SEACRAFT-2

Patient Inclusion Criteria

1. Willing and able to provide written informed consent

2. Age ≥ 18 years

3. Have histologically or cytologically confirmed unresectable Stage III or Stage IV cutaneous (includes acral) melanoma, per American Joint Committee on Cancer (AJCC) staging system version 8, not amenable to local therapy.

4. 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.

5. Archival tumor tissue collected within 5 years prior to Cycle 1 Day 1 (C1D1) must be confirmed to be available at the time of Screening. The tissue may be submitted before or after C1D1. If archival tissue is not available, please discuss it with the Sponsor.

Alternatively, tumor tissue obtained from a biopsy using a low-risk, medically routine procedure (e.g., no more than 2% risk of serious complication requiring hospitalization) may be provided.

6. Must have received SOC ICI therapy as defined by local institutional standards.

• At a minimum, the patient must have received an anti-PD-1/L1-based regimen (monotherapy or combination).

• For those institutions where anti-CTLA-4 therapy is available and for those patients for whom this therapy is not contra-indicated as determined by the investigator, patients must also have received an anti-CTLA-4-based regimen (monotherapy or combination).

• Patients must have documented disease progression either while receiving therapy or within 12 weeks of the last dose of the most recent SOC ICI therapy; the patient is eligible if they have received other therapies between the most recent SOC ICI therapy and enrollment.

• Progression is defined by meeting all of the following criteria:

− Received at least two doses of SOC ICI therapy

− Progression defined by RECIST 1.1

• Patients who have withdrawn from standard SOC ICI therapy due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent before progression of disease are eligible.

• Patients who have received treatment with an anti-LAG-3 inhibitor or tumorinfiltrating-lymphocyte-based therapy are eligible.

7. Stage 1: measurable disease according to RECIST, version 1.1. Stage 2: measurable or

evaluable disease according to RECIST, version 1.1.

8. ECOG 0, 1 or 2

9. LDH ≤2.5 x ULN.

10. Adequate bone marrow and organ function based on laboratory results obtained during Screening:

• Absolute neutrophil count (ANC) ≥1.5 x 109/L

• Platelets >100 x 109/L without transfusions within 2 weeks prior to C1D1

• Hemoglobin (Hgb) ≥10 g/dL without transfusions within 2 weeks prior to C1D1

• Total bilirubin ≤ULN except for patients with liver metastases at baseline, who will be eligible if total bilirubin ≤1.5 x ULN. Patients with Gilbert Syndrome are eligible if total bilirubin <3.0 mg/dL)

• Aspartate aminotransferase (AST) ≤3.0 x ULN or ≤5.0 x ULN if liver metastases are present

• Alanine aminotransferase (ALT) ≤3.0 x ULN or ≤5.0 x ULN if liver metastases are present

• Estimated creatinine clearance per institutional standards ≥30 mL/min

11. Able to swallow oral medication.

12. Able to receive oral antibiotics (e.g., doxycycline, minocycline, or oxytetracycline) and use topical low potency corticosteroids for required rash prophylaxis.

13. Recovered from all toxicities associated with prior treatment to acceptable baseline status (for laboratory toxicities, see limits for inclusion) or NCI CTCAE version 5.0 Grade 1, except for toxicities not considered a safety risk (e.g., alopecia or vitiligo). Patients with Grade 2 endocrinopathies being treated with replacement therapy that are no longer symptomatic are eligible.

14. Human immunodeficiency virus (HIV) positive patients are eligible to enroll provided the following criteria have been met:

• Cluster of differentiation (CD)4+ T cell counts ≥350 µL

• No history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months

• Have been on established antiretroviral therapy (ART) for at least 4 weeks and have an HIV ribonucleic acid (RNA) viral load of <400 copies/mL prior to the first dose of study drug

15. Patients with a history of chronic hepatitis C virus (HCV) are eligible to enroll provided the following criteria have been met:

• Have completed curative antiviral treatment OR been on established antiviral therapy for HCV for at least 4 weeks prior to the first dose of study drug

• Have an HCV RNA viral load below the limit of quantification

16. Patients with a history of hepatitis B virus (HBV) infection are eligible to enroll provided the following criteria have been met:

• On HBV prophylaxis for at least 1 week prior to first dose of study drug

• Have an HBV DNA viral load below the lower limit of quantification

17. Female patients of childbearing potential must have a negative serum beta-human chorionic gonadotropin pregnancy test before the first dose of study drug(s).

