Clinical Trials /

Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.

NCT02964689

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Binimetinib in Addition to Standard Chemotherapy in KRAS Mutated NSCLC.
  • Official Title: 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.

Clinical Trial IDs

  • ORG STUDY ID: SAKK 19/16
  • NCT ID: NCT02964689

Conditions

  • Advanced Non-small Cell Lung Cancer
  • KRAS Gene Mutation
  • Lung Cancer

Interventions

DrugSynonymsArms
BinimetinibMEK162Combination of binimetinib, pemetrexed and cisplatin
PemetrexedCombination of binimetinib, pemetrexed and cisplatin
CisplatinCombination of binimetinib, pemetrexed and cisplatin

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Combination of binimetinib, pemetrexed and cisplatinExperimentalThe 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
  • Binimetinib
  • Pemetrexed
  • Cisplatin

Eligibility Criteria

        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.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicities (DLTs)
Time Frame:within 21 days from the first dose
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Objective response (OR)
Time Frame:at 30 months after start of trial
Safety Issue:
Description: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.
Measure:Progression-free survival (PFS)
Time Frame:at 30 months after start of trial
Safety Issue:
Description:PFS will be calculated from registration until documented tumor progression according to RECIST 1.1 or death due to any reason, whichever occurs first.
Measure:Overall survival (OS)
Time Frame:at 30 months after start of trial
Safety Issue:
Description:OS will be calculated from registration until death due to any reason.
Measure:Adverse events (AEs)
Time Frame:at 30 months after start of trial
Safety Issue:
Description:AEs will be assessed according to NCI CTCAE V.4.03.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Swiss Group for Clinical Cancer Research

Trial Keywords

  • Advanced non-small cell lung cancer
  • KRAS mutations
  • Binimetinib
  • Pemetrexed
  • Cisplatin
  • Phase IB trial

Last Updated

May 3, 2018