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

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TPS3637 General Poster Session (Board #39B), Mon, 8:00 AM-12:00 PM<br />

The GAIN-C study (BP25438): Randomized phase II trial <strong>of</strong> RG7160<br />

(GA201) plus FOLFIRI, compared to cetuximab plus FOLFIRI or FOLFIRI<br />

alone in second-line KRAS wild type (WT) or mutant metastatic colorectal<br />

cancer (mCRC). Presenting Author: Andres Cervantes-Ruiperez, Department<br />

<strong>of</strong> Hematology and Medical Oncology, INCLIVA, University <strong>of</strong> Valencia,<br />

Valencia, Spain<br />

Background: GA201 is a novel, dual-acting, humanized, glycoengineered<br />

IgG1 anti-EGFR monoclonal antibody, with enhanced antibody-dependent<br />

cellular cytotoxicity (ADCC) activity in combination with signal inhibition.<br />

GA201 demonstrates significantly enhanced in vitro/vivo activity compared<br />

to cetuximab (cet) both as a single agent and in combination with<br />

irinotecan, in both KRAS mutant and BRAF mutant models and promising<br />

clinical activity in ph I and neo-adjuvant trials (Paz Ares et al, JCO 2011)<br />

including KRAS mutant mCRC. A randomized ph II program was launched:<br />

one study in NSCLC and GAIN-C in mCRC (NCT01326000), which is<br />

presented here. Methods: Main inclusion criteria are progression on 1L<br />

containing oxaliplatin, ECOG 0-1, and adequate hematological and liver<br />

function. Main exclusion criteria: prior anti-EGFR treatment. A total <strong>of</strong> 160<br />

patients in 2L mCRC (stratified for EGFR expression, disease progression<br />

before or after 6 months after starting 1L, prior treatment with bevacizumab<br />

Y vs N) will be randomized to receive either GA201 (day 1, 8 <strong>of</strong> cycle<br />

1 then q2W) or cet (qW) � FOLFIRI q2W (KRAS WT) or to receive GA201�<br />

FOLFIRI or FOLFIRI alone (KRAS mutant). Collection <strong>of</strong> archival tumor<br />

plus a mandatory fresh tumor biopsy at baseline were implemented<br />

because ph I data showed that EGFR expression is not concordant between<br />

the two specimen types and to optimize assessment <strong>of</strong> potential immune<br />

related biomarkers. The fresh tumor biopsy will be centrally analyzed for<br />

EGFR (immunohistochemistry) and KRAS status. Primary objective is<br />

progression free survival; secondary endpoints are to define objective<br />

response rates, the safety pr<strong>of</strong>ile, pharmacokinetics and pharmacodynamics.<br />

A comprehensive biomarker program (blood and tumor), mainly<br />

immune-phenotyping, immunohistochemistry in tumor samples (Ventana)<br />

and immune functional tests (including adaptive responses) were set up to<br />

investigate potential predictive biomarkers and the mode <strong>of</strong> action <strong>of</strong><br />

GA201. Study is ongoing worldwide in 9 countries with the safety run-in<br />

phase completed in Nov 2011. Recruitment is planned to be completed by<br />

end <strong>of</strong> April 2012.<br />

TPS3639 General Poster Session (Board #39D), Mon, 8:00 AM-12:00 PM<br />

Sequential first-line treatment for metastatic colorectal cancer with capecitabine,<br />

irinotecan, and bevacizumab: Capecitabine plus bevacizumab<br />

(Cape-Bev) versus capecitabine, irinotecan plus bevacizumab (CAPIRI-<br />

Bev): The AIO KRK 0110/ML22011 randomized, phase III trial. Presenting<br />

Author: Clemens Albrecht Giessen, Department <strong>of</strong> Hematology and Oncology,<br />

