The main purpose of this study is to assess investigate the effect of encorafenib and binimetinib (the study drugs) on the activity of other common drugs and the effect of modafinil on the activity of encorafenib. The study will also look at the…
ID
Source
Brief title
Condition
- Other condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Skin neoplasms malignant and unspecified
Synonym
Health condition
Melanoma, Colorectal cancers, Biliary tract tumors, Non-small cell lung cancers, Glioblastoma, Papillary thyroid cancer, Multiple myeloma.
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint
• Changes in plasma maximum concentration (Cmax) and area under the
concentration time curve from time zero to the time of last quantifiable
concentration (AUClast): midazolam, 1-OH midazolam, caffeine, paraxanthine,
omeprazole, 5-hydroxy omeprazole, rosuvastatin, bupropion and hydroxybupropion.
• Changes in the amount eliminated via urine over an 8-hour period (Ae0-8):
losartan and its metabolite (E 3174), dextromethorphan and dextrorphan
• Changes in plasma encorafenib and LHY746 Cmax and area under the
concentration time curve over the dosing interval (AUC) in Arm 3.
Secondary outcome
Secondary Endpoints
• Metabolite ratios (MRAUC and MRCmax) for 1-OH midazolam/midazolam,
paraxanthine/caffeine, 5-hydroxy omeprazole/omeprazole,
hydroxybupropion/bupropion and LHY746/encorafenib and MRAe0-8 for E
3174/losartan and dextrorphan/dextomethorphan.
• Pharmacokinetic parameters (e.g., time to reach Cmax [Tmax], AUC from time
zero extrapolated to infinity [AUCinf], percent of AUC extrapolated
[AUC%extrap], apparent terminal elimination rate constant [Kel], apparent T1/2,
apparent total body clearance after extravascular administration [CL/F] and
apparent total volume of distribution after extravascular administration
[Vz/F]) where calculable, for midazolam, 1-OH midazolam, caffeine,
paraxanthine, omeprazole, 5-hydroxyomeprazole, rosuvastatin, bupropion and
hydroxybupropion.
• Pharmacokinetic parameters (e.g., urine concentration [Curine], quantity of
urine excreted during each collection interval [Vol], cumulative amount
excreted in urine during each collection interval [CumAe], and percentage of
dose recovered in urine [Fe %]) for losartan, E-3174, dextromethorphan and
dextrorphan.
• Pharmacokinetic parameters (e.g., Cmax, AUClast, Tmax, AUCinf, AUC%extrap,
Kel, T1/2, CL/F, and Vz/F) for encorafenib, LHY746, binimetinib and AR00426032
where calculable.
• Safety will be evaluated by monitoring AEs, physical examinations, ophthalmic
examinations, vital sign measurements, 12 lead ECGs, echocardiogram
(ECHO)/multigated acquisition scan (MUGA), and clinical laboratory tests.
Exploratory Endpoints
• Assessment of correlations between PK parameter estimates and genotype for
drug metabolizing enzymes such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A,
CYP2B6 and OATP1B1.
Background summary
The body is built of bricks of cells and the way of how the bricks are build is
decided by the information that is stored in our genes (DNA). If unwanted
changes (mutations) occur in those genes there may be issues with the
construction of the cells and how they work within the body. The changes in the
BRAF gene that is studied in this trial cause overactivation of the BRAF gene
which results in excessive cell growth. Increasing numbers of patients are
identified that have a cancer type with such a mutation of the BRAF gene.
Especially this mutation is found in patients with melanoma which increases the
need for suitable treatments.
Previous study results suggest that a combination of the study drugs is an
effective treatment.
Preclinical and clinical data suggest that the combination of a BRAF inhibitor
and a MEK inhibitor may be more effective than BRAF inhibitor monotherapy in
patients with BRAF mutant cancer. By simultaneous, dual, vertical pathway
inhibition of the RAF/MEK/ERK signaling pathway, the combination of encorafenib
and binimetinib may possibly improve the duration of response and delay the
emergence of resistance to single-agent treatment in patients with BRAF
V600-mutant unresectable or metastatic melanoma or other advanced solid tumors.
This study is being conducted in patients with BRAF-mutant advanced solid
tumors rather than in healthy volunteers due to its repeat-dose administration
design and the risk of carcinogenicity (secondary neoplasm) with selective BRAF
inhibitors
The study will be conducted in 3 arms to mitigate any unknown interaction
between the substrates and inducer.
Study objective
The main purpose of this study is to assess investigate the effect of
encorafenib and binimetinib (the study drugs) on the activity of other common
drugs and the effect of modafinil on the activity of encorafenib. The study
will also look at the safety and how you tolerate the study drugs when
administered with the other common drugs.
