A Study of MEK162 and AMG 479 in Patients With Selected Solid Tumors

Study Description

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Brief Summary:

This is a multi-center, open-label, phase Ib/II study. First, the aim of the phase Ib part is to estimate the MTD(s) and/or to identify the recommended phase II dose(s) (RP2D) for the combination of MEK162 and AMG 479 (ganitumab), followed by the phase II part to assess the clinical efficacy and to further assess the safety of the combination in selected patient populations. The dose escalation part of the study will be guided by a Bayesian Logistic Regression Model (BLRM). At least 18 patients are expected to be enrolled in the dose escalation part.

Following MTD/ RP2D declaration, patients will be enrolled in three phase II arms to assess efficacy of the combination as well as to better understand the safety, tolerability, PK, antibody concentrations and PD of the combination at MTD/RP2D. Phase II arm 1 will consist of approximately 25 patients with KRAS-mutant colorectal adenocarcinoma. Phase II arm 2 will consist of approximately 20 patients with metastatic pancreatic adenocarcinoma. Phase II arm 3 will consist of approximately 28 patients with mutant BRAFV600 melanoma.

Patients will be treated until progression of disease, unacceptable toxicity develops, or withdrawal of informed consent, whichever occurs first. All patients will be followed up - at minimum patients must complete the safety follow-up assessments 30 days after the last dose of the study treatment.

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Adenocarcinoma; BRAF Mutated Melanoma	Drug: MEK162; Drug: AMG 479	Phase 2

Study Design

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	77 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase Ib/II Open-label, Multi-center Study of the Combination of MEK162 Plus AMG 479 (Ganitumab) in Adult Patients With Selected Advanced Solid Tumors
Study Start Date :	August 2012
Actual Primary Completion Date :	April 2015
Actual Study Completion Date :	April 2015

Arms and Interventions

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Arm	Intervention/treatment
Experimental: Dose escalation; Dose finding group chosen in order to establish a safe and tolerated dose of binimetinib in combination with ganitumab in patients with selected advanced solid tumors.	Drug: MEK162; Supplied as tablets of dosage strength 15 mg in high-density polyethylene bottles with child-resistant closure.; Other Name: Binimetinib Drug: AMG 479; Supplied as sterile liquid for intravenous infusion in vials in boxes. Until April 2013 a frozen formulation with a concentration of 30 mg/ml was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/ml was used.; Other Name: Ganitumab
Experimental: KRAS mutated colorectal adenocarcinoma; Patients with KRAS mutant colorectal cancer. The starting dose (30 mg bid) of binimetinib chosen for this study was a fraction of the MTD (60 mg bid) and the RP2D (45 mg bid) determined for single agent use. The starting dose for ganitumab was 12 mg/kg q2w which had been shown to be a well-tolerated dose in combination with other anti-cancer agents.	Drug: MEK162; Supplied as tablets of dosage strength 15 mg in high-density polyethylene bottles with child-resistant closure.; Other Name: Binimetinib Drug: AMG 479; Supplied as sterile liquid for intravenous infusion in vials in boxes. Until April 2013 a frozen formulation with a concentration of 30 mg/ml was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/ml was used.; Other Name: Ganitumab
Experimental: Metastatic pancreatic adenocarcinoma; Patients with metastatic pancreatic cancer. The starting dose (30 mg bid) of binimetinib chosen for this study was a fraction of the MTD (60 mg bid) and the RP2D (45 mg bid) determined for single agent use. The starting dose for ganitumab was 12 mg/kg q2w which had been shown to be a well-tolerated dose in combination with other anti-cancer agents.	Drug: MEK162; Supplied as tablets of dosage strength 15 mg in high-density polyethylene bottles with child-resistant closure.; Other Name: Binimetinib Drug: AMG 479; Supplied as sterile liquid for intravenous infusion in vials in boxes. Until April 2013 a frozen formulation with a concentration of 30 mg/ml was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/ml was used.; Other Name: Ganitumab
Experimental: BRAF mutated melanoma; Patients with mutant BRAF V600 melanoma. The starting dose (30 mg bid) of binimetinib chosen for this study was a fraction of the MTD (60 mg bid) and the RP2D (45 mg bid) determined for single agent use. The starting dose for ganitumab was 12 mg/kg q2w which had been shown to be a well-tolerated dose in combination with other anti-cancer agents.	Drug: MEK162; Supplied as tablets of dosage strength 15 mg in high-density polyethylene bottles with child-resistant closure.; Other Name: Binimetinib Drug: AMG 479; Supplied as sterile liquid for intravenous infusion in vials in boxes. Until April 2013 a frozen formulation with a concentration of 30 mg/ml was used; from May 2013 onwards a refrigerated formulation with a concentration of 70 mg/ml was used.; Other Name: Ganitumab

Outcome Measures

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Primary Outcome Measures :

1. Phase Ib: Estimation of Maximum Tolerated Doses (MTDs) and/or recommended Phase II doses (RP2Ds) by measuring incidence of dose limiting toxicities [ Time Frame: Approximately 6 months ]
   To estimate the MTDs and/or RP2Ds of MEK162 in combination with AMG479 by measuring incidence of dose limiting toxicities in Cycle 1 (Cycle 1 = 28 days)
2. Phase II: Antitumor activity of MEK162 in combination with AMG 479 by evaluating Objective Response Rate (ORR) in colorectal carcinoma and melanoma and by evaluating Disease Control Rate (DCR) at week 10 in pancreatic carcinoma [ Time Frame: Approximately 24 months ]
   To estimate the antitumor activity of MEK162 in combination with AMG479 by evaluating Objective Response Rate (ORR) according to RECIST 1.1 in colorectal carcinoma and melanoma and by evaluating the Disease Control Rate (DCR) per RECIST 1.1 at week 10 in pancreatic carcinoma

