EMD 525797 in Combination With Cetuximab and Irinotecan in K-ras Wild Type Metastatic Colorectal Cancer

Phase 1

Completed

• Conditions: Metastatic Colorectal Cancer
• Interventions: Drug: EMD 525797 250 mg; Drug: EMD 525797 500 mg; Drug: EMD 525797 750 mg; Drug: EMD 525797 1000 mg; Drug: Cetuximab; Drug: Irinotecan

• Registration Number: NCT01008475
• Lead Sponsor: Merck KGaA, Darmstadt, Germany

Brief Summary

The purpose of this study is to assess the safety and clinical activity of the experimental drug EMD 525797 (study drug), a monoclonal antibody targeting alfa integrins, in combination with irinotecan and cetuximab in K-ras wildtype metastatic colorectal cancer patients.

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations

Study Timeline

• Study Start: 2009-10
• Study First Submitted: 2009-10-19
• Study First Submitted QC: 2009-11-04
• Study First Posted: 2009-11-05
• Primary Completion: 2015-04
• Study Completion: 2015-04
• Status Verified: 2016-02
• Results First Submitted: 2016-02-26
• Results First Submitted QC: 2016-02-26
• Last Update Submitted: 2016-02-26
• Results First Posted: 2016-03-30
• Last Update Posted: 2016-03-30

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 232

Inclusion Criteria

Subjects with histologically confirmed kras wildtype (WT) colorectal carcinoma (CRC) with documented distant metastasis

• Prior oxaliplatin/fluoropyrimidine-containing regimen for the first-line treatment of metastatic disease
• Failed an oxaliplatin regimen for metastatic colorectal carcinoma (mCRC). Failure is defined as either progressive disease (PD) (clinical or radiologic) within 6 months of the last dose of any agent of an oxaliplatin-based regimen or intolerance to an oxaliplatin regimen. Intolerance to an oxaliplatin regimen is defined as discontinuation due to any of the following: severe allergic reaction, persistent severe neurotoxicity, or delayed recovery from toxicity preventing retreatment
• At least 1 radiographically documented measurable lesion in a previously non irradiated area according to Response Evaluation Criteria In Solid Tumors (RECIST, Version 1.0), i.e., this lesion must be adequately measurable in at least 1 dimension (longest diameter to be recorded) as greater than or equal to (>=) 2 centimeter (cm) by conventional techniques or >=1 cm by spiral computed tomography (CT) scan
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, or Karnofsky performance status (KPS) >= 80 percent (%)
• Absolute Neutrophil Count (ANC) >=1.5 x 10^9/Liter
• Platelets >=100 x 10^9/Liter
• Hemoglobin >=9 gram per deciliter (g/dL) (without transfusions)
• Bilirubin less than or equal to (<=) 1.5 x upper limit normal (ULN)
• Aspartate transaminase (AST) <=5 x ULN and alanine transaminase (ALT) <=5 x ULN
• Serum creatinine <=1.25 x ULN and/or creatinine clearance >=50 milliliter per minute (mL/min)
• International Nationalized Ratio (INR), and partial thromboplastin time (PTT) within normal limits
• Sodium and potassium within normal limits or <=10% above or below (supplementation permitted)

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Exclusion Criteria

• Previous treatment with any inhibitor of Epidermal Growth Factor Receptor (EGFR)
• Known brain metastasis and/or leptomeningeal disease
• Radiotherapy (except localized radiotherapy for pain relief), major surgery, or any investigational drug in the 30 days before the start of trial treatment entry; planned major surgery during the trial
• Concurrent chronic systemic immune or hormone therapy not indicated in this trial protocol (except for physiologic replacement; steroids up to 10 mg of prednisone equivalent or topical and inhaled steroids are allowed)
• Clinically relevant coronary artery disease (New York Heart Association [NYHA] functional angina classification III/IV), congestive heart failure (NYHA III/IV), clinically relevant cardiomyopathy, history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia
• Uncontrolled hypertension defined as systolic blood pressure >=160 millimeter of mercury (mmHg) and/or diastolic blood pressure >=100 mmHg under resting conditions
• History of coagulation disorder associated with bleeding or recurrent thrombotic events
• History of recent peptic ulcer disease (endoscopically proven gastric, duodenal or esophageal ulcer) within 6 months of trial treatment start
• Chronic inflammatory bowel disease, or acute/chronic ileus
• Active infection (requiring i.v. antibiotics), including active tuberculosis, active or chronic Hepatitis B or C, or ongoing HIV infection

