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

• Sponsor: Ludwig Institute for Cancer Research (Other)
• Overall Status: Completed
• CT.gov ID: NCT00679289
• Collaborator: University of Pittsburgh (Other), University of Chicago (Other), Life Science Pharmaceuticals (Other)
• Enrollment: 36
• Locations: 2
• Arms: 3
• Actual Duration (Months): 70.2
• Patients Per Site: 18
• Patients Per Site Per Month: 0.3

Study Details

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]).

Condition or Disease	Intervention/Treatment	Phase
Metastatic Melanoma; Cutaneous Melanoma	Drug: HDI; Drug: KW2871; Drug: KW2871; Drug: KW2871	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 36 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Dose-escalation cohortsDose-escalation cohorts
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Mar 28, 2008
• Actual Primary Completion Date: Feb 3, 2014
• Actual Study Completion Date: Feb 3, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 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; 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; Other Names: Interferon-α2b Intron A ; Drug: KW2871; 5 mg/m^2 IV every 2 weeks until disease progression; Other Names: Ecromeximab
Experimental: Cohort 2 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; 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; Other Names: Interferon-α2b Intron A ; Drug: KW2871; 10 mg/m^2 IV every 2 weeks until disease progression; Other Names: Ecromeximab
Experimental: Cohort 3 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; 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; Other Names: Interferon-α2b Intron A ; Drug: KW2871; 20 mg/m^2 IV every 2 weeks until disease progression; Other Names: Ecromeximab

Outcome Measures

Primary Outcome Measures

1. Median Progression-free Survival (PFS) With 95% Confidence Intervals [From baseline through up to 17 months post-baseline]

   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.

2. Number of Patients With Treatment-emergent Adverse Events (TEAEs) [From baseline through up to 17 months post-baseline]

   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

1. Number of Patients With Best Overall Tumor Response [From baseline through up to 17 months post-baseline]

   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.

2. Number of Patients With Human Antichimeric Antibody (HACA) Reactivity To KW2871 [From baseline through up to 17 months post-baseline]

   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.

3. Maximum KW2871 Antibody Levels in Plasma Following the First Infusion [At Baseline and Study Day 3]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Chicago Hospital	Chicago	Illinois	United States	60637
2	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Ludwig Institute for Cancer Research
• University of Pittsburgh
• University of Chicago
• Life Science Pharmaceuticals

Investigators

• Study Chair: John M. Kirkwood, MD, University of Pittsburgh

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Abstract with option to purchase full text

Publications

None provided.

• Responsible Party: Ludwig Institute for Cancer Research
• ClinicalTrials.gov Identifier: NCT00679289
• Other Study ID Numbers: LUD2007-001; UPCI07-023; UCH15689B
• First Posted: May 16, 2008
• Last Update Posted: Mar 16, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ludwig Institute for Cancer Research: KW2871; Ecromeximab; Anti-ganglioside; Antibody; Interferon alpha; Metastatic melanoma
• Additional relevant MeSH terms: Melanoma; Interferons; Ecromeximab

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
Period Title: Overall Study
STARTED	6	6	24
COMPLETED	1	0	1
NOT COMPLETED	5	6	23

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Total
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	Total of all reporting groups
Overall Participants	6	6	24	36
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	61	54	54
Sex: Female, Male (Count of Participants)
Female	2 33.3%	3 50%	13 54.2%	18 50%
Male	4 66.7%	3 50%	11 45.8%	18 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	6 100%	6 100%	24 100%	36 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	6 100%	6 100%	24 100%	36 100%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%	6 100%	24 100%	36 100%
Body Mass Index (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	24.4	29.4	26.3	26.5

Outcome Measures

1. Primary Outcome

Title	Median Progression-free Survival (PFS) With 95% Confidence Intervals
Description	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.
Time Frame	From baseline through up to 17 months post-baseline

Outcome Measure Data

Analysis Population Description

Patients who received initial treatment with HDI and at least 1 infusion of KW2871 and experienced a PFS event (progression or death).

Arm/Group Title	Cohort 3	Total
Arm/Group Description	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	All evaluable patients in Cohorts 1, 2, and 3 combined
Measure Participants	24	34
Median (95% Confidence Interval) [months]	1.93	2.53

2. Primary Outcome

Title	Number of Patients With Treatment-emergent Adverse Events (TEAEs)
Description	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.
Time Frame	From baseline through up to 17 months post-baseline

