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Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02964689
Recruitment Status : Active, not recruiting
First Posted : November 16, 2016
Last Update Posted : February 5, 2020
Sponsor:
Information provided by (Responsible Party):
Swiss Group for Clinical Cancer Research

Tracking Information
First Submitted Date  ICMJE November 14, 2016
First Posted Date  ICMJE November 16, 2016
Last Update Posted Date February 5, 2020
Actual Study Start Date  ICMJE April 12, 2017
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 13, 2017)
Dose-limiting toxicities (DLTs) [ Time Frame: within 21 days from the first dose ]
A DLT is defined as an AE or abnormal laboratory value assessed as at least possibly related to trial treatment (binimetinib in combination with pemetrexed and cisplatin), which occurs ≤ 21 days following the first dose of trial treatment during cycle 1.
Original Primary Outcome Measures  ICMJE
 (submitted: November 14, 2016)
Dose-limiting toxicities (DLTs) [ Time Frame: within 21 days from the first dose ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 13, 2017)
  • Objective response (OR) [ Time Frame: at 30 months after start of trial ]
    OR will include complete and partial responses based on RECIST 1.1 criteria. Best response will be the best result by investigator and RECIST 1.1 in the planned follow-up CT scans.
  • Progression-free survival (PFS) [ Time Frame: at 30 months after start of trial ]
    PFS will be calculated from registration until documented tumor progression according to RECIST 1.1 or death due to any reason, whichever occurs first.
  • Overall survival (OS) [ Time Frame: at 30 months after start of trial ]
    OS will be calculated from registration until death due to any reason.
  • Adverse events (AEs) [ Time Frame: at 30 months after start of trial ]
    AEs will be assessed according to NCI CTCAE V.4.03.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 14, 2016)
  • Objective response (OR) [ Time Frame: at 30 months after start of trial ]
  • Progression-free survival (PFS) [ Time Frame: at 30 months after start of trial ]
  • Overall survival (OS) [ Time Frame: at 30 months after start of trial ]
  • Adverse events (AEs) [ Time Frame: at 30 months after start of trial ]
    AEs will be assessed according to NCI CTCAE V.4.03.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.
Official Title  ICMJE Binimetinib, Pemetrexed and Cisplatin, Followed by Maintenance With Binimetinib and Pemetrexed, in Patients With Advanced Non-small Cell Lung Cancer NSCLC With KRAS Mutations. A Multicenter Phase IB Trial.
Brief Summary The aim is to determine the recommended phase 2 dose (RP2D) of binimetinib in combination with pemetrexed and cisplatin, and to demonstrate that the combination is feasible and has preliminary activity in previously untreated patients with advanced NSCLC and documented KRAS mutations.
Detailed Description

There is a need for more effective therapies for patients with advanced NSCLC driven by the RAS/MEK/ERK pathway. These tumors are generally aggressive, are almost exclusively of non-squamous histology, and represent the largest group of patients with advanced NSCLC harboring specific driver mutations in Western populations.

Based on recent preclinical and clinical evidence, mitogen-activated protein kinase kinase (MEK)-inhibition plus first-line chemotherapy is a promising new treatment for patients with NSCLC and KRAS [v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog] mutations.

Binimetinib is a medication without marketing authorization. Pemetrexed and cisplatin have marketing authorization in Switzerland and in EU for the treatment of non-small cell lung cancer (NSCLC) and will be administered as standard backbone treatment according to their Swissmedic-approved indication, dose and route of administration. Binimetinib, pemetrexed and cisplatin are IMP in the context of this phase I trial.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Non-small Cell Lung Cancer
  • KRAS Gene Mutation
  • Lung Cancer
Intervention  ICMJE
  • Drug: Binimetinib
    Binimetinib will be administered in combination with pemetrexed and cisplatin (induction therapy), and with pemetrexed only (maintenance therapy), during the first 2 weeks of each cycle. Cycles will be repeated every 21 days.
    Other Name: MEK162
  • Drug: Pemetrexed
    Pemetrexed 500 mg/m2 i.v. is applied on day 1 of each cycle, before cisplatin administration
  • Drug: Cisplatin
    Cisplatin 75 mg/m2 i.v. is applied on day 1 of each induction therapy cycle. The drug must be administered after pemetrexed infusion
Study Arms  ICMJE Experimental: Combination of binimetinib, pemetrexed and cisplatin

The trial consists of two parts:

