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

Phase 1

Completed

Conditions: Multiple Myeloma

Interventions: Drug: KW-2478
Drug: Bortezomib

Registration Number: NCT01063907

Lead Sponsor: Kyowa Kirin Co., Ltd.

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 95

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Phase 1: Cohort 1	KW-2478	Cohort 1: KW 2478 130 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 1: Cohort 4	KW-2478	Cohort 4: KW 2478 175 mg/m\^2 and Bortezomib 1.3 mg/m\^2
Phase 1: Cohort 2	Bortezomib	Cohort 2: KW 2478 130 mg/m\^2 and Bortezomib 1.3 mg/m\^2
Phase 1: Cohort 2	KW-2478	Cohort 2: KW 2478 130 mg/m\^2 and Bortezomib 1.3 mg/m\^2
Phase 1: Cohort 3	KW-2478	Cohort 3: KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 2	KW-2478	KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 1: Cohort 1	Bortezomib	Cohort 1: KW 2478 130 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 1: Cohort 3	Bortezomib	Cohort 3: KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 2	Bortezomib	KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2
Phase 1: Cohort 4	Bortezomib	Cohort 4: KW 2478 175 mg/m\^2 and Bortezomib 1.3 mg/m\^2

Primary Outcome Measures

Name	Time	Method
To Establish the Safety, Tolerability, and RP2D (Phase 1); To Assess the Overall Response Rate in Subjects With Advanced Multiple Myeloma (Phase 2).	21 day cycle, up to 52 weeks	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).

Secondary Outcome Measures

Name	Time	Method
Phase 1: PK Exposure Cmax ng/mL Day 11	PK collected Day 11 of 21-day cycle	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.
Phase 1: PK Absorption Tmax hr Day 11	PK collected Day 11 of 21-day cycle	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.
Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11	PK collected Day 11 of 21-day cycle	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.
Phase 1: PK Elimination t½ hr Day 11	PK collected Day 11 of 21-day cycle	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.

Trial Locations

Locations (26): Arizona Clinical Research Center, Inc. / Arizona Oncology Associates, 1825 N Kolb,
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Tucson, Arizona, United States
Pacific Shores Medical Group 1043 Elm Ave, Suite 104
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Long Beach, California, United States
Collaborative Research Group 2320 S Seacrest Blvd, Suite 202
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Boynton Beach, Florida, United States
UCLA Medical Center Hematology / Oncology Division, 10945 Le Conte Ave #2333,
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Los Angeles, California, United States
The Jones Clinic 7710 Wolf River Circle
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Germantown, Tennessee, United States
Gundersen Clinic Center for Cancer and Blood Disorders, 1900 South Ave, EB2-001,
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La Crosse, Wisconsin, United States
UT MD Anderson Cancer Center, 1515 Holcombe Boulevard,
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Houston, Texas, United States
National Kidney and Transplant Institute, Rm 3215 Doctors Clinic, East Avenue
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Diliman, Quezon City, Philippines
Makati Medical Center, New Wing Hall C372, #2 Amorsolo Street, Legaspi Village,
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Makati City, Philippines
Hillingdon Hospital Dept of Haematology, Pield Health Road
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Uxbridge, Middlesex, United Kingdom
St Bartholomew's Hospital Haematology Department, 1st Floor, Pathology
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Barbican, London, United Kingdom
Christie Hospital - Department Haematology, 550 Wilmslow Road
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Withington, Manchester, Greater Manchester, United Kingdom
Royal Bournemouth Hospital, Dept. of Haematolgy, Castle Lane East,
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Bournemouth, United Kingdom
Royal Devon & Exeter Hospital Haematology Centre, Barrack Road
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Exeter, United Kingdom
Northwick Park Hospital Dept of Haematology, Watford Road
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Harrow, United Kingdom
St James Hospital, St James' Institute of Oncology, Department of Haematology, Level 03, Bexley Wing,
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Leeds, United Kingdom
Nottingham University Hospitals NHS Trust, Centre for Clinical Haemotology
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Nottingham, United Kingdom
Royal Cornwall Hospital Haematology Clinic
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Truro, United Kingdom
Manchester Royal Infirmary Dept of Haematology, Oxford Road
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Manchester, United Kingdom
UCL Cancer Institute, Paul O'Gorman Building, University College London,72 Huntley Street
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London, United Kingdom
Darent Valley Hospital Dept of Haematology, Acorn House, Darenth Wood Road
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Dartford, Kent, United Kingdom
Saint Lukes Medical Center, Rm 222 MAB Saint Lukes Medical Center, E. Rodriguez
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Quezon City, Philippines
Royal Marsden Hospital, Orchard House
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Sutton, Surrey, United Kingdom
Cancer Institute of New Jersey 195 Little Albany Street
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New Brunswick, New Jersey, United States
The Medical City, 1609 MATI Building, The Medical City, Ortigas Avenue,
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Pasig City, Manila, Philippines
Rush University Medical Center / Division of Hematology/Oncology Research 1725 W Harrison Street, Suite 834
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Chicago, Illinois, United States