Last updated: 11/03/2018 20:49:50

A Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity of Trametinib in combination with Palbociclib in Subjects with Solid Tumors

GSK study ID
200344
See study documents
Clinicaltrials.gov ID
NCT02065063
EudraCT ID
Not applicable
EU CT Number
Not applicable
Trial status
Completed
Completed
Overview
Eligibility
Locations
Study documents
Results summary
Plain language summaries
Additional information

Trial overview

Official title: A Dose-Escalation, Phase I/II, Open-Label, Three-Part Study of the MEK Inhibitor, trametinib, Combined with the CDK4/6 Inhibitor, palbociclib, To Investigate the Safety, Pharmacokinetics, Pharmacodynamics, and Anti-Cancer Activity in Subjects with Solid Tumors
Trial description: This is a dose-escalation, Phase I/II, open-label, three-part study. Part 1 is designed to determine the recommended dose and schedule for the orally administered MEK inhibitor trametinib, given together with the CDK4/6 inhibitor palbociclib in subjects with solid tumors. Multiple dose levels of each inhibitor will be tested to determine the recommended dose and schedule. Part 2 will evaluate the effect of the combination on tumor biomarkers safety, and anti-cancer activity in subjects with cutaneous melanoma that do not have a change at BRAFV600. Approximately 100-200 subjects will be enrolled. All subjects will receive trametinib and/or palbociclib until disease progression, death, consent withdrawal or unacceptable adverse event (AE).
Data was only collected and analyzed for the Phase I component of the study, the Phase II component of the study was terminated without data collection
Primary purpose:
Treatment
Trial design:
Crossover Assignment
Masking:
None (Open Label)
Allocation:
Non-randomized
Primary outcomes:

Part 1: Change from baseline in vital signs

Timeframe: Up to 36 months

Part 1: Change from baseline in physical examination findings

Timeframe: Up to 36 months

Part 1: Change from baseline in 12-lead electrocardiograms (ECG) assessment

Timeframe: Up to 36 months

Part 1: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment

Timeframe: Up to 36 months

Part 1: Change from baseline in chemistry and hematology laboratory values

Timeframe: Up to 36 months

Part 1: Number of subjects with adverse events (AEs)

Timeframe: From the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment

Part 1: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration

Timeframe: Cycle 1 Day 15 (pre-dose, and 1, 2, 4, 6, 8, and 10 hours post dose) and Cycle 2 Day 15 (pre-dose)

Part 1: Number of subjects with anti-cancer activity

Timeframe: Up to 36 months

Part 2: Change from baseline in tumor biomarkers

Timeframe: Screening and Cycle 1 Day 15 (pre-dose)

Secondary outcomes:

Part 1: GSK1120212 and PD-0332991 PK parameters following repeat-dose administration of trametinib and palbociclib

Timeframe: Cycle 1 Day 15 (pre-dose, and 1, 2, 4, 6, 8, and 10 hours post dose) and Cycle 2 Day 15 (pre-dose)

Part 1 and Part 2: Number of subjects with response rate

Timeframe: Up to 36 months for part 1 and 24 months for part 2

Part 1 and Part 2 : Number of subjects with Duration of response (DOR)

Timeframe: Up to 36 months for part 1 and 24 months for part 2

Part 1 and Part 2: Number of subjects with Progression-free survival (PFS)

Timeframe: Up to 36 months for part 1 and 24 months for part 2

Part 2 : Change from baseline in vital signs

Timeframe: Up to 24 months

Part 2: Change from baseline in physical examination findings

Timeframe: Up to 24 months

Part 2: Change from baseline in 12-lead electrocardiograms (ECG) assessment

Timeframe: Up to 24 months

Part 2: Change from baseline in echocardiogram (ECHO) or Multi Gated Acquisition (MUGA) scans assessment

Timeframe: Up to 24 months

Part 2 : Change from baseline in chemistry and hematology laboratory values

Timeframe: Up to 24 months

Part 2 : Number of subjects with adverse events (AEs)

Timeframe: From the time the first dose of study treatment is administered until 30 days following discontinuation of study treatment

Part 2: Composite of pharmacokinetic (PK) parameters following trametinib and palbociclib administration

Timeframe: Cycle 1 Day 15

Interventions:
Drug: Trametinib
Drug: Palbociclib
Enrollment:
28
Observational study model:
Not applicable
Primary completion date:
2016-23-06
Time perspective:
Not applicable
Clinical publications:
Not applicable
Medical condition
Cancer
Product
palbociclib, trametinib
Collaborators
Pfizer
Study date(s)
April 2014 to June 2016
Type
Interventional
Phase
1

