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.
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.
