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CancerPhase 1NCT02292732

A Pharmacokinetics (PK) and Safety Study to Determine the Effect of Repeat Dosing of Trametinib on Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) in Female Subjects With Solid Tumors

A Phase 1 study testing Trametinib 0.5 mg, Trametinib 2 mg and ORTHO-NOVUM® tablet 1/35 in people with Cancer, run by GlaxoSmithKline.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

This is a Phase I, open-label, non-randomized, sequential, two-period, repeat-dose study to evaluate the effect of trametinib 2 milligram (mg) once daily on the repeat-dose pharmacokinetic (PK) of an oral contraceptive (OC) containing norethindrone (NE) and ethinyl estradiol (EE) (ORTHO-NOVUM® tablets: 1 mg NE + 0.035… Read more about this study

Who is it for?
Ages 18 to 58 years, women only
Conditions the study is for
Cancer
What is being tested?
Trametinib 0.5 mg, Trametinib 2 mg and ORTHO-NOVUM® tablet 1/35
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
0 participants
Where
No sites listed yet
Study dates
Feb 2016to May 2017
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 to 58 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • Is a female subject >=18 years but <59 years of age at the time of signing the informed consent.
  • Has a histologically or cytologically confirmed diagnosis of a solid tumor malignancy (except for any excluded malignancies listed in Exclusion Criteria) that is not responsive to standard therapy(ies) or for which there is no approved therapy.
  • Is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF).
  • Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Has a body mass index (BMI) within the range of 19 to 40 kilogram/squared meter (kg/m^2) (inclusive)
  • Is a non-smoker or is willing to abstain from use of tobacco and/or nicotine-containing products from time of Screening until the post-treatment follow-up visit or transition to MEK rollover study (MEK114375).
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  • Meets one of the following criteria: Is currently on a stable regimen of ORTHO-NOVUM® tablet 1/35, or Is willing to switch to a regimen of ORTHO-NOVUM® tablet 1/35 from a stable regimen of an alternate OC, or Is willing to start a regimen of ORTHO-NOVUM® tablet 1/35
  • Has a negative serum beta-human chorionic gonadotropin (Beta-hCG) pregnancy test within 7 days of first dose of study treatment
  • Meets one of the following criteria: Is of non-childbearing potential - defined as females with a documented bilateral tubal ligation or tubal occlusion or hysterectomy without oophorectomy (at least one functioning ovary required); Is of childbearing potential and agrees to use an appropriate method of contraception in addition to the OC provided for at least 14 days prior to the first dose of study treatment until completion of the post-treatment follow-up visit or transition to the Mitogen-activated extracellular signal-regulated kinase (MEK) rollover study (MEK114375)
  • Has no prior treatment- related toxicities >Grade 1 (except alopecia) at the time of enrollment
  • Is able to swallow and retain orally administered medication
  • Has adequate baseline organ function as follows: Hematologic (Absolute neutrophil count >=1.2 × 10^9/L; Hemoglobin >=9 g/dL; Platelets >=75 × 10^9/L; prothrombin time/international normalized ratio [PT/INR] and partial thromboplastin time [PTT] <=1.5x upper limit of normal [ULN]) ; Hepatic (Albumin >=2.5 g/dL; Total bilirubin <=1.5xULN [isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%]); alanine aminotransferase (ALT) <=2.5xULN; ALT with documented liver metastases or tumor infiltration; >2.5xULN but <=5xULN) ; Renal (Creatinine or <=1.5 ULN; Calculated creatinine clearance [calculated by the Cockcroft-Gault formula] >=50 milliliters/minute [mL/min]) ; Cardiac (left ventricular ejection fraction [LVEF] >= lower limit of normal [LLN] by echocardiogram [ECHO] or Multigated acquisition scan [MUGA])