Study design
This is an open-label, 3-arm, fixed-sequence study. Enrollment to Arms 1 and 2
will occur in parallel. Patients will be assigned in an alternating fashion to
Arm 1 or 2, where eligible, as assigned by the study team management.
Once enrollment to Arms 1 and 2 is completed, enrollment in Arm 3 (modafinil
arm) may begin.
The study will have 2 treatment phases, a DDI phase followed by a post DDI
phase for each study arm.
DDI Phase:
Arm 1
Twenty patients will be enrolled into Arm 1 (CYP probe cocktail arm). Patients
will receive a single oral dose of the CYP probe cocktail (losartan,
dextromethorphan, caffeine, omeprazole, and midazolam) on Day -7. Encorafenib,
administered once daily (QD) and binimetinib, administered twice daily (BID)
will be initiated on Day 1. Patients will then receive a single oral dose of
the CYP probe cocktail on Day 1 and Day 14. Blood and urine PK sampling will be
conducted from 0 to 8 hours on Day -7, Day 1 and Day 14.
Arm 2
Ten patients will receive a single oral dose of rosuvastatin and bupropion on
Day -7. Encorafenib, administered QD and binimetinib, administered BID will be
initiated on Day 1. Patients will then receive a single oral dose of
rosuvastatin and bupropion on Day 1 and Day 14. Blood PK sampling will be
conducted from 0 to 8 hours on Day -7, Day 1 and Day 14.
Arm 3
Six to 12 patients will inititate continuous treatment with encorafenib QD and
binimetinib BID on Day 1. Patients will then receive continuous treatment of
modafinil QD on Day 15 through Day 21. Blood PK sampling will be conducted from
0 to 8 hours on Day 14 and Day 21.
PK data will be analysed after the first 6 patients to look for an indication
that the moderate inducer is having a significant effect on encorafenib PK. If
there is a >= 20% change in geometric mean encorafenib AUC then an additional 6
patients will be enrolled to more fully characterize the effect.
All Arms
Patients who discontinue or require a dose reduction of study drug(s) prior to
the final sample collection on Day 14 in Arms 1 and 2 or prior to Day 21 in Arm
3 will be considered to be unevaluable for PK analyses and replaced. If a
patient misses 3 or more consecutive doses of encorafenib and binimetinib in
any arm or 3 or more doses of modafinil in Arm 3 during the DDI phase due to
noncompliance, the patient may remain on treatment but may be replaced if
limited data are available from the patient. In addition, patients who miss any
dose of study drugs on any of the PK days, or who vomit within 4 hours after
dosing on any of the PK days, may be replaced but may remain on treatment.
Safety Analysis
DDI Phase (through Day 28)
All safety data will be recorded in the patient*s source documents and
electronic case report forms (eCRFs). Adverse events including serious adverse
events (SAEs), laboratory profiles (hematology, biochemistry, coagulation,
cardiac/muscle enzymes, urinalysis), physical examination (including vital
signs, ophthalmic and dermatological examinations), Eastern Cooperative
Oncology Group (ECOG) performance status (PS) assessment, and cardiac profiles
(ECG and MUGA or ECHO), concomitant medications and/or therapies will be
recorded.
Post DDI Phase:
If a patient chooses to not continue in the post-DDI phase, the Day 30 Safety
Follow-up Visit assessments will still be performed.
During the post-DDI phase patients may continue to receive
encorafenib/binimetinib combination until disease progression, unacceptable
toxicity, withdrawal of consent, pregnancy, significant protocol deviation,
lost to follow up, investigator decision, death, or study termination by
Sponsor.
It is recommended that safety evaluations occur every 3 to 4 weeks, unless
otherwise specified. Safety should be monitored by assessing physical
examination, hematology and chemistry laboratory testing and any other
pertinent testing required as part of the safety profile of the compound
(dermatological examinations, ophthalmic exams, cardiac profiles) until
discontinuation. Adverse events will be collected at every visit. Investigators
will be required to record all Grade 3 or 4 AEs. All SAEs are to be reported
to the Sponsor or designee using the SAE form.
Although this study does not formally assess efficacy, efficacy assessment are
required every 8--12 weeks in order for the Investigator to assess continued
benefit.
Intervention
Treatments are described as follows:
Encorafenib/binimetinib (continuous daily dosing starting on Day 1 for all
arms):
450 mg (6 x 75 mg) encorafenib oral capsules QD
45 mg (3 x 15 mg) binimetinib oral tablet BID
CYP Probe Cocktail (once on Day -7, Day 1 and Day 14 for Arm 1 only) taken in
the following order:
25 mg losartan oral tablet
30 mg dextromethorphan oral capsule
100 mg caffeine 20 mg/mL oral liquid
20 mg omeprazole oral capsule
2 mg midazolam 2 mg/mL oral syrup
Rosuvastatin and bupropion (once on Day -7, Day 1 and Day 14 for Arm 2 only):
10 mg rosuvastatin oral tablet
75 mg bupropion immediate release (IR) oral tablet
Modafinil (continuous daily dosing starting on Day 15 through Day 21 for Arm 3
only):
400 mg (2 × 200 mg) modafinil tablet QD
For each arm, all drugs will be taken within 10 minutes total time.
Study burden and risks
Side effects in patients with cancer treated with encorafenib may include
those described below.
Most likely side effects (in more than 1 out of 5 patients):
• Reddening, swelling, numbness and peeling on palms and soles (hand foot skin
reaction)
• Skin rash including redness, itching and raised areas of skin
• Thickening of external part of the skin
• Dry skin
• Nausea
• Feeling tired
• Muscle pain or joint pain
• Hair loss
• Headache
• Itching
Side effects in patients with cancer treated with binimetinib may include those
described below
Most likely side effects (more than 1 out of 5 patients):
• Alteration of the light sensing part of the back of the eye that may affect
your vision including blurred or impaired vision
• Feeling weak, tired, or lacking in energy
• Rash, acne or skin irritation including redness, raised bumps, dryness or
itching•
• Swelling due to fluid retention or a worsening of pre-existing fluid
retention in specific areas of the body. This can occur throughout your body
or in specific areas such as your abdomen, or arms, legs, hands, feet, face or
eyes.
More side affects on the study drugs and other treatments can be found in the
study documents in this dossier (ICF, IB).
Drawing blood may be painful or cause some bruising.
The test results might have unexpected findings and/or unwanted outcomes.
Subjects are not allowed to become pregnant/father a child and will have
dietary/behavioural (smoking/drugs/alcohol) restrictions.
Most of these toxicities were generally reversible and manageable by supportive
medical care, dose modifications or discontinuation.
The sponsor feels that the side effects and the burden associated with
participation are in proportion considering the
positive effects that participation in the study might have on the patient's
disease progression.
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Age
Inclusion criteria
1. Signed written informed consent;
2. Male or female patient, age >= 18 years;
3. Histologically confirmed diagnosis of locally advanced, unresectable or
metastatic cutaneous melanoma or unknown primary melanoma American Joint
Committee on Cancer (AJCC) Stage IIIB, IIIC or IV; or other BRAF V600-mutant
advanced solid tumors;
4. Presence of BRAF V600E and/or V600K mutation in tumor tissue prior to
enrollment, as determined using a local test;
5. Evidence of measurable or non-measurable lesions as detected by radiological
or photographic methods according to guidelines based onResponse Evaluation
Criteria in Solid Tumors (RECIST) v. 1.1;
6. Patient with unresectable locally advanced or metastatic melanoma who has
progressed on standard therapy and for whom no additional standard therapies
are available.
Note: Prior therapy with a BRAF inhibitor (e.g., vemurafenib, dabrafenib,
encorafenib and XL281/BMS-908662) and/or a MEK inhibitor (e.g., trametinib,
binimetinib, selumetinib, cobimetinib and refametinib) is permitted except in
the regimen immediately prior to study entry. Progression during prior BRAF/MEK
inhibitor treatment is not required;
7. Patient with other (non-melanoma) BRAF V600E and/or V600K -mutant advanced
solid tumors who has progressed on standard therapy or for whom there are no
available standard therapies
Note: Prior therapy with a BRAF inhibitor and/or a MEK inhibitor is permitted
except in the regimen immediately prior to study entry. Progression during
prior BRAF/MEK inhibitor treatment is not required; if it occurred, the
patient*s circumstances (e.g., >= 1 year since prior BRAF and/or MEK inhibitor,
equivocal progression, refractory to available therapies) must be discussed
with the Sponsor prior to enrollment;
8. ECOG PS of 0 or 1;
9. Adequate bone marrow, organ function and laboratory parameters:
a. Absolute neutrophil count (ANC) >= 1.5 x 109/L,
b. Hemoglobin (Hgb) >= 9 g/dL without transfusions,
c. Platelets (PLT) >= 100 x 109/L without transfusions,
d. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) <= 2.5
× upper limit of normal (ULN); patient with liver metastases <= 5 ×ULN,
e. Total bilirubin <= 2 × ULN,
f. Creatinine <= 1.5 mg/dL, or calculated creatinine clearance (determined as
per Cockcroft-Gault) >= 50 mL/min;
10. Able to take oral medications;
11. Patient is deemed by the Investigator to have the initiative and means to
be compliant with the protocol (treatment and follow-up);
12. Negative serum beta-human chorionic gonadotropin (β-HCG) test (female
patient of childbearing potential only) performed within 72 hours prior to
first dose and consent to ongoing urine pregnancy testing during the course of
the study;
13. Male patients and female patients of childbearing potential must agree to
use an acceptable method of contraception as defined in the study protocol;
ARM 1 ONLY:
1. Non-smoker who has not used nicotine containing products for at least 3
months prior to the first dose.
