Primary Objective:To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC as measured by ORR.Secondary objectives:1. To evaluate the efficacy of encorafenib + binimetinib…
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Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
- Respiratory tract neoplasms
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint:
ORR defined as the proportion of patients who have achieved a confirmed best
overall response (CR or PR) as determined by Investigator review of
radiographic disease assessments per RECIST v1.1 both in the treatment-naïve
setting and in previously treated setting.
Secondary outcome
Secondary endpoints:
1. DOR defined as the time from the date of the first documented response (CR
or PR) to the earliest date of disease progression, as determined by
Investigator review of radiographic disease assessments per RECIST v1.1, or
death due to any cause.
2. DCR defined as the proportion of patients who have achieved a confirmed best
overall response of CR, PR or SD, as determined by Investigator review of
radiographic disease assessments per RECIST v1.1.
3. PFS defined as the time from the date of first dose of study drug to the
earliest date of disease progression, as determined by Investigator review of
radiographic disease assessments
4. OS defined as the time from the date of first dose of study drug to the date
of death due to any cause
Incidence and severity of AEs graded according to the
5. NCI CTCAE v4.03 and changes in clinical laboratory parameters, vital signs,
ECGs and ECHO/MUGA scans
6. TRR (by independent radiology review (IRR) and by Investigator), defined as
the time from the date of first dose to the first documentation of objective
response (CR or PR) which is subsequently confirmed (by IRR and by
Investigator, respectively)
Background summary
Based on a parallel-group trial of the BRAF inhibitor dabrafenib with or
without the MEK inhibitor trametinib, the combination of dabrafenib plus
trametinib is now a standard-of-care regimen for the treatment of this
molecular subtype of NSCLC either as first-line therapy for metastatic disease,
or after progression on first line platinum-based therapy with or without a
PD-1/PD-L1 inhibitor.
Preclinical data has demonstrated the enhanced activity of combining BRAF and
MEK inhibition in BRAFV600-driven tumors. This combination has been validated
clinically by the efficacy observed for the combination in BRAFV600-mutant
NSCLC, and also in the treatment of BRAFV600-mutant melanoma where the
combination of BRAF and MEK inhibition is an established standard-of-care based
on 4 pivotal trials of various BRAF/MEK inhibitor combinations.
Encorafenib is a potent and selective BRAF inhibitor and binimetinib is a
potent and selective MEK inhibitor. Although the combination of encorafenib
plus binimetinib was not studied in direct comparison to the combination of
dabrafenib plus trametinib in melanoma, the numerically superior outcomes with
encorafenib plus binimetinib, particularly when compared to results from trials
that incorporated a common control arm (vemurafenib) that performed similarly
across trials, provides reassurance that there is at least comparable efficacy
in the setting of melanoma. These results also suggest that the efficacy of
encorafenib plus binimetinib in other BRAFV600-driven settings such as
BRAFV600E NSCLC may be similar or potentially superior to that observed with
dabrafenib and trametinib.
Importantly, the combination of encorafenib plus binimetinib has a different
safety and tolerability profile from dabrafenib plus trametinib. Pyrexia,
manifesting as a distinctive recurrent febrile syndrome refractory to NSAIDs
and associated in a minority of patients with chills, dehydration and renal
failure, is a significant toxicity associated with dabrafenib and trametinib,
and is seen in over 50% of patients. Treatment with encorafenib and binimetinib
was associated with a lower incidence of pyrexia (18% of patients) and these
events were generally low grade, nonrecurrent and not associated with other
manifestations.
Therefore, encorafenib plus binimetinib may represent an alternative BRAF/MEK
inhibitor combination regimen for the treatment of BRAFV600E-mutant NSCLC and
potentially for other V600 Class 1 BRAF mutations (e.g. K or D), though very
rare. Encorafenib plus binimetinib has a differentiated safety profile and may
have enhanced efficacy based on results observed in the treatment of
BRAFV600-mutant melanoma. This study seeks to generate data to explore the
efficacy and safety of this new combination in NSCLC.
