| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAF V600E-mutant Metastatic Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic Colorectal Cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Safety Lead-in: Assess the safety/tolerability of the combination of encorafenib + binimetinib + cetuximab
Randomized Phase III: Compare the acitivity of encorafenib + binimetinib + cetuximab (Triplet Arm) vs. irinotecan + cetuximab or 5-fluorouracil (5-FU)/folinic acid (FA)/irinotecan (FOLFIRI)/cetuximab (Control Arm) as measured by overall survival (OS)
- Compare the activity of encorafenib + binimetinib + cetuximab (Triplet
Arm) vs. irinotecan/cetuximab or FOLFIRI/cetuximab (Control Arm) as
measured by ORR (objective response rate) per BICR (blinded
independent central review)
|
|
| E.2.2 | Secondary objectives of the trial |
Safety Lead-in:
- Assess the activity of encorafenib + binimetinib + cetuximab as
measured by blinded independent central review (BICR) determined and
Investigator-determined objective response rate (ORR), duration of
response (DOR), progression-free survival (PFS) and time to response
- Characterize the pharmacokinetics (PK) of encorafenib, cetuximab,
binimetinib and the active metabolite of binimetinib (AR00426032)
Exploratory:
- Assess the activity of encorafenib + binimetinib + cetuximab as
measured by overall survival (OS)
Randomized Phase III:
- Compare the activity of encorafenib + cetuximab (Doublet Arm) vs.
irinotecan + cetuximab or FOLFIRI/cetuximab (Control Arm) as
measured by OS
- Other Secondary as per Protocol
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide a signed and dated informed consent document.
2. Age ≥ 18 years at time of informed consent.
3. Histologically or cytologically confirmed CRC that is metastatic.
4. Presence of BRAFV600E in tumor tissue previously determined by a local assay at any time prior to Screening or by the central laboratory.
Notes:
a. Only PCR and NGS-based local assays results will be acceptable.
b. Central testing cannot be repeated to resolve discordances with a local result once the central laboratory delivers a definitive result (positive or negative).
c. If the result from the central laboratory is indeterminate or the sample is deemed is inadequate for testing, additional samples may be submitted.
d. If at any time in the Phase 3 portion of the study there is lack of
BRAFV600E confirmation by the central laboratory (for any reason
including discordance and inadequate available tissue) in 37 total
patients or discordance (a valid result of "no BRAFV600E mutation" as
determined by central laboratory) between the local assay and the
central laboratory in 18 patients, all subsequent patients will be required
to have BRAFV600E determined by the central laboratory prior to
enrollment (section 7.1.1)
e. Results from local laboratories with more than 1 discordant result leading to patient enrollment will not be accepted for further patient enrollment.
f. Sites with more than 2 randomized patients having indeterminate
results after initiation of protocol version 6 will be required to enroll all
subsequent patients based only on central laboratory assay results.
5. Able to provide a sufficient amount of representative tumor specimen (primary or metastatic, archival or newly obtained) for confirmatory central laboratory testing of BRAF and KRAS mutation status (minimum of 6 slides; optimally up to 15 slides)
Note: Tumor samples must be submitted to the central laboratory for BRAF testing as soon as possible following the signing of the Molecular Prescreening informed consent. The BRAF status must be confirmed no later than 30 days following first dose of study drug.
6. Eligible to receive cetuximab per locally approved label with regard to tumor RAS status
7. Progression of disease after 1 or 2 prior regimens in the metastatic setting
Notes:
a. Disease relapse during treatment or within 6 months following adjuvant therapy will be considered metastatic disease.
b. Patients who have received 2 prior regimens (i.e., those entering the study in the 3rd line setting), must have received or have been offered and refused prior oxaliplatin unless it was contraindicated due to underlying conditions.
c. Maintenance therapy given in the metastatic setting will not be considered a separate regimen.
d. In the Phase 3 portion of study, the number of patients having received 2 prior regimens will be limited to 215 (35% of the total randomized). Patients with 2 prior regimens who have entered Screening at the time that the limit has been reached will be permitted to continue into the study if they are otherwise determined to be eligible.
8. Evidence of measurable or evaluable non measurable disease per RECIST, v1.1
9. ECOG PS of 0 or 1
10. Adequate bone marrow function characterized by the following at screening:
a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L;
b. Platelets ≥ 100 × 109/L;
c. Hemoglobin ≥ 9.0 g/dL
Note: Transfusions will be allowed to achieve this. Transfusions will be permitted provided the patient has not received more than 2 units red blood cells in the prior 4 weeks to achieve this criteria.
