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

3056 General Poster Session (Board #14F), Mon, 8:00 AM-12:00 PM
A phase I/II study to evaluate the ability of decitabine and panobinostat to
improve temozolomide chemosensitivity in metastatic melanoma. Presenting
Author: Chang Xia, Hematology, Oncology, and Blood & Marrow
Transplantation, UIHC, Iowa City, IA
Background: Epigenetic gene regulation is likely a contributing mechanism
of cancer initiation and progression. Emerging evidence indicates that
epigenetics may also play a key role in the development of chemoresistance
in melanoma. We proposed combining the histone deacetylase inhibitor
panobinostat (PT) and the demethylator decitabine (D) to overcome the
development of epigenetic mediated temozolomide (TMZ) resistance in
metastatic melanoma. Methods: Eligible patients must be �18, stage IV
melanoma, and naïve or previously treated, with good performance status
(ECOG � 2) and normal organ functions. Patients with previous exposure to
TMZ were allowed on study. The study includes the dose escalation of D
and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on
days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting
day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle.
TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia.
Primary endpoints of phase I study are to determine the toxicity, safety
and maximum tolerated dose (MTD) of the D, PT and TMZ combination.
Results: To date, the phase I portion of this trial is completed. We report on
the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median
age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least
one cycle (n�14). Median number of cycles given: 2 (0-6). To date, no
DLTs have occurred. The MTD was not reached. The only grade (G) 4
adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved
within 3 days. G3 AEs included lymphopenia (n�4, 23%), anemia (n�2,
12%), leukopenia (n�2, 12%) and fatigue (n�2, 12%). Common G2
toxicities were leukopenia (n�5, 30%), neutropenia (n�4, 23%), nausea
(n�4, 23%) and lymphopenia (n�3, 18%). Conclusions: The combination
of D, PT, and TMZ appears to be safe and well-tolerated. The recommended
dose for the phase II study remains to be determined.
3058 General Poster Session (Board #14H), Mon, 8:00 AM-12:00 PM
A phase I trial of the histone deacetylase inhibitor panobinostat (LBH589)
and epirubicin in patients with solid tumor malignancies. Presenting
Author: Amy Patricia Moore, UCSF, San Francisco, CA
Background: Preclinical and clinical data suggest pre-exposure of cancer
cells to a histone deacetylase inhibitor (HDACi) potentiates topoisomerase
inhibitors. HDACi-induced histone acetylation and chromatin modulation
facilitates DNA access and target recruitment for topo II inhibitors. In vitro
data further suggest effective inhibition of HDAC2 is necessary for
enhanced epirubicin-induced apoptosis. Methods: This phase I trial explores
the safety, tolerability, and maximum tolerated dose (MTD) of
escalating doses of panobinostat given orally on days 1, 3, and 5 followed
by epirubicin administered intravenously at 75 mg/m2 on day 5 in 21-day
cycles. Histone acetylation and HDAC2 expression are evaluated in preand
post-treatment peripheral blood mononuclear cells (PBMCs) in all
patients and in tumor cells of 16 patients treated at the MTD. Results: 36
patients have enrolled [10M/26F, median age 47 years (22-80)] in 5
panobinostat cohorts: 20, 30, 40, 50, 60 mg. Tumor types include
melanoma (n�6), breast (n�6), sarcoma (n�16), ovarian (n�2), lung
(n�2), and one each of neuroblastoma, pancreatic, testicular, and colon
cancer. Prior to enrollment, patients received a median of 3 (0-8) prior
chemotherapy regimens and 40% had anthracyclines. Dose-limiting toxicities
(DLTs) included 1/3 grade 3 fatigue and 1/3 grade 4 thrombocytopenia
at 60 mg of panobinostat, 1/6 patient experienced grade 3 atrial fibrillation
at 50 mg, defining 50 mg panobinostat as the MTD. Non-dose–limiting
grade 3/4 hematological toxicities include neutropenia (n�19, 53%),
febrile neutropenia (n�6, 17%), thrombocytopenia (n�6, 17%), and
anemia (n�4, 11%). Of 34 evaluable patients, 5 had partial responses and
14 had stable disease in anthracycline-refractory sarcomas (4) and
Her2neu positive breast cancer (2), and small cell lung cancer. Correlative
studies demonstrate increased H4 acetylation in PBMCs on day 3 and 5
suggesting sufficient histone deacetylase inhibition. Conclusions: Sequencespecific
combination of panobinostat and epirubicin shows early activity
without potentiating epirubicin toxicity. Dose expansion in anthracyclinepretreated
sarcoma patients is ongoing.