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Safety part: EMD 525797 250 mg + Standard of Care (SoC)	EMD 525797 250 mg	EMD 525797 250 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 500 mg + SoC	EMD 525797 500 mg	EMD 525797 500 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 750 mg + SoC	EMD 525797 750 mg	EMD 525797 750 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 750 mg + SoC	Irinotecan	EMD 525797 750 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 1000 mg + SoC	EMD 525797 1000 mg	EMD 525797 1000 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 1000 mg + SoC	Irinotecan	EMD 525797 1000 mg in combination with cetuximab and irinotecan
Randomized part: EMD 525797 500 mg + SoC	EMD 525797 500 mg	EMD 525797 500 mg in combination with cetuximab and irinotecan
Randomized Part: EMD 525797 1000 mg + SoC	EMD 525797 1000 mg	EMD 525797 1000 mg (or dose as defined by safety monitoring committee (SMC)\] in combination with cetuximab and irinotecan.
Randomized Part: EMD 525797 1000 mg + SoC	Irinotecan	EMD 525797 1000 mg (or dose as defined by safety monitoring committee (SMC)\] in combination with cetuximab and irinotecan.
Randomized Part: SoC	Irinotecan	Cetuximab and irinotecan
Safety part: EMD 525797 250 mg + Standard of Care (SoC)	Irinotecan	EMD 525797 250 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 250 mg + Standard of Care (SoC)	Cetuximab	EMD 525797 250 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 500 mg + SoC	Cetuximab	EMD 525797 500 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 500 mg + SoC	Irinotecan	EMD 525797 500 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 750 mg + SoC	Cetuximab	EMD 525797 750 mg in combination with cetuximab and irinotecan
Safety part: EMD 525797 1000 mg + SoC	Cetuximab	EMD 525797 1000 mg in combination with cetuximab and irinotecan
Randomized part: EMD 525797 500 mg + SoC	Cetuximab	EMD 525797 500 mg in combination with cetuximab and irinotecan
Randomized part: EMD 525797 500 mg + SoC	Irinotecan	EMD 525797 500 mg in combination with cetuximab and irinotecan
Randomized Part: EMD 525797 1000 mg + SoC	Cetuximab	EMD 525797 1000 mg (or dose as defined by safety monitoring committee (SMC)\] in combination with cetuximab and irinotecan.
Randomized Part: SoC	Cetuximab	Cetuximab and irinotecan

Primary Outcome Measures

Name	Time	Method
Safety Part: Number of Subjects Experiencing DLTs (Dose Limiting Toxicity)	Time from the first dose of study drug up to 2 weeks	DLT was defined as any Grade 4 hematologic toxicity or Grade 3/4 non-hematologic toxicity assessed as related to trial treatment by the Investigator and/or Sponsor and confirmed by the safety monitoring committee (SMC) to be relevant to the combination treatment within the first cycle of therapy. Any Grade 3 or 4 non haematological toxicity, any Grade 4 hematological toxicity, treatment related deaths within the first 2 weeks of therapy. Toxicities excluded from DLT: alopecia, rash, nausea, vomiting and hypomagnesemia of Grade 3 or 4 severity, Grade 4 neutropenia or leukopenia lasting for =\< 5 days and not associated with fever; Single laboratory values out of normal range without any clinical correlation and resolve within 7 days; Grade 3 or 4 diarrhoea without adequate supportive care. Adequate supportive care has been administered and Grade 4 diarrhea persists (investigator decision); isolated Grade 4 lymphocytopenia and thrombocytopenia without clinical correlation.
Randomized Part: Progression Free Survival (PFS)	Time from randomization until progressive disease or death; assessed up to 18 months (i.e data cut-off date: 09 Oct 2013)	PFS was defined as the time from the randomization date to first documented sign of objective radio-graphic disease progression (PD) as per Response Evaluation Criteria In Solid Tumors version 1. (RECIST 1.0) or death from any cause if reported within 12 weeks from the last tumor assessment. PD per RECIST v 1.0 was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as the reference the smallest sum of longest diameters recorded since treatment started, or unequivocal progression of existing non-target lesion or appearance of new lesions. Subjects who did not progress or died at the time of analyses, or subjects who died without previously radio-graphically documented PD and death was observed after more than 12 weeks of last tumor assessment without progression, these subjects were censored at their last tumor assessment date or date of randomization, whichever occurred last.

Secondary Outcome Measures

Name	Time	Method
Time to Progression (TTP)	Time from randomization until disease progression assessed up to 18 months (i.e data cut-off date: 09 Oct 2013)	TTP was defined as the time from the date of randomization to the date of objective radiographic disease progression (PD). PD per RECIST v 1.0 was defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as the reference the smallest sum of longest diameters recorded since treatment started, or unequivocal progression of existing non-target lesion or appearance of new lesions. For subjects who did not progress or who were without any post baseline tumor assessment, TTP was censored at their last tumor assessment date, or at the randomization date, whichever occurred last.
Overall Survival (OS) Time	Time from randomization until death assessed up to 18 months (i.e data cut-off date: 09 Oct 2013)	OS was defined as the time from the date of randomization to the date of death from any cause. For subjects who were still alive at the analysis cut off date or lost to follow up, survival was censored at the last recorded date the subject was known to be alive or at the analysis cut off date, whichever occurred first.
Number of Subjects With Tumor Response	Time from randomization up to 18 months (i.e data cut-off date: 09 Oct 2013)	Tumor response was defined as the presence of at least 1 confirmed complete response (CR) or confirmed partial response (PR) as judged by RECIST version 1.0. CR was defined for target lesions (TLs) as the disappearance of all lesions, and for non-target lesions (NTLs) as the disappearance of all non-target non-measurable lesions and/or normalization of serum levels of tumor markers. PR was defined for TLs as at least a 30 percent (%) decrease from baseline (BL) in the sum of longest diameter (SLD) of TLs.
Time to Treatment Failure (TTF)	Time from randomization until discontinuation assessed up to 18 months (i.e data cut-off date: 09 Oct 2013)	TTF was defined as the time from randomization to treatment discontinuation for any reason. For subjects on drug at the analysis cut off date or lost to follow up, TTF was censored at the trial discontinuation date or at the analysis cut off date, whichever occurred first.

Trial Locations

Locations (3)

Research Site; 🇬🇧 Sutton, United Kingdom

Research; 🇷🇺 Arkhangelsk, Russian Federation

Research site; 🇩🇪 Hannover, Germany