11. Adequate renal function characterized by serum creatinine ≤ 1.5 × upper limit of normal (ULN), or calculated by Cockroft-Gault formula or directly measured creatinine clearance ≥ 50 mL/min at screening
12. Adequate electrolytes at Baseline, defined as serum potassium and magnesium levels within institutional normal limits
Note: replacement treatment to achieve adequate electrolytes will be allowed
13. Adequate hepatic function characterized by the following at screening:
a. Serum total bilirubin ≤ 1.5 × ULN and < 2 mg/dL
Note: Patients who have a total bilirubin level > 1.5 × ULN will be allowed if their indirect bilirubin level is ≤ 1.5 × ULN
b. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤ 2.5 × ULN, or ≤ 5 × ULN in presence of liver metastases
14. Adequate cardiac function characterized by the following at screening:
a. Left ventricular ejection fraction (LVEF) ≥ 50% as determined by a MUGA scan or ECHO;
b. Mean triplicate QT interval corrected for heart rate using Fridericia's formula (QTcF) value ≤480 msec
15. Able to take oral medications
16. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures
Inclusion Criteria No. 17, 18 and 19 can be found in the Study Protocol
|
|
| E.4 | Principal exclusion criteria |
1.Prior treatment with any RAF inhibitor, MEK inhibitor, cetuximab, panitumumab or other EGFR inhibitors
2.Prior irinotecan hypersensitivity or toxicity that would suggest an inability to tolerate irinotecan 180 mg/m2 every 2 weeks
3.Symptomatic brain metastasis
Notes: Patients previously treated or untreated for this condition who are asymptomatic in the absence of corticosteroid and anti-epileptic therapy are allowed. Brain metastases must be stable for ≥ 4 weeks, with imaging (e.g., magnetic resonance imaging [MRI] or computed tomography [CT]) demonstrating no current evidence of progressive brain metastases at screening
4.Leptomeningeal disease
5.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)
6.Use of any herbal medications/supplements or any medications or foods that are strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study treatment
7.Known history of acute or chronic pancreatitis
8.History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to randomization
9.Impaired cardiovascular function or clinically significant cardiovascular diseases, including any of the following:
a. History of acute myocardial infarction, acute coronary syndromes ≤ 6 months prior to start of study treatment;
b. Symptomatic congestive heart failure (i.e., Grade 2 or higher), history or current evidence of clinically significant cardiac arrhythmia and/or conduction abnormality ≤ 6 months prior to start of study treatment, except atrial fibrillation and paroxysmal
supraventricular tachycardia
10.Uncontrolled hypertension defined as persistent systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg despite current therapy
11.Impaired hepatic function, defined as Child-Pugh class B or C
12.Impaired gastrointestinal (GI) function or disease that may significantly alter the absorption of encorafenib or binimetinib (e.g. ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)
13.Concurrent or previous other malignancy within 5 years of study entry, except cured basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in-situ of the cervix, or other noninvasive or indolent malignancy without Sponsor approval
14.History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment, including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli
15.Concurrent neuromuscular disorder that is associated with the potential of elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
16.Treatment with any of the following:
a. Cyclical chemotherapy within a period of time that was shorter than the cycle length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to starting study treatment
b. Biologic therapy (e.g., antibodies) except bevacizumab or aflibercept, continuous or intermittent small molecule therapeutics, or any other investigational agents within a period of time that is ≤ 5 half-lives (t1/2) or ≤ 4 weeks (whichever is shorter) prior to starting study treatment
c. Bevacizumab or aflibercept therapy ≤ 3 weeks prior to starting study treatment
d. Radiation therapy that included > 30% of the bone marrow
17.Residual CTCAE ≥ Grade 2 toxicity from any prior anticancer therapy, with the exception of Grade 2 alopecia or Grade 2 neuropathy
18.Known history of HIV infection
19.Active hepatitis B or hepatitis C infection
20.Known history of Gilbert's syndrome or is known to have any of the following genotypes: UGT1A1*6/*6, UGT1A1*28/*28, or UGT1A1*6/*28
21.Known contraindication to receive cetuximab or irinotecan at the planned doses; refer to the most recent cetuximab and irinotecan SPC or local label as applicable
22.Current treatment with a non-topical medication known to be a strong inhibitor of CYP3A4. However, patients who either discontinue this treatment or switch to another medication at least 7 days prior to starting study treatment are eligible
23.Concomitant use of St. John's Wort (hypericum perforatum)