Developmental Therapeutics—Experimental Therapeutics
187s
3057 General Poster Session (Board #14G), Mon, 8:00 AM-12:00 PM
Testing targeted demethylation to overcome resistance to epidermal growth
factor receptor (EGFR) blocking agents in wild-type (wt) KRAS metastatic
colorectal cancer patients (mCRC). Presenting Author: Ignacio Garrido-
Laguna, Division of Oncology and Center for Investigational Therapeutics at
Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT
Background: Panitumumab, a monoclonal antibody against EGFR, led to
improved progression-free survival (PFS) in patients with (wt)KRAS mCRC.
However, the benefit of panitumumab is limited to a not yet identified small
subset of (wt)KRAS patients. The CpG island methylator phenotype
(CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing
through methylation of PTEN and/or genes in the EGFR pathway might play
a role in resistance to therapy. We assessed whether decitabine (a
hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods:
Patients (n�19) with (wt)KRAS mCRC previously treated with anti-EGFR
therapies were enrolled. Patients were treated with decitabine 45mg/kg IV
on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days.
Peripheral blood, skin biopsies and buccal smear samples were collected
on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A
and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA
mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as
well as for PTEN by immunohistochemistry. Results: Median age was 53
(range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG
PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of
previous therapies was 4. The most common toxicities were rash (68%),
hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most
common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia
(5%). Of 19 (wt)KRAS mCRC patients previously treated with
anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and
-30%, respectively) and 3 (16%) had stable disease (SD) �4 months (7.8,
5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN.
Clinical benefit rate (PR�SD) was 27%. Median PFS was 60 days (95% CI
45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95%
CI 50.6-71.3). Conclusions: Panitumumab � decitabine is an active
combination in a subset of patients with mCRC previously treated with
anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an
anti-EGFR therapy naïve population is warranted. Methylation studies are
ongoing.
3059 General Poster Session (Board #15A), Mon, 8:00 AM-12:00 PM
Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies
for treatment of patients with solid tumors. Presenting Author: Antonio
Calles, START-Madrid, Centro Integral Oncológico Clara Campal, Madrid,
Spain
Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies,
implicated in angiogenesis, proliferation and metastasis. CNTO888
is a hIgG1� mAb with selective high CCL2 binding affinity and showed
preclinical antitumor activity. Methods: Primary objectives were safety and
a recommended dose of CNTO 888 in combination with chemotherapy:
Arm1-15mg/kg CNTO 888 � docetaxel 75 mg/m2 Q3W; Arm 2-15
mg/kg CNTO 888 � gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 -
15 mg/kg CNTO 888 � paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W;
Arm4-10mg/kg CNTO 888 Q2W � pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced
disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and
chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were
evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were
evaluated after 6 subjects completed 1 cycle. Results: 53 subjects
(22F/31M) were treated: Arm 1 n�15, Arm 2 n�12, Arm 3 n�12, Arm 4
n�14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a
grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and
tolerable and continued enrolment to a minimum of 12 subjects evaluable
for safety and PK. Best overall response were partial response (PR) (1) and
stable disease (18; 2 � 4 months). One subject with pancreatic adenocarcinoma
achieved PR, allowing for surgical resection. Most frequently
reported (� 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis,
Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia,
Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia,
Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia,
Neutropenia. CNTO 888 did not affect the chemotherapy PK profile;
similarly, chemotherapy did not affect the CNTO 888 PK profile. No
subjects (n�38) tested positive for antibodies to CNTO 888. Free CCL2
declined 2 hrs post treatment and returned to baseline levels by 48 hrs and
continued to increase with further administrations in all treatment arms.
There were no consistent changes with other biomarkers. Conclusions:
CNTO 888 in combination with standard chemotherapy was well tolerated
but few objective responses were seen.
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