18. Willingness to adhere to the study drug(s) -specific contraception requirements for the course of the study through at least 4 months after the last dose of trametinib, at least 30 days after the last dose of naporafenib (monotherapy), whichever is longer, or at least 6 months after the last dose of dacarbazine or temozolomide. 

Patient Exclusion Criteria

1. Patients with uveal or mucosal melanoma

2. Prior ERK, MEK, RAF, or RAS inhibitor

3. Treatment with any of the following anticancer therapies prior to the first dose of study drug(s) in this study within the stated timeframes:

• ≤4 weeks for radiation therapy or ≤2 weeks for limited field radiation for palliation

• ≤2 weeks or 5 half-lives, whichever is shorter, for small molecule therapeutics

• ≤4 weeks or 5 half-lives, whichever is shorter, for any immunotherapy treatment including checkpoint inhibitors

• ≤2 weeks or 5 half-lives, whichever is shorter, for chemotherapy agents, locally directed anti-neoplastic agents, or other investigational agents

• ≤6 weeks for cytotoxic agents with major delayed toxicities, such as nitrosourea and mitomycin c

4. Impairment of 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)

5. 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)

6. Corrected QT interval using Fridericia’s formula (QTcF) at Screening >450 ms based on triplicate average

NOTE: criterion does not apply to patients with a right or left bundle branch block

7. Cardiac disease or cardiac repolarization abnormality, including any of the following:

• Congestive heart failure requiring treatment (New York Heart Association Grade ≥2)

• LVEF <50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO)

• Uncontrolled hypertension defined by blood pressure ≥150 (systolic) / 100 (diastolic) mm Hg at rest (average of 3 consecutive readings) despite medical treatment

• History of myocardial infarction, angina pectoris, coronary artery bypass graft within 6 months prior to first dose of study drug(s)

• History or presence of clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block). Patients with atrial fibrillation controlled for ≥30 days prior to the first dose of study drug(s) are eligible.

• Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following:

− Risk factors for Torsade de Pointes including uncorrected hypokalemia, hypomagnesemia, hypocalcemia, or significant/symptomatic bradycardia

− Inability to measure QT interval

8. Symptomatic CNS metastases that are neurologically unstable. Patients with controlled CNS metastases are eligible.

• Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the identical imaging modality for each assessment, either magnetic resonance imaging (MRI) or computed tomography (CT) scan] prior to the first dose of study drug(s) and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.

• If patients require steroids for management of CNS metastases, they must be on a stable dose of steroids for 2 weeks preceding the first dose of study drug(s). If steroid dose is increased between imaging and initiation of study drug(s), a new CT/MRI is required before initiating dosing.

9. History of severe hypersensitivity reaction to any ingredient of the study drug(s) or their excipients

10. Patients receiving treatment with medications that are known to be strong inhibitors and/or inducers of CYP3A; sensitive substrates of CYP2C8, CYP2C9, and CYP3A with a narrow therapeutic index; herbal medicines 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.

11. Any evidence of severe or uncontrolled systemic disease or evidence of any other significant clinical disorder or laboratory finding that renders the patient inappropriate to participate in the study.

12. Have a planned major surgery, or incomplete recovery from any prior surgery prior to the start of study therapy.

13. History of another invasive cancer except for the following:

• If the patient has been disease-free for at least 2 years and is deemed by the Investigator to be low risk for recurrence

• A patient with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, in situ cervical cancer, localized prostate cancer or breast cancer managed with endocrine suppression, or local papillary thyroid cancer, who have undergone therapy with curative intent.

14. Pregnant or breastfeeding females. 

Research Nurse: Carolyn Hatch (x3921) Carolyn.Hatch@lthtr.nhs.uk

Administrator: Bethany Webster (x8475)