Klinikum Grosshadern and Comprehensive Cancer Center, LMU<br />

Munich, Munich, Germany<br />

Background: Several randomized trials have indicated that combination<br />

chemotherapy applied in metastatic colorectal cancer (mCRC) does not<br />

significantly improve overall survival when compared to the sequential use<br />

<strong>of</strong> cytotoxic agents (CAIRO, MRC Focus, FFCD 2000-05). The present<br />

study investigates the question in bevacizumab-based first-line treatment<br />

including escalation- and de-escalation strategies. Methods: The AIO KRK<br />

0110/ML22011 trial (<strong>Clinical</strong>Trials.gov NCT01249638) is a two-arm,<br />

multicenter, open-label randomized phase III trial comparing the efficacy<br />

and safety <strong>of</strong> Cape-Bev versus CAPIRI-Bev in the first-line treatment <strong>of</strong><br />

metastatic colorectal cancer. Patients with unresectable metastatic colorectal<br />

cancer, ECOG PS 0-1, will be assigned in a 1:1 ratio to receive either<br />

capecitabine 1250 mg/m2 bid for 14d (d1-14) plus bevacizumab 7.5<br />

mg/kg (d1) q3w (Arm A) or capecitabine 800 mg/m2 BID for 14d (d1-14),<br />

irinotecan 200 mg/m2 (d1) and bevacizumab 7.5 mg/kg (d1) q3w (Arm B).<br />

Patients included into this trial are required to consent to the analysis <strong>of</strong><br />

tumor tissue and blood for translational investigations. In Arm A, treatment<br />

escalation from Cape-Bev to CAPIRI-Bev is recommended in case <strong>of</strong><br />

progressive disease (PD). In Arm B, de-escalation from CAPIRI-Bev to<br />

Cape-Bev is possible after 6 months <strong>of</strong> treatment or in case <strong>of</strong> irinotecanassociated<br />

toxicity. Re-escalation to CAPIRI-Bev after PD is possible. The<br />

primary endpoint is time to failure <strong>of</strong> strategy (TFS). Secondary endpoints<br />

are ORR, OS, PFS, safety and quality <strong>of</strong> life. Conclusion: The AIO KRK<br />

0110 trial is designed for patients with disseminated, but asymptomatic<br />

mCRC who are not potential candidates for surgical resection <strong>of</strong> metastasis.<br />

Two bevacizumab-based strategies are compared: one starting as singleagent<br />

chemotherapy (Cape-Bev) allowing escalation to CAPIRI-Bev and<br />

another starting with CAPIRI-Bev and allowing de-escalation to Cape-Bev<br />

and subsequent re-escalation if necessary. By January 2012, 79 <strong>of</strong><br />

planned 516 patients have been enrolled.<br />

Gastrointestinal (Colorectal) Cancer<br />

237s<br />

TPS3638 General Poster Session (Board #39C), Mon, 8:00 AM-12:00 PM<br />

A pilot trial <strong>of</strong> a combination <strong>of</strong> therapeutic vaccines (GI-4000 and<br />

GI-6207) as adjunctive therapy with first-line therapy with bevacizumab<br />

plus either FOLFOX or FOLFIRI in stage IV patients with newly diagnosed<br />

Ras-mutant positive or negative metastatic colorectal cancer. Presenting<br />

Author: John Marshall, Lombardi Comprehensive Cancer Center, Georgetown<br />

University, Washington, DC<br />

Background: A promising approach for the treatment <strong>of</strong> cancer is the<br />

development <strong>of</strong> vaccines that target specific tumor antigens. In the<br />

metastatic CRC patient population, targeted and active immunotherapy<br />

may inhibit cancer progression and improve survival. This trial is designed<br />

to evaluate the efficacy, immunogenicity, and safety <strong>of</strong> GI-4000 plus<br />

standard therapy in patients with metastatic colorectal cancer. GI-4000 is<br />

a proprietary immunotherapy that uses whole, heat-killed recombinant<br />

Saccharomyces cerevisiae yeast (called Tarmogens � Targeted Molecular<br />

Immunogens). GI-4000 is designed to activate a cellular immune response<br />

to target cells with activating ras mutations. Tarmogens have been shown to<br />

elicit selective killing <strong>of</strong> target cells that express a number <strong>of</strong> cancer<br />

antigens, including mutated Ras, by activation <strong>of</strong> antigenspecific T cell<br />

mediated responses. Methods: The study population consists <strong>of</strong> subjects<br />

with metastatic colorectal cancer with an activating mutation in ras. Newly<br />

diagnosed subjects receive FOLFOX (or FOLFIRI) � bevacizumab (Bev) �<br />

GI- 4000; 3 weekly injections <strong>of</strong> GI-4000 are followed by 8 cycles <strong>of</strong> Bev �<br />

