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

164s Developmental Therapeutics—Clinical Pharmacology and Immunotherapy
2589 General Poster Session (Board #7F), Mon, 8:00 AM-12:00 PM
Phase I/II study of resiquimod as an immunologic adjuvant for NY-ESO-1
protein vaccination in patients with melanoma. Presenting Author: Rachel
Lubong Sabado, New York University Cancer Institute, New York, NY
Background: The TLR 7/8 agonist, Resiquimod has been shown to induce
local activation of immune cells, production of cytokines, and antigenpresentation
by dendritic cells, features desirable for cancer vaccine
adjuvants. In this study, we evaluated the safety and immunogenicity of
vaccination with NY-ESO-1 protein emulsified in Montanide ISA-51 VG
when given with or without Resiquimod in patients with surgically resected
stage IIB-IV melanoma patients. Methods: This is a two-part study design.
Part I represents an open-label dose-escalation with Resiquimod using 2
cohorts treated with 100ug NY-ESO-1 protein emulsified in 1.25mL
Montanide (day1) followed by topical application of 1000mg of the 0.2%
Resiquimod gel on days 1 and 3 for cohort-1 (N�3) or days 1, 3, and 5 for
cohort-2 (N�3). The cycles were repeated every 3 weeks, total of 4 cycles.
Part II of the study is blinded. Patients were randomized to receive 100ug
NY-ESO-1 protein emulsified in 1.25mL Montanide (day1) followed by
topical application of placebo gel (Arm-A; N�8) or 1000mg of 0.2%
Resiquimod gel (Arm-B; N�12) using the dosing regimen established in
Part I. Blood samples were collected at baseline, one week after each cycle
of vaccination, and at follow-up visit for the assessment of NY-ESO-1specific
humoral and cellular immune responses. Results: Enrollment has
been completed. 25/26 patients received all 4 vaccinations. The treatment
was generally well-tolerated, with no grade 4 adverse events or studyrelated
deaths. The most common toxicities were mild to moderate and
included local injection site reactions (granuloma, pruritus, induration) and
systemic flu-like symptoms. One patient experienced a grade 3 syncopal
episode that was deemed unrelated to the drug. Another patient experienced
a grade 3 injection site necrosis that was possibly related to the study
drug and was removed from the study prior to receiving the 4th vaccine.
Conclusions: This study demonstrates the safety of Resiquimod as an
adjuvant for NY-ESO-1 protein vaccination. The study will remain blinded
until all immune monitoring assays have been completed. An updated
abstract will be submitted once the study is unblinded.
2591 General Poster Session (Board #7H), Mon, 8:00 AM-12:00 PM
Cellular function of the mononuclear phagocyte system (MPS) as a
phenotypic probe for pharmacokinetics (PK) and pharmacodynamics (PD)
of PEGylated liposomal doxorubicin (PLD) in patients with recurrent
ovarian cancer. Presenting Author: Whitney Paige Caron, University of
North Carolina at Chapel Hill, Chapel Hill, NC
Background: A phenotypic probe is a test that can be administered to a
patient as a potential indicator of a drug’s PK/PD which can then be used to
individualize therapy. Since nanoparticles are cleared via the MPS,
including blood monocytes (MO), we hypothesize that circulating MO could
potentially play a major role in, and be a surrogate marker of nanoparticle
clearance (CL). Furthermore, we postulate that the ability to measure MO
functional activity in blood samples can be used to predict CL and
subsequently PD endpoints such as progression free survival (PFS) and
hand-foot syndrome (HFS), in patients (pt). Methods: PLD 30/40 mg/m2 IV
x 1 with or without carboplatin (AUC � 5 mg/mL/min) was administered to
pts (n�10) with recurrent ovarian cancer. Serial PK samples were obtained
at time 0 to day 28 post dose. Plasma was processed to measure
encapsulated and released doxorubicin using solid phase separation and
HPLC. Data was analyzed with WinNonlin to obtain PK parameters. MO and
granulocyte phagocytic function (uptake of FITC-labeled opsonized E. Coli)
and oxidative burst activity (intracellular oxidation of dihydrorhodamine
123) were assessed via flow cytometry at 0, 48, 96 h, and on day 28. For
both assays, changes in mean fluorescence intensity of the gated MO
population, following incubation of whole blood with the appropriate
substrate, served as an index of activity. Pts were followed from the first
dose of PLD until time of disease progression. Results: There was a direct
linear relationship between encapsulated doxorubicin CL and both phagocytosis
(R2 � 0.87) and oxidative burst activity (R2 � 0.64) in blood MO.
Similarly, phagocytosis (R2 � 0.77) and oxidative burst probes correlated
with PFS (R2 � 0.67) in the 4 pts who progressed while on PLD. Oxidative
burst also correlated with degree of HFS (R2 � 0.56). There was no
relationship between phagocytosis and oxidative burst in granulocytes and
PK/PD of PLD. Conclusions: These findings indicate that probes of MPS
function predict PLD CL, HFS and PFS and thus may be useful for
individualizing PLD therapy in ovarian cancer and other malignancies.
