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  1. TPS3634 • A Randomized, Double-Blind, Multicenter Phase III Study of Irinotecan, Folinic Acid, and 5-Fluorouracil (FOLFIRI) Plus Ramucirumab or Placebo in Patients With Metastatic Colorectal Carcinoma Progressive During or Following First-line Combination Therapy With Bevacizumab, Oxaliplatin, and a Fluoropyrimidine • Axel Grothey,1Josep Tabernero,2 Philippe Rougier,3Shaila Ballal,4 Heidi Crane,5 Federico Nasroulah,4 Mark D. Rutstein4 • 1Mayo Clinic College of Medicine, Rochester, MN, USA; 2Vall d'Hebron University Hospital, Valld'Hebron Institute of Oncology, Barcelona, Spain; 3CHU Européen Georges Pompidou, University of Versailles Saint Quentin, APHP University Hospital AmbroiseParé, Paris, France; 4ImClone Systems, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ, USA; 5Eli Lilly and Company, Indianapolis, IN, USA Figure 3. VEGFR-2 Expression In Metastatic Colon Cancer Preliminary Results: Phase II mCRCClinical Trial Figure 6. Phase III Study Schema Key Inclusion Criteria (continued) ABSTRACT (UPDATED) • KDR (VEGFR-2) expression has been reported to be higher in metastatic colon cancer than in nonmetastatic neoplasms.5 • Correlation of KDR (VEGFR-2) expression with the extent of neovascularization and the degree of tumor cell proliferation is also reported.5 • The patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. • The patient has adequate hematologic, coagulation, hepatic, and renal function. • The patient, either male or female, agrees to use a reliable method of birth control during the study period and for 12 weeks after the last dose of study treatment. • Women of child-bearing potential must test negative for pregnancy at the time of enrollment based on serum pregnancy test within 7 days prior to randomization. • A Phase II, open-label study evaluating the safety and efficacy of RAM combined with mFOLFOX‑6 as first‑line therapy in patients with mCRC was reported.11 • An increase in progression-free survival (PFS) from 8 m to 11 m was reported11 in patients with mCRC when treated with the anti-VEGFR-2 monoclonal antibody RAM (IMC-1121B) in combination with mFOLFOX-6 chemotherapy. • The observed objective response rate (58%), disease control rate (94%), and median PFS (11.5 m) suggested that RAM enhances the efficacy of mFOLFOX-6 in treatment of mCRC. • The most frequent AEs of any grade (reported in ≥10% of pts) considered to be at least possibly related to RAM included: asthenia and hypertension (each in 22 of 48 pts [46%]); diarrhea (15 of 48 pts [31%]); nausea and infusion-related reactions (each in 9 of 48 pts [19%]); epistaxis and peripheral edema (each in 8 of 48 pts [17%]); proteinuria(6 of 48 pts [13%]); and thrombocytopenia, vomiting, mucosal inflammation (each in 5 of 48 pts [10%]) • The most frequently reported RAM-related Grade 3 AE (reported in ≥10% of patients) was hypertension (7 of 48 patients [15%]) • The Grade ≥4 RAM-related AEs (in any patient) included: coagulopathy; acute myocardial infarction; cardiorespiratory arrest; increased gamma-glutamyltransferase; nephrotic syndrome; and pulmonary embolism (each event occurred once). • Background: Vascular endothelial growth factor (VEGF) and the VEGF receptor-2 (VEGFR-2) regulate angiogenesis and are overexpressed in colorectal cancer. Ramucirumab (RAM) is a fully human Immunoglobulin G1 monoclonal antibody that inhibits binding of VEGF ligands to VEGFR-2 and inhibits VEGFR-2 activation and signaling. In a preclinical study, antiangiogenic and antitumor effects were observed when DC101, an antibody that targets murine VEGFR-2, was administered to mice bearing human colon cancer xenografts. Antitumor activity for RAM has been demonstrated in a Ph I study in pts with solid tumors over a wide range of RAM dose levels and in a Ph II study with RAM + mFOLFOX-6 (regimen of oxaliplatin, folinic acid, and 5-fluorouracil) as 1st-line therapy in pts with metastatic colorectal cancer (mCRC). • Methods: This ongoing, randomized, double-blind, placebo-controlled Ph III study includes mCRC pts with measurable or nonmeasurable disease and Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 who have experienced disease progression during or within 6 months following 1st-line therapy with bevacizumab (BEV), oxaliplatin (OXALI), and any fluoropyrimidine. Randomization is stratified by geographic region, Kirsten Rasoncogene homolog (KRAS) status, and time to progression after initiation of 1st-line therapy. Pts are randomized 1:1 to either RAM 8 mg/kg or placebo every 14 days. Pts in both arms receive FOLFIRI (irinotecan: 180 mg/m2, folinic acid: 400 mg/m2, 5-fluorouracil: 400 mg/m2 bolus followed by 2400 mg/m2 continuousinfusion over 46-48 hours). The primary endpoint is overall survival (OS). The sample-size estimate assumes 85% power to detect at least a 2.5-month median OS difference (Hazard Ratio = 0.8) between treatment arms with a 1-sided alpha of 0.025. Secondary endpoints include progression-free survival, tumor response, safety, pharmacokinetics, immunogenicity, and correlations between biomarkers and clinical outcome. CRC tissue and blood collection is mandatory for biomarker analyses. As of 7-May-2012, a total of 419 patients were enrolled from 217 sites in North America, South America, Europe, Asia and Australia. Key Exclusion Criteria • The patient has received bevacizumab within 28 days prior to randomization. • The patient has received chemotherapy within 21 days prior to randomization. • The patient has received wide-field (full-dose pelvic) radiotherapy within 28 days prior to randomization. • The patient has received any investigational therapy within 28 days prior to randomization. • The patient has received any previous systemic therapy, other than a combination of bevacizumab, oxaliplatin, and a fluoropyrimidine, for first-line treatment of metastatic CRC. • The patient has a history of uncontrolled hereditary or acquired bleeding or thrombotic disorders. • The patient has an uncontrolled intercurrent illness, including, but not limited to, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, symptomatic or poorly controlled cardiac arrhythmia, psychiatric illness/social situations, or any other serious uncontrolled medical disorders in the opinion of the investigator. • The patient has experienced any arterial thrombotic or arterial thromboembolic events, including, but not limited to myocardial infarction, transient ischemic attack, or cerebrovascular accident, within 12 months prior to randomization. • The patient has known leptomeningeal disease or brain metastasis or uncontrolled spinal cord compression. • The patient has an ongoing or active infection requiring parenteral antibiotic, antifungal, or antiviral therapy. • The patient has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. • The patient has received a prior autologous or allogeneic organ or transplantation. • The patient has undergone major surgery within 28 days prior to randomization, or subcutaneous venous access device placement within 7 days prior to randomization. Adapted from Takahashi et al., Cancer Res, 1995 Figure 4. VEGFR-2: A Target in Metastatic Colon Cancer • Futility Analysis of PFS (122 events; ~ 250 patients) • Futility Analysis of OS (227 events; ~ 627 patients) • Final Analysis of OS (756 events; ~1050 patients) Colon carcinoma liver metastasis studies6 using immunohistochemical and immunofluorescent staining in nude mice treated with phosphate-buffered saline (PBS) or DC101 (neutralizing antibody against the mouse VEGFR-2) showed: RAM = ramucirumab; FOLFIRI = irinotecan, folinic acid, and 5-fluorouracil; Q = every; N = number of patients; OS = overall survival; PFS = progression-free survival Study Duration Study Rationale • In this randomized, double-blind, placebo-controlled Phase III study, a treatment cycle is defined as a period of 2 weeks. • Treatment will continue until disease progression, the development of unacceptable toxicity, noncompliance or withdrawal of consent by the patient, or investigator decision.  