demonstrated increased efficacy when an mTOR
antagonist is combined with cytotoxic chemotherapy. Methods: Patients
(pts) with advanced malignancies and adequate hepatic and renal function
were eligible for enrollment. An alternating dose escalation of TEM and CAP
was employed in separate q2week and q3week arms. Planned dose levels
were: TEM 15 and 25mg IV weekly; and CAP 500, 750, 1000, and 1250
mg/m2 orally twice daily (BID). Restaging occurred every 4 cycles for the
q2week arm, and every 3 cycles for the q3week arm. PK samples assessed
serum levels of sirolimus at Day 0, 8, and 15 of the q2week arm. Archived
tumor specimens were assayed by immunohistochemistry (IHC) for expression
of phospho-AKT, phospo-4EBP1, phoshpo-p70S6, and PTEN. Results:
Thirty-two pts were enrolled, 30 of whom were evaluable for toxicity, of
which 18 were male, age range 30-72 years, 25 with colorectal cancer. Pts
had received an average of 4 prior lines of therapy. The most common
adverse events (AEs) were mucositis and fatigue. The most common grade
3/4 AEs were fatigue (n�4), diarrhea (n�2), and hypophosphatemia
(n�2). In 16/30 pts, the dose of CAP was reduced. There were two DLTs,
both hypophosphatemia in the q3week arm (TEM�25mg and
CAP�1000mg/m2 ). For the q2week arm, the recommended phase II dose
(RP2D) was TEM 25 mg � CAP 1000mg/m2 . For the q3week arm, the
RP2D was TEM 25mg � CAP 750mg/m2 . Twenty-five pts were evaluable
for response (18 for OS). There were no PRs or CRs, but 14/25 pts (56%)
had SD, with 4/24 (16%) having prolonged SD of �6 months. Median TTP
and OS were 3 and 7 months, respectively. Five pts are still on study. PK
assessment of serum sirolimus levels, and the results of the IHC on
archived tumor samples will be presented. Conclusions: The combination of
TEM and CAP is safe on both a q2week and a q3week schedule. The
combination demonstrated promising evidence of disease control in this
highly refractory population and should be tested in disease-specific phase
II trials.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.