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

3008 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
A first-in-human phase I study of the oral Notch inhibitor LY900009 in
patients with advanced cancer. Presenting Author: Shubham Pant, Sarah
Cannon Research Institute/University of Oklahoma Health Sciences Center,
Oklahoma City, OK
Background: Notch signaling plays a critical role during stem cell selfrenewal
and is deregulated in multiple human cancers. The Notch pathway
may be activated inappropriately by receptor mutation and overexpression
as well as aberrant signals from the tumor microenvironment. LY900009 is
a selective small-molecule inhibitor of gamma secretase, the enzyme that
cleaves and thereby activates Notch receptors. Methods: Dose escalation
was performed in cohorts of 3 patients (pts) using a modified continual
reassessment method. LY900009 was taken orally thrice weekly (every
MWF) during a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic,
and clinical endpoints were evaluated. Results: 22 patients received
LY900009 across 6 dose levels: 2mg (3pts), 4mg (4pts), 8mg (3pts),
15mg (3pts), 30mg (6pts), and 60mg (3pts). The most common treatment
emergent adverse events possibly related to LY900009 across all grades
included diarrhea (27%), vomiting (23%), nausea (18%), fatigue (23%),
anorexia (23%), hypophosphatemia (14%), and rash (18%). Dose-limiting
toxicities of fatigue/N/V (G3) and diarrhea (G3) were seen in 2 patients,
respectively, treated at 60mg. The maximum tolerated dose (MTD) was
tentatively identified at 30mg. After a single dose, mean Cmax increased
from 4 to 158 ng/ml and mean AUC0-t(last) increased from 14 to 1160
ng-hr/ml. Both Cmax and AUC0-t(last) increased in a dose-dependent
manner. Elimination half-life of LY900009 was approximately 2-3 hrs.
LY900009 inhibited plasma levels of amyloid-� peptide (a downstream
product of gamma secretase) in a dose-dependent manner with 80-90%
inhibition observed in the 30 and 60mg cohorts. In the 15mg cohort, one
patient had colonic biopsy that showed markedly increased glandular
mucin consistent with pharmacologic inhibition of the Notch pathway. Two
patients (10%) with leiomyosarcoma and ovarian cancer received 4 cycles
of therapy. Conclusions: LY900009 demonstrates acceptable safety and
pharmacokinetics in patients with advanced cancer. Pharmacodynamic
endpoints show pathway inhibition at tolerable doses. One more cohort at
45mg is ongoing to refine the MTD and will be followed by an expansion
cohort for patients with ovarian cancer.
3010 Poster Discussion Session (Board #2), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I/II study of the investigational aurora A kinase (AAK) inhibitor
MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer
(NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck
cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary
phase II results. Presenting Author: Peter Lee, Tower Cancer Research
Foundation, Beverly Hills, CA
Background: AAK is a key mitotic regulator that is amplified or overexpressed
in multiple tumor types. MLN8237 is an investigational oral,
selective AAK inhibitor being studied in both hematologic (phase III) and
nonhematologic malignancies. In the phase 1 part of this study, MLN8237
was generally well tolerated in pts with solid tumors. The maximum
tolerated dose was 50 mg BID for 7d � 2 wks rest in 21-d cycles; this dose
was recommended for phase II evaluation. Here we report preliminary data
from the 5-arm phase 2 part (NCT01045421). Methods: 20 pts each with
one of 5 tumor types in the relapsed/refractory setting were enrolled in
phase II for efficacy evaluation: NSCLC (inc. 8–10 pts with mainly
squamous-cell histology), SCLC (inc. 8–12 chemotherapy refractory pts),
BrC (inc. 8–10 pts with a basal-like intrinsic subtype, and 8–10 HER2�
pts), H&N (inc. 8–12 pts with tonsillar or base-of-tongue disease), or GE
adenocarcinoma. Pts were aged �18 y, and had ECOG PS 0–1, measurable
disease by RECIST, and �2 prior cytotoxic chemotherapy regimens
(�4 in BrC). Oral MLN8237 was administered as an enteric-coated tablet
at 50 mg BID for 7d � 2 wks rest in 21-d cycles. The primary endpoint was
overall response rate. Response was determined by RECIST v1.1. Each arm
with �2 partial responses (PR) is being expanded with 25 additional pts.
Results: In 100 efficacy-evaluable pts, median age was 59 y (range 33–88)
and 89% were caucasian. Pts received a median of 3 cycles (range 1–9).
PRs were observed in 11 pts: H&N, SCLC (each n�3), BrC, GE adenocarcinoma
(each n�2), and NSCLC (n�1). 45 pts had a best response of stable
disease. In the safety population (n�196), most frequent grade �3
drug-related AEs were neutropenia (37%), leukopenia (12%), fatigue,
anemia, stomatitis, and thrombocytopenia (each 6%). Updated data will be
presented. Conclusions: Preliminary phase II data suggest that oral
MLN8237 is tolerable and has antineoplastic activity in a range of solid
tumors studied. This study is currently ongoing to further evaluate
MLN8237 in the expansion cohorts.
