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

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2016 by National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI) Identifier:
First received: March 4, 2014
Last updated: April 15, 2016
Last verified: April 2016
This phase I/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
Extensive Stage Small Cell Lung Carcinoma
Recurrent Colorectal Carcinoma
Recurrent Non-Small Cell Lung Carcinoma
Recurrent Pancreatic Carcinoma
Recurrent Small Cell Lung Carcinoma
Solid Neoplasm
Stage III Pancreatic Cancer
Stage IIIA Colorectal Cancer
Stage IIIA Non-Small Cell Lung Cancer
Stage IIIB Colorectal Cancer
Stage IIIB Non-Small Cell Lung Cancer
Stage IIIC Colorectal Cancer
Stage IV Non-Small Cell 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: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
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 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 30 days ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • Response rate (partial response [PR] + complete response [CR]) assessed according to RECIST version 1.1 (Phase II) [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 BCL2 family signaling (Phase Ib and II) [ Time Frame: Baseline to up to 30 days ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
  • Response rate (PR + CR) (Phase Ib) [ Time Frame: Up to 30 days ] [ Designated as safety issue: No ]
    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.
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 Kirsten rat sarcoma viral oncogene homolog (KRAS) 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 I, 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.

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


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Patients must have histologically- or cytologically-confirmed diagnosis of KRAS 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 will be allowed on study if they have brain metastases that have been treated and have been stable for at least 2 months
  • 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 Recruiting
Boston, Massachusetts, United States, 02114
Contact: Ryan B. Corcoran    617-726-8599   
Principal Investigator: Ryan B. Corcoran         
Dana-Farber/Harvard Cancer Center Recruiting
Boston, Massachusetts, United States, 02115
Contact: Ryan B. Corcoran    617-643-0798   
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  13-505  13-505  9525  P30CA006516  U01CA062490  UM1CA186709 
Study First Received: March 4, 2014
Last Updated: April 15, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Lung Neoplasms
Pancreatic Neoplasms
Small Cell Lung Carcinoma
Bronchial Neoplasms
Carcinoma, Bronchogenic
Colonic Diseases
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Lung Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Glandular and Epithelial
Pancreatic Diseases
Rectal Diseases
Respiratory Tract Diseases
Respiratory Tract Neoplasms
Thoracic Neoplasms
Antineoplastic Agents processed this record on May 04, 2016