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

Primary Purpose

Metastatic Melanoma, Cutaneous Melanoma

Status

Completed

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

HDI

KW2871

About this trial

This is an interventional treatment trial for Metastatic Melanoma focused on measuring KW2871, Ecromeximab, Anti-ganglioside, Antibody, Interferon alpha, Metastatic melanoma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Chicago Hospital
University of Pittsburgh Cancer Institute

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Cohort 1

Cohort 2

Cohort 3

Arm Description

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

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

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

Outcomes

Primary Outcome Measures

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.

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.

Secondary Outcome Measures

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.

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.

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.

Full Information

NCT ID

NCT00679289

First Posted

May 14, 2008

Last Updated

October 3, 2022

Sponsor

Ludwig Institute for Cancer Research

Collaborators

University of Pittsburgh, University of Chicago, Life Science Pharmaceuticals

1. Study Identification

Unique Protocol Identification Number

NCT00679289

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Completed

Study Start Date

March 28, 2008 (Actual)

Primary Completion Date

February 3, 2014 (Actual)

Study Completion Date

February 3, 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Ludwig Institute for Cancer Research

Collaborators

University of Pittsburgh, University of Chicago, Life Science Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Metastatic Melanoma, Cutaneous Melanoma

Keywords

KW2871, Ecromeximab, Anti-ganglioside, Antibody, Interferon alpha, Metastatic melanoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Model Description

Dose-escalation cohorts

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

36 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Cohort 1

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 2

Arm Type

Experimental

Arm Description

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

Arm Title

Cohort 3

Arm Type

Experimental

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

HDI

Other Intervention Name(s)

Interferon-α2b, Intron A

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

KW2871

Other Intervention Name(s)

Ecromeximab

Intervention Description

5 mg/m^2 IV every 2 weeks until disease progression

Intervention Type

Drug

Intervention Name(s)

KW2871

Other Intervention Name(s)

Ecromeximab

Intervention Description

10 mg/m^2 IV every 2 weeks until disease progression

Intervention Type

Drug

Intervention Name(s)

KW2871

Other Intervention Name(s)

Ecromeximab

Intervention Description

20 mg/m^2 IV every 2 weeks until disease progression

Primary Outcome Measure Information:

Title

Median Progression-free Survival (PFS) With 95% Confidence Intervals

Description

Time Frame

From baseline through up to 17 months post-baseline

Title

Number of Patients With Treatment-emergent Adverse Events (TEAEs)

Description

Time Frame

From baseline through up to 17 months post-baseline

Secondary Outcome Measure Information:

Title

Number of Patients With Best Overall Tumor Response

Description

Time Frame

From baseline through up to 17 months post-baseline

Title

Number of Patients With Human Antichimeric Antibody (HACA) Reactivity To KW2871

Description

Time Frame

From baseline through up to 17 months post-baseline

Title

Maximum KW2871 Antibody Levels in Plasma Following the First Infusion

Description

Time Frame

At Baseline and Study Day 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

John M. Kirkwood, MD

Organizational Affiliation

University of Pittsburgh

Official's Role

Study Chair

Facility Information:

Facility Name

University of Chicago Hospital

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60637

Country

United States

Facility Name

University of Pittsburgh Cancer Institute

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15213

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Undecided

Citations:

PubMed Identifier

28489678

Citation

Tarhini AA, Moschos SJ, Lin Y, Lin HM, Sander C, Yin Y, Venhaus R, Gajewski TF, Kirkwood JM. Safety and efficacy of the antiganglioside GD3 antibody ecromeximab (KW2871) combined with high-dose interferon-alpha2b in patients with metastatic melanoma. Melanoma Res. 2017 Aug;27(4):342-350. doi: 10.1097/CMR.0000000000000353.

Results Reference

result

Links:

URL

http://journals.lww.com/melanomaresearch/Abstract/2017/08000/Safety_and_efficacy_of_the_antiganglioside_GD3.8.aspx

Description

Abstract with option to purchase full text

Learn more about this trial

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

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