PRIMARY OBJECTIVES:
I. To evaluate the response rate (confirmed and unconfirmed) to trametinib plus docetaxel in
the entire study population of Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation
positive non-small cell lung cancer (NSCLC) patients following one or two prior systemic
therapies.
SECONDARY OBJECTIVES:
I. To evaluate if trametinib plus docetaxel is consistent with promise of activity measured
by the response rate in G12C KRAS mutation positive NSCLC patients following one or two prior
systemic therapies.
II. To assess the response rate of this combination in non-G12C KRAS mutation positive NSCLC
patients.
III. To assess progression-free survival within the G12C and non-G12C KRAS positive subgroups
and the entire study population.
IV. To evaluate the toxicity of the regimen. V. To assess overall survival within G12C
positive patients, non-G12C positive patients, and the entire study population.
TRANSLATIONAL MEDICINE OBJECTIVES:
I. To evaluate the response rates in the presence of comutations p53 and LKB1. II. To bank
specimens for future research.
OUTLINE:
Patients receive trametinib orally (PO) on days 1-21. Patients also receive docetaxel
intravenously (IV) on day 1. Cycles repeat every 21 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for 3 years.
Inclusion Criteria:
- DISEASE RELATED CRITERIA: Patients must have pathologically confirmed KRAS mutation
(at codon 12, 13 and 61) positive non-small cell lung cancer (NSCLC) that is stage IV
or recurrent; the specific subtype of KRAS mutation must be known; KRAS mutation
testing must have been performed in a Clinical Laboratory Improvement Act (CLIA)
certified laboratory; CLIA certified commercially available tests are acceptable
- DISEASE RELATED CRITERIA: Patients must have measurable disease documented by computed
tomography (CT) or magnetic resonance imaging (MRI) within 28 days prior to
registration; the CT from a combined positron emission tomography (PET)/CT may be used
only if it is of diagnostic quality; non-measurable disease must be assessed within 42
days prior to registration; all known sites of disease must be assessed and documented
on the baseline tumor assessment form (Response Evaluation Criteria in Solid Tumors
[RECIST 1.1])
- DISEASE RELATED CRITERIA: Patients must not have known brain metastases,
leptomeningeal carcinomatosis or spinal cord compression unless: (1) metastases have
been locally treated (including stereotactic body radiation therapy [SBRT], whole
brain radiotherapy [WBRT], and surgical resection) and have remained clinically
controlled and asymptomatic for at least 14 days following treatment and prior to
registration, AND (2) patient has no residual neurological dysfunction and has been
off corticosteroids for at least 2 days prior to registration
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients must have documented progressive cancer
following at least one but no more than two prior regimens of systemic therapy for
lung cancer, one of which must have been platinum based combination chemotherapy;
treatment with an immune therapy or targeted therapy for advanced disease will be
considered a separate regimen and will count toward the prior regimens; maintenance
therapy will not be counted as a separate regimen; adjuvant chemotherapy or
chemotherapy administered as part of concurrent chemotherapy and radiation therapy for
the treatment of lung cancer will not count as a prior regimen of systemic therapy as
long as recurrence of patient's lung cancer occurred more than 12 months after the
last day of chemotherapy
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients must not have received any chemotherapy,
biologic agent, or any investigational agent within 14 days prior to registration.
Patients must have recovered from any adverse events to Common Terminology Criteria
for Adverse Events (CTCAE) grade 0-1 prior to registration
- PRIOR/CONCURRENT THERAPY CRITERIA: Prior treatment with an anti-PD-1 or anti-PDL1 is
not required
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients must not have received prior docetaxel;
patients must not have received therapy with a drug known to be either a
mitogen-activated protein kinase (MEK) inhibitor or a phosphatidylinositol 3 kinase
(PI3K)/v-akt murine thymoma viral oncogene homolog 1 (AKT)/mammalian target of
rapamycin (mTOR) pathway inhibitor
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients must have recovered from any adverse
effects from prior therapy (except alopecia) to =< CTCAE grade 1 prior to registration
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients may have had prior radiation therapy as
long as it has not affected greater than 25% of the bone marrow and at least one
measurable lesion is outside the area of prior radiation; at least 7 days must have
elapsed since last radiation treatment; patients must have recovered from any adverse
events from prior radiation therapy to =< CTCAE grade 1
- PRIOR/CONCURRENT THERAPY CRITERIA: Patients must not have had a major surgery within
28 days prior to registration; patients must have recovered from any adverse effects
of prior surgery to the satisfaction of the treating physician; biopsies and central
IV access placement are not considered major surgery
- PRIOR/CONCURRENT THERAPY CRITERIA: Because the composition, pharmacokinetics (PK), and
metabolism of many herbal supplements are unknown, the concurrent use of all herbal
supplements is prohibited during the study (including but not limited to St. John's
wort, kava, ephedra [ma huang], ginko biloba, dehydroepiandrosterone [DHEA], yohimbe,
saw palmetto, or ginseng)