Who cannot join

  • A subject will not be eligible for inclusion in this study if any of the following criteria apply:
  • Had prior exposure to a MEK inhibitor
  • Has one of the following excluded tumor types as trametinib therapy has been shown to have minimal benefit in these populations: BRAF V600E mutant melanoma and failed prior BRAF inhibitor therapy; Metastatic pancreatic cancer
  • Has had any major surgery extensive radiotherapy, or anti-cancer therapy (e.g., chemotherapy with delayed toxicity, biologic therapy, or immunotherapy) within 21 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment. Prolonged immobilization must have resolved prior to start of study.
  • Has a known or suspected carcinoma listed below that is excluded as administration of ORTHO-NOVUM® tablet would be contraindicated: carcinoma of the breast, or carcinoma of the endometrium, or BRCA+ ovarian cancer, or other known or suspected estrogen-dependent neoplasia, or hepatocellular carcinoma
  • Has a history of another malignancy: Exception: A subject who: has been disease-free for 3 years, or; has a history of completely resected non-melanoma skin cancer, or; has an indolent second malignancy, other than any of the excluded malignancies listed in the previous exclusion Criteria.
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  • Has a life expectancy of <3 months
  • Has a history of interstitial lung disease or pneumonitis.
  • Has a history of Retinal vein occlusion (RVO)
  • Has a history of any of the following conditions that would contraindicate administration of an Oral contraceptive (OC): Uncontrolled or treatment refractory hypertension. NOTE: Treatment-refractory hypertension is 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; Diabetes mellitus (type 1 and 2) with vascular involvement (neuropathy./retinopathy/nephropathy); Stroke; Acute or past history of venous thromboembolism or known thrombophilia including factor V Leiden mutation; prothrombin mutation; protein S, protein C, and antithrombin deficiencies; or antiphospholipid antibodies; Migraine headaches (headaches with focal neurological symptoms); Undiagnosed abnormal uterine bleeding
  • Has a Bazett-corrected QT (QTcB) interval >=480 milliseconds (msec) at Screening
  • Has a LVEF, as measured by ECHO (preferred) or MUGA scan, below the institutional LLN, or if a LLN does not exist at an institution, <50%
  • Has a history or current evidence of cardiovascular risk including any of the following: History or evidence of current clinically significant uncontrolled arrhythmias. NOTE: Subjects with controlled atrial fibrillation for >30 days prior to enrollment are eligible. History or evidence of current acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to enrolment. History or evidence of current >=Class II congestive heart failure as defined by New York Heart Association (NYHA); Has an intra-cardiac defibrillator
  • Has symptomatic or untreated leptomeningeal, brain metastases, or spinal cord compression. Note: Subjects previously treated for these conditions that have had stable central nervous system disease (verified with consecutive imaging studies) for >3 months, are asymptomatic and are not currently taking corticosteroids, or are on stable dose of corticosteroids for at least 30 days prior to Day 1 are permitted.
  • Has any clinically significant gastrointestinal (GI) abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
  • Is pregnant, lactating or actively breastfeeding.
  • Is currently receiving a prohibited medication(s) or requires the use of any of the prohibited medication(s) during the study. NOTE: Use of anticoagulants such as warfarin is permitted; however, INR must be monitored in accordance with local institutional practice.
  • Presence of hepatitis B surface antigen (HBsAg) or positive hepatitis C antibody at Screening or within 3 months prior to first dose of study treatment . NOTE: Subjects with laboratory evidence of cleared hepatitis B virus and hepatitis C virus infection will be permitted.
  • Has current or chronic history of liver disease or known hepatic or biliary abnormality (with the exception of Gilbert's syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic liver disease per investigator assessment ). NOTE: Stable chronic liver disease defined by the absence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, or persistent jaundice.
  • Has participated in a clinical trial and received investigational drug(s) within 30 days, 5 half-lives or twice the duration of the biological effect of trametinib whichever is longer, prior to enrollment in this study.
  • Has participated in a study that resulted in or made a donation of blood or blood products in excess of 500 mL within 56 days of the first dose of study treatment.
  • Has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to study treatment, or excipients.
  • Has any serious and/or unstable pre-existing medical disorder (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures

About this study

Official title: A Phase I, Open-Label Study to Determine the Effect of Repeat Dosing of Trametinib on the Pharmacokinetics and Safety of a Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) and to Characterize the Pharmacokinetics of Trametinib's Metabolite M5 in Female Subjects With Solid Tumors

This is a Phase I, open-label, non-randomized, sequential, two-period, repeat-dose study to evaluate the effect of trametinib 2 milligram (mg) once daily on the repeat-dose pharmacokinetic (PK) of an oral contraceptive (OC) containing norethindrone (NE) and ethinyl estradiol (EE) (ORTHO-NOVUM® tablets: 1 mg NE + 0.035 mg EE) in female subjects with solid tumors.

The study will determine PK interaction between trametinib and the components of combination oral contraceptives that would compromise the effectiveness of the contraceptives.

Read more

The study will also evaluate the repeat dose PK of trametinib and its metabolite M5 using a validated assay.

The study will enroll approximately 24 subjects. Each subject will participate in the study for approximately up to 13 to 15 weeks which will consist of a 30 day screening period, followed by 2 treatment periods (Period 1: 28 days and Period 2: ranging from 12 days to up to 21 days), and a transition visit or post-treatment follow-up visit. In Period 1, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 21 days (Days 1 through 21), followed by one inert (referred to as placebo) tablet once daily at approximately the same time each day for 7 days (Days 22 through 28). In addition, subjects will take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for a total of 17 days (Days 12 through 28). In Period 2, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 11 days (Days 1 through 11). In addition, subjects will continue taking trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11). ORTHO-NOVUM® is a registered trademark of Ortho Pharmaceutical Corporation.