Outcome Measure Data

Analysis Population Description

Patients who received initial treatment with HDI and at least 1 infusion of KW2871.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
Measure Participants	6	6	24
Any TEAE	6 100%	6 100%	24 100%
Maximum TEAE Severity Grade 1/2	0 0%	1 16.7%	2 8.3%
Maximum TEAE Severity Grade 3	5 83.3%	2 33.3%	20 83.3%
Maximum TEAE Severity Grade 4	1 16.7%	2 33.3%	1 4.2%
Maximum TEAE Severity Grade 5	0 0%	1 16.7%	1 4.2%
Any HDI-related TEAE	6 100%	6 100%	24 100%
Any KW2871-related TEAE	4 66.7%	5 83.3%	7 29.2%
Any SAE	2 33.3%	1 16.7%	7 29.2%
Any TEAE leading to withdrawal of HDI+KW2871	0 0%	1 16.7%	3 12.5%
Any TEAE leading to withdrawal of HDI only	0 0%	0 0%	1 4.2%
Any TEAE leading to withdrawal of KW2871 only	0 0%	0 0%	1 4.2%
Regimen-limiting toxicity	0 0%	0 0%	2 8.3%

3. Secondary Outcome

Title	Number of Patients With Best Overall Tumor Response
Description	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.
Time Frame	From baseline through up to 17 months post-baseline

Outcome Measure Data

Analysis Population Description

Patients who received initial treatment with HDI and at least 1 infusion of KW2871.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
Measure Participants	6	6	24
CR	0 0%	0 0%	1 4.2%
PR	1 16.7%	0 0%	0 0%
SD	5 83.3%	5 83.3%	16 66.7%
PD	0 0%	1 16.7%	7 29.2%

4. Secondary Outcome

Title	Number of Patients With Human Antichimeric Antibody (HACA) Reactivity To KW2871
Description	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.
Time Frame	From baseline through up to 17 months post-baseline

Outcome Measure Data

Analysis Population Description

Patients who received initial treatment with HDI and at least 1 infusion of KW2871 and had at least 1 post-baseline plasma sample evaluated for HACA.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
Measure Participants	6	6	16
Baseline negative, post-baseline negative	5 83.3%	6 100%	16 66.7%
Baseline negative, post-baseline positive	1 16.7%	0 0%	0 0%

5. Secondary Outcome

Title	Maximum KW2871 Antibody Levels in Plasma Following the First Infusion
Description	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.
Time Frame	At Baseline and Study Day 3

Outcome Measure Data

Analysis Population Description

Patients who received initial treatment with HDI and at least 1 infusion of KW2871 and had at least 1 plasma sample evaluated for KW2871 antibody levels.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week	KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
Measure Participants	5	6	19
Mean (Standard Deviation) [µg/mL]	3.22 (3.02)	5.17 (5.07)	9.18 (4.26)