- CLINICAL/LABORATORY CRITERIA: Patients must have Zubrod performance status of 0-2
- CLINICAL/LABORATORY CRITERIA: Absolute neutrophil count (ANC) >= 1500/mcL; these
results must be obtained within 28 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Platelet count >= 100,000/mcL; these results must be
obtained within 28 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Hemoglobin >= 9 grams/dl; these results must be obtained
within 28 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Total bilirubin =< 1.5 x institutional upper limit of
normal (IULN); these results must be obtained within 28 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) =< 2.5 x IULN (or =< 5 x IULN for patients with known liver
metastases); these results must be obtained within 28 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Serum creatinine =< 1.5 x IULN OR measured or calculated
creatinine clearance >= 40 mL/min; this result must have been obtained within 28 days
prior to registration
- CLINICAL/LABORATORY CRITERIA: Patients must be able to swallow oral medications and
must not have a gastro-intestinal disorder with diarrhea as a major symptom or that
may alter absorption such as malabsorption syndromes or gastric resection
- CLINICAL/LABORATORY CRITERIA: Patient must not have prior history of interstitial lung
disease or pneumonitis
- CLINICAL/LABORATORY CRITERIA: Patients must not have history of significant co-morbid
illness inclusive of but not restricted to New York Heart Association class II,
congestive cardiac failure, uncontrolled hypertension, history of myocardial
infarction, unstable angina, coronary angioplasty, stenting or cerebrovascular
accident within 6 months prior to registration or any other illness that in the
assessment of the treating physician would compromise the ability of the patient to
participate in this study
- CLINICAL/LABORATORY CRITERIA: Patients must have corrected QT (QTc) interval =< 480
msec (using the Bazett's formula) on electrocardiogram (ECG) performed within 42 days
prior to registration; history or evidence of current clinically significant
uncontrolled arrhythmias are not eligible; however, patients with controlled atrial
fibrillation for > 30 days prior to randomization are eligible; patients must not have
atrial fibrillation > grade 2 on the screening ECG; patients with CTCAE grade 1-2
atrial fibrillation on their screening ECG must have a second ECG performed prior to
registration and more than 30 days from the screening ECG (either before or after)
with the most recent ECG showing stable or improving grade of atrial fibrillation
- CLINICAL/LABORATORY CRITERIA: Patients must have a left ventricular ejection fraction
(LVEF) >= institutional lower limit of normal (ILLN) by echocardiography (ECHO) or
multi-gated acquisition scan (MUGA) within 42 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Patients must not have untreated or unresolved
retinopathy or have a history (or current evidence) of retinal vein occlusion
determined by an ophthalmology exam within 42 days prior to registration
- CLINICAL/LABORATORY CRITERIA: Patients must not have an immediate or delayed
hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib,
or excipients, or to dimethyl sulfoxide (DMSO) or other agents used in the study
- CLINICAL/LABORATORY CRITERIA: Patients must not have a known history of active
hepatitis B or C infection (defined as presence of hepatitis [Hep] B surface antigen
[sAg] and/or Hep B deoxyribonucleic acid [DNA] and/or Hep C ribonucleic acid [RNA]);
patients must not have a known history of human immunodeficiency virus (HIV)
seropositivity
- CLINICAL/LABORATORY CRITERIA: No other prior malignancy is allowed except for the
following: adequately treated basal cell or squamous cell skin cancer, in situ
cervical cancer, adequately treated stage I or II cancer from which the patient is
currently in complete remission, or any other cancer from which the patient has been
disease free for three years; patients with localized prostate cancer who are being
followed by an active surveillance program are also eligible
- CLINICAL/LABORATORY CRITERIA: Patients must not be pregnant or nursing due to the risk
of fetal or nursing infant harm; women/men of reproductive potential must have agreed
to use an effective contraceptive method (hormonal or barrier method of birth control;
abstinence) prior to study entry, during the study participation and for 4 months
after the last dose of the drug; a woman is considered to be of "reproductive
potential" if she has had menses at any time in the preceding 12 consecutive months;
in addition to routine contraceptive methods, "effective contraception" also includes
heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect
of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or
bilateral tubal ligation; however, if at any point a previously celibate patient
chooses to become heterosexually active during the time period for use of
contraceptive measures outlined in the protocol, he/she is responsible for beginning
contraceptive measures
- SPECIMEN SUBMISSION CRITERIA: Patients must be offered optional participation in
banking of specimens for future research
- REGULATORY CRITERIA: Patients must be informed of the investigational nature of this
study and must sign and give written informed consent in accordance with institutional
and federal guidelines
- REGULATORY CRITERIA: As a part of the Oncology Patient Enrollment Network (OPEN)
registration process the treating institution's identity is provided in order to
ensure that the current (within 365 days) date of institutional review board approval
for this study has been entered in the system
