This drug-drug interaction (DDI) study is being conducted to determine if there is a pharmacokinetic (PK) interaction between trametinib and the components of combination oral contraceptives (OCs), norethindrone (NE) and ethinyl estradiol (EE).…
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Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To evaluate the effect of multiple daily dose of trametinib on the steady state
PK of combination OC (NE and EE) in female patients with solid tumors.
Secondary outcome
Objective 1: To characterize the steady state PK of metabolite M5 when
trametinib is administered in combination with combination OC in female
patients with solid tumors
Objective 2: To evaluate the safety and tolerability of trametinib in female
patients with solid tumors.
Background summary
Trametinib has been approved in several countries including USA, Canada and the
EU for the treatment of patients with unresectable or metastatic melanoma with
a BRAF V600 mutation. Trametinib (TMT212, GSK1120212, MEKINIST®) is an orally
administered, potent and selective allosteric inhibitor of mitogen-activated
extracellular signal-regulated kinase 1 and 2 (MEK1/MEK2) activation and kinase
activity. Trametinib has potent anti-proliferative activity against multiple
cancer cell lines, but has minimal effect on normal, non-proliferating cells.
Novartis is developing trametinib for a variety of cancers. For this study
trametinib is being investigated in patients with solid tumors.
Trametinib may impair female fertility in humans based on the reduction of
corpora lutea in rats (0.3-times clinical steady state AUC). There were no
effects on male reproductive organs in toxicology studies in rats or dogs,
indicating that trametinib is unlikely to affect male fertility. In embryofetal
development studies, maternal toxicity and developmental toxicity, including
total loss of pregnancy and post-implantation loss, were observed in rats
and/or rabbits given trametinib (0.3- and 0.1-times clinical steady state AUC,
respectively). These effects are consistent with literature reports that
inhibition of MEK1/MEK2 activity impacts granulosa cell survival and
folliculogenesis, while genetic ablation of MEK1, ERK2 or skinrestricted
MEK1/MEK2 has been shown to cause embryolethality and decreased progeny size.
Taken together, trametinib treatment may result in adverse effects on
pregnancy. There are no
adequate and well-controlled studies of trametinib in pregnant women. Women of
childbearing potential must be advised to avoid becoming pregnant while
receiving treatment with trametinib. It is not known if trametinib is excreted
in milk.
Oral contraceptives containing Norethindrone (NE) and Ethinyl estradiol (EE)
are commonly prescribed combination oral contraceptives (OC). The metabolism of
OC components is complex and involves oxidative, reductive, and conjugative
pathways. A drug interaction which lowers the systemic concentrations of either
NE or EE could lead to reduced contraceptive efficacy, resulting in ovulation
and pregnancy.
In addition, a definitive embryofetal development study in pregnant rats and
dose ranging and definitive embryofetal development studies in pregnant rabbits
have been conducted with trametinib, where maternal and developmental
toxicities have been observed. Based on these findings, and according to the
European Medicines Agency (EMA) Guideline on the Investigation of Drug
Interactions 2012 for such substances, mechanisms of induction may be present
that are unknown; therefore, trametinib should be studied in vivo for effects
on OCs if the drug is intended to be administered to women of childbearing
potential, regardless of in vitro induction study results.
This drug-drug interaction (DDI) study is being conducted to determine if there
is a PK interaction between trametinib and the components of combination OCs
(NE and EE). Since a potential DDI that would lower the systemic concentrations
of either NE or EE could lead to reduced contraceptive efficacy, it is
appropriate to conduct this DDI study with trametinib.
Please refer to section 1 and 2 of the study protocol for further information.
Study objective
This drug-drug interaction (DDI) study is being conducted to determine if there
is a pharmacokinetic (PK) interaction between trametinib and the components of
combination oral contraceptives (OCs), norethindrone (NE) and ethinyl estradiol
(EE). Since a potential DDI that would lower the systemic concentrations of
either NE or EE could lead to reduced contraceptive efficacy, it is appropriate
to conduct this DDI study with trametinib. The current study is also designed
to evaluate, using a validated assay, the PK of the trametinib and its
metabolite M5 after multiple daily dose of trametinib.
Study design
This is a Phase I, open-label, single sequence, two-period crossover study
evaluating the effect of trametinib once daily on the PK of a daily dosing OC
containing NE and EE in female patients with solid tumors. The PK of trametinib
and its metabolite M5 will also be assessed. The study will consist of a
Screening Period (within 30 days of Day 1) followed by the PK phase which
consists of Period 1 (5 days from Day 1 to Day 5) and Period 2 (17 days from
Day 6 to Day 22). After completing the PK phase of the study, patients will
continue in the post-PK treatment part of the study unless they experience
disease progression, intolerance of study drug, withdrawal of consent or lost
to follow-up. An End of Treatment will be performed within 7 days of their last
dose of study treatment. The duration of the Screening and PK phase is expected
to be approximately 52 days.
Intervention
This study investigates the effect of trametinib once daily on the PK of a
daily dosing OC containing NE and EE in female patients with solid tumors.
Study burden and risks
Based on preclinical safety findings, there were no clinically relevant
findings in single dose safety pharmacology studies in rats and dogs evaluating
the cardiovascular, respiratory and central nervous systems conducted with
trametinib. Trametinib may impair female fertility in humans based on the
reduction of corpora lutea in rats. For more information about the preclinical
and clinical safety data, please refer to Section 1.2.1.1 and Section 1.2.1.2,
respectively. Single agent trametinib or in combination with dabrafenib had
demonstrated clinical benefit in BRAF mutant melanoma in phase 3 studies and
other cancer types. Trametinib monotherapy is generally tolerable. The most
frequent adverse events (AEs) (* 20%) with trametinib were rash, diarrhea,
fatigue and edema. Known MEK inhibitor class effects were observed including
ocular-visual impairment and decreased ejection fraction.