Adverse Events

Time Frame	All adverse events (AEs) occurring between the signing of informed consent and the off-study date were documented, regardless of the causal relationship to study drug. AEs occurring after the first dose of study drug were considered treatment emergent (i.e., TEAEs). The AE reporting period for this study was up to 17 months.
Adverse Event Reporting Description	AE documentation included onset/resolution dates, severity using the NCI CTCAE (version 3.0), seriousness, study drug action taken, treatment, and outcome. Relationship to study drug was evaluated for both KW2871 and HDI. Treatment-related AEs included those with a "possible", "probable", or "definite" relationship to study drug; preferred terms were counted only once per patient at the maximum reported grade.
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3
Arm/Group Description	KW2871: 5 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week		KW2871: 10 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week		KW2871: 20 mg/m^2 IV every 2 weeks HDI: 20 MU/m^2 IV QD for 5 days/week for 4 weeks, then 10 MU/m^2 SC 3 days/week
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/6 (0%)		1/6 (16.7%)		1/24 (4.2%)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/6 (33.3%)		1/6 (16.7%)		7/24 (29.2%)
Cardiac disorders
Atrial fibrillation	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Cardiac tamponade	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Gastrointestinal disorders
Nausea	0/6 (0%)		1/6 (16.7%)		2/24 (8.3%)
Vomiting	0/6 (0%)		1/6 (16.7%)		2/24 (8.3%)
Colitis	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
General disorders
Asthenia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Immune system disorders
Hypersensitivity	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Infections and infestations
Appendicitis	2/6 (33.3%)		0/6 (0%)		0/24 (0%)
Septic shock	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic malignant melanoma	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Neoplasm progression	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Nervous system disorders
Neuralgia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Dyspnoea	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Vascular disorders
Hypotension	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Deep vein thrombosis	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 3
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		24/24 (100%)
Blood and lymphatic system disorders
Leukopenia	4/6 (66.7%)		4/6 (66.7%)		14/24 (58.3%)
Neutropenia	4/6 (66.7%)		5/6 (83.3%)		13/24 (54.2%)
Lymphopenia	2/6 (33.3%)		1/6 (16.7%)		11/24 (45.8%)
Thrombocytopenia	1/6 (16.7%)		4/6 (66.7%)		8/24 (33.3%)
Anaemia	0/6 (0%)		0/6 (0%)		6/24 (25%)
Haemoglobinaemia	0/6 (0%)		0/6 (0%)		5/24 (20.8%)
Basophilia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Eosinophilia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Iron deficiency anaemia	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Monocytopenia	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Cardiac disorders
Supraventricular tachycardia	1/6 (16.7%)		1/6 (16.7%)		1/24 (4.2%)
Atrial fibrillation	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Sinus tachycardia	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Ear and labyrinth disorders
Ear pain	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Vertigo	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Eye disorders
Dry eye	0/6 (0%)		1/6 (16.7%)		2/24 (8.3%)
Visual impairment	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Eye pruritus	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Vision blurred	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Gastrointestinal disorders
Nausea	6/6 (100%)		4/6 (66.7%)		18/24 (75%)
Vomiting	2/6 (33.3%)		2/6 (33.3%)		12/24 (50%)
Constipation	2/6 (33.3%)		2/6 (33.3%)		12/24 (50%)
Diarrhoea	4/6 (66.7%)		1/6 (16.7%)		11/24 (45.8%)
Abdominal pain	1/6 (16.7%)		2/6 (33.3%)		6/24 (25%)
Dry mouth	0/6 (0%)		0/6 (0%)		5/24 (20.8%)
Abdominal pain upper	0/6 (0%)		1/6 (16.7%)		3/24 (12.5%)
Early satiety	0/6 (0%)		0/6 (0%)		3/24 (12.5%)
Oral pain	0/6 (0%)		0/6 (0%)		3/24 (12.5%)
Stomatitis	1/6 (16.7%)		0/6 (0%)		1/24 (4.2%)
Abdominal discomfort	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Abdominal distension	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Abdominal pain lower	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Cheilitis	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Dysphagia	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Gingival bleeding	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Gingival ulceration	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Lip pain	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
General disorders
Chills	6/6 (100%)		6/6 (100%)		22/24 (91.7%)
Fatigue	6/6 (100%)		6/6 (100%)		21/24 (87.5%)
Pyrexia	6/6 (100%)		3/6 (50%)		21/24 (87.5%)
Oedema peripheral	0/6 (0%)		1/6 (16.7%)		4/24 (16.7%)
Pain	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Asthenia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Catheter site pain	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Axillary pain	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Catheter site erythema	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Chest pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Generalised oedema	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Mucosal inflammation	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Nodule	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Immune system disorders
Hypersensitivity	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Infections and infestations
Oral candidiasis	0/6 (0%)		0/6 (0%)		5/24 (20.8%)
Candidiasis	2/6 (33.3%)		0/6 (0%)		2/24 (8.3%)
Cellulitis	0/6 (0%)		1/6 (16.7%)		1/24 (4.2%)
Urinary tract infection	0/6 (0%)		1/6 (16.7%)		1/24 (4.2%)
Cystitis	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Otitis media	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Pharyngitis	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Sinusitis	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Skin infection	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Injury, poisoning and procedural complications
Procedural site reaction	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Thermal burn	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Investigations
Aspartate aminotransferase increased	3/6 (50%)		5/6 (83.3%)		18/24 (75%)
Gamma-glutamyltransferase increased	3/6 (50%)		4/6 (66.7%)		17/24 (70.8%)
Blood lactate dehydrogenase increased	3/6 (50%)		5/6 (83.3%)		15/24 (62.5%)
Alanine aminotransferase increased	4/6 (66.7%)		2/6 (33.3%)		14/24 (58.3%)
Haemoglobin decreased	3/6 (50%)		6/6 (100%)		9/24 (37.5%)
Blood creatine phosphokinase increased	3/6 (50%)		4/6 (66.7%)		8/24 (33.3%)
Weight decreased	0/6 (0%)		4/6 (66.7%)		11/24 (45.8%)
Blood alkaline phosphatase increased	1/6 (16.7%)		3/6 (50%)		7/24 (29.2%)
Platelet count decreased	0/6 (0%)		0/6 (0%)		6/24 (25%)
Lymphocyte count decreased	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Neutrophil count decreased	0/6 (0%)		0/6 (0%)		3/24 (12.5%)