Conditions
Cancer
Being tested
Trametinib 0.5 mg, Trametinib 2 mg, ORTHO-NOVUM® tablet 1/35, Placebo
Keywords
Pharmacokinetics, Solid Tumors, Safety, Trametinib, MEK Inhibitor, Combined Oral Contraceptive, Trametinib's Metabolite M5, Norethindrone, Ethinyl Estradiol
Medical subject headings
Neoplasms

What participants receive

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

  • Trametinib 0.5 mgDrug

    Each tablet will contain GSK1120212B equivalent to 0.5 mg of Trametinib. Tablets are yellow, oval, biconvex, film-coated (4.85 x 8.86 millimeter [mm]) to be taken orally and once daily

  • Trametinib 2 mgDrug

    Each tablet will contain GSK1120212B equivalent to 2 mg Trametinib. Tablets are pink, round, biconvex and film-coated tablets (7.5 mm in diameter) to be taken orally and once daily.

  • ORTHO-NOVUM® tablet 1/35Drug

    Each peach tablet will contain 1 mg of NE and 0.035 mg of EE. Other inactive ingredients will include lactose, magnesium stearate and pregelatinized corn starch

  • PlaceboDrug

    Each green tablet will contain only inert ingredients: D\&C yellow No. 10 Aluminum Lake, FD\&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized cornstarch. The tablets are to be taken orally and once daily

Study groups in NCT02292732
Study groupRoleWhat they receive
Trametinib/ ORTHO-NOVUM® tabletExperimentalSubjects in treatment period 1will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 21 days (Days 1 through 21), followed by one placebo tablet once daily at approximately the same time each day for 7 days (Days 22 through 28). In addition, subjects will take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for a total of 17 days (Days 12 through 28). Subjects in treatment period 2 will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 11 days (Days 1 through 11). In addition, subjects will take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11).
Receives: Drug: Trametinib 0.5 mg; Drug: Trametinib 2 mg; Drug: ORTHO-NOVUM® tablet 1/35; Drug: Placebo

What is being measured

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

  1. Composite of steady state PK parameters of NE and EE

    Steady state PK parameters will include Area under the concentration-time curve over the dosing interval (AUC[0-tau]), Maximum observed plasma concentration (Cmax), Pre-dose concentration (C0) and Time to Cmax (Tmax)

    Measured: Day 11 and Day 12 of both the treatment periods

  2. Composite of steady state PK parameters of NE and EE in combination with trametinib

    Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax

    Measured: Day 11 and Day 12 of both the treatment periods

Secondary outcomes (6)

  1. Composite of steady state PK parameters of Plasma trametinib and M5

    Steady-state PK parameters will include AUC(0-tau), Cmax, C0, Tmax, and metabolite/parent AUC ratio

    Measured: Day 11 and Day 12 of treatment period 2

  2. Safety and tolerability as assessed by measuring vital signs

    Vital signs will include measurement of blood pressure, temperature and pulse rate

    Measured: Up to 107 days

  3. Safety and tolerability as assessed by measuring electrocardiogram (ECGs)

    Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT interval (QTc) intervals. Electrocardiograms (ECGs) will be performed by qualified site personnel after the subject has rested at least 5 minutes in a semi-recumbent or supine position.

    Measured: Up to 107 days

  4. Safety and tolerability by assessing ECHOs

    The evaluation of the echocardiographer will include an evaluation for Left ventricular ejection fraction (LVEF) and both right and left-sided valvular lesions

    Measured: Up to 107 days

  5. Safety and tolerability by assessing clinical laboratory tests

    Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters

    Measured: Up to 107 days

  6. Safety and tolerability by assessing adverse events (AEs)

    AEs will be collected throughout the treatment periods up to follow up

    Measured: Up to 107 days

Timeline

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

  1. First posted17 Nov 2014 (estimated)
  2. Study startFeb 2016
  3. Primary completionMay 2017 (estimated)
  4. Study completionMay 2017 (estimated)

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
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02292732
Sponsor's protocol ID
113707
Status last verified
Jan 2016
First submitted
13 Nov 2014
Last updated
26 Jan 2016
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Trametinib 0.5 mg, Trametinib 2 mg and ORTHO-NOVUM® tablet 1/35 in people with Cancer, run by GlaxoSmithKline.

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 12 inclusion and 23 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: withdrawn, as of the sponsor's last update on 26 Jan 2016. Status can change between updates, so confirm with the study contact before making plans.

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 was withdrawn before enrolling participants, so there are no results.

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?

Composite of steady state PK parameters of NE and EE (time frame: Day 11 and Day 12 of both the treatment periods). The study lists 2 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 NCT02292732.

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 26 Jan 2016.

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