Exclusion criteria
1. Symptomatic brain metastasis. Patients previously treated or untreated for
these conditions who are asymptomatic in the absence of corticosteroid and
anti-epileptic therapy are allowed. ;
2. History of reaction to any of the study medications in the arm the patient
is enrolled in this trial;
3. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment
on Day 1 and through DDI phase (Day 28), of any herbal medications/supplements
or any medications or foods that are moderate or strong inhibitors or inducers
of CYP3A4/5;
4. Consumption of grapefruit, pomegranates, star fruits, Seville oranges or
products containing the juice of each starting from Day -14 and through the DDI
phase (Day 28), due to potential CYP3A4 interaction with the study drugs.
Orange juice is allowed;
5. Symptomatic or untreated leptomeningeal disease;
6. History or current evidence of retinal vein occlusion (RVO) or current risk
factors for RVO (e.g., uncontrolled glaucoma or ocular hypertension, history of
hyperviscosity or hypercoagulability syndromes);
7. Clinically significant cardiac disease including any of the following:
a. Congestive heart failure requiring treatment (New York Heart Association
Grade >= 2)
b. Left ventricular ejection fraction (LVEF) < 50% as determined by MUGA or
ECHO
c. Uncontrolled hypertension defined as persistent systolic blood pressure >=
150 mmHg or diastolic blood pressure >= 100 mmHg despite current therapy
d. History or presence of clinically significant ventricular arrhythmiasor
atrial fibrillation
e. Clinically significant resting bradycardia
f. Unstable angina pectoris <= 3 months prior to start of study drug
g. Acute myocardial infarction <= 3 months prior to start of study drug
h. QT interval corrected for heart rate using the Fridericia formula (QTcF)
> 480 msec at screening;
8. Impaired hepatic function as defined by Child-Pugh class B or C;
9. Impaired gastrointestinal function or disease which may significantly alter
the absorption of study drugs (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, small bowel resection);
10. Known hyper-coagulability risks other than malignancy (e.g., Factor V
Leiden syndrome);
11. Thromboembolic event (e.g. including transient ischemic attacks,
cerebrovascular accidents, deep vein thrombosis or pulmonary emboli) except
catheter-related venous thrombosis <= 12 weeks prior to starting study
treatment. Note: Patients with catheter-related thromboembolic events are
allowed;
12. Any of the following:
a. Nitrosourea or mitomycin-C within 6 weeks prior to start of study drug
b. Other chemotherapy, radiation therapy that included > 30% of the bone
marrow reserve, or biological therapy (e.g., antibodies) within 4 weeks prior
to start of study drug
c. Continuous or intermittent small-molecule therapeutics or investigational
agents within 5 half-lives of the agent (or within 4 weeks prior to start of
study drug, when half-life is unknown)
d. Residual Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 side
effects of any such therapy (residual Grade 2 alopecia is permitted);
13. Discontinuation of prior BRAF and/or MEK inhibitor treatment due to left
ventricular dysfunction, pneumonitis/interstitial lung disease, or retinal vein
occlusion;
14. Known positive serology for human immunodeficiency virus (HIV) infection,
active hepatitis B and/or active hepatitis C infection;
15. History of Gilbert*s syndrome;
16. Other severe, acute, or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or study drug administration or that may interfere with the
interpretation of study results and, in the judgement of the Investigator,
would make the patient inappropriate for the study;
17. Pregnant or nursing (lactating) women, where pregnancy is defined as the
state of a female after conception and until termination of gestation,
confirmed by a positive β-hCG laboratory test (> 5 mIU/mL).
ARM 1 ONLY:
1. Positive urine cotinine test at screening;
2. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment
on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or
inducers of CYP3A4, CYP2C9, CYP1A2, or CYP2C19 and any substrates or inhibitors
CYP2D6.
ARM 2 ONLY:
1. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment
on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or
inducers of CYP2B6 or any substrates or inhibitors of BCRP, OATP1B1 or OATP1B3.
ARM 3 ONLY:
1. History of psychosis, depression or mania;
2. History of angioedema;
3. History of mitral valve prolapse;
4. History of left ventricular hypertrophy;
5. Use, within 2 weeks prior to the start of encorafenib/binimetinib treatment
on Day 1 and through DDI phase (Day 28), of any substrates, inhibitors or
inducers of CYP3A4.
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 | EUCTR2019-001036-66-NL |
| ClinicalTrials.gov | NCT03864042 |
| CCMO | NL69465.041.19 |