It is estimated that the required number of OS events will be observed after approximately 40 months from the time the first patient is randomized; this includes approximately 30 months for patient accrual. • Patients who are off study treatment and in survival follow-up (long-term follow-up) after the required number of OS events has been observed, may continue to be followed for survival for up to 24 months from randomization. TUNEL • Bevacizumab, a recombinant humanized mAb that selectively inhibits VEGF-A, is known to be highly effective in the treatment of metastatic CRC. This approved agent provides proof-of-concept for the use of RAM in metastatic CRC, which also shows a similar mechanism of action. • Since RAM blocks the binding of several VEGF ligands (VEGF-A, VEGF-C, and possibly VEGF-D) to VEGFR-2, its use may be efficacious in the case of patients who have previously had disease progression on a first-line regimen containing bevacizumab. • Recent data suggest that the clinical benefit of bevacizumab in metastatic CRC is independent of KRAS mutation status, suggesting that patients with both an activating mutation in KRAS, as well as those who are KRAS wild-type may derive benefit from treatment with RAM.12 • Phase I studies and initial Phase II studies aimed at investigating the efficacy of RAM have provided valuable information on safety and tolerability levels at clinically relevant doses, besides providing preliminary evidence of clinical efficacy in treating a variety of human cancers including advanced colorectal cancer. Figure 1. Tumor Angiogenesis and Lymphangiogenesis • The VEGF family of ligands and receptors plays a central role in tumor angiogenesis and lymphangiogenesis.1,2 CD31 Objectives • Stratification • Geography, KRAS mutation status, time to disease progression after beginning first-line treatment Primary Objective Comparison of OS in patients with mCRC when treated with FOLFIRI in combination with placebo versus FOLFIRI in combination with RAM. CD31 &TUNEL Study Sites Secondary Objectives RANDOMIZE (1:1) • As of 7-May-2012, approximately 40% (419 patients) of the 1050 planned patients have been randomized in 22 countries. • The DMC last met on September 12, 2011 and December 12, 2011 and recommended to continue the study without any modifications. • Comparison of FOLFIRI plus placebo treatment with FOLFIRI plus RAM treatment for: • progression-free survival (PFS) • objective response rate (ORR) • patient-reported outcome (PRO) measures (using European Organisation for Research and Treatment of Cancer [EORTC] Quality of Life-Core 30 Questionnaire (QLQ-C30), and EuroQolEQ-5D) • safety profile • assessment of the association between biomarkers and clinical outcome Study Design Adapted from Bruns et al., Cancer, 2000 • Phase III multicenter, double-blinded, randomized study was planned for 1050 patients (525 in each arm) and the study will be carried out at approximately 249 sites in North America, South America, Europe, Asia, and Australia. • This study is designed to evaluate the efficacy of RAM versus placebo, each in combination with FOLFIRI, in patients with metastatic CRC who have had disease progression during or following first-line combination therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. • The study is designed to detect an increase in overall survival (OS) (median 10 months with placebo to 12.5 months with RAM; 1-sided α = 2.5%, 85% power; Hazard Ratio = 0.8). • Eligible patients will be randomized on a 1:1 basis to receive either FOLFIRI plus placebo or FOLFIRI plus RAM. • Patients will receive RAM or placebo by IV infusion over 1 hour at 8 mg/kg every 2 weeks (Q2W) in the absence of disease progression or on the basis of other withdrawal criteria (a treatment cycle is defined as 2 weeks). • Pts will be given FOLFIRI every 2 weeks in the absence of disease progression or on the basis of other withdrawal criteria (irinotecan (IRI), 180 mg/m2 IV over 90 min); followed by folinicacid (FA) (400 mg/m2; IV over 120 min); followed by 5-fluorouracil (5-FU) (400 mg/m2 bolus IV over 2 to 4 min); followed by 5-fluorouracil (5-FU) ( 2400 mg/m2 IV over 46 to 48 hours (continuously)). • Imaging will be conducted Q6W following the first dose of study therapy for the first 6 months, and thereafter Q12W. • Following discontinuation of study therapy, all patients will be followed for survival at regular scheduled intervals (Q3M) for as long as the patient is alive. PBS DC101 • N~525 • RAM 8 mg/kg (Q2W) • Plus • FOLFIRI (Q2W) • N~525 • Placebo (Q2W) • Plus • FOLFIRI (Q2W) Figure 5. Ramucirumab(IMC-1121B, RAM) Countries That are Recruiting mCRC Patients* PIG=placental growth factor; NRP=neuropilin; KDR=kinase-insert domain-receptor; Flt-1=fms-like tyrosine kinase 1; Flk-1=fetal liver kinase 1 • RAM is a