Study objective
Primary Objective:
To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and
previously treated patients with BRAFV600E-mutant NSCLC as measured by ORR.
Secondary objectives:
1. To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and
previously treated patients with BRAFV600E-mutant NSCLC as measured by DOR,
DCR, PFS and time to response (TRR)
2. To evaluate the efficacy of encorafenib + binimetinib in treatment-naïve and
previously treated pateintes with BRAFV600E-mutant NSCLC with respect to OS
3. To evaluate the safety and tolerability of encorafenib + binimetinib in
treatment-naïve and previously treated patients with BRAFV600E-mutant NSCLC
Study design
This is an open-label, multicenter, non-randomized, Phase 2 study to determine
the safety, tolerability and efficacy of encorafenib (450 mg orally QD) given
in combination with binimetinib (45 mg orally BID) in patients with
BRAFV600E-mutant metastatic NSCLC. Although very rare in NSCLC, patients with
other V600 Class 1 BRAF mutations (e.g., K or D) are also allowed.
Approximately 117 patients who are either treatment-naïve, OR who have received
1) first-line treatment with standard platinum-based chemotherapy, OR 2)
first-line treatment with an anti-PD-1/PD-L1 inhibitor given alone or in
combination with platinum-based chemotherapy or in combination with
immunotherapy (e.g., ipilimumab) with or without platinum-based chemotherapy
will be enrolled. Treatment will be administered in 28-day (± 3 days) cycles
and will continue until the patient meets the protocol-defined criteria for
treatment withdrawal. Once the patient discontinues study treatment, the
treatment period will end, and the patient will enter the follow-up period for
safety, subsequent anticancer therapy, disease status, and survival status.
Study participation, including post-treatment follow-up is expected to average
approximately 12-18 months per individual patient.
The end of study will occur 2 years after treatment initiation of the last
enrolled patient or the point at which all patients have died or withdrawn
consent or have been lost to follow up, whichever occurs first. At the end of
the study, access to study treatment will be provided in accordance with
applicable regulations and requirements to all patients who have not met the
protocol-defined criteria for treatment withdrawal.
Intervention
Study treatment with encorafenib and binimetinib will be self-administered
orally without regard to food.
Patients will receive the following per 28-day (± 3 days) cycle:
• Encorafenib: 450 mg (6 × 75 mg capsule) QD
• Binimetinib: 45 mg (3 × 15 mg tablet) BID
Alternate starting doses may also be explored based on safety of the
combination regimen. For an individual patient, the dose of study
treatment may be reduced or interrupted as appropriate based on
protocol-defined treatment modifications.
Study burden and risks
The combination encorafenib + binimetinib is known to cause side effects.
Among patients receiving encorafenib, the most likely side effects of
encorafenib (occurring in more than 20 of subjects out of 100)
include the following:
• Decreased appetite
• Diarrhea
• Difficulty sleeping
• Dry skin
• Feeling tired
• Fever
• Hair loss
• Headache
• Itching
• Muscle pain or joint pain
• Nausea
• Pain including pain the arms, legs and back
• Reddening, swelling, numbness and peeling on palms and soles (hand foot skin
reaction)
• Skin rash including redness, itching, hives and raised areas of skin
• Small, rough bumps on the skin
• Thickening of external part of the skin
• Tingling, numbness or abnormal sensitivity to pain or touch and nerve pain
• Vomiting
• Weakness
Among patients receiving binimetinib, the most likely side effects of
encorafenib (occurring in more than 20 of subjects out of 100)
include the following:
• Alteration of the light sensing part of the back of the eye that may affect
your vision including blurred or impaired vision
• Fatigue
• Rash, acne, or skin irritation such as redness, raised bumps, dryness, or
itching
• Swelling in the abdomen, arms, legs, hands, feet, or face
• Muscle spasms, muscle pain, or inflammation
Side effects in cancer patients treated with encorafenib in combination with
binimetinib may also include those described below.
