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

176s Developmental Therapeutics—Experimental Therapeutics
3012 Poster Discussion Session (Board #4), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in
patients with advanced solid tumors: Dose escalation with an intermittent 3
days on/4 days off schedule. Presenting Author: Rastislav Bahleda, Institut
Gustave Roussy, Villejuif, France
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
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 in a 3
days on / 4 days off schedule (cycle length 21 days, 3�3 design). PK was
evaluated on cycle 1 day 1 and day 10. Response rate was assessed
according to RECIST 1.1. PD markers included CK18 fragments in plasma.
Results: As of Jan 08 2011, 34 pts were treated at doses of 0.6 (3 pts), 1.2
(4), 2.4 (3), 4.8 (3), 9.6 (3), 19.2 (6) mg per day as oral solution and at
doses of 10 (4), 15 (6) and 20 (2) mg per day as tablet. Tumor types
included 10 colorectal, 4 mesothelioma and 20 others. Cohort 9 (20 mg
tablet) is ongoing. Frequent CTCAEv4 grade 1/2 drug related AEs occurring
in more than 25% of patients up to cohort 8 were asthenia, diarrhea,
nausea, vomiting and anorexia. DLTs (grade 3, 1 pt each) were hyponatremia,
aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15
mg tablet. Aphthous stomatitis (20%) has not been observed with the
tablet formulation. Other grade 3 related AEs were asthenia in 2 and
nausea and vomiting in one pt each. Nausea and vomiting on treatment
days were observed despite antiemetic treatment (aprepitant �/- setron).
PK was dose proportional up to 9.6 mg, T1/2 was 10 hours, and relative
bioavailability of tablet formulation was excellent; major metabolite levels
were low (�10%). Levels of CK18 fragments did not correlate with dose or
tumor response. Stable disease (SD) lasting for 2-4 months was observed in
9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts.
One additional pt with cholangiocarcinoma has ongoing SD lasting for 5
months. One of the ovarian pts had a significant decline of CA125 lasting
for 3 months. Conclusions: The tablet formulation of BAY 1000394 was
better tolerated than oral solution. So far, doses up to a 15 mg per day with
concomitant antiemetic treatment showed an acceptable tolerability. SD
was observed in 10 of 25 heavily pretreated pts across cohorts3–8.
3014 Poster Discussion Session (Board #6), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Molecular profiling of patients (pts) with colorectal cancer (CRC) and
matched targeted therapy (MTA) in phase I clinical trials. Presenting
Author: Rodrigo Dienstmann, Molecular Therapeutics Research Unit, Vall
d’Hebron University Hospital, Barcelona, Spain
Background: Molecular prescreening and biomarker enrichment strategies
in Phase 1 trials with targeted therapies are anticipated to improve the
outcomes of affected pts. Methods: As part of our personalized oncology
program, tumors from pts with advanced chemorefractory CRC were
analyzed for specific molecular aberrations (KRAS/ BRAF/ PIK3CA mutations
[mut], PTEN and pMET expression) at the Vall d’Hebron Molecular
Pathology and Genomics Labs. Those whose tumors were found to have a
dysregulation were offered a Phase 1 trial with MTA. Results: During 2010
and 2011, tumor molecular analysis was performed in 254 pts: KRAS mut
(80/254, 31.5%), BRAF mut (24/196, 12.2%), PIK3CA mut (15/114,
13.2%), KRAS�PIK3CA mut (9/114, 7.9%), PTEN low (97/183, 53.0% -
HSCORE�50; 45/183, 24.6% - PTEN null), KRAS mut � PTEN low
(38/138, 20.8%), pMET high (38/64, 59.4% with HSCORE�30). In total,
68 pts (median, age 63 yrs; prior therapies 3), received 82 different
matched therapies. Type of MTA: PI3K pathway inh (if PIK3CA mut, n�10;
or PTEN low, n�32), MEK�PI3K pathway inh (if KRAS mut, n�10; or
BRAF mut, n�1), second-generation anti-EGFR mAbs (if KRAS wild-type,
n�11), anti-HGF mAb (if pMET high, n�10), mTOR inh � anti-IGFR-1R
mAb (if PTEN low, n�5) and BRAF inh (if BRAF mut, n�3). Median time to
treatment failure (TTF) with MTA was 7.9 weeks (CI95%:7.6-8.1) vs. 16.3
weeks (CI95%:13.9-18.7) for their prior systemic antitumor therapy
(p�0.001). If prior therapy non-standard (according to NCCN guidelines,
n�39), TTF with MTA 7.9 weeks (CI95%:6.8-8.9) vs. TTF with prior
therapy 8.7 weeks (CI95%:7.3-10.1). If an approved standard regimen
(n�43), TTF with MTA 7.9 weeks (CI95%:7.6-8.1) vs. TTF with prior
therapy 21.9 weeks (CI95%:15.0-28.7). Partial response was seen in one
pt (1.2%, PI3K inh with PIK3CA mut) and stable disease � 16 weeks in 10
cases (12.2%). Clinical benefit, defined as a TTF ratio � 1.3 (TTF on MTA/
TTF on prior therapy), was seen with 15.9% of the therapies (13/82).
