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A Study of MEK162 and AMG 479 in Patients With Selected Solid Tumors
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Purpose
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 | Intervention | Phase |
|---|---|---|
| Metastatic Pancreatic Adenocarcinoma BRAF Mutated Melanoma | Drug: MEK162 Drug: AMG 479 | Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Non-Randomized Intervention Model: Single Group Assignment Masking: No masking 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 |
- 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)
- 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
- 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
- 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.
- 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
- 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
| Enrollment: | 77 |
| Study Start Date: | August 2012 |
| Study Completion Date: | April 2015 |
| Primary Completion Date: | April 2015 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
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
|
Eligibility| Ages Eligible for Study: | 18 Years and older (Adult, Senior) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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 LocationsPlease refer to this study by its ClinicalTrials.gov identifier: NCT01562899
| 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 | |
| Study Director: | Array BioPharma | 303-381-6604 |
More Information
| Responsible Party: | Array BioPharma |
| ClinicalTrials.gov Identifier: | NCT01562899 History of Changes |
| Other Study ID Numbers: |
CMEK162X2111 2012-000305-76 ( EudraCT Number ) |
| Study First Received: | March 22, 2012 |
| Last Updated: | February 14, 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 |
ClinicalTrials.gov processed this record on July 24, 2017