Clinical Trials /

Trametinib in Patients With Advanced Neurofibromatosis Type 1 (NF1)-Mutant Non-small Cell Lung Cancer

NCT03232892

Description:

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trametinib in Patients With Advanced Neurofibromatosis Type 1 (NF1)-Mutant Non-small Cell Lung Cancer
  • Official Title: Phase II Trial to Evaluate Trametinib in Patients With Advanced NF1-mutant Non-small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 166521
  • SECONDARY ID: NCI-2017-02295
  • NCT ID: NCT03232892

Conditions

  • Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
TrametinibMekinistTrametinib 2.0mg PO daily

Purpose

Phase II trial to evaluate trametinib in patients with locally advanced non-squamous, non-small cell lung cancer (NSCLC) whose tumors harbor a non-synonymous NF-1 mutation, with progressive disease on at least one prior line of therapy.

Detailed Description

      This is a phase II, single-arm, open-label, multicenter clinical trial evaluating the
      efficacy and safety of trametinib monotherapy in patients with advanced non-squamous NSCLC
      whose tumors non-synonymous NF1 mutations and are KRAS wildtype. Eligible patients must have
      documented disease progression either during or after treatment with most recent therapy and
      may not have received prior treatment with a MEK inhibitor. Patients with activating
      alterations in EGFR, ALK, and ROS-1 must also have received appropriate TKI treatment.
      Patients who meet eligibility criteria will receive trametinib monotherapy and followed for
      the primary endpoint of objective response rate and additional secondary endpoints. A total
      of 27 patients will be enrolled into the study, with the goals of obtaining 24 evaluable
      patients. Patients may continue treatment until disease progression or up to 24 months from
      the time of study entry or until the study is closed. All patients will be followed for 12
      months.
    

Trial Arms

NameTypeDescriptionInterventions
Trametinib 2.0mg PO dailyExperimentalTrametinib 2.0mg PO daily in 28-day cycles. A maximum of two trametinib dose level reductions are allowed (1.5mg and 1mg) in the case of adverse reactions.
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          1. Histologically or cytologically confirmed metastatic or unresectable locally advanced,
             non-squamous, NSCLC.

          2. Documented non-synonymous somatic mutation in NF1 in any tumor specimen or cell-free
             DNA assay by Clinical Laboratory Improvement Amendments (CLIA)-approved laboratory.

          3. Received at least one prior line of cancer therapy for the treatment of NSCLC; this
             should include at least one of the following: platinum (carboplatin or cisplatin)
             doublet chemotherapy (acceptable combinations include: paclitaxel, docetaxel,
             abraxane, pemetrexed, gemcitabine, vinorelbine, or etoposide), anti-PD1/PDL1 therapy
             (pembrolizumab, nivolumab, or atezolizumab), or appropriate targeted therapy in
             patients with activating EGFR (osimertinib, erlotinib, gefitinib, or afatinib), ALK
             (alectinib, crizotinib, ceritinib, brigatinib, or loralatinib), or ROS-1 (crizotininb
             or entrectinib) alterations; therapy may be given as monotherapy or in combination
             with other cancer therapy (e.g. bevacizumab, ipilumimab)

          4. Patients with a known activating mutation in epidermal growth factor receptor (EGFR)
             (Exon 19 deletion, G719A, S768I, V769L, T790M, L833F, L858R, L861Q), must have
             progressed or been intolerant to treatment with a first-line EGFR tyrosine kinase
             inhibitor (TKI) (erlotinib, afatinib, or gefitinib). Patients whose tumors were found
             to have an EGFR T790M mutation must also have progressed or been intolerable to
             treatment with osimertinib.

          5. Patients with a known Anaplastic lymphoma kinase (ALK)-rearrangement must have
             progressed or been intolerant to treatment with at least one ALK TKI: crizotinib
             ceritinib, alectinib,brigatinib, or loralatinib

          6. Patients with a known ROS-1-rearrangement must have progressed or been intolerant to
             treatment with crizotinib or entrectinib

          7. Patients with PDL1 level of >= 50%, who do not have an ALK-rearrangement or
             EGFR-mutation, must have progressed or been intolerant to treatment with anti-PD1/PDL1
             therapy (pembrolizumab, nivolumab, or atezolizumab)

          8. Documented disease progression or intolerance to treatment either during or after
             treatment with most recent therapy.

          9. Willingness to undergo research biopsy.

         10. Measurable disease defined by RECIST 1.1 criteria.

         11. Life expectancy of at least 3 months.

         12. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.

         13. Age ≥ 18 years.

         14. Resolution of all acute toxic effects of prior chemotherapy, immunotherapy,
             radiotherapy or surgical procedures to National Cancer Institute (NCI) Common
             Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grade 1.