  • Part 1: dose escalation based on the 3+3 design with 2 doses of binimetinib
  • Part 2: expansion cohort at the recommended maximum tolerated dose (MTD) level of binimetinib
Interventions:
  • Drug: Binimetinib
  • Drug: Pemetrexed
  • Drug: Cisplatin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: November 14, 2016)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2020
Estimated Primary Completion Date September 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Written informed consent according to the Swiss HRA and ICH-GCP regulation before registration and prior to any trial-specific procedure.
  • Histologically or cytologically confirmed diagnosis of NSCLC, predominantly non-squamous subtype (adenocarcinoma, large cell carcinoma, NOS).
  • Locally advanced or metastatic stage III-IV disease according to the 7th TNM classification, ineligible for curative treatment.
  • Presence of KRAS exon 2 or 3 (codon 12, 13 or 61) mutations by local testing (concomitant EGFR and ALK mutations are excluded).
  • CT scan showing measurable disease, which is defined as at least one lesion that can be measured in at least one dimension (non-nodal lesions ≥10 mm in longest diameter, lymph nodes ≥15 mm in short axis) according to RECIST 1.1.
  • Eligible for cisplatin-based chemotherapy and able to take oral medications.
  • WHO performance status 0-1.
  • Age from 18 to 75 years.
  • Adequate hematological values: hemoglobin ≥ 90 g/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L.
  • Adequate hepatic function: total bilirubin ≤ 1.5 x ULN and < 34.2 μmol/L; ALT and alkaline phosphatase ≤ 2.5 x ULN.
  • Adequate renal function: calculated creatinine clearance ≥ 60 mL/min, according to the formula of Cockcroft-Gault.
  • Adequate cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% as determined by echocardiogram; QTcF interval must be ≤ 480 ms.
  • Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and 6 months thereafter. A negative serum pregnancy test before inclusion into the trial is required for all women with child-bearing potential.
  • Men agree not to father a child during trial treatment and 6 months thereafter.

Exclusion Criteria:

  • NSCLC with any additional small cell carcinoma (SCLC) component by local diagnostic pathology report.
  • Meningeosis carcinomatosa, symptomatic or untreated central nervous system (CNS) metastases. Patients with treated, controlled CNS metastases can be enrolled 2 weeks after the end of radiotherapy if asymptomatic (no residual neurologic deficits) and no longer on corticosteroids.
  • Previous or concurrent malignancy with the following exceptions:

    • adequately treated basal cell or squamous cell carcinoma of the skin (adequate wound healing is required prior registration),
    • in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 5 years prior registration,
    • superficial bladder cancer, prostate intraepithelial neoplasm, other noninvasive or indolent malignancy, or other solid tumor treated curatively and without evidence of recurrence for at least 5 years prior registration.
  • Leptomeningeal disease.
  • Concurrent radiotherapy (patients with prior radiotherapy other than for brain metastases ≥ 7 days prior to registration can be enrolled).
  • Previous systemic therapy for advanced NSCLC; previous adjuvant or neoadjuvant chemotherapy allowed if last dose was administered at least 6 months ago.
  • Major surgery within 3 weeks before registration.
  • Concurrent treatment with any other experimental drug or other anticancer therapy.
  • Impaired cardiovascular function or clinically severe or uncontrolled cardiovascular diseases, including any of the following:

    • congestive heart failure NYHA III or IV,
    • history of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) < 6 months prior to registration,
    • symptomatic chronic heart failure (G2 or higher), history or current evidence of clinically significant cardiac arrhythmia requiring medication and/or conduction abnormality < 6 months prior to registration except atrial fibrillation and paroxysmal supraventricular tachycardia.
  • Uncontrolled arterial hypertension defined as persistent elevation of systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite medical treatment.
  • History or current evidence of retinal vein occlusion (RVO) or current risk factors to RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyper-viscosity or hypercoagulability syndromes); history of retinal degenerative disease.
  • History of Gilbert's syndrome.
  • Neuromuscular disorders that are associated with elevated creatine phosphokinase (CPK; e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy).
  • Neuropathy (> G1) or hearing impairment/ tinnitus (> G1).
  • Impairment of gastrointestinal function or gastrointestinal disease (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection).
  • History of thromboembolic or cerebrovascular events within 6 months prior to registration, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli.
  • Known history of acute or chronic pancreatitis.
  • History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) within 12 months prior to registration.
  • Known positive serology for HIV (human immunodeficiency virus), active hepatitis B, and/or active hepatitis C infection.
  • Active infection within 14 days prior to registration.
  • Planning on embarking on a new strenuous exercise regimen after first dose of binimetinib (NB: muscular activities, such as strenuous exercise, that can result in significant increases in plasma CPK levels should be avoided while on binimetinib treatment).
  • Known lactose intolerance.
  • Known hypersensitivity to the trial drugs or hypersensitivity to any other component of the trial treatment, including premedication.
  • Any concomitant drugs contraindicated for use with pemetrexed and cisplatin according to the Swissmedic-approved current product information or with binimetinib according to the latest version of the Investigator's Brochure.
  • Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Switzerland
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02964689
Other Study ID Numbers  ICMJE SAKK 19/16
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Swiss Group for Clinical Cancer Research
Study Sponsor  ICMJE Swiss Group for Clinical Cancer Research
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Chair: Martin Früh, MD Cantonal Hospital of St. Gallen
PRS Account Swiss Group for Clinical Cancer Research
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP