Description:
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and
pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in
patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will
be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a
Screening Period, treatment will be administered in 28-day cycles and will continue until
disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent
anticancer therapy, death.
Title
- Brief Title: An Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-mutant Melanoma Brain Metastasis
- Official Title: A Phase 2, Open-Label, Randomized, Multicenter Trial of Encorafenib + Binimetinib Evaluating a Standard-dose and a High-dose Regimen in Patients With BRAFV600-Mutant Melanoma Brain Metastasis
Clinical Trial IDs
- ORG STUDY ID:
ARRAY-818-201
- SECONDARY ID:
C4221006
- SECONDARY ID:
2018-004555-21
- NCT ID:
NCT03911869
Conditions
Interventions
Drug | Synonyms | Arms |
---|
encorafenib | | High Dose Arm |
binimetinib | | High Dose Arm |
Purpose
This is a multicenter, randomized open-label Phase 2 study to assess the safety, efficacy and
pharmacokinetic (PK) of 2 dosing regimens of encorafenib + binimetinib combination in
patients with BRAFV600-mutant melanoma with brain metastasis. Approximately 100 patients will
be enrolled, including 9 patients in a Safety Lead-in of the high-dose treatment arm. After a
Screening Period, treatment will be administered in 28-day cycles and will continue until
disease progression, unacceptable toxicity, withdrawal of consent, start of subsequent
anticancer therapy, death.
Trial Arms
Name | Type | Description | Interventions |
---|
Standard Dose Arm | Experimental | Patients in the standard-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.
450 mg encorafenib orally once a day (QD)
45 mg binimetinib orally twice a day (BID)
Patients who are able to tolerate the standard dose during the first 4 weeks of treatment (Cycle 1) should be dose-escalated to 600 mg encorafenib QD plus 45 mg binimetinib BID provided they meet protocol-defined criteria. | |
High Dose Arm | Experimental | Patients in the high-dose treatment arm will receive encorafenib and binimetinib in 28-day cycles.
300 mg encorafenib orally twice a day (BID)
45 mg binimetinib orally twice a day (BID) | |
Eligibility Criteria
Key Inclusion Criteria:
- Histologically confirmed diagnosis of cutaneous melanoma with metastases to the brain.
- Presence of B-RAF proto-oncogene, V600 mutant (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.
- Must have at least 1 parenchymal brain lesion ≥ 0.5 cm and ≤ 4 cm, defined as a
magnetic resonance imaging (MRI) contrast-enhancing lesion that may be accurately
measured in at least 1 dimension. (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).
- Patients may have received the following prior therapies:
1. 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, stereotactic radiotherapy or stereotactic
radiosurgery. 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.
2. Phase 2 Arm A Cohort 2: Received no prior local therapy (e.g., brain surgery,
craniotomy, SRS or SRT) for brain metastases.
3. All patients (Safety Lead-In and Phase 2): May have received prior immunotherapy.
4. All patients (Safety Lead-In and Phase 2): If receiving concomitant
corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior
to first dose of study treatment (up to a total daily dose of 4mg of
dexamethasone or equivalent).
- An Eastern Cooperation Oncology Group Performance Status (ECOG PS) of 0 or 1 and
Karnofsky score ≥ 80
- Adequate bone marrow, organ function and laboratory parameters
Key Exclusion Criteria:
- Patients with symptomatic brain metastasis.
- Uveal or mucosal melanoma.
- History of or current leptomeningeal metastases.
- 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.
- Either of the following:
1. Radiation therapy to non-brain visceral metastasis within 2 weeks prior to start
of study treatment;
2. 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).
- 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.
- Patient has not recovered to ≤ Grade 1 from toxic effects of prior therapy before
starting study treatment.
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Safety Lead-in: Incidence of dose-limiting toxicities (DLTs) |
Time Frame: | Up to 28 days |
Safety Issue: | |
Description: | |
Secondary Outcome Measures
Measure: | Extracranial response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Global response rate (brain metastasis response per mRECIST v1.1 and extracranial response per RECIST v1.1) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | Global response rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) per Investigator assessment for brain metastasis and extracranial lesions according to mRECIST v1.1 and RECIST v1.1, respectively. |
Measure: | Disease control rate (DCR) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Duration of Response (DOR) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Progression-free survival (PFS) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Brain metastasis response rate (BMRR) per mRECIST v1.1 for Safety Lead-in only |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Overall survival (OS) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Incidence and severity of adverse events (AEs) |
Time Frame: | Up to 24 months |
Safety Issue: | |
Description: | |
Measure: | Pharmacokinetics (PK) of binimetinib and its metabolite |
Time Frame: | Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 2 and Cycle 3; 28 day cycles |
Safety Issue: | |
Description: | Plasma concentrations of binimetinib |
Measure: | Pharmacokinetics (PK) of encorafenib and its metabolite |
Time Frame: | Day 1 and Day 15 of Cycle 1 and Day 1 of Cycle 2 and 3; 28 day cycles |
Safety Issue: | |
Description: | Plasma concentrations of encorafenib |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Active, not recruiting |
Lead Sponsor: | Pfizer |
Trial Keywords
- BRAFV600-mutant
- melanoma
- brain metastasis
Last Updated
July 8, 2021