Developmental Therapeutics—Experimental Therapeutics
175s
3009 Poster Discussion Session (Board #1), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in
adult patients (pts) with advanced solid tumors. Presenting Author:
Michael Anthony Carducci, The Johns Hopkins University School of
Medicine and Sidney Kimmel Comprehensive Cancer, Baltimore, MD
Background: Aurora kinases A, B, and, C play essential roles in regulating
cell division. Overexpression of aurora A and B in human tumors is
associated with high proliferation rates and poor prognosis. AMG 900 is an
investigational, orally administered, highly selective inhibitor of aurora A,
B, and C that demonstrated activity in drug-resistant cell lines and human
tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics
(PK), and pharmacodynamics of AMG 900. Methods: Key eligibility
criteria: � 18 years old, advanced solid tumors, measurable disease, ECOG
� 2, and adequate organ function. AMG 900 was administered orally daily
for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation
phase, the starting dose was 1 mg and was escalated by 100% in
subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade
2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation
continued in a standard 3�3 design at � 25% if DLT occurred or � 50% if
G2 related toxicity occurred. The maximum tolerated dose (MTD) was
determined without prophylactic G-CSF support. Results: As of OCT 2011,
19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30
mg) had received � 1 dose of AMG 900. Demographics were 58% women,
median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4
DLTs: G4 neutropenia � 7 days at 24 mg (n�1) and 30 mg (n�1); G4
neutropenia � 7 days � G4 thrombocytopenia at 30 mg (n�1); and febrile
neutropenia (FN) at 30 mg (n�1). MTD without G-CSF support was 24 mg.
89% of pts had treatment-related adverse events (AEs). G�3 treatmentrelated
AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2
(11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed
no obvious departures from dose-proportionality with a half-life of ~16 h.
Tumor-response data were available for 17 pts: stable disease, 13 pts
(range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort)
with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease
in CA-125 (SD � 6 months). Conclusions: AMG 900 administered at 24 mg
daily for 4D Q2W is the recommended dose for phase 2 trials. Dose
escalation is now ongoing to determine the MTD with prophylactic G-CSF.
3011 Poster Discussion Session (Board #3), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase I study of selective cyclin dependent kinase inhibitor P1446A-05
administered on an intermittent schedule in patients with advanced
refractory tumors. Presenting Author: Sudeep Gupta, Tata Memorial
Centre, Mumbai, India
Background: Cyclin-dependent kinases (Cdks) have emerged as important
targets in anticancer drug development. P1446A-05 is a potent and
specific inhibitor of Cdk4-D1 (IC50-0.09�M), Cdk1-B (IC50-0.025�M), and Cdk9-T (IC50-0.022�M). This study was designed to determine the
maximum tolerated dose (MTD), dose limiting toxicity (DLT), safety profile,
pharmacokinetics, and antitumor activity of orally administered P1446A-05
in patients with advanced refractory tumors. Methods: This study was
conducted at 5 centers in India. P1446A-05 was administered in escalating
doses across 5 cohorts of eligible pts starting with a dose of 75 mg once
a day (OD) for 14 days in a 21 day cycle utilizing a modified Fibonacci
scheme for dose escalation. 10 pts positive for cyclin D1 expression in the
tumor were enrolled at MTD. Treatment was continued until unacceptable
toxicity or disease progression. For pharmacokinetic analysis, blood samples
were collected on days 1 and 13/14 of cycle 1 at multiple time points. In
consenting pts, skin and tumor tissue biopsies were collected on days 1
(pre-dose), 8 and 15 of cycle 1. Results: A total of 29 patients were dosed.
Two DLTs (abdominal pain and acute renal failure) were reported at 850
mg/d. The MTD was 600 mg/d and diarrhea was reported as 1 DLT at this
dose level. Six SAEs including one death related to study drug were
reported. Pharmacokinetic analysis demonstrated a median half-life of 16
to 26 h and linear increase in exposure at steady state across tested doses.
Plasma concentration at 300 mg/d dose level crossed efficacy exposure of
100mg/kg of five day dosing in SCID mice. The recommended phase II dose
is 600 mg OD on this schedule. Stable disease for 4 to 6 cycles was
reported in 5 pts. Of them, one patient each with breast cancer, spindle cell
sarcoma in neck, and nasopharyngeal carcinoma had cyclin D1 over
expression. No objective responses were observed in this group of heavily
pretreated patients. Conclusions: The safety profile of P1446A-05 is
considered acceptable. On this dosing schedule, the MTD is determined as
600 mg/day. Further testing of P1446A-05 in phase II studies is planned.
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