To address the potential risks and ensure patients* safety, appropriate
inclusion and exclusion criteria, as well as dose modification and stopping
rules are provided in this protocol. It is strongly recommended that the
treating physician informs Novartis Drug Safety and Epidemiology (DS&E)
department if, during treatment, any signs or symptoms are observed that are
not consistent with the toxicities discussed in the current Investigator
Brochure. In addition, this study incorporates routine safety monitoring and
regularly scheduled assessments to identify and report any adverse event or
potential safety issues. Safety will be monitored by the assessment of
hematology, blood chemistry, coagulation, pregnancy test and urinalysis,
ophthalmic examinations, cardiac assessment, the regular monitoring of vital
signs,
performance status and physical condition as well as the collection of
concomitant medications and serious and non-serious adverse events at every
visit. All patients must have safety evaluations within 30 days after the last
dose of study drug.
This study is not the initial clinical experience with trametinib, therefore,
the benefit:risk has been established and is considered favorable if the
anticipated level of efficacy is demonstrated. The risk to patients in this
trial may be minimized by compliance with the eligibility criteria and study
procedures, close clinical monitoring, and following the guidance on stopping
criteria and adverse events of special interest. There may be unforeseen risks
with trametinib which could be serious.
Other considerations for patients who participate in this study are that they
may make a contribution to the ongoing process of developing a new treatment.
In summary, the data from trametinib clinical program indicates that the
majority of adverse events in cancer patients receiving trametinib as single
agent have been mild or moderate. In this study, any potential risks are
minimized by appropriate inclusion/exclusion criteria and adequate clinical and
laboratory monitoring and study procedures like dose modifications and stopping
rules guidelines. Based on the available preclinical and clinical data,
Novartis considers the potential risks identified in association with
trametinib therapy are justified by the anticipated benefits that may be
afforded to patients.
Lichtstrasse 35
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CH
Lichtstrasse 35
Basel 4056
CH
Listed location countries
Age
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:;1. Is a female patient * 18 years but < 59 years of age at the time of signing the informed consent.;2. Has a histologically or cytologically confirmed diagnosis of a solid tumor malignancy (except for any excluded malignancies listed in Section 5.3 Exclusion Criteria) that is not responsive to standard therapy(ies) or for which there is no approved therapy.;3. Has a body mass index (BMI) within the range of 19 to 40 kg/m2 (inclusive).;4. Is a non-smoker or is willing to abstain from use of tobacco and/or nicotine-containing products from time of Screening until the EoT visit.;5. Meets one of the following criteria:
- Is currently on a stable regimen of an oral contraceptive containing 1mg NE and 0.035mg EE, or
- Is willing to switch to a regimen of an oral contraceptive containing 1mg NE and 0.035mg EE from a stable regimen of an alternate OC, or
- Is willing to start a regimen of an oral contraceptive containing 1mg NE and 0.035mg EE.;6. Meets one of the following criteria:
- Is post-menopausal. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before enrollment. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (based on local practice) is she considered not of child bearing potential.;- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during dosing and for four months after stopping medication. Highly effective contraception methods include
- Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.;- Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment (based on local practice).;- Male partner sterilization (at least 6 months prior to screening). The vasectomized male partner must be the sole partner for that patient. ;- Non-drug eluting intrauterine device (IUD) or intrauterine system (IUS) with a documented failure rate of less than 1% per year. Note: use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception (for example hormone vaginal ring or transdermal hormone contraception) are not permitted.;Note: Females who no longer have regular periods or are menopausal as a result of prior anti-cancer treatment may participate providing they agree to use a highly effective method of contraception as outlined above for at least 14 days prior to the first dose of study treatment until four months after the last dose of study treatment.;7. Has no prior treatment-related toxicities > Grade 1 (except alopecia) at the time of enrolment.;8. Is able to swallow and retain orally administered medication. ;Further inclusion criteria and details are described in the protocol.
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:;1. Had prior exposure to a MEK inhibitor.;2. 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.;3. History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease, including any of the following:
- Recent myocardial infarction (within last 6 months).
- Uncontrolled congestive heart failure.
- Unstable angina (within last 6 months).
- Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, and clinically significant second or third degree AV block without a pacemaker). Note: Patients with controlled atrial fibrillation for >30 days prior to enrolment are eligible.;- History of coronary angioplasty, or stenting within last 6 months.;- History or evidence of current * Class II congestive heart failure as defined by New York Heart Association (NYHA).;- Has an intra-cardiac defibrillator.;- Has a Fridericia-corrected QT (QTcF) interval *460 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%.;4. 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 enrolment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. Prolonged immobilization must have resolved prior to enrolment.;5. Has a known or suspected carcinoma listed below that is excluded (as administration of a combination OC would be contraindicated):;- Carcinoma of the breast.;- Carcinoma of the endometrium.;- BRCA+ ovarian cancer.;- Other known or suspected estrogen-dependent neoplasia.;- Hepatocellular carcinoma.;6. Has a history of another malignancy.;Exception: A patient who has at least one of the following conditions:;- Been disease-free for 3 years.;- History of completely resected non-melanoma skin cancer.;- Indolent second malignancy, other than any of the excluded malignancies listed in;Exclusion Criteria 3.;7. Has a life expectancy of < 3 months.;8. Has a history of interstitial lung disease or pneumonitis.;Further exclusion criteria and details are described in the protocol
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2015-004621-14-NL |
| CCMO | NL56240.056.16 |