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

Study Overview
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Brief Summary
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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]).

Detailed Description
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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.

Official Title
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Phase II Study of the Anti-Ganglioside GD3 Mouse/Human Chimeric Antibody KW2871 Combined With High Dose Interferon-α2b in Patients With Metastatic Melanoma

Conditions
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Metastatic Melanoma, Cutaneous Melanoma

Intervention / Treatment
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* Drug: HDI
* Drug: KW2871
* Drug: KW2871
* Drug: KW2871


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years of age. Histologically proven metastatic cutaneous, mucosal, or unknown primary melanoma. Measurable disease using Response Evaluation Criteria in Solid Tumors (RECIST). Ambulatory (Eastern Cooperative Oncology Group [ECOG] performance status 0 or 1) or expected survival ≥ 4 months. 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 Able and willing to give valid written informed consent. Exclusion Criteria: 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. Mental impairment that may have compromised the ability to give informed consent and comply with the study requirements. Participation in any other clinical trial involving chemotherapy, radiotherapy, or other immunotherapy within 4 weeks prior to study enrollment. Prior exposure to anti-GD3 antibodies. Pregnancy or breastfeeding. Women of childbearing potential who refused or were unable to use effective means of contraception. 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. 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). Autoimmune-related hypothyroidism and vitiligo-like depigmentation were allowed provided the patient was medically stable with treatment (thyroid-hormone replacement or observation). 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. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Dose-escalation cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>KW2871: 5 mg/m^2 IV every 2 weeks until disease progression HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression | Drug: HDI<br>* 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression<br>* Other names: Intron A;Drug: KW2871<br>* 5 mg/m^2 IV every 2 weeks until disease progression<br>* Other names: Ecromeximab;|
| Experimental: Cohort 2<br>KW2871: 10 mg/m^2 IV every 2 weeks until disease progression HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression | Drug: HDI<br>* 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression<br>* Other names: Intron A;Drug: KW2871<br>* 10 mg/m^2 IV every 2 weeks until disease progression<br>* Other names: Ecromeximab;|
| Experimental: Cohort 3<br>KW2871: 20 mg/m^2 IV every 2 weeks until disease progression HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression | Drug: HDI<br>* 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week until disease progression<br>* Other names: Intron A;Drug: KW2871<br>* 20 mg/m^2 IV every 2 weeks until disease progression<br>* Other names: Ecromeximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival (PFS) With 95% Confidence Intervals | PFS was calculated from the date of the first infusion to the date of documented progression or death, whichever occurred first. PFS analyses were performed using Kaplan-Meier methods for all patients combined and for patients in Cohort 3. Based on published results from Phase 3 randomized clinical trials in patients with metastatic melanoma at the time of study initiation, 2.5 months was estimated as a conservative (i.e., somewhat high) external standard of median PFS. The intent of this study was to improve this standard by ≥ 70% to a median PFS of ≥ 4.3 months for patients treated with KW2871 combined with HDI. If the therapeutic target of 4.3 months for median PFS represented the true underlying treatment effect of KW2871 plus HDI, then 23 patients would provide 80% power to detect a statistically significant improvement (α = 0.05; 1-sided test) over the 2.5-month external standard. | From baseline through up to 17 months post-baseline | 
| Number of Patients With Treatment-emergent Adverse Events (TEAEs) | Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, as Grade 1 (mild), Grade 2 (moderate), Grade 3 (severe), Grade 4 (life-threatening), or Grade 5 (fatal). TEAEs were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period. Causal relationship of each TEAE to study treatment was evaluated by the investigator separately for HDI and KW2871. Regimen-limiting toxicity was defined as an HDI-related dose-limiting toxicity (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. | From baseline through up to 17 months post-baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Best Overall Tumor Response | Tumor responses were evaluated using whole body computed tomography and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) at Screening, on Days 29, 57, 85, 115, 143, 171, 227, 283, 339, and at the End of Study Visit. Patients who were treated beyond 49 weeks were to undergo clinical and radiologic assessments per the standard of care. Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions [no evidence of disease]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. | From baseline through up to 17 months post-baseline | 
| Number of Patients With Human Antichimeric Antibody (HACA) Reactivity To KW2871 | Blood samples were collected for the analysis of HACA at baseline, on Days 29, 115, 143, 171, 199, 227, 255, 283, 311, 339, and at the End of Study visit. Measurement of HACA development in plasma was performed with a BIAcore 2000 biosensor (Biacore AB, Uppsala, Sweden), using the BDF TM015 method. HACA positivity was defined as an increase in binding evident in the test channel but not in the control channel, with positivity assigned for values exceeding a uniform test threshold. | From baseline through up to 17 months post-baseline | 
| Maximum KW2871 Antibody Levels in Plasma Following the First Infusion | Blood samples for pharmacokinetic (PK) measurements were collected at baseline and before and 30 minutes after the initial KW2871 infusion on Day 3. The KW2871 antibody protein in patient serum was measured using an enzyme-linked immunosorbent assay (ELISA). The lower limit of quantitation was determined to be 100 ng/mL. | At Baseline and Study Day 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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KW2871, Ecromeximab, Anti-ganglioside, Antibody, Interferon alpha, Metastatic melanoma