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Trametinib and Docetaxel in Treating Patients With Recurrent or Stage IV KRAS Mutation Positive Non-small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT02642042
Recruitment Status : Active, not recruiting
First Posted : December 30, 2015
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well trametinib and docetaxel work in treating patients with stage IV KRAS mutation positive non-small cell lung cancer or cancer that has come back. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as docetaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving trametinib with docetaxel may work better in treating non-small cell lung cancer.

Condition or disease Intervention/treatment Phase
KRAS Gene Mutation Recurrent Lung Non-Small Cell Carcinoma Stage IV Non-Small Cell Lung Cancer AJCC v7 Drug: Docetaxel Other: Laboratory Biomarker Analysis Drug: Trametinib Phase 2

Detailed Description:

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.

TERTIARY 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. Courses 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 53 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Trial of Trametinib With Docetaxel in Patients With KRAS Mutation Positive Non-small Cell Lung Cancer (NSCLC) and Progressive Disease Following One or Two Prior Systemic Therapies
Actual Study Start Date : July 18, 2016
Estimated Primary Completion Date : October 15, 2020
Estimated Study Completion Date : October 15, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: Treatment (trametinib, docetaxel)
Patients receive trametinib PO on days 1-21. Patients also receive docetaxel IV on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Docetaxel
Given IV
Other Names:
  • Docecad
  • RP56976
  • Taxotere
  • Taxotere Injection Concentrate

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist




Primary Outcome Measures :
  1. Response rate (confirmed and unconfirmed complete and partial responses) in all KRAS mutant patients (both those with G12C mutations and those with non-G12C mutations) [ Time Frame: Up to 3 years ]

Secondary Outcome Measures :
  1. Response rate in patients with a G12C mutation [ Time Frame: Up to 3 years ]
  2. Progression free survival [ Time Frame: From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 3 years ]
    Progression free survival estimates will be calculated using the method of Kaplan-Meier. 95% confidence for the medians will be constructed using the method of Brookmeyer-Crowley.

  3. Overall survival [ Time Frame: Up to 3 years ]
    Overall survival estimates will be calculated using the method of Kaplan-Meier. 95% confidence for the medians will be constructed using the method of Brookmeyer-Crowley.

  4. Incidence of toxicity graded according to the National Cancer Institute CTCAE version 4.0 [ Time Frame: Up to 3 years ]
    Toxicity rates can be estimated to within ± 14% with 95% confidence.


Other Outcome Measures:
  1. Response rates in the presence of p53 mutations [ Time Frame: Up to 3 years ]
    The response rate between patients with dysfunctional p53 will be compared to the response rate in patients without p53 dysfunction.

  2. Response rates in the presence of LKB1 mutations [ Time Frame: Up to 3 years ]
    The response rate between patients with LKB1 disruption will be compared to the response rate in patients without LKB1 disruption. The response rate will be estimated by LKB1 disruption status (yes/no), along with 95% confidence intervals around the estimated proportions. This analysis will evaluate if disruption in LKB1 is associated with a lower probability of response.



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 24 hours 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: 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 uncontrolled 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; 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02642042


  Show 607 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Shirish M Gadgeel Southwest Oncology Group

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02642042     History of Changes
Other Study ID Numbers: NCI-2015-02250
NCI-2015-02250 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1507
S1507 ( Other Identifier: SWOG )
S1507 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: December 30, 2015    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: October 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Docetaxel
Trametinib
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Protein Kinase Inhibitors
Enzyme Inhibitors