Phase II Study of KW2871 Combined With High Dose Interferon-α2b in Patients With Metastatic Melanoma

This was a Phase 2, open-label study of KW2871 (ecromeximab) in combination with high-dose interferon-α2b (HDI) in patients with metastatic melanoma. The primary objectives of this study were to assess progression-free survival (PFS) and safety. The secondary objectives were to assess the objective response rate, KW2871 pharmacokinetics (PK), and other exploratory immunology as indicated (e.g., development of human anti-chimeric antibodies \[HACA\], activity of antibody-dependent cell-mediated cytotoxicity \[ADCC\] and complement-dependent cytotoxicity \[CDC\] in peripheral blood, number and functional state of tumor-infiltrating immune cells and expression of GD3 in immune and tumor cells of tumor biopsies, and markers of interferon \[IFN\] response/resistance and markers of resistance to ADCC/CDC in peripheral blood mononuclear cells \[PBMCs\]).

Eligible patients were sequentially enrolled into dose-escalating cohorts to receive KW2871 intravenously (IV) once every 2 weeks starting on Day 3 of Week 1 at the following doses: 5 mg/m\^2 in Cohort 1, 10 mg/m\^2 in Cohort 2, and 20 mg/m\^2 in Cohort 3. HDI was administered concurrently at a dose of 20 million units (MU)/m\^2 IV once daily (QD) for 5 consecutive days per week for 4 weeks (induction phase), followed by 10 MU/m\^2 administered subcutaneously (SC) 3 times per week (maintenance phase). Patients received KW2871 and HDI combination therapy until disease progression requiring treatment intervention that would have interfered with the interpretation of the study results.

Initially, 3 patients were enrolled within a cohort and evaluated for dose-limiting toxicity (DLT) and regimen-limiting toxicity (RLT) for the first 8 weeks of study treatment. If 1 of 3 patients experienced an RLT, the cohort was expanded to 6 patients. Escalation to the next higher dose cohort proceeded if the RLT rate was \<33% (0/3 or 1/6 patients) in a given cohort. The combination treatment was considered safe if ≤ 20% patients experienced RLT.

DLT was defined as any adverse event (AE) that required reduction of the HDI dose or discontinuation of KW2871. RLT was defined as an HDI-related DLT that required more than 2 dose reductions of HDI during the induction phase or the first 4 weeks of the maintenance phase, or any KW2871- or regimen-related DLT.

Eligibility Criteria:
Inclusion Criteria:

1. Age ≥ 18 years of age.
2. Histologically proven metastatic cutaneous, mucosal, or unknown primary melanoma.
3. Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST).
4. Ambulatory (Eastern Cooperative Oncology Group \[ECOG\] performance status 0 or 1) or expected survival ≥ 4 months.
5. Within the last 2 weeks prior to study day 1, the following laboratory parameters within the ranges specified:

   * Hemoglobin: ≥ 9 g/dL
   * Platelets: ≥ 100 x 10\^9/L
   * Neutrophils: ≥ 1.5 x 10\^9/L
   * International normalized ratio: ≤ 2.0 (≤ 3.0 if on warfarin therapy)
   * Serum creatinine: ≤ 1.5 x upper limit of normal (ULN)
   * Serum total bilirubin: ≤ 1.5 x ULN
   * Aspartate aminotransferase/alanine aminotransferase: ≤ 2.5 x ULN
6. Able and willing to give valid written informed consent.

Exclusion Criteria:

1. Other malignancy within 3 years prior to study entry for which the patient received active treatment, except for treated melanoma or non-melanoma skin cancer, cervical cancer, and breast carcinoma in situ.
2. Mental impairment that may have compromised the ability to give informed consent and comply with the study requirements.
3. Participation in any other clinical trial involving chemotherapy, radiotherapy, or other immunotherapy within 4 weeks prior to study enrollment.
4. Prior exposure to anti-GD3 antibodies.
5. Pregnancy or breastfeeding.
6. Women of childbearing potential who refused or were unable to use effective means of contraception.
7. Active autoimmune or other disorders that required systemic treatment with immunomodulatory or immunosuppressant medications (i.e., corticosteroids, cyclophosphamide, methotrexate, other biologics). Corticosteroids at substitution doses were allowed.
8. Metastatic brain disease was allowed provided that appropriate treatment had been administered (surgery or irradiation) and 2-month follow-up by brain magnetic resonance imaging (MRI) showed disease control (stability or regression).
9. Autoimmune-related hypothyroidism and vitiligo-like depigmentation were allowed provided the patient was medically stable with treatment (thyroid-hormone replacement or observation).
10. Serious medical illness, such as cardiovascular disease (uncontrolled congestive heart failure or hypertension, active ischemic disease of the heart \[angina\], recent \[\<3 months\] myocardial infarction, severe cardiac arrhythmia), bleeding disorders, obstructive or restrictive pulmonary diseases, active systemic infections requiring antibiotics, serious intercurrent illness requiring hospitalization, inflammatory bowel disorders, or significant psychiatric disease, which in the opinion of the principal investigator would have prevented adequate informed consent or rendered study treatment unsafe or contraindicated.
11. Patients with clinical suspicion of human immunodeficiency virus (HIV) or hepatitis underwent the following viral tests: patients with HIV must have had negative antibodies; patients with hepatitis B virus must have had negative antigens; patients with hepatitis C virus must have had a negative test for serum antibodies. If any of the tests were positive, patients were excluded from the study.