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Trametinib and Navitoclax in Treating Patients With Advanced or Metastatic Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2017 by National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: March 4, 2014
Last updated: May 11, 2017
Last verified: May 2017
This phase Ib/II trial studies the side effects and best dose of trametinib and navitoclax in treating patients with solid tumors that have spread to other places in the body or cannot be cured or controlled with treatment. Trametinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Advanced Malignant Solid Neoplasm
KRAS Gene Mutation
Metastatic Malignant Solid Neoplasm
NRAS Gene Mutation
Recurrent Colorectal Carcinoma
Recurrent Lung Carcinoma
Recurrent Pancreatic Carcinoma
Stage III Colorectal Cancer
Stage III Lung Cancer
Stage III Pancreatic Cancer
Stage IIIA Colorectal Cancer
Stage IIIB Colorectal Cancer
Stage IIIC Colorectal Cancer
Stage IV Colorectal Cancer
Stage IV Lung Cancer
Stage IV Pancreatic Cancer
Stage IVA Colorectal Cancer
Stage IVB Colorectal Cancer
Other: Laboratory Biomarker Analysis
Biological: Navitoclax
Other: Pharmacological Study
Drug: Trametinib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: An Open Label, Two-Part, Phase Ib/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of the MEK Inhibitor Trametinib and the BCL2-Family Inhibitor Navitoclax (ABT-263) in Combination in Subjects With KRAS or NRAS Mutation-Positive Advanced Solid Tumors

Resource links provided by NLM:

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Incidence of adverse events graded according to National Cancer Institute CTCAE v4.0 (Phase Ib and II) [ Time Frame: Up to 42 days ]
  • Progression-free survival (Phase II) [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 30 days ]
  • Response rate (partial response [PR] + complete response [CR]) assessed according to RECIST version 1.1 (Phase II) [ Time Frame: Up to 30 days ]
    The 95% confidence intervals should be provided.

Secondary Outcome Measures:
  • Percent change in levels of apoptosis markers (cleaved caspase-3) (Phase Ib and II) [ Time Frame: Baseline to up to 30 days ]
    Results will be reported as a % increase or decrease in level of a given marker after treatment initiation (post treatment biopsy) relative to before treatment (pre-treatment biopsy).

  • Percent change in levels of proliferation markers (Ki67) (Phase Ib and II) [ Time Frame: Baseline to up to 30 days ]
    Results will be reported as a % increase or decrease in level of a given marker after treatment initiation (post treatment biopsy) relative to before treatment (pre-treatment biopsy).

  • Percent change in levels of proteins/messenger ribonucleic acids (mRNAs) implicated in mitogen-activated protein kinase signaling (Phase Ib and II) [ Time Frame: Baseline to up to 30 days ]
    Results will be reported as a percent (%) increase or decrease in level of a given marker after treatment initiation (post treatment biopsy) relative to before treatment (pre-treatment biopsy).

  • Percent change in levels of proteins/mRNAs implicated in B-cell lymphoma 2 family signaling (Phase Ib and II) [ Time Frame: Baseline to up to 30 days ]
    Results will be reported as a % increase or decrease in level of a given marker after treatment initiation (post treatment biopsy) relative to before treatment (pre-treatment biopsy).

  • Pharmacokinetic parameters (observed plasma drug concentration, area under the curve, half-life) for trametinib and navitoclax when administered in combination (Phase Ib) [ Time Frame: Pre-dose trametinib (-1 hours [h]), pre-dose navitoclax (0 h), 2h, 4h, 6h, 8h, day 1 of courses 4, 8, and 12 ]
  • Response rate (PR + CR) (Phase Ib) [ Time Frame: Up to 30 days ]
    The 95% confidence intervals should be provided.

Estimated Enrollment: 130
Study Start Date: March 2014
Estimated Primary Completion Date: September 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (trametinib, navitoclax)
Patients receive trametinib PO QD and navitoclax PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14.
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Navitoclax
Given PO
Other Names:
  • A-855071.0
  • ABT-263
  • BcI-2 Family Protein Inhibitor ABT-263
Other: Pharmacological Study
Correlative studies
Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist

Detailed Description:


I. To determine the dose-limiting toxicities of trametinib in combination with navitoclax, and the maximal doses at which both drugs can be safely administered together. (Phase Ib) II. To determine the response rate of the combination of trametinib and navitoclax in subjects with KRAS or NRAS mutation-positive advanced or metastatic solid tumors in disease-specific expansion cohorts. (Phase II) III. To confirm the safety and tolerability of trametinib and navitoclax in combination at the recommended phase 2 dose (RP2D) determined in the Phase 1b portion. (Phase II)


I. To determine the pharmacokinetics of both drugs administered together. (Phase Ib) II. To assess for evidence of response to therapy. (Phase Ib) III. To evaluate the pharmacodynamic response to therapy in tumor biopsies. (Phase Ib) IV. To evaluate the pharmacodynamic response to therapy in tumor biopsies (first 15 patients enrolled overall). (Phase II)

OUTLINE: This is a phase Ib, dose-escalation study followed by a phase II study.

Patients receive trametinib orally (PO) once daily (QD) and navitoclax PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If unacceptable toxicity is observed, patients may receive trametinib PO QD on days 1-14.