Most likely side effects (in more than 20 out of 100 subjects):
• alteration of the light sensing part of the back of the eye that may affect
your vision
• increase in a lab test result for creatine phosphokinase (an enzyme found in
the blood) that may indicate muscle inflammation or damage
Less likely side effects (10-20 out of 100 subjects):
• swelling of or damage to the light sensing part of the eye or impaired vision
Most of these toxicities were generally reversible and manageable by supportive
medical care, dose modifications or discontinuation.
Also the study procedures may be accompanied by risks and discomforts. In
addition the study drug, the study procedures and the
combination of these may lead to risks that are as yet unknown.
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 and
less side effect compared with dabrafenib + trametinib.
East 42nd Street 235
New York 6721 AH
US
East 42nd Street 235
New York 6721 AH
US
Listed location countries
Age
Inclusion criteria
Patients must meet all of the following criteria to be eligible for enrollment
in the study:
1. Able to provide written informed consent. Adult patients under guardianship
may participate with the consent of their legally authorized guardian if
permitted by local regulations.
2. Age >= 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of NSCLC that is currently Stage IV (M1a,
M1b, M1c- AJCC 8th edition).
4. Presence of a BRAFV600E mutation in tumor tissue or blood (e.g., ctDNA
genetic testing) as determined by a local laboratory assay. Other Class 1
BRAFv600 mutations (e.g., K or D) will be permitted with prior discussion with
the Sponsor.
5. The Investigator must obtain prior to enrollment that the patient has
adequate tumor tissue for submission to a central laboratory for confirmation
of BRAFV600 mutation status.
6. Patients who are either treatment-naïve (e.g., no prior systemic therapy for
advanced/metastatic disease), OR who have received 1) first-line platinum-based
chemotherapy OR 2) first-line treatment with an anti-PD-1/PD-L1 inhibitor given
alone or in combination with platinum-based chemotherapy, or in combination
with immunotherapy (e.g., ipilimumab) with or without given alone or in
combination with platinum-based chemotherapy.
7. Presence of measurable disease based on RECIST v1.1.
8. ECOG performance status of 0 or 1.
9. Adequate bone marrow function characterized by the following at screening:
a. ANC >= 1.5 × 109/L;
b. Platelets >= 100 × 109/L;
c. Hemoglobin >= 8.5 g/dL (with or without blood transfusions).
10. Adequate hepatic and renal function characterized by the following at
screening:
a. Total bilirubin <= 1.5 × ULN
b. ALT and AST <= 2.5 × ULN, or <= 5 × ULN in presence of liver metastases;
c. Serum creatinine <= 1.5 × ULN; or calculated creatinine clearance
>= 50 mL/min by Cockcroft-Gault formula; or estimated glomerular filtration rate
> 50 mL/min/1.73m2.
11. Able to swallow, retain and absorb oral medications.
12. Willingness and ability to comply with scheduled visits, treatment plan,
laboratory tests and other study procedures.
13. Female patients of childbearing potential, must have a negative serum β-HCG
test result.
14. Female patients of childbearing potential must agree to use methods of
contraception that are highly effective or acceptable and to not donate ova
from Screening until 30 days after the last dose of study treatment.
15. Male patients must agree to use methods of contraception that are highly
effective or acceptable, and to not donate sperm from Screening until 90 days
after the last dose of study drug.
Exclusion criteria
Patients meeting any of the following criteria are ineligible for enrollment in
the study.
1. Patients who have documentation of any of the following: EGFR mutation, ALK
fusion oncogene or ROS1 rearrangement.
2. Patients who have received more than 1 prior line of systemic therapy in the
advanced/metastatic setting. Prior therapies can be reviewed with the Array
Medical Monitor.
3. Previous treatment with any BRAF inhibitor (e.g., dabrafenib, vemurafenib,
XL281/BMS-908662, etc.), or any MEK inhibitor (e.g., trametinib, cobimetinib,
selumetinib, RDEA119, etc.) prior to screening and enrollment.
