A Randomized, Open-label Phase 3 Study in Patients With Previously Treated Unresectable or Metastatic NRAS Mutant Cutaneous Melanoma Comparing the Combination of Naporafenib + Trametinib to Physician's Choice of Therapy (Dacarbazine, Temozolomide or Trametinib Monotherapy) With a Dose Optimization Lead-in [SEACRAFT-2]

Cancer Categories

Karmanos Trial ID

NCT ID

Age Group

Scope

Phase

Principal Investigator

Dose Optimization (Stage 1)

Primary Objective:

To select an optimal dose based on an analysis of the totality of safety, PK, and preliminary efficacy data, including exposure response relationships for tolerability, safety, and efficacy from Stage 1 and throughout the naporafenib clinical program.

Secondary Objectives:

To evaluate the preliminary clinical activity (e.g., ORR, DOR, etc.) of naporafenib + trametinib (administered at two doses) or trametinib monotherapy in patients with NRASm melanoma.
To evaluate the safety and tolerability of naporafenib + trametinib (administered at two dose regimens) or trametinib monotherapy in patients with NRASm melanoma.
To evaluate the PK of naporafenib and trametinib when administered as combination therapy (administered at two doses) and the PK of trametinib when administered as monotherapy in patients with NRASm melanoma.

Registration-Enabling (Stage 2)

Primary Objective:

To compare the PFS, as assessed by blinded independent central review (BICR), and OS of patients with NRASm melanoma who are randomized to receive the combination of naporafenib + trametinib or physician’s choice of therapy.

Secondary Objectives:

To compare measures of clinical activity (e.g., ORR, DOR, etc.) for patients with NRASm melanoma who are randomized to receive the combination of naporafenib + trametinib or physician’s choice of therapy.
To evaluate the safety and tolerability for patients with NRASm melanoma in each treatment arm.
To evaluate the PK of naporafenib and trametinib when administered as combination therapy in patients with NRASm melanoma.
To compare changes from baseline in measures of QOL using the EORTC QLQ-C30 subscales and PRO CTCAE® symptom items specific to the potential cutaneous toxicities that the targeted metastatic melanoma population for patients with NRASm melanoma who are randomized to receive the combination of naporafenib + trametinib or physician’s choice of therapy might experience.

Eligibility

Inclusion Criteria:

Willing and able to provide written informed consent
Age ≥ 18 years
Histologically or cytologically confirmed unresectable or metastatic cutaneous (includes acral) melanoma.
Documentation of an NRAS mutation (tumor tissue or blood) prior to first dose of study drug(s) as determined locally with an analytically validated assay in a certified testing laboratory.
Archival tumor tissue collected within 5 years prior to enrollment must be confirmed to be available at the time of Screening, which may be submitted before or after enrollment for exploratory biomarker analysis.
Must have received an anti-PD-1/L1 based regimen (monotherapy or combination). Patient must have documented disease progression either while receiving therapy or within 12 weeks of last dose of the most recent anti-PD-1/L1 based regimen; the patient is eligible if they have received other therapies between the most recent anti-PD-1/L1 based regimen and enrollment.
ECOG performance status 0, 1 or 2
Presence of at least 1 measurable lesion according to RECIST v1.1
Able to swallow oral medication.

Exclusion Criteria:

Patients with uveal or mucosal melanoma
Prior therapy with an ERK-, MEK-, RAF-, or RAS-inhibitor
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug(s) (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection)
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 syndrome)
LVEF <50%
Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.
Patients receiving treatment with herbal medicine known to cause liver toxicity, which cannot be discontinued 7 days prior to first dose of study drug(s) and for the duration of the study.

Locations

4100 John R
Detroit, MI 48201
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Phone: 800-527-6266

31995 Northwestern Hwy
Farmington Hills, MI 48334
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Phone: 800-527-6266

Applicable Disease Site

Therapies, Drugs, Devices