After completion of study treatment, patients are followed up for 30 days.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have histologically- or cytologically-confirmed diagnosis of KRAS or NRAS mutation-positive malignancy that is metastatic or unresectable and for which standard curative measures do not exist or are no longer effective; patients must have activating mutations affecting codons 12, 13, 61, or 146 as determined in a Clinical Laboratory Improvement Amendments (CLIA)-certified lab to be eligible for this study
  • Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm by chest x-ray or as >= 10 mm with computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Participants must have received at least one line of prior systemic chemotherapy and must have experienced documented radiographic progression or intolerance on this therapy
  • Paired pre-treatment and post-treatment biopsies are required for all patients on Part 1 and first 15 patients in Part 2; participants must have available archival tumor tissue (at least 20 unstained slides); if archival tissue is not available or is found not to contain tumor tissue, a fresh biopsy is required; if a patient is having a tumor biopsy, less than 20 unstained slides are acceptable with approval of the principal investigator (PI); biopsies will only be performed in a given patient if they are not deemed to involve unacceptable risk based on the sites of disease and other concurrent medical conditions
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1
  • Life expectancy of greater than 3 months
  • 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
  • All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events version 4 (CTCAE v 4) grade =< 1 (except alopecia) at the time of enrollment
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count (ANC) >= 1,200/mcL (subjects may be treated with hematopoietic growth factors to achieve or maintain this level)
  • Hemoglobin >= 9 g/dL
  • Platelets >= 100 x 10^9/L
  • Albumin >= 2.5 g/dL
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients with Gilbert's syndrome may have serum bilirubin > 1.5 × ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN
  • Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.2 x institutional ULN
  • Left ventricular ejection fraction >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)
  • Women of child-bearing potential and men with a female partner of child bearing potential must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and up to 4 months following completion of therapy:

    • Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration)
    • Vasectomized male subject or vasectomized partner of female subjects
    • Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 1 month after study completion
    • Intrauterine device (IUD)
    • Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams)
    • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 4 months following completion of therapy
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months); 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; the potential hazard to the fetus should be explained to the patient and partner (as applicable)
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer or any carcinoma in situ and/or patients with indolent second malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements
  • History of interstitial lung disease or pneumonitis
  • Any major surgery, extensive radiotherapy (> 15 days of treatment), chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to first dose of study treatment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to first dose of study treatment
  • Use of other investigational drugs within 28 days (or five half-lives, whichever is shorter; with a minimum of 14 days from the last dose) preceding the first dose of study drug(s) and during the study
  • Patients with known brain metastases should be excluded from this clinical trial; exception: patients with brain metastases will be allowed on study if they have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 21 days of stable neurologic function and no evidence of central nervous system (CNS) disease progression as determined by computed tomography (CT) or magnetic resonance imaging (MRI) within 21 days prior to the first dose of study drug
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO), or to compounds of similar chemical or biologic composition to navitoclax
  • Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

    • Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed)
    • Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis
    • 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], ginkgo biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)
    • The following concomitant medications are not allowed during navitoclax administration: warfarin, clopidogrel (Plavix), ibuprofen, tirofiban (Aggrastat), and other anticoagulants, drugs, or herbal supplements that affect platelet function are excluded, with the exception of low-dose anticoagulation medications (such as heparin) that are used to maintain the patency of a central intravenous catheter; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm^3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor
  • Caution should be exercised when dosing navitoclax concurrently with cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) substrates; common CYP2C8 substrates include paclitaxel, statins, and glitazones, whereas CYP2C9 substrates include phenytoin and warfarin; when possible, investigators should switch to alternative medications or monitor the patients closely (particularly in the case of medications that have a narrow therapeutic window such as warfarin; use of warfarin is specifically prohibited while on study); cytochrome P450, family 3, subfamily A (CYP3A) inhibitors such as ketoconazole and clarithromycin are not allowed 7 days prior to the first dose of navitoclax or during navitoclax administration; as part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product; patient instructions and information of possible drug interactions will be given to all patients upon enrollment in this study
  • History or current evidence/risk of retinal vein occlusion (RVO)
  • History or evidence of cardiovascular risk including any of the following:

    • Left ventricle ejection fraction (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 (exception: patients with controlled atrial fibrillation for > 30 days prior to enrollment are eligible)
    • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
    • History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system
    • Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy
    • Known cardiac metastases
    • Patients with intra-cardiac defibrillators
  • Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible); patients with human immunodeficiency virus (HIV) are not eligible if on anti-retroviral medications
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Subject has an underlying condition predisposing them to bleeding or currently exhibits signs of clinically significant bleeding
  • Subject has a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug
  • Subject has a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months)
  • Pregnant women or nursing mothers
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02079740

United States, Massachusetts
Massachusetts General Hospital Cancer Center Suspended
Boston, Massachusetts, United States, 02114
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Ryan B. Corcoran    877-726-5130      
Principal Investigator: Ryan B. Corcoran         
Sponsors and Collaborators
National Cancer Institute (NCI)
Principal Investigator: Ryan Corcoran Dana-Farber Cancer Institute
  More Information

Responsible Party: National Cancer Institute (NCI) Identifier: NCT02079740     History of Changes
Other Study ID Numbers: NCI-2014-00461
NCI-2014-00461 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9525 ( Other Identifier: Dana-Farber Cancer Institute )
9525 ( Other Identifier: CTEP )
P30CA006516 ( US NIH Grant/Contract Award Number )
P50CA127003 ( US NIH Grant/Contract Award Number )
U01CA062490 ( US NIH Grant/Contract Award Number )
UM1CA186709 ( US NIH Grant/Contract Award Number )
Study First Received: March 4, 2014
Last Updated: May 11, 2017

Additional relevant MeSH terms:
Lung Neoplasms
Colorectal Neoplasms
Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Pancreatic Diseases
Endocrine System Diseases
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action processed this record on May 25, 2017