Participation criteria

Sex
Female & Male
Age
18+ years
Accepts healthy volunteers
No
  • Inclusion Criteria for Part 1 and Part 2
  • Subjects >=18 years old.
  • Prior treatment with a MEK inhibitor or a CDK4/6 inhibitor.
  • BRAFV600 mutation positive.
Inclusion and exclusion criteria
Inclusion criteria:
  • Inclusion Criteria for Part 1 and Part 2
  • Subjects >=18 years old.
  • Signed written informed consent.
  • All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as listed in the protocol) must be <=grade 1 according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE version 4.0) at the time of randomization.
  • Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • Women of childbearing potential must have a negative serum pregnancy test within 7 days of first dose of study treatment and agree to use effective contraception as defined in the protocol.
  • Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in the protocol.
  • An Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Adequate baseline organ function as defined in the protocol.
  • Other Inclusion criteria for Part 1
  • Histologically or cytologically confirmed diagnosis of solid tumor malignancy that is not responsive to standard therapies or for which there is no approved or curative therapy.
  • Subjects with cutaneous melanoma must provide either a fresh or archived tumor sample for genetic analysis including determination of or confirmation of BRAF and NRAS genetic status based on local laboratory results. To ensure prompt delivery of tumor samples, tissue shipment tracking information must be provided before administration of study treatment can be initiated.
  • Other Inclusion criteria for Part 2
  • Measurable disease (i.e., present with at least one measurable lesion per RECIST, version 1.1).
  • Histologically or cytologically confirmed diagnosis of advanced or metastatic cutaneous melanoma that is determined to be BRAFV600 wild type and either NRAS wild type or NRAS mutation type. Note: Subjects with a melanoma of unknown primary origin may be allowed to enrol if all other types of melanoma (e.g., uveal, mucosal, or acral) can be reasonably ruled out.
  • Must provide either a fresh or archived tumor sample for genetic analysis.
  • Accessible tumor for biopsy and willingness to provide pre-dose tumor biopsies on Days 1 and Day 15.
  • Inclusion Criteria for Part 3
  • The inclusion criteria for Part 3 will be based on emerging data from Parts 1 and 2 and will be specified in an amendment.
Exclusion criteria:
  • Prior treatment with a MEK inhibitor or a CDK4/6 inhibitor.
  • BRAFV600 mutation positive.
  • For Part 1, subjects may have had any number of prior systemic anti-cancer treatments, but may not have received more than 2 schedules of myeloablative chemotherapy. For Parts 2 and 3, more than two prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma are not permitted. Prior systemic treatment in the adjuvant setting is allowed. (Note: Ipilimumab treatment must end at least 8 weeks prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3.)
  • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3), or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3).
  • Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3).
  • Current use of a prohibited medication as described in the protocol.
  • History of another malignancy (Part 3 only). Exception: Subjects who have been disease-free for 3 years, or subjects with a history of completely resected, non-melanoma skin cancer, or subjects with indolent second malignancies are eligible. T1a melanoma and melanoma in situ are permitted. Consult GlaxoSmithKline (GSK) Medical Monitor if unsure whether second malignancies meet requirements specified above.
  • Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
  • 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).
  • History of leptomeningeal disease or spinal cord compression secondary to metastasis.
  • Brain metastasis, unless previously treated with surgery or stereotactic radiosurgery and the disease has been confirmed stable (i.e., no increase in lesion size, and stable or decreased doses of corticosteroids) for at least 6 weeks with two consecutive scans prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3). (Enzyme inducing anticonvulsants are not allowed while subjects are on study treatment. Prior whole-brain radiation as adjuvant treatment is allowed.)
  • A history or evidence of cardiovascular risk including any of the following: A QT interval corrected for heart rate using the Fridericia’s formula (QTcF) >=480 millisecond (msec); A history or evidence of current clinically significant uncontrolled arrhythmias; Exception: Subjects with atrial fibrillation controlled for >30 days prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3); History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to Study Day 1 (Parts 1 and 2) or randomization (Part 3); A history or evidence of current >=Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines; Treatment refractory hypertension defined as a blood pressure of systolic>140 millimeters of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by anti-hypertensive therapy; Patients with intra-cardiac defibrillators or permanent pacemakers; Known cardiac metastases.
  • A history or current evidence/risk of Retinal Vein Occlusion (RVO) or Central Serous Retinopathy (CSR) including: History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes); or Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as: Evidence of new optic disc cupping; Evidence of new visual field defects; Intraocular pressure >21 mmHg as measured by tonography.
  • Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
  • History of interstitial lung disease or pneumonitis.
  • Females who are nursing.

Trial location(s)

Location
Status
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Location
GSK Investigational Site
Boston, Massachusetts, United States, 02114
Status
Study Complete
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Location
GSK Investigational Site
Nashville, Tennessee, United States, 37232
Status
Study Complete
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Location
GSK Investigational Site
Houston, Texas, United States, 77030-4009
Status
Study Complete
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Study documents

Scientific result summary
Available language(s): English
Download document(s)

If you wish to request for full study report, please contact - [email protected]

Results overview

Refer to study documents

Recruitment status
Completed
Actual primary completion date
2016-23-06
Actual study completion date
2016-23-06

Plain language summaries

Plain language summaries of clinical trial results for Phase 2-4 clinical trials that were initiated on or after January 2022 will be posted by GSK within one year following study completion.

Additional information about the trial

Additional information
Not applicable
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