2590 General Poster Session (Board #7G), Mon, 8:00 AM-12:00 PM
A phase I study of lapatinib (LPT) and cetuximab (CTX) in patients with
CTX-sensitive solid tumors. Presenting Author: John F. Deeken, Lombardi
Comprehensive Cancer Center, Georgetown University, Washington, DC
Background: Preclinical research has shown that one mechanism of
acquired resistance to CTX is via EGFR-ErbB2 heterodimerization, which
can reactivate oncogenic pathways. LPT is a dual EGFR and ErbB2
intracellular tyrosine kinase inhibitor. A phase I translational clinical study
was performed to determine the maximum tolerated dose (MTD), dose
limiting toxicities (DLTs), and clinical activity of CTX and LPT in patients
with EGFR-driven solid tumor malignancies that can be treated with CTX.
Methods: Patients (Pts) were enrolled in a 3�3 dose escalation trial. Prior
CTX therapy was allowed. CTX was given at 400mg/m2 on Cycle 1, Day 1
(C1D1), then 250 mg/m2 weekly. LPT dose levels (DL) were (1) 750mg, (2)
1000mg, and (3) 1250mg orally daily. Rash management included daily
sunblock, steroid cream, and doxycycline. Cycle length was 21 days, and
patients were assessed for toxicity through the end of C2, and for efficacy
after every 2 cycles. Fresh tumor biopsies were obtained at baseline and at
the end of C1 to compare EGFR and ErbB2 expression levels and EGFR
related pathway activation. DNA from blood samples was analyzed for
pharmacogenetic (PGx) variations and correlations with toxicity and pharmacokinetics
(PK). Results: Between October, 2010 to January 2012, 13
pts were enrolled, with colon (4), lung (3), head and neck (3), and anal
cancers (3); 10 were evaluable for toxicity. Treatment-related toxicities of
any grade included: rash (67%), diarrhea (42%), fatigue (33%), nausea/
vomiting (17%), and dehydration (8%). DLTs included G3 rash in 1 of 6 pts
on DL1, and G3 diarrhea despite optimal therapy in 1 of 4 pts on DL2.
Enrollment to DL2 continues. Of 7 pts evaluable for response, 1 had an
uPR, 3 had SD, including 1 with SD of �4 cycles, and 3 had DP. Both
patients with uPR and prolonged SD were treated on DL1. Tumor
EGFR-ErbB2 and EGFR pathway phosphorylation analyses and PGx results
will be presented. Conclusions: The combination of CTX and LPT is well
tolerated with expected toxicities. Efficacy was seen even on DL 1. Phase II
clinical studies in CTX-sensitive diseases such as colon and head and neck
cancer are planned.
2592 General Poster Session (Board #8A), Mon, 8:00 AM-12:00 PM
Phase I study of docetaxel injection concentrate for nano-dispersion
(DICN), a novel polysorbate 80-free formulation of docetaxel. Presenting
Author: Minish Mahendra Jain, KEM Hospital and Research Center, Pune,
India
Background: A polysorbate 80-free formulation of docetaxel may preclude
the need for dexamethasone pre-medication and may also reduce toxic
effects associated with polysorbate 80. DICN is a novel polysorbate 80-free
formulation of docetaxel stabilized with lipid and polymer using NanotectonTM
technology. We studied safety, tolerability, and the pharmacokinetics
(PK) of DICN in patients with advanced solid malignancies. Methods: Entry
criteria included: age 18-65 years, histologically/cytologically confirmed
advanced malignancy, performance status � ECOG 2, estimated survival �
12 weeks, and adequate organ function. A standard phase I 3�3 dose
escalation schema was employed with an increase of 12.5 to 50% over
previous DICN dose level as per safety profile. The infusion was 60 min for
1 cycle and major objectives were to determine maximum tolerated dose
(MTD), and PK and safety profiles. Premedication to prevent hypersensitivity
was not administered to patients receiving DICN. Three patients were
treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed
for docetaxel level using a validated assay. Results: Twenty-seven patients
treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were
females; and entered with metastatic breast cancer (MBC; n�14), nonsmall
cell lung carcinoma (NSCLC; n�6), ovarian (n�2), and other (n�5).
Doses (mg/m2 ) studied were 60 (n�7), 75 (n�5), 100 (n�3), 125 (n�3),
150 (n�6), and 170 (n�3). Despite lack of dexamethasone premedication,
no patient receiving DICN reported a hypersensitivity reaction. Two
DLTs (febrile neutropenia) were reported at DICN 170 mg/m2 . DICN PK
(AUC AUC 0-24, 0-�, and Cmax) increased in a dose proportionate manner from
60 to 170 mg/m2 . Compared with docetaxel 75 mg/m2 ,Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and
1.8 times higher, respectively for DICN 150 mg/m2 . The median Tmax of
DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours,
respectively. Conclusions: In this study,DICN demonstrated acceptable
tolerability and a favorable PK profile. A 150 mg/m2 is the recommended
phase II dose for DICN.
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