Study of CDX-3379, a Human Monoclonal Antibody Targeting ERBB3, in Combination With the MEK Inhibitor, Trametinib, in Patients With Advanced Stage NRAS Mutant and BRAF/NRAS Wildtype (WT) Melanoma

1\. Read, understood, and provided written informed consent and, if applicable, Health Insurance Portability and Accountability Act (HIPAA) authorization after the nature of the study has been fully explained and must be willing to comply with all study requirements and procedures.

2\. Male or female patients who are 18 years of age or older. 3. Patients with a diagnosis of histologically confirmed advanced (defined as unresectable stage III or IV) melanoma with the NRAS Q61 mutation or BRAF/NRAS WT for which there is no remaining standard therapy with curative potential or patients are ineligible or unable to tolerate therapy with curative potential.

* Any standard of care mutation testing is acceptable to document mutation status.

4.Patients must have archival tissue and at least one disease site amenable to biopsy:

* For phase Ib, all patients will undergo fresh tumor biopsy

* For phase II, five patients with NRAS mutation and five patients with BRAF/NRAS WT melanoma will undergo fresh tumor biopsy 5.Measurable (target) disease by Response Evaluation Criteria In Solid Tumors (RECIST 1.1) criteria. Target lesions selected for tumor measurements should be those where additional (eg palliative) treatments are not indicated or anticipated.

* Measurable disease per RECIST 1.1 requirements: defined as longest diameter to be recorded for non-nodal lesions \> 10mm and short axis for nodal lesions \>15 mm using conventional techniques 6.All residual toxicity related to prior radiotherapy or anticancer therapies (excluding alopecia, grade 2 fatigue, vitiligo or endocrinopathies on stable replacement therapy) must resolve to grade 1 severity or less (or returned to baseline) prior to receipt of study treatment.

7.Adequate electrolytes, liver, renal, and hematology function as defined below:

a.Hemoglobin ≥ 9 g/dL b.Absolute neutrophil count ≥ 1500/mm3 c.Platelet count ≥ 100,000/mm3 d.Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) (≤ 5 × ULN for cases involving liver metastasis) e.Bilirubin ≤ 1.5 × ULN (≤ 5 × ULN for cases of documented or suspected Gilbert's disease) f.Serum creatinine ≤ 1.5 g/dL or calculated creatinine clearance (CrCl) ≥60 mL/min for patients with serum creatinine \> 1.5 x ULN g.Serum magnesium, calcium and potassium within normal limits 8.Life expectancy ≥ 12 weeks 9.ECOG performance status (PS) \< 1 10.Willing and able to comply with scheduled visits, treatment plan, and laboratory tests.

11.Screening EKG without clinically significant abnormalities. 12.Corrected (Fridericia's) QTcF must be \< 480 milliseconds. 13.Allowance of prior therapy regimens:

* No limit on prior number of regimens

* Must have completed prior cytotoxic chemotherapy a minimum of 4 weeks prior to starting study treatment (except for bis-chlorethynitrosurea (BCNU)), which must have been completed a minimum of 6 weeks prior to starting therapy.

* Prior localized radiation therapy must have been completed a minimum of 2 weeks prior to starting therapy and the patient must have baseline imaging with a full body PET-CT or CT scans of the chest, abdomen, and pelvis and within 4 weeks prior to study enrollment.

* For CNS metastases, disease must be treated and demonstrate stability with Brain MRI a minimum of 2 weeks prior to starting therapy.

14.Both male and female patients enrolled in this trial must agree to use highly effective contraception during the course of the trial and for at least for 6 months after the final dose of CDX-3379 (an effective form of contraception is an oral contraceptive or a double barrier method), or greater, as in accordance with the label requirements for trametinib. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.

* Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 3 months after stopping study drug. Highly effective contraception methods include:

* Total abstinence or

* Male or female sterilization or

* Combination of any two of the following (a+b or a+c or b+c):

1. Use of oral, injected or implanted hormonal methods of contraception; hormonal contraceptives are not acceptable as a sole method of contraception.

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 15. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.

What this study is about