24.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 judgment of the Investigator, would make the patient an inappropriate candidate for the study
25.Pregnant, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test result, or nursing (lactating)
26.Prior enrollment into this clinical study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Lead-in:
- Incidence of dose-limiting toxicities (DLTs)
- Incidence and severity of adverse events (AEs) graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (v.4.03), and changes in clinical laboratory parameters, vital signs, electrocardiograms (ECGs), echocardiogram (ECHO)/multi-gated acquisition (MUGA) scans and ophthalmic examinations
- Incidence of dose interruptions, dose modifications and discontinuations due to AEs
Randomized Phase III:
- OS, defined as the time from randomization to death due to any cause, of Triplet Arm vs. Control Arm
- Confirmed ORR (by BICR) per RECIST, v1.1 of Triplet Arm vs. Control
Arm
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Safety Lead-in: The Data Monitoring Committee (DMC) will evaluate the safety data at pre-specified intervals and at additional points during the conduct of the Safety Lead-in, if necessary. Randomized Phase III: Interim analysis at approximately 30 months. End-of-study evaluations at approximately 48 months. |
|
| E.5.2 | Secondary end point(s) |
Safety Lead-in:
- ORR (by BICR and Investigator) per the Response Evaluation Criteria in
Solid Tumors
(RECIST), version 1.1 (v1.1), defined as the number of patients
achieving an overall best response of complete
response (CR) or partial response (PR) divided by the total
number of patients
- DOR (by BICR and Investigator), defined as the time from first
radiographic evidence of
response to the earliest documented disease progression or
death due to underlying disease
- PFS (by BICR and Investigator), defined as the time from first dose to
the earliest documented disease progression or death due to any cause
- Time to response (by BICR and Investigator), defined as the time from
first dose to first
radiographic evidence of response
- PK parameters of encorafenib, cetuximab, binimetinib and the active
metabolite of binimetinib (AR00426032)
Exploratory:
-OS, defined as the time from first dose to death due to any cause.
Randomized Phase III:
1. Key Secondary:
- OS of Doublet Arm vs. Control Arm
2. Other Secondary:
- Confirmed ORR (by Investigator) per RECIST, v1.1 of Triplet Arm vs.
Control Arm
- Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Doublet
Arm vs. Control Arm
- PFS (by BICR and Investigator), defined as the time from
randomization to the earliest
documented disease progression or death due to any cause, of Triplet
Arm vs. Control Arm
- PFS (by BICR and Investigator) of Doublet Arm vs. Control Arm
- OS of Triplet Arm vs. Doublet Arm
- Confirmed ORR (by BICR and Investigator) per RECIST, v1.1 of Triplet
Arm vs. Doublet
Arm
- PFS (by BICR and Investigator) of Triplet Arm vs. Doublet Arm
- DOR (by BICR and Investigator) of Triplet Arm vs. Control Arm, of
Doublet Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm
- Time to response (by BICR and Investigator), defined as the time from
randomization to
first radiographic evidence of response, of Triplet Arm vs.
Control Arm, of Doublet Arm vs. Control Arm and of Triplet
Arm vs. Doublet Arm
- Incidence and severity of AEs, graded according to NCI
CTCAE, v 4.03, and changes in clinical laboratory parameters,
vital signs, ECGs, ECHO/MUGA scans and ophthalmic examinations
- Change from baseline in the European Organization for Research and
Treatment of Cancer (EORTC) Quality of Life
Questionnaire for Cancer Patients (QLQ-C30), Functional
Assessment of Cancer Therapy-Colon Cancer (FACT-C),
EuroQol-5D-5L (EQ-5D-5L), and Patient Global Impression of
Change (PGIC) of Triplet Arm vs. Control Arm, of Doublet
Arm vs. Control Arm and of Triplet Arm vs. Doublet Arm
- Model-based PK parameters of encorafenib, cetuximab,
binimetinib and the active metabolite of binimetinib (AR00426032)
- Model-based PK assessment of drug-drug interactions between
encorafenib, cetuximab, binimetinib and the active metabolite of
binimetinib (AR00426032)
3. Exploratory:
- Changes in CEA and CA19-9
- Genomic and proteomic analysis of blood and tissue samples at
baseline and at end of treatment (optional for tumor samples at end of
treatment)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| In addition to end-of-study evaluations at approximately 48 months interim safety reviews will be performed by an independent DMC as detailed in the protocol, and an interim analysis will be performed at approximately 30 months. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| Israel |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| Austria |
| Belgium |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
End of study will be defined as the point when all patients have the opportunity to be followed for at least 1 year after the randomization date of the last patient enrolled and at least 80% of patients have an OS event (or are lost to follow-up).
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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