fully human IgG1, neutralizing monoclonal antibody that • selectively blocks, with high affinity, (approximately 50 pM), the human VEGFR-2 receptor.7 • neutralizes VEGF-induced mitogenesis of human endothelial cells. • may also mediate anticancer effects through ADCC.4 • RAM and DC101 (an antibody to murine VEGFR-2) • strongly inhibit VEGF ligand binding to the extracellular domain of VEGFR-2. • also inhibit the subsequent activation and downstream signaling of pathways that result in endothelial cell permeability, migration, and proliferation.8-10 Figure 2. Rationale For Therapeutic Anti–VEGFR-2 mAbs • VEGFR-2 is a central target for antiangiogenic therapy.1 • VEGFR-2 is a unique molecular target that mediates several angiogenic signals.2 • mAbs against VEGFR-2 specifically block ligand receptor interactions3 • Small molecule tyrosine kinase inhibitors (TKIs) are often multi-kinaseinhibitors.3 • May exhibit increased risk of adverse events.3 • There are fewer concerns of bioavailability and interpatient variability with mAbs.3 • In tumor cells expressing VEGFR-2, there is the possibility of direct cell killing by the induction of immune-effector mechanisms such as antibody-dependent cellular cytotoxicity (ADCC).4 Key Inclusion Criteria Disease Progression or other withdrawal criteria met Disease Progression or other withdrawal criteria met • The patient has histologically or cytologically confirmed CRC. • The patient has confirmed metastatic CRC. • The KRAS mutation status (wild-type versus mutant) of the patient is known prior to randomization. • The patient has received first-line combination therapy of bevacizumab, oxaliplatin, and a fluoropyrimidine for metastatic disease and: • experienced radiographic disease progression during first-line therapy, or • experienced radiographic disease progression within 6 months after the last dose of first-line therapy, or • discontinued part or all of first-line therapy due to toxicity and experienced radiographic disease progression within 6 months after the last dose of first-line therapy. • The patient must have received a minimum of 2 doses of bevacizumab as part of a first-line regimen containing chemotherapy. • The patient must not have received more than 2 different fluoropyrimidines as part of a first-line regimen; disease progression is not an acceptable reason for discontinuing one fluoropyrimidine and starting a second fluoropyrimidine. • The patient has received no more than 2 prior systemic chemotherapy regimens in any setting (only 1 prior regimen for metastatic disease is permitted). • The patient has measurable or nonmeasurable disease based on the Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v. 1.1). *Countries to start enrollment in the near future: Hungary, Slovenia and Brazil. References: Holmes K et al. Cell Signal. 2007;19:2003-2012.   Hicklin DM, Ellis LM. J ClinOncol. 2005;23:1011-1027. Youssoufian H, et al. Clin Cancer Res. 2007;13(suppl 18):5544s-5548s. Adams GP, Weiner LM. Nat Biotechnol. 2005;23(9):1147-1157. Takahashi et al. Cancer Res. 1995; 55(18):3964-3968. Bruns CJ et al. Cancer. 2000;89(3):488-499. Lu D, et al. J Biol Chem. 2003;278(44):43496-43507. Miao H-Q, et al. BiochemBiophys Res Commun. 2006;345(1):438-445. Prewett M, et al. Cancer Res. 1999;59(20):5209-5218. Watanabe H et al. Exp Dermatol. 2004;13(11):671-681. Garcia-Carbonero R, et al. Poster 533 presented at the American Society of Clinical Oncology 2012 Gastrointestinal Cancers Symposium; San Francisco, CA; January 19-21, 2012. Hurwitz HI et al. Oncologist. 2009;14(1):22-28. Stratification Details BAD=Bcl-2 associated death promoter; eNOS=endothelial nitric oxide synthase; ERK=extracellular regulated kinases; FAK=focal adhesion kinase; HSP27=heat-shock protein 27; MEK=MAPK/Erkkinase; NO=nitric oxide; p38MAPK=p38 mitogen-activated protein kinase; PI3K=phosphoinositide 3-kinase; PKC=protein kinase C; PLC-γ=phospholipase C gamma • Patients will be stratified by geographic region (North America versus Europe versus all other regions), KRAS status (mutant versus wild-type), and time to disease progression after beginning first-line treatment (<6 months versus ≥6 months). American Society of Clinical Oncology (ASCO) Annual Meeting; Chicago, IL, USA; June 1 – 5, 2012 Sponsored by Eli Lilly and Company