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CancerPhase 1NCT02065063

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

A Phase 1 study testing Trametinib and Palbociclib in people with Cancer, run by GlaxoSmithKline at 3 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Cancer
What is being tested?
Trametinib and Palbociclib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
3 sitesUnited States
Study dates
22 Apr 2014to 23 Jun 2016
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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.
  • The inclusion criteria for Part 3 will be based on emerging data from Parts 1 and 2 and will be specified in an amendment.

Who cannot join

  • 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.
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  • 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 locations and contacts

3 sites in 1 country.

United States3 sites

  • GSK Investigational Site

    Boston, Massachusetts, 02114

  • GSK Investigational Site

    Houston, Texas, 77030-4009

  • GSK Investigational Site

    Nashville, Tennessee, 37232

Other trials in United States

About this study

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

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

Conditions
Cancer
Being tested
Trametinib, Palbociclib
Keywords
MEK inhibitor, PD-0332991, CDK4/6 inhibitor, palbociclib, NRAS wild type, cutaneous melanoma, GSK1120212, trametinib, NRAS mutant, BRAFV600 wild type
Medical subject headings
Neoplasms, Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • TrametinibDrug

    Trametinib is available as a 0.5 mg yellow oval tablet or as a 2.0 mg pink round tablet.

  • PalbociclibDrug

    Palbociclib is available as a 75 mg (size 2 sunset yellow) or 100 mg (size 1 sunset yellow/caramel) or 125 mg (size 0 caramel) capsule.

Study groups in NCT02065063
Study groupRoleWhat they receive
Part 1ExperimentalPart 1 is a dose finding phase in which subjects will be initially administered 75 milligram (mg) of palbociclib (21 days on/7 days off) and 1.5 mg of trametinib (once daily continuous dosing) in each 28-day cycle. Dose escalations will continue based on predefined parameters until the RCR is identified. The RCR will not exceed the maximum tolerated dose (MTD).
Receives: Drug: Trametinib; Drug: Palbociclib
Part 2ExperimentalOnce the MTD and schedule have been determined, two expansion cohorts of up to 20 subjects each will be enrolled. The cohorts will enroll subjects with BRAF-WT (wild type) cutaneous melanoma that are either NRAS-WT or NRAS-MUT (mutated). Subjects will be dosed at or below the RCR to determine the inhibition of selected tumor biomarkers at each dose level.
Receives: Drug: Trametinib; Drug: Palbociclib
Part 3ExperimentalPart 3 will be a randomized Phase II study in which subjects will be administered the RCR as previously identified. Part 3 will be initiated only if an RCR is identified, and sufficient anticancer activity is observed in Parts 1 and 2.
Receives: Drug: Trametinib; Drug: Palbociclib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Part 1: Change from baseline in vital signs

    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate

    Measured: Up to 36 months

  2. Part 1: Change from baseline in physical examination findings

    A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities

    Measured: Up to 36 months

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

    Measured: Up to 36 months

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

    An ECHO (preferred) or a MUGA scan will be performed at baseline to assess cardiac ejection fraction and cardiac valve morphology for the purpose of study eligibility

    Measured: Up to 36 months

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

    Measured: Up to 36 months

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

    All subjects (approximately 50)

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

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

    PK parameters will include: maximum observed plasma concentration (Cmax), time to Cmax (tmax), area under the plasma concentration-time curve (AUC[0-t]), oral clearance (CL/F), minimum observed concentration (Cmin). Blood samples of approximately 2 mL for trametinib and 2 mL for palbociclib (4 mL total) will be collected for PK analysis at each timepoint shown for all subjects (approximately 50)

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

  8. Part 1: Number of subjects with anti-cancer activity

    Disease progression and response evaluations will be determined according to the definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) for all subjects (approximately 50 in Part 1)

    Measured: Up to 36 months

  9. Part 2: Change from baseline in tumor biomarkers

    Change from baseline in biomarkers like pERK, total Rb, Ki67, FoxM1, p16, and CCDN1 will be calculated. These markers will be evaluated in formalin-fixed, paraffin-embedded tissue via immunohistochemistry (IHC)

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

Secondary outcomes (11)

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

    The following PK parameters will be calculated: Area under the concentration-time curve over the dosing interval (AUC[0-tau]), minimum observed concentration (Cmin), pre-dose (trough) concentration at the end of the dosing interval (Ctau), maximum observed concentration (Cmax), time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2) (if data permits)

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

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

    Subjects whose disease responds (either complete response [CR] or partial response [PR]), using RECIST Version 1.1 (up to approximately 100 subjects)

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

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

    up to approximately 100 subjects

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

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

    up to approximately 100 subjects

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

  5. Part 2 : Change from baseline in vital signs

    Vital sign measurements will include systolic and diastolic blood pressure, temperature, respiration rate and pulse rate

    Measured: Up to 24 months

  6. Part 2: Change from baseline in physical examination findings

    A complete physical examination will include assessments of the head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes and extremities

    Measured: Up to 24 months

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

    Measured: Up to 24 months

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

    An ECHO (preferred) or a MUGA scan will be performed at baseline to assess cardiac ejection fraction and cardiac valve morphology for the purpose of study eligibility

    Measured: Up to 24 months

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

    Measured: Up to 24 months

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

    up to 40 subjects

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

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

    PK parameters will include: Cmax, tmax, AUC(0-t), CL/F, Cmin. Blood samples of approximately 2 mL for trametinib and 2 mL for palbociclib (4 mL total) will be collected for PK analysis (up to 40 subjects)

    Measured: Cycle 1 Day 15

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Feb 2014 (estimated)
  2. Study start22 Apr 2014
  3. Primary completion23 Jun 2016
  4. Study completion23 Jun 2016

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Crossover
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02065063
Sponsor's protocol ID
200344
Status last verified
May 2018
First submitted
5 Dec 2013
Last updated
1 Jun 2018
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Trametinib and Palbociclib in people with Cancer, run by GlaxoSmithKline at 3 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 1 Jun 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Part 1: Change from baseline in vital signs (time frame: Up to 36 months). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02065063.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Jun 2018.

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