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Bortezomib

Cohort 1: KW 2478 130 mg/m\^2 and Bortezomib 1.0 mg/m\^2

Cohort 2: KW 2478 130 mg/m\^2 and Bortezomib 1.3 mg/m\^2

Cohort 3: KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2

Cohort 4: KW 2478 175 mg/m\^2 and Bortezomib 1.3 mg/m\^2

KW 2478 175 mg/m\^2 and Bortezomib 1.0 mg/m\^2

Administered Days 1, 4, 8 and 11 of a 21 day cycle

KW-2478

Administered on Days 1, 4, 8 and 11 of a 21 day cycle

Michael Kurman, MD

Loan Hoang-Sayag, MD

Noel Pingoy, MD

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).

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.

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 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).

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.

Kyowa Hakko Kirin Pharma, Inc.

Kyowa Kirin Co., Ltd.

KW-2478 and bortezomib: KW 2478 and bortezomib given on Days 1, 4, 8 and 11 of a 21 day cycle

Phase 1 and 2: KW-2478 and Bortezomib

Cohort 1: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0 mg/m^2

Cohort 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3 mg/m^2

Cohort 3: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0 mg/m^2

Cohort 4: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle with a standard 3+3 study design.

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2

Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 + BTZ at the RP2D (KW-2478 175 mg/m\^2/BTZ 1.3 mg/m\^2).

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3 mg/m^2

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine.

For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m\^2) and Bortezomib(1.0 or 1.3 mg/m\^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts (overall N=15). The Phase 2 portion of the study enrolled 80 subjects to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m\^2 / Bortezomib 1.3 mg/m\^2).

KW-2478 and Bortezomib

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Philippines

United Kingdom

Region of Enrollment

Body Surface Area (BSA)

A total of up to 101 male and female subjects at least 18 years of age with a confirmed diagnosis of MM, who failed at least 1 and no more than 3 prior chemotherapy regimens and met other inclusion criteria and none of exclusion criteria, were to be enrolled in this study over a period of 22 months (up to 24 subject in P1 and 77 subjects in P2).

Senior VP Drug Development

Subjects with Any TEAE

Related TEAE

Moderate (CTCAE 2) TEAE

Severe (CTCAE 3) TEAE

Life Threatening TEAE

Serious Treatment-Emergent AE

Subjects with Any DLT

The target population in both Phase 1 and 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine.

The Phase 1 portion of the study was a standard 3+3 study design of KW-2478 (130 or 175 mg/m\^2) and Bortezomib (1.0 or 1.3 mg/m\^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts.

The Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m\^2/Bortezomib 1.3 mg/m\^2).

Phase 1 & 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Phase 1 Cohort 1: KW-2478 130 mg/m^2 and Bortezomib 1.0mg/m^2

Phase 1 Cohort 2: KW-2478 130 mg/m^2 and Bortezomib 1.3mg/m^2

Phase 1 Cohort 3: KW-2478 175 mg/m^2 and Bortezomib 1.0mg/m^2

Phase 1 Cohort 4: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

Phase 2: Both agents administered on Days 1, 4, 8, and 11 of a 21-day cycle designed to determine the preliminary efficacy of KW 2478 and Bortezomib at the RP2D (KW-2478 175 mg/m\^2/Bortezomib 1.3 mg/m\^2).

Phase 2: KW-2478 175 mg/m^2 and Bortezomib 1.3mg/m^2

All subjects who received at least 1 dose, including a partial dose, of KW-2478 were evaluated for safety.

To Establish the Safety, Tolerability, and RP2D (Phase 1); To Assess the Overall Response Rate in Subjects With Advanced Multiple Myeloma (Phase 2).

Both agents administered on Days 1, 4, 8 and 11 of a 21 day cycle

The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11in Phase 1 only.

Phase 1: PK Absorption Tmax hr Day 11

The PK of KW-2478 was characterized after single administrations through @25 hours post start of infusion dose on Day 1 and through @7 hours post start of infusion dose on Day 11 in Phase 1 only.

Phase 1: PK Exposure Cmax ng/mL Day 11

Phase 1: PK Exposure AUC0-t hr*ng/mL Day 11

Phase 1: PK Elimination t½ hr Day 11

The target population in Phase 1 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine.

For Phase 1, the design was a standard 3+3 study of KW-2478 (130 or 175 mg/m\^2) and bortezomib(1.0 or 1.3 mg/m\^2) on Days 1, 4, 8, and 11 of a 21-day cycle utilizing four dose-escalation cohorts.

Phase 1: KW-2478 and Bortezomib

The target population in Phase 2 were adults (≥18 years) of either gender with a confirmed history of MM by IMWG criteria had relapsed or failed to respond to 1-3 prior MM regimens with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and a life expectancy ≥ 3 months. Subjects had to have disease that could be evaluated by serum or urinary levels of M protein or serum free light chains in the absence of measurable M protein in serum or urine.

For the Phase 2 portion of the study was designed to determine the preliminary efficacy of KW 2478 and bortezomib at the RP2D (KW-2478 175 mg/m\^2/bortezomib1.3 mg/m\^2).

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