Conclusions: Preliminary results suggest that matching chemorefractory
CRC patients with targeted agents in early clinical trials based on the
current molecular profile does not result in longer TTF compared to their
prior therapy.
3013 Poster Discussion Session (Board #5), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase I and pharmacokinetic (PK) study of continuous daily administration
of P1446A-05, a potent and specific oral Cdk4 inhibitor. Presenting
Author: Desiree Hao, Tom Baker Cancer Centre, Calgary, AB, Canada
Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and
Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo.
Pharmacodynamic studies demonstrate that activation of Cdk1 reappears
within 48 hours after P1446A-05 is withdrawn, suggesting the need for
prolonged administration hence, we sought to evaluate the feasibility, safety
and tolerability of a continuous daily schedule of P1446A-05 in patients (pts)
with advanced malignancies. Methods: P1446A-05 was given at escalating
doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at
multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single
time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts
(median age�63 years, 51% male, 51% ECOG PS�1) collectively received
more than 100 cycles of P1446A-05. The majority of drug-related toxicities
were �Grade 2, the most common of which were diarrhea (n�54), nausea/
vomiting (n�27/17), fatigue (n�22) and anorexia (n�16). Two pts developed
study-drug related diarrhea with hypokalemia/elevated creatinine and died
during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to
subsequent de-escalation and expansion of the 350mg cohort. A total of 24
pts were treated at 350mg; only one patient experienced dose-limiting
diarrhea. PK data are summarized below. Accumulation ratios across dose
levels suggest moderate accumulation with continuous dosing. Nine pts
achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft
tissue sarcoma, whose disease was progressing at enrollment, remains on
treatment with SD after 11 cycles. Conclusions: The recommend phase II dose
of P1446A-05 is 350mg. Further phase II studies at this dose will be
conducted with potential enrichment strategies.
DLTs and PK data.
Dose
level
(mg)
No. of
pts in
cohort
No. of
pts with
DLT
DLT event
description
Tmax (h) Cmax (ng/mL) AUC0-inf (ng.h/mL)
Accumulation
Day 1 Day 15 Day 1 Day 15 Day 1 Day 15 ratio
75 3 0 4 2 107 195 3,033 24,893 2.22
150 3 0 6 6 255 748 14,753 164,073 3.45
250 3 0 4 4 446 1,027 15,208 54,503 3.07
350 3�9�12 1 Diarrhea 4 4 512 992 16,700 38,099 2.30
500 6 3 Elevated INR
Sudden death
Diarrhea
6 2 1,040 2,239 38,125 76,779 2.43
3015 Poster Discussion Session (Board #7), Sat, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Phase I study of BPM 31510 in advanced solid tumors: Updated analysis of
a novel treatment with promising activity. Presenting Author: Andrew
Eugene Hendifar, Sarcoma Oncology Center, Santa Monica, CA
Background: BPM 31510 is a novel small molecule that targets the
metabolic machinery of the cancer microenvironment to reverse the aerobic
glycolytic phenotype of cancer cells. Effector downstream signaling results
in re-capitulation of BCL-2 mediated apoptosis and disruption in tumor
vasculature by modulation of VEGF. (NR Narain et al., Proceedings of AACR
Meeting Abstracts 2011). Methods: A standard 3�3 phase I, doseescalation
study design was used in patients with advanced solid tumors
refractory to standard treatment. Primary objectives were establishment of
the maximum tolerated dose (MTD) and safety/pharmacokinetic (PK)
correlates. Secondary objectives included exploratory pharmacodynamics
(PD) and preliminary efficacy (RECIST-1.1) of BPM 31510 in sequential
cohorts of 3 to 6 pts. Results: At time of submission, 34 patients with
advanced cancer who had failed multiple chemotherapeutic regimens had
been enrolled in 7 dose cohorts (ranging from 5.6 mg/kg to 78.2 mg/kg).
Patients received a median of 2 cycles (1-7). 2 patients have had grade 3
elevation in PT/INR, otherwise there have been no grade 3/4 treatment
related toxicities to date. The pharmacokinetics of BPM 31510 are linear
and there were no sex differences in the parameters normalized by dose and
body surface area. Tmax and Cmax are associated with the end of the
infusion. The values for t1/2 ranged from 2.18 to 13.3 hr, with little or no
dependence of t1/2 on dose. Objective tumor responses have been noted at
the dose of 58.6mg/kg with 1 partial response (myxoid liposarcoma) and 1
minor response (pleomorphic sarcoma). Six patients (19%) have had
disease stabilization (� 4 months). Conclusions: Interim data from this
phase I study indicate that BPM 31510 is well tolerated with no dose
limiting toxicities to date. A partial response and minor response were
observed and correlates with dose escalation. Taken together, there is
strong rationale for further clinical development of this compound as an
anti-cancer agent.
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