MEK Inhibitor MEK162 in Combination With Leucovorin Calcium, Fluorouracil, and Oxaliplatin in Treating Patients With Advanced Metastatic Colorectal Cancer

NCT02041481 | Completed Phase 1 DMC

• 3 other identifiers: 13355NCI-2014-00051CMEK162AUS09T
• Study Type: interventional
• Target: 26
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of MEK inhibitor MEK162 when given together with leucovorin calcium, fluorouracil, and oxaliplatin in treating patients with advanced metastatic colorectal cancer. MEK inhibitor MEK162 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and oxaliplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving MEK inhibitor MEK162 with leucovorin calcium, fluorouracil, and oxaliplatin may kill more tumor cells.

Conditions

Recurrent Colon Cancer; Recurrent Rectal Cancer; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer

Outcome Measures

Primary Outcomes (2)

• MTD of MEK inhibitory MEK162 on a continuous and an intermittent schedule in combination with FOLFOX assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03

  The MTD for each schedule will be defined as the highest level safely tested or the level below the level at which 2 or more patients (in a cohort of up to 6 patients) develop a dose-limiting toxicity (DLT).

  Up to 4 weeks

• DLT defined as an adverse event or abnormal laboratory value assessed as at least possibly related to the combination of MEK inhibitor MEK162 and FOLFOX graded according to NCI CTCAE v4.03

  The toxicities observed at each dose level will be summarized in terms of type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE 4.03 and nadir or maximum values for the laboratory measures), time of onset (i.e. cycle number), duration, and reversibility or outcome. Tables will be created to summarize these toxicities, cycles delivered and total dose delivered, and side effects by dose and by cycle. Tabular and graphical summaries will be used to explore the relationship of type and grade of toxicity to dose, cycle, and pharmacokinetics.

  Up to 4 weeks

Secondary Outcomes (3)

• Progression-free survival

  Time from start of treatment to time of progression or death, assessed up to 2 years

• Time to failure

  Up to 2 years

• Survival

  Up to 2 years

Study Arms (2)

Arm I (continuous MEK inhibitor MEK162, FOLFOX)

EXPERIMENTAL

Patients receive MEK inhibitor MEK162 PO BID on days 1-14, and leucovorin calcium IV over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 1 and 2. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: MEK inhibitor MEK162; Drug: leucovorin calcium; Drug: fluorouracil; Drug: oxaliplatin; Other: pharmacological study; Other: Laboratory Biomarker Analysis

Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

EXPERIMENTAL

Patients receive MEK inhibitor MEK162 PO BID on days 1-5, and leucovorin calcium IV over 2 hours, oxaliplatin IV over 2 hours, and fluorouracil IV continuously over 46 hours on days 6 and 7. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Drug: MEK inhibitor MEK162; Drug: leucovorin calcium; Drug: fluorouracil; Drug: oxaliplatin; Other: Laboratory Biomarker Analysis

Interventions

MEK inhibitor MEK162 DRUG

Given PO

Also known as: ARRY-162, ARRY-438162, Binimetinib, MEK inhibitor ARRY-438162, MEK162

Arm I (continuous MEK inhibitor MEK162, FOLFOX); Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

leucovorin calcium DRUG

Given IV

Also known as: CF, CFR, LV

Arm I (continuous MEK inhibitor MEK162, FOLFOX); Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

fluorouracil DRUG

Given IV

Also known as: 5-fluorouracil, 5-Fluracil, 5-FU

Arm I (continuous MEK inhibitor MEK162, FOLFOX); Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

oxaliplatin DRUG

Given IV

Also known as: 1-OHP, Dacotin, Dacplat, Eloxatin, L-OHP

Arm I (continuous MEK inhibitor MEK162, FOLFOX); Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Arm I (continuous MEK inhibitor MEK162, FOLFOX)

Laboratory Biomarker Analysis OTHER

Correlative Studies

Arm I (continuous MEK inhibitor MEK162, FOLFOX); Arm II (intermittent MEK inhibitor MEK162, FOLFOX)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with pathologically confirmed colon or rectal cancer who have received and progressed or failed following a fluoropyrimidine, irinotecan, and oxaliplatin based chemotherapy regimens will be eligible for this study; patients who have a known Kirsten rat sarcoma viral oncogene homolog (KRAS)/v-raf murine sarcoma viral oncogene homolog B (BRAF) wild type tumor should have progressed or failed following cetuximab or panitumumab based chemotherapy; prior bevacizumab or regorafenib exposure is not mandated on this study as some patients are deemed poor candidates for anti-angiogenesis therapy and never receive these agents
• Patients should have measurable disease defined as a minimum of one tumor measuring \>= 10 mm on computed tomography (CT) scans
• Signed written informed consent
• Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L
• Hemoglobin (Hgb) \>= 9 g/dL without transfusions
• Platelets (PLT) \>= 100 x 10\^9/L without transfusions
• Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =\< 2.5 × upper limit of normal (ULN); patient with liver metastases =\< 5 ×ULN
• Total bilirubin =\< ULN
• Creatinine =\< 1.5 mg/dL
• Left ventricular ejection fraction (LVEF) \>= 50% as determined by a multigated acquisition (MUGA) scan or echocardiogram
• Corrected QT (QTc) interval =\< 480 ms
• Able to take oral medications
• Patient is deemed by the investigator to have the initiative and means to be compliant with the protocol (treatment and follow-up)
• Negative serum beta-human chorionic gonadotropin (HCG) test (female patient of childbearing potential only) performed locally within 72 hrs prior to first dose
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 1

You may not qualify if:

• History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
• Patients who have had chemotherapy, biologic, targeted, or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from grade 2 and above adverse events due to agents administered more than 4 weeks earlier (with the exception of alopecia or neuropathy)
• History of retinal degenerative disease
• History of Gilbert's syndrome
• Previous or concurrent malignancy with the following exceptions:
• Adequately treated skin basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
• In situ carcinoma of the cervix, treated curatively and without evidence of recurrence
• A primary malignancy which has been completely resected and in complete remission for \>= 1 years
• Prior therapy with a MEK- inhibitor
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting \[CABG\], coronary angioplasty, or stenting) \< 6 months prior to screening
• Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following: symptomatic chronic heart failure; evidence of clinically significant cardiac arrhythmias and/or conduction abnormalities \< 6 months prior to screening except atrial fibrillation and paroxysmal supraventricular tachycardia
• Uncontrolled arterial hypertension despite appropriate medical therapy (defined as systolic blood pressure \> 160 or diastolic blood pressure \> 100)
• Known positive serology for human immunodeficiency virus (HIV), active hepatitis B, and/or active hepatitis C infection
• Patients who have neuromuscular disorders that are associated with elevated creatine kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
• Patients who are planning on embarking on a new strenuous exercise regimen after first dose of study treatment; NB: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CK levels should be avoided while on MEK162 treatment

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator
• Array BioPharma: collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

Colonic Neoplasms; Rectal Neoplasms

Interventions

binimetinib; Leucovorin; Fluorouracil; Oxaliplatin

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes; Organic Chemicals

Study Officials

• Marwan Fakih

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 17, 2014
• First Posted: January 22, 2014
• Study Start: June 1, 2014
• Primary Completion: January 19, 2018
• Study Completion: January 19, 2018
• Last Updated: January 25, 2018

Record last verified: 2018-01

Locations

US (1)