Secondary Outcome Measures :

1. Both Phases: Safety and tolerability of MEK162 & AMG 479 (ganitumab) in combination by evaluating the adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs; dose interruptions, reductions and dose intensity [ Time Frame: Phase Ib: Approximately 6 months; Phase II: Approximately 24 months ]
   To characterize the safety and tolerability of MEK162 and AMG 479 (ganitumab) in combination by evaluating the incidence and severity of adverse events, serious adverse events (as per CTCAE grading), changes in hematology and chemistry values, vital signs, ECGs; dose interruptions, reductions and dose intensity
2. Both Phases: Determination of single and multiple dose pharmacokinetics (PK) profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentrations and basic PK parameters of MEK162 [ Time Frame: Phase Ib: Approximately 6 months; Phase II: Approximately 24 months ]
   To determine single and multiple dose PK profile of MEK162 in combination with AMG 479 (ganitumab) by measuring time vs. plasma concentration as well as basic PK parameters of MEK162 at different timepoints prior and post study drug combination dosing.
3. Phase Ib: Preliminary anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating the Overall Response Rate (ORR), Duration of Response (DOR) and Progression Free Survival (PFS) [ Time Frame: Approximately 6 months ]
   To assess preliminary anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating Overall Response Rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS) as assessed by the investigator according to RECIST 1.1
4. Phase II: Further anti-tumor activity of MEK162 & AMG 479 (ganitumab) in combination by evaluating the DOR, PFS and OS by evaluating Disease Control Rate for colorectal carcinoma and melanoma; Overall Response Rate for pancreatic carcinoma patients [ Time Frame: Approximately 24 months ]
   To further assess the anti-tumor activity of MEK162 and AMG 479 (ganitumab) in combination by evaluating the Duration of Response (DOR) and Progression Free Survival (PFS) per RECIST 1.1 and Overall Survival in all phase II patients and by evaluating the Disease Control Rate (DCR) per RECIST 1.1 for colorectal carcinoma and melanoma and Overall Response Rate (ORR) per RECIST 1.1 for pancreatic carcinoma patients

Eligibility Criteria

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patients aged ≥ 18 years
• Patients with advanced solid tumors (CRC, melanoma) with documented somatic KRAS or BRAFV600 mutations in tumor tissue. Patients with metastatic pancreatic adenocarcinoma may be enrolled irrespectively of KRAS or BRAFV600 mutational status.
• Patients must have relapsed or progressed following standard therapy or patients for whom no standard anticancer therapy exists.
• Measurable disease as determined by RECIST v1.1. World Health Organization (WHO) Performance Status (PS) ≤ 2.
• Adequate organ function
• Negative serum pregnancy test

Exclusion Criteria:

• Prior therapy with MEK- or IGF-1R- inhibitor
• History or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO) or retinal degenerative disease
• Patients with known history of severe infusion reactions to monoclonal antibodies
• Patients with primary CNS tumor or CNS tumor involvement
• History of thromboembolic event requiring full-dose anticoagulation therapy
• Clinically significant cardiac disease
• History of another malignancy within 2 years
• Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Massachusetts
Massachusetts General Hospital Mass General 2
Boston, Massachusetts, United States, 02114
United States, Utah
University of Utah / Huntsman Cancer Institute Huntsman
Salt Lake City, Utah, United States, 84103
Australia, Victoria
Novartis Investigative Site
Parkville, Victoria, Australia, 3050
Belgium
Novartis Investigative Site
Leuven, Belgium, 3000
Canada, Ontario
Novartis Investigative Site
Toronto, Ontario, Canada, M5G 2M9
France
Novartis Investigative Site
Toulouse Cedex 9, France, 31059
Italy
Novartis Investigative Site
Napoli, Italy, 80131
Spain
Novartis Investigative Site
Barcelona, Catalunya, Spain, 08035
United Kingdom
Novartis Investigative Site
Sutton, Surrey, United Kingdom, SM2 5PT

Sponsors and Collaborators

Array BioPharma

Investigators

Study Director:	Array BioPharma	303-381-6604

More Information

Go to 

Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Array BioPharma
ClinicalTrials.gov Identifier:	NCT01562899 History of Changes
Other Study ID Numbers:	CMEK162X2111; 2012-000305-76 ( EudraCT Number )
First Posted:	March 26, 2012
Last Update Posted:	February 15, 2017
Last Verified:	February 2017

Keywords provided by Array BioPharma:

MEK162; AMG 479; Ganitumab; colorectal adenocarcinoma	pancreatic adenocarcinoma; melanoma; KRAS; BRAF

Additional relevant MeSH terms:

Melanoma; Adenocarcinoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms	Neoplasms, Nerve Tissue; Nevi and Melanomas; Carcinoma; Neoplasms, Glandular and Epithelial; Antibodies, Monoclonal; Immunologic Factors; Physiological Effects of Drugs