         15. Adequate baseline organ function defined as follows:

             Hematologic:

               -  Absolute neutrophil count: ≥ 1.2 x 10^9/L

               -  Hemoglobin: ≥ 9 g/dL

               -  Platelets: ≥ 100 x 10^9/L

               -  PT/INR and PTT: ≤ 1.5 x upper limit of normal (ULN)

             Hepatic:

               -  Albumin: ≥ 2.5 g/dL

               -  Total bilirubin: ≤ 1.5 x ULN

               -  AST and ALT: ≤ 2.5 x ULN

             Renal:

               -  Creatine: ≤ 1.5 ULN or

               -  Calculated creatinine clearance (calculated by the Cockcroft-Gault formula): ≥ 50
                  mL/min

             Cardiac:

             - Left Ventricular Ejection Fraction (LVEF): ≥ lower limit of normal (LLN) by
             echocardiogram (ECHO) or multiple-gated acquisition (MUGA)

         16. Women of childbearing potential must have a negative serum or urine pregnancy test
             within 3 days prior to study enrollment. The effects of trametinib on the developing
             human fetus are unknown. For this reason and because animal studies with trametinib
             have shown reproductive toxicity, women of child-bearing potential and men must agree
             to use effective methods of contraception (hormonal or barrier method of birth
             control) prior to study entry, for the duration of study participation, and for 4
             months following discontinuation of trametinib. Should a woman become pregnant or
             suspect she is pregnant while she or her partner is participating in this study, she
             should inform her treating physician immediately. Men treated or enrolled on this
             protocol must also agree to use adequate contraception prior to the study, for the
             duration of study participation, and 4 months after completion of study drug
             administration.

         17. Able to swallow and retain orally administered medication and does not have any
             clinically significant gastrointestinal abnormalities that may alter absorption such
             as malabsorption syndrome or major resection of the stomach or bowels.

         18. All prior treatment- related toxicities must be CTCAE (Version 4.03) ≤ Grade 1 (except
             alopecia) at the time of randomization

         19. Ability to understand a written informed consent document, and the willingness to sign
             it.

        Exclusion Criteria:

          1. Known mutation in KRAS at position G12, G13, or Q61.

          2. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
             compression. Treated brain metastases are allowed as long as they are stable for at
             least 28 days post-treatment.

          3. Pregnant women are excluded from this study; breastfeeding should be discontinued if
             the mother is treated with trametinib . Because there is an unknown but potential risk
             for adverse events in nursing infants secondary to treatment of the mother with
             trametinib, breastfeeding should be discontinued if the mother is treated with
             trametinib.

          4. History of another malignancy. Exception: Subjects who have been disease-free for 3
             years, or subjects with a history of completely resected non-melanoma skin cancer
             and/or subjects with indolent second malignancies are eligible.

          5. Any serious and/or unstable pre-existing medical disorder (aside from malignancy
             exception above), psychiatric disorder, or other conditions that could interfere with
             subject's safety, obtaining informed consent or compliance to the study procedures.

          6. The subject has received cytotoxic chemotherapy, molecular targeted therapy, or
             immunotherapy within 21 days before the first dose of study drug (trametinib).

          7. Prior treatment with MEK inhibitor.

          8. History of interstitial lung disease or pneumonitis.

          9. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

         10. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity,
             biologic therapy, or immunotherapy within 21 days prior to study enrollment and/or
             daily or weekly chemotherapy without the potential for delayed toxicity within 14 days
             prior to study enrollment.

         11. History of retinal vein occlusion (RVO).

         12. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C
             Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV
             infection will be permitted).

         13. History or evidence of cardiovascular risk including any of the following:

               -  LVEF < LLN

               -  A QT interval corrected for heart rate using the Bazett's formula (QTcB) ≥ 480
                  msec;

               -  History or evidence of current clinically significant uncontrolled arrhythmias.

               -  Clarification: Subjects with atrial fibrillation controlled (defined as not
                  requiring change in cardiac drug dosing, emergency room visit, or hospital
                  admission) for > 30 days prior to dosing are eligible.

               -  History of acute coronary syndromes (including myocardial infarction and unstable
                  angina), coronary angioplasty, or stenting within 6 months prior to study
                  enrollment.

               -  History or evidence of current ≥ Class II congestive heart failure as defined by
                  New York Heart Association (NYHA).

               -  Treatment refractory hypertension defined as a blood pressure of systolic > 140
                  mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive
                  therapy;

               -  Patients with intra-cardiac defibrillators.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria.
Time Frame:From start of treatment up to 4 years, or until disease progression, whichever comes first
Safety Issue:
Description:The ORR is defined as the best overall response recorded from the start of the treatment until disease progression or recurrence from the start of treatment.

Secondary Outcome Measures

Measure:Duration of Response (DR) according to RECIST Version 1.1 criteria.
Time Frame:From start of treatment up to 4 years, or until disease progression, whichever comes first
Safety Issue:
Description:The DR for Complete Response (CR) and Partial Response (PR) will be measured from the date that the best response is first recorded until the date that PD is documented. For patients who continue treatment post progression, the date of Disease Progression (PD) documentation will be used for analysis.
Measure:Disease Control Rate (DCR) according to RECIST Version 1.1 criteria.
Time Frame:From start of treatment up to 4 years, or until disease progression, whichever comes first
Safety Issue:
Description:DCR will be defined as the percentage of patients who have achieved CR, PR, or Stable Disease (SD) for at least 12 weeks.
Measure:Progression Free Survival (PFS) according to RECIST Version 1.1 criteria.
Time Frame:From start of treatment up to 4 years, or until disease progression, whichever comes first
Safety Issue:
Description:PFS will be calculated as 1+ the number of days from the first dose of study drugs to documented radiographic progression or death due to any cause over a period of 1 year. For patients who continue treatment post-progression, the date of radiographic progression will be used for PFS analysis.
Measure:Overall Survival (OS) according to RECIST Version 1.1 criteria.
Time Frame:From start of treatment up to 4 years, or until disease progression, whichever comes first
Safety Issue:
Description:OS will be calculated as 1+ the number of days from the first dose of study drugs to death due to any cause over a period of 1 year.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Collin Blakely

Trial Keywords

  • NSCLC
  • NF-1 mutant

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