A Study of KW-2478 in Combination With Bortezomib in Subjects With Relapsed and/or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety and benefits of the investigational study drug, KW-2478, when given with bortezomib (Velcade®), a drug approved for the treatment of Multiple Myeloma (MM). The primary objectives: To establish the safety, tolerability, and recommended Phase II dose (RP2D) of KW-2478 in combination with bortezomib (Phase I); To assess the overall response rate (ORR) when subjects with advanced MM are treated (Phase II). The secondary objectives: To characterize the Pharmacokinetic (PK) and Pharmacodynamic (PD) of KW-2478 with bortezomib (Phase I only); To evaluate for preliminary evidence of efficacy (Phase I); To determine progression free survival (PFS) and duration of response of KW-2478 with bortezomib (Phase II).

Detailed Description
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This is a multicenter, open label, dose escalation, Phase I / II study in subjects with relapsed and/or refractory MM. Up to 24 subjects to be enrolled in the Phase I to determine the RP2D. Up to 77 additional evaluable subjects to be enrolled in Phase II for a maximum up to 101 subjects treated in the study. Study centers in the USA and the UK will participate in Phase I and II. Centers in the Philippines will be participating in Phase II only. The planned enrollment period is 22 months and the planned study duration is 28 months.

Official Title
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An Open Label, Dose Escalation, Multicenter Phase 1/2 Study of KW-2478 in Combination With Bortezomib in Subjects With Relapsed and/or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: KW-2478
* Drug: Bortezomib


Participation Criteria
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Eligibility Criteria
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Accepts Healthy Volunteers: No Inclusion Criteria: Subjects with a confirmed diagnosis of Multiple Myeloma who have had one and no more than three prior regimens for MM to which they did not respond (failed) or from which they have relapsed. Signed either an IRB or IEC approved informed consent ECOG performance status of ≤ 2 Life expectancy of at least 3 months M protein in either serum or urine, or free light chains if not measurable M protein in serum or urine, and clonal bone marrow plasma cells > 10%, and evidence of end organ damage Adequate hematologic status, liver and renal function Subjects of reproductive potential must agree to follow accepted pregnancy prevention methods during the study. Exclusion Criteria: No anti-cancer treatment for ≥ 4 weeks and no bortezomib treatment ≥ 60 days prior to receiving study drug Any other severe, acute or chronic illness No other prior or concurrent malignancy No immunosuppressant therapy

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Cohort 1<br>Cohort 1: KW 2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2 | Drug: KW-2478<br>* Administered Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: HSP90 Inhibitor;Drug: Bortezomib<br>* Administered on Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: Velcade;|
| Experimental: Phase 1: Cohort 2<br>Cohort 2: KW 2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2 | Drug: KW-2478<br>* Administered Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: HSP90 Inhibitor;Drug: Bortezomib<br>* Administered on Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: Velcade;|
| Experimental: Phase 1: Cohort 3<br>Cohort 3: KW 2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 | Drug: KW-2478<br>* Administered Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: HSP90 Inhibitor;Drug: Bortezomib<br>* Administered on Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: Velcade;|
| Experimental: Phase 1: Cohort 4<br>Cohort 4: KW 2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2 | Drug: KW-2478<br>* Administered Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: HSP90 Inhibitor;Drug: Bortezomib<br>* Administered on Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: Velcade;|
| Experimental: Phase 2<br>KW 2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2 | Drug: KW-2478<br>* Administered Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: HSP90 Inhibitor;Drug: Bortezomib<br>* Administered on Days 1, 4, 8 and 11 of a 21 day cycle<br>* Other names: Velcade;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Establish the Safety, Tolerability, and RP2D (Phase 1); To Assess the Overall Response Rate in Subjects With Advanced Multiple Myeloma (Phase 2). | The safety of KW-2478 was determined by reported TEAEs, observed DLTs, changes in PEs, vital sign measurements, ECGs, and laboratory analyses. The ORR, was defined as the best response over a specified number of cycles (calculated and summarized). Disease control rate (DCR) was defined as the best response over a specified number of cycles (calculated and summarized). Progression-free survival was defined as the time from the first day of treatment until the date of disease progression or death is first reported (calculated and summarized). | 21 day cycle, up to 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: PK Absorption Tmax hr Day 11 | Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day. | PK collected Day 11 of 21-day cycle | 
| Phase 1: PK Exposure Cmax ng/mL Day 11 | Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day. | PK collected Day 11 of 21-day cycle | 
| Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11 | Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day. | PK collected Day 11 of 21-day cycle | 
| Phase 1: PK Elimination t½ hr Day 11 | Descriptive summary statistics (number, arithmetic mean, standard deviation [SDev], coefficient of variation [CV%]) for concentration and PK data for KW-2478 and Bortezomib in Phase 1 were presented by cohort, dose level and day. | PK collected Day 11 of 21-day cycle | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Leukemia, Immunoproliferative Disorder, Neoplasma by Histologic Type, Immune System Diseases, Hematologic Diseases, Blood Protein Disorders, Paraproteinemias, Multiple Myeloma, Hematologic Disorders, Leukemia, Chronic, B-cell, Leukemia, B-cell, Leukemia, Chronic, Neoplasms, Plasma Cell, Monoclonal Gammopathy of unknown significance (MGUS)