| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BRAFV600-Mutant Melanoma Brain Metastasis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Mutant Melanoma Brain Metastasis |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053571 |
| E.1.2 | Term | Melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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:
-Evaluate the safety of a high-dose regimen of encorafenib + binimetinib combination therapy in patients with BRAFV600-mutant melanoma who have asymptomatic brain metastasis.
Phase 2:
If the high-dose regimen is determined to be safe based on the results of the safety Lead-in phase then
-Evaluate the antitumor activity in brain metastases of the standard and high-dose regimens of encorafenib + binimetinib combination therapy in patients with BRAFV600-mutant melanoma whohave asymptomatic brain metastasis
If the high-dose regimen is determined not to be safe based on the results of the Safety Lead in phase, then
- Evaluate the antitumor activity in brain metastases of the standard dosing regimen of encorafenib + binimetinib combination in patients with BRAFV600-mutant melanoma who have asymptomatic brain metastasis. |
|
| E.2.2 | Secondary objectives of the trial |
•Further evaluate the antitumor activity of encorafenib + binimetinib combination therapy in patients with BRAFV600-mutant melanoma who have asymptomatic brain metastasis;
•Evaluate the efficacy of encorafenib + binimetinib combination therapy as measured by OS in patients with BRAFV600-mutant melanoma who have asymptomatic brain metastasis;
Further evaluate the safety profile of encorafenib + binimetinib combination therapy in patients with BRAFV600-mutant melanoma who have asymptomatic brain metastasis;
•Characterize the PK of encorafenib and its metabolite LHY746, and binimetinib in the 2 dosing regiens (standard dose and high-dose) and its metabolite AR00426032 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Able to provide written informed consent. Adult patients under guardianship may participate if permitted by local regulations with the consent of their legally authorized guardian. All local regulations concerning patients under guardianship must be followed.
2. Age ≥ 18 years at the time of informed consent.
3. Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.
4. Presence of BRAFV600 mutation in tumor tissue previously determined by a local PCR or NGS-based assay at any time prior to Screening or by a central laboratory during Screening.
5. Patients are required to submit archival or fresh tumor tissue and a blood sample prior to enrollment. Tissue samples will be used to determine BRAFV600-mutation status by central laboratory.
6. Must have at least 1parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as an MRI contrast-enhancing lesion that may be accurately measured in at least 1 dimension.
Note: Measurable intracranial lesions that have been previously irradiated and have not been shown to be progressing following irradiation should not be considered as target lesions.
7. Patients may have received the following prior therapies:
a.Safety Lead-in, Phase 2 Randomized , Phase 2 Arm A Cohort 1: May have received prior local therapy for brain metastases including but not restricted to brain surgery, whole brain radiotherapy (WBRT), stereotactic radiotherapy or stereotactic radiosurgery (e.g. gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). Multiple local (brain) therapies or combinations of local therapies are allowed. For patients receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For patients receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated.
b.Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery, craniotomy, SRS or SRT) for brain metastases.
c.All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy.
d.All patients (Safety Lead-In and Phase 2): If receiving concomitant corticosteroids must be on a stable or decreasing dose (up to a total daily dose of 4 mg of dexamethasone or equivalent) for at least 2 weeks prior to first dose of study treatment.
8. An ECOG PS of 0 or 1 and Karnofsky score ≥ 80
9. Adequate bone marrow, organ function and laboratory parameters:
a. ANC ≥ 1.5 × 109/L;
b. Hemoglobin ≥ 9 g/dL with or without transfusions;
c. Platelets ≥ 100 × 109/L;
d. AST and ALT ≤ 2.5 × ULN; in patients with liver metastases ≤ 5 × ULN;
e. Total bilirubin ≤ 1.5 × ULN; NOTE: Patients with documented Gilbert syndrome or hyperbilirubinemia due to non-hepatic cause (e.g., hemolysis, hematoma) may be enrolled following discussion and agreement with the Sponsor Medical Monitor.
f. 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.
10. Female patients of childbearing potential, as described in Appendix 1, must have a negative serum β-HCG test result.
11. Female patients of childbearing potential must agree to protocol-approved methods of contraception, as described in Appendix 1 of the Protocol, and to not donate ova from Screening until 30 days after the last dose of study drug.
12. Male patients must agree to use methods of contraception that are highly effective or acceptable, as described in Appendix 1 of the Protocol, and to not donate sperm from Screening until 90 days after the last dose of study drug.