FOLFOX (or FOLFIRI); day 1 and 2 every 14 days. Doses <strong>of</strong> GI-4000 are<br />

administered on day 8 <strong>of</strong> each cycle. Upon completion <strong>of</strong> chemotherapy,<br />

GI-4000 continues along with Bev maintenance every 2 weeks for up to 5<br />

years or until subjects experience intolerance, disease recurrence, or death.<br />

If Bev is stopped, GI-4000 may continue on the same maintenance<br />

schedule alone. Subjects that have already completed standard chemotherapy<br />

(FOLFOX or FOLFIRI) may enter the study and receive Bev �<br />

GI-4000 every 2 weeks for up to 5 years. Enrollment is ongoing and will<br />

continue up to 52 subjects.<br />

TPS3640 General Poster Session (Board #39E), Mon, 8:00 AM-12:00 PM<br />

A randomized, phase II, multicenter, double-blind, placebo-controlled<br />

study evaluating onartuzumab (MetMAb) in combination with mFOLFOX6<br />

plus bevacizumab in patients with metastatic colorectal cancer. Presenting<br />

Author: Johanna C. Bendell, Sarah Cannon Research Institute, Nashville,<br />

TN<br />

Background: Dysregulation <strong>of</strong> the HGF/Met (Met) pathway has been linked<br />

with poor prognosis in colorectal cancer. Crosstalk between the Met and<br />

vascular endothelial growth factor (VEGF) pathways may be important<br />

during tumorigenesis. Aberrant activation <strong>of</strong> the HGF/Met pathway may<br />

promote angiogenesis via tumor cell secretion <strong>of</strong> angiogenic factors or<br />

directly activating endothelial cells. Onartuzumab (MetMAb) is a monovalent,<br />

monoclonal antibody that specifically binds to the Met receptor. The<br />

combination <strong>of</strong> onartuzumab and VEGF inhibition in preclinical models<br />

resulted in enhanced antitumor activity over either treatment alone.<br />

Preclinical efficacy data support the combination <strong>of</strong> onartuzumab with<br />

platinum agents. In phase I studies, onartuzumab has been generally well<br />

tolerated alone and in combination with bevacizumab. Adverse events most<br />

commonly associated with onartuzumab are peripheral edema and fatigue.<br />

Methods: This is a randomized, two-arm, phase II study in patients with<br />

previously untreated metastatic colorectal cancer. Patients (n�188) will<br />

be randomized (1:1) to either mFOLFOX6/bevacizumab/placebo or mFOL-<br />

FOX6/bevacizumab/onartuzumab. Oxaliplatin will be discontinued after 8<br />

cycles with remaining drugs continued until progression. The primary<br />

endpoint <strong>of</strong> this study is PFS in all patients. PFS by Met IHC diagnostic<br />

status (Met positive vs Met negative) will also be analyzed. Secondary<br />

endpoints include OS, ORR, safety, and biomarker analyses. Primary and<br />

secondary analyses will include all randomized patients and will be<br />

conducted according to assigned treatment arm. Kaplan–Meier methodology<br />

will be used to estimate median PFS for each treatment arm. An<br />

estimate <strong>of</strong> HR with 95% CI will be determined using a Cox regression<br />

model. Safety will be assessed in all patients receiving at least one dose <strong>of</strong><br />

any treatment. This study is open for accrual; further details can be found<br />

on <strong>Clinical</strong>Trials.gov (NCT01418222).<br />

Visit abstract.asco.org and search by abstract for the full list <strong>of</strong> abstract authors and their disclosure information.

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