4. Receipt of anticancer medications or investigational drugs within the
following intervals before the first administration of study treatment:
a. <= 14 days for chemotherapy, targeted small-molecule therapy, radiation
therapy, immunotherapy, or antineoplastic biologic therapy (e.g., erlotinib,
crizotinib, bevacizumab, etc.).
b. <= 14 days or 5 half-lives (minimum of 14 days) for investigational agents or
devices. For investigational agents with long half-lives (e.g., > 5 days),
enrollment before the fifth half-life requires medical monitor approval.
c. Palliative radiation therapy must be complete 7 days prior to the first dose
of
study treatment.
5. Patients who have had major surgery (e.g., inpatient procedure with regional
or general anesthesia) <= 6 weeks prior to start of study treatment.
6. Patient has not recovered to <= Grade 1 from toxic effects of prior therapy
and/or complications from prior surgical intervention before starting study
treatment.
7. Current use of a prohibited medication (including herbal medications,
supplements or foods) or use of a prohibited medication <= 1 week prior to
the start of study treatment.
8. Impairment of gastrointestinal function or disease which may significantly
alter the absorption of oral study treatment (e.g., uncontrolled nausea,
vomiting or diarrhea, malabsorption syndrome, small bowel resection).
9. Impaired cardiovascular function or clinically significant cardiovascular
diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes (including
unstable angina, coronary artery bypass graft, coronary angioplasty or stenting)
<= 6 months prior to start of study treatment;
b. Congestive heart failure requiring treatment (New York Heart Association
Grade >= 2);
c. LVEF < 50% as determined by MUGA or ECHO;
d. Uncontrolled hypertension defined as persistent systolic blood pressure
>= 150 mmHg or diastolic blood pressure >= 100 mmHg despite optimal therapy;
e. History or presence of clinically significant cardiac arrhythmias (including
uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular
tachycardia);
f. Triplicate average baseline QTcF interval >= 480 ms or a history of prolonged
QT
syndrome.
10. History of thromboembolic or cerebrovascular events <= 12 weeks prior to the
first dose of study treatment. Examples include transient ischemic attacks,
cerebrovascular accidents, hemodynamically significant (i.e. massive or
sub-massive) deep vein thrombosis or pulmonary emboli.
11. History or current evidence of RVO or current risk factors for RVO (e.g.,
uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or
hypercoagulability syndromes); history of retinal degenerative disease.
12. Concurrent neuromuscular disorder that is associated with the potential of
elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic
lateral sclerosis, spinal muscular atrophy).
13. Evidence of active, noninfectious pneumonitis or history of interstitial
lung disease.
14. Evidence of HBV or HCV infection.
15. Known history of a positive test for HIV or known AIDS. Testing for HIV
must be performed at sites where mandated locally.
16. Active infection requiring systemic therapy.
17. Patients with symptomatic brain metastasis, leptomeningeal disease or other
active CNS metastases are not eligible.
18. Concurrent or previous other malignancy within 2 years of study entry,
except curatively treated basal or squamous cell skin cancer, prostate
intraepithelial neoplasm, carcinoma in-situ of the cervix, Bowen*s disease and
Gleason cancer <= 6 prostate cancer. Patients with a history of other curatively
treated cancers must be reviewed with the Sponsor prior to entering the study.
19. Known sensitivity or contraindication to any component of study treatment
(binimetinib and encorafenib), or their excipients.
20. Pregnancy or breastfeeding or patients who plan to become pregnant during
the duration of the study.
21. Other severe, acute or chronic medical or psychiatric condition(s) or
laboratory abnormality that may increase the risk associated with study
participation or study treatment administration or that may interfere with the
interpretation of study results and, in the judgment of the Investigator, would
make the patient an inappropriate candidate for the study.
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 | EUCTR2019-000417-37-NL |
| CCMO | NL70221.031.19 |