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

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

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).

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: KW-2478; Drug: Bortezomib

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.

• Study Type: Interventional
• Enrollment (Actual): 95
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Philippines
  • Makati City, Philippines
    • Makati Medical Center, New Wing Hall C372, #2 Amorsolo Street, Legaspi Village,
  • Pasig City, Metro Manila, Philippines
    • The Medical City, 1609 MATI Building, The Medical City, Ortigas Avenue,
  • Quezon City, Philippines
    • Saint Lukes Medical Center, Rm 222 MAB Saint Lukes Medical Center, E. Rodriguez
  • Quezon City
    • Diliman, Quezon City, Philippines
      • National Kidney and Transplant Institute, Rm 3215 Doctors Clinic, East Avenue
• United Kingdom
  • Bournemouth, United Kingdom, BH7 7DW
    • Royal Bournemouth Hospital, Dept. of Haematolgy, Castle Lane East,
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon & Exeter Hospital Haematology Centre, Barrack Road
  • Harrow, United Kingdom, HA1 3UJ
    • Northwick Park Hospital Dept of Haematology, Watford Road
  • Leeds, United Kingdom, LS9 7TF
    • St James Hospital, St James' Institute of Oncology, Department of Haematology, Level 03, Bexley Wing,
  • London, United Kingdom, WC1E 6DD
    • UCL Cancer Institute, Paul O'Gorman Building, University College London,72 Huntley Street
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary Dept of Haematology, Oxford Road
  • Truro, United Kingdom, TR1 3LS
    • Royal Cornwall Hospital Haematology Clinic
  • Kent
    • Dartford, Kent, United Kingdom, DA2 8DA
      • Darent Valley Hospital Dept of Haematology, Acorn House, Darenth Wood Road
  • London
    • Dominion House, 59 Bartholomew Close, London, United Kingdom, EC1 7ED
      • St Bartholomew's Hospital Haematology Department, 1st Floor, Pathology
  • Manchester, Greater Manchester
    • Withington, Manchester, Greater Manchester, United Kingdom, M20 4BX
      • Christie Hospital - Department Haematology, 550 Wilmslow Road
  • Middlesex
    • Uxbridge, Middlesex, United Kingdom, UB8 3NN
      • Hillingdon Hospital Dept of Haematology, Pield Health Road
  • Nottingham
    • Hucknall Road, Nottingham, United Kingdom, NG5 1PB
      • Nottingham University Hospitals NHS Trust, Centre for Clinical Haemotology
  • Sutton, Surrey
    • Downs Road, Sutton, Surrey, United Kingdom, SM2 5PT
      • Royal Marsden Hospital, Orchard House
• United States
  • Arizona
    • Tucson, Arizona, United States, 85715
      • Arizona Clinical Research Center, Inc. / Arizona Oncology Associates, 1825 N Kolb,
  • California
    • Long Beach, California, United States, 90813
      • Pacific Shores Medical Group 1043 Elm Ave, Suite 104
    • Los Angeles, California, United States, 90095-7059
      • UCLA Medical Center Hematology / Oncology Division, 10945 Le Conte Ave #2333,
  • Florida
    • Boynton Beach, Florida, United States, 33435
      • Collaborative Research Group 2320 S Seacrest Blvd, Suite 202
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center / Division of Hematology/Oncology Research 1725 W Harrison Street, Suite 834
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903-2681
      • Cancer Institute of New Jersey 195 Little Albany Street
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • The Jones Clinic 7710 Wolf River Circle
  • Texas
    • Houston, Texas, United States, 77030
      • UT MD Anderson Cancer Center, 1515 Holcombe Boulevard,
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Clinic Center for Cancer and Blood Disorders, 1900 South Ave, EB2-001,

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Accepts Healthy Volunteers: No

Inclusion Criteria:

1. 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.
2. Signed either an IRB or IEC approved informed consent
3. ECOG performance status of ≤ 2
4. Life expectancy of at least 3 months
5. 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
6. Adequate hematologic status, liver and renal function
7. Subjects of reproductive potential must agree to follow accepted pregnancy prevention methods during the study.

Exclusion Criteria:

1. No anti-cancer treatment for ≥ 4 weeks and no bortezomib treatment ≥ 60 days prior to receiving study drug
2. Any other severe, acute or chronic illness
3. No other prior or concurrent malignancy
4. No immunosuppressant therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Kyowa Hakko Kirin Pharma, Inc.
• Collaborators: Kyowa Kirin Co., Ltd.
• Investigators: Study Chair: Loan Hoang-Sayag, MD, Quintiles, Inc.; Study Chair: Noel Pingoy, MD, Gleneagles CRC

Study record dates

Study Major Dates

• Study Start: March 1, 2010
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: February 4, 2010
• First Submitted That Met QC Criteria: February 4, 2010
• First Posted (Estimate): February 5, 2010

Study Record Updates

• Last Update Posted (Estimate): December 16, 2014
• Last Update Submitted That Met QC Criteria: December 1, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Immune System Diseases; Leukemia; Hematologic Diseases; Neoplasms, Plasma Cell; Paraproteinemias; Blood Protein Disorders; Hematologic Disorders; Leukemia, B-cell; Immunoproliferative Disorder; Neoplasma by Histologic Type; Leukemia, Chronic, B-cell; Leukemia, Chronic; Monoclonal Gammopathy of unknown significance (MGUS)
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Antineoplastic Agents; Bortezomib
• Other Study ID Numbers: 2478-INT-001; 2009-016223-56 (EudraCT Number)