Blood alkaline phosphatase	0/6 (0%)		1/6 (16.7%)		1/24 (4.2%)
International normalised ratio increased	1/6 (16.7%)		1/6 (16.7%)		0/24 (0%)
Neutrophil count	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
White blood cell count decreased	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Biopsy site unspecified abnormal	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Blood bicarbonate decreased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Blood calcium decreased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Blood folate decreased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Blood urea increased	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Body temperature fluctuation	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Breath sounds abnormal	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Cardiac murmur	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Haemoglobin	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Liver function test abnormal	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Mean cell haemoglobin concentration decreased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Monocyte count increased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Neutrophil count increased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Protein total decreased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Protein total increased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Red cell distribution width increased	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Metabolism and nutrition disorders
Anorexia	5/6 (83.3%)		5/6 (83.3%)		17/24 (70.8%)
Hypoalbuminaemia	0/6 (0%)		2/6 (33.3%)		14/24 (58.3%)
Dehydration	2/6 (33.3%)		3/6 (50%)		10/24 (41.7%)
Hyponatraemia	0/6 (0%)		1/6 (16.7%)		12/24 (50%)
Hypocalcaemia	1/6 (16.7%)		1/6 (16.7%)		6/24 (25%)
Hypokalaemia	0/6 (0%)		0/6 (0%)		8/24 (33.3%)
Hyperkalaemia	0/6 (0%)		1/6 (16.7%)		2/24 (8.3%)
Hypophosphataemia	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Hyperglycaemia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Hypernatraemia	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Hyperuricaemia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Musculoskeletal and connective tissue disorders
Myalgia	3/6 (50%)		4/6 (66.7%)		8/24 (33.3%)
Pain in extremity	3/6 (50%)		1/6 (16.7%)		6/24 (25%)
Back pain	0/6 (0%)		1/6 (16.7%)		5/24 (20.8%)
Muscular weakness	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Arthralgia	2/6 (33.3%)		1/6 (16.7%)		0/24 (0%)
Muscle spasms	1/6 (16.7%)		1/6 (16.7%)		0/24 (0%)
Neck pain	0/6 (0%)		1/6 (16.7%)		1/24 (4.2%)
Bone pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Flank pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Muscle tightness	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Musculoskeletal chest pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Musculoskeletal pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Rotator cuff syndrome	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Oncologic complication	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Tumour pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Nervous system disorders
Dysgeusia	4/6 (66.7%)		6/6 (100%)		13/24 (54.2%)
Headache	4/6 (66.7%)		3/6 (50%)		11/24 (45.8%)
Dizziness	1/6 (16.7%)		0/6 (0%)		9/24 (37.5%)
Nystagmus	0/6 (0%)		1/6 (16.7%)		4/24 (16.7%)
Tremor	1/6 (16.7%)		1/6 (16.7%)		3/24 (12.5%)
Peripheral sensory neuropathy	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Anosmia	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Dizziness postural	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Hypoaesthesia	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Memory impairment	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Neuropathy peripheral	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Restless legs syndrome	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Syncope	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Psychiatric disorders
Anxiety	2/6 (33.3%)		1/6 (16.7%)		7/24 (29.2%)
Depression	2/6 (33.3%)		2/6 (33.3%)		5/24 (20.8%)
Insomnia	3/6 (50%)		0/6 (0%)		4/24 (16.7%)
Confusional state	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Restlessness	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Agitation	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Delirium	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Mood altered	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Renal and urinary disorders
Dysuria	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Nocturia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Pollakiuria	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Urinary tract pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Reproductive system and breast disorders
Menstruation irregular	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Perineal pain	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Respiratory, thoracic and mediastinal disorders
Cough	2/6 (33.3%)		1/6 (16.7%)		5/24 (20.8%)
Dyspnoea	1/6 (16.7%)		0/6 (0%)		5/24 (20.8%)
Nasal congestion	1/6 (16.7%)		0/6 (0%)		3/24 (12.5%)
Dyspnoea exertional	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Oropharyngeal pain	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Rhinorrhoea	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Bronchospasm	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Epistaxis	0/6 (0%)		1/6 (16.7%)		0/24 (0%)
Hypocapnia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Paranasal sinus hypersecretion	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Pharyngeal hypoaesthesia	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Pharyngeal oedema	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Postnasal drip	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Productive cough	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Sinus congestion	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Sneezing	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Wheezing	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Skin and subcutaneous tissue disorders
Pruritus	0/6 (0%)		1/6 (16.7%)		4/24 (16.7%)
Rash	1/6 (16.7%)		0/6 (0%)		4/24 (16.7%)
Erythema	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Exfoliative rash	2/6 (33.3%)		1/6 (16.7%)		0/24 (0%)
Alopecia	2/6 (33.3%)		0/6 (0%)		0/24 (0%)
Dry skin	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Hyperhidrosis	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Urticaria	0/6 (0%)		0/6 (0%)		2/24 (8.3%)
Decubitus ulcer	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Erythema multiforme	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Night sweats	1/6 (16.7%)		0/6 (0%)		0/24 (0%)
Rash maculo-papular	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Skin disorder	0/6 (0%)		0/6 (0%)		1/24 (4.2%)
Vascular disorders
Hypotension	1/6 (16.7%)		2/6 (33.3%)		3/24 (12.5%)
Orthostatic hypotension	0/6 (0%)		2/6 (33.3%)		3/24 (12.5%)
Hypertension	0/6 (0%)		0/6 (0%)		4/24 (16.7%)
Haematoma	0/6 (0%)		0/6 (0%)		1/24 (4.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.