13. The patient is deemed by the Investigator to have the initiative and means to comply with scheduled visits, treatment plan and study procedures. |
|
| E.4 | Principal exclusion criteria |
1.Patients with symptomatic brain metastasis (e.g., have neurologic symptoms related to brain metastases)
2.Prophylactic or preventive anti-epileptic therapy
Note: anti-epileptic therapy indicated in order to prevent neurologic symptoms caused by a preexisting condition and not related to brain metastasis is allowed
3.Known hypersensitivity or contraindication to any component of study treatment or their excipients
4.Inability to swallow and retain study treatment
5.Uveal or mucosal melanoma
6.History of or current leptomeningeal metastases
7.Treatment with SRS or craniotomy within 14 days prior to start of study treatment, or treatment with whole-brain radiation within 28 days prior to study treatment. Patients who received local therapy should have complete recovery with no neurological sequelae
8.Either of the following:
a.Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start of study treatment;
b.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 treatment, when half-life is unknown)
9.Patients treated in the adjuvant setting with BRAF or MEK inhibitor(s) < 6 months prior to enrollment. Patients who received BRAF or MEK inhibitors in the metastatic setting are excluded
10.Is currently participating in a study and receiving an investigational agent; has received an investigational agent or used an investigational device within 14 days prior to start of study treatment
11.Patients who have undergone major surgery (e.g., inpatient procedure with regional or general anesthesia) ≤ 6 weeks prior to start of study treatment. For minor surgical procedures ≤ 6 weeks prior to start of study treatment, consult the Sponsor Medical Monitor
12.Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before starting study treatment.
Note: Stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as neuropathy, myalgia, alopecia, prior therapy-related endocrinopathies) are exceptions and patients with these may enroll
13.Impaired cardiovascular function or clinically significant cardiovascular disease including, but not limited to, the following:
a.History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty or stenting) < 6 months prior to Screening;
b.Congestive heart failure requiring treatment (New York Heart Association Grade ≥ 2);
c.An 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 current therapy;
e.History or presence of clinically significant cardiac arrhythmias (including resting bradycardia, uncontrolled atrial fibrillation or uncontrolled paroxysmal supraventricular tachycardia);
f.Triplicate average baseline QTcF interval ≥ 480 msec
14.Impairment of gastrointestinal function or disease which may significantly alter the absorption of study treatment (e.g., active ulcerative disease; uncontrolled nausea, vomiting or diarrhea; malabsorption syndrome; small bowel resection)
15.Concurrent neuromuscular disorder that is associated with elevated CK (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
16.Known history of acute or chronic pancreatitis
17.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
18.Use of herbal supplements, medications or foods that are moderate or strong inhibitors or inducers of cytochrome P450 (CYP) 3A4/5 ≤ 1 week prior to the start of study treatment
19.History of a thromboembolic event < 12 weeks prior to starting study treatment. Examples of thromboembolic events include transient ischemia attack, cerebrovascular accident, deep vein thrombosis or pulmonary embolism. Catheter-related venous thrombosis is not considered a thromboembolic event for this trial even if < 12 weeks prior to starting study treatment
20.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 ≤ 6 Gleason prostate cancer. Patients with a history of other curatively treated cancers must be reviewed by the Sponsor prior to entering the study
21.Active infection requiring systemic therapy
22.Known history of positive test for HIV or known AIDS. Testing for HIV must be performed at sites where mandated locally
For more detail splease see Page 48 of Protocol Amendment 2 dated 13-Mar-2020 (version with track changes) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Lead-In:
• Incidence of DLTs
• Incidence and severity of AEs graded according to the NCI CTCAE version 4.03 and changes in clinical laboratory parameters, vital signs, ECGs
• Incidence of dose interruptions, dose modifications and discontinuations due to AEs
Phase 2:
• BMRR per mRECIST v1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As per the enclosed Protocol |
|
| E.5.2 | Secondary end point(s) |
• Extracranial response rate per RECIST v1.1
• Global response rate (brain metastasis response per mRECIST v1.1 and extracranial response per RECIST v1.1)
• DCR
o for brain metastasis response per mRECIST v1.1 criteria
o for extracranial response per RECIST v1.1
o for global response (brain metastasis per mRECIST v1.1 and extracranial per RECIST v1.1)
• DOR
o for brain metastasis response per mRECIST v1.1 criteria
o for extracranial response per RECIST v1.1
o for global response (brain metastasis per mRECIST v1.1 and extracranial per RECIST v1.1)
• PFS
o for brain metastasis per mRECIST v1.1
o for global assessment (brain metastasis per mRECIST v1.1 and extracranial disease per RECIST v1.1)
• BMRR per mRECIST v1.1 for Safety Lead-in only
• OS
• Incidence and severity of AEs graded according to the NCI CTCAE version 4.03 and changes in clinical laboratory parameters, vital signs and ECGs.
• Plasma concentration-time profiles and PK parameter estimates for encorafenib and its metabolite LHY746, and binimetinib and its metabolite AR00426032 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As per the enclosed Protocol |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 12 |
| 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 |
| Belgium |
| Canada |
| Italy |
| Netherlands |
| New Zealand |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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 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. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 5 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 5 |
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