Safety, Tolerability, and Efficacy Study in Subjects With Advanced or Metastatic Breast Cancer

A Phase 1/2 Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of KW-2450 in Combination With Lapatinib and Letrozole in Subjects With Advanced or Metastatic Breast Cancer Whose Tumors Overexpress HER2

This study will determine the highest dose of KW-2450 in combination with lapatinib and letrozole that can be administered safely to subjects with advanced or metastatic breast cancer and to evaluate its effectiveness.

This study was terminated in Phase 1 and never proceeded to the Phase 2 portion of the study.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: KW-2450 in combination with lapatinib and letrozole

Detailed Description

This open-label, sequential, ascending, multi-dose, Phase 1/2 study will enroll up to 198 post-menopausal subjects with advanced or metastatic breast cancer whose tumors overexpress HER2. Subjects at each dose level will receive KW-2450 orally, on a continuous daily schedule in combination with lapatinib and letrozole.

In the Phase 1 portion of the study, dose escalation may proceed once ≥ 3 subjects have completed Day 30. The safety of each dose level will be established prior to enrollment of subjects in the next dose level. Dose escalation will proceed sequentially. Up to 6 subjects may be enrolled at each dose level. Enrollment will proceed until the MTD has been established or the highest dose level has been reached.

The Phase 2 portion of the trial will enroll 168 additional subjects. The dose level will be based on overall safety and tolerability assessments from the Phase 1 portion of the study. The subjects will be randomized into two treatment arms (1) Arm A, KW-2450 plus lapatinib plus letrozole: (2) Arm B, lapatinib plus letrozole.

This study was terminated in Phase 1 and never proceeded to the Phase 2 portion of the study.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Long Beach, California, United States, 90250
      • Breastlink Research Group
    • Los Angeles, California, United States, 90057
      • Associates in Hematology-Oncology
  • Florida
    • Deerfield Beach, Florida, United States, 33136
      • Sylvester Comprehensive Cancer Center
  • Michigan
    • Farmington Hills, Michigan, United States, 48336
      • Clinical Oncology Associates
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

1. Histopathologically or cytologically confirmed, advanced or metastatic breast cancer (stage IIIb, IIIc or IV disease) including inflammatory breast cancer or inoperable locally advanced disease.
2. Documented ErbB2 overexpression
3. Estrogen receptor positive (ER+) and/or progesterone positive (PgR+) tumors
4. Measurable or non-measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria
5. A life expectancy of > 3 months for Phase 1 and > 6 months for Phase 2
6. Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 2 at study entry in Phase 1 and ≤ 1 in Phase 2;
7. Normal cardiac ejection fraction
8. Adequate hematologic, hepatic and renal function
9. Post-menopausal female (defined as the absence of a menstrual cycle for at least 12 consecutive months) or male subjects ≥ 18 years of age.
10. Sign an IRB or EC approved informed consent

Exclusion Criteria

1. Type 1 diabetes or uncontrolled Type 2 diabetes
2. Subjects showing clinical evidence or with a history of cataract(s), proliferate retinopathy or significant macular edema
3. Subjects with abnormal free T4 values and a history or evidence of thyroid disease
4. Subjects who are unable or unwilling to take metformin
5. Uncontrolled intercurrent illness
6. Known or suspected human immunodeficiency virus (HIV) infection or hepatitis B or C
7. Subjects with inflammatory diseases of the gastrointestinal tract
8. History of other malignancy. Subjects who have been disease free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible;
9. Subjects with extensive symptomatic visceral disease including hepatic involvement and pulmonary lymphangitic spread of tumor
10. A history of prior treatment with other agents specifically targeting IGFRs
11. Subjects who require pharmacological doses of glucocorticoids beyond replacement doses. The use of topical, intra-ocular or inhalation glucocorticoids is permitted

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose escallation

Drug: KW-2450 in combination with lapatinib and letrozole; Three subjects will be assigned to each of 4 sequential cohorts. Dose escalation may proceed once at least 3 subjects have completed 30 days of study treatment. Subjects who withdraw prior to completing Day 30 for reasons other than DLT will be replaced. If a DLT is observed, additional subjects may be enrolled so that up to 6 subjects are enrolled at that dose level.; Other Names: KW-2450 lapatinib and letrozole

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To establish the safety, tolerability, and recommended Phase 2 dose of KW-2450 administered in combination with lapatinib and letrozole in subjects with previously treated or untreated advanced breast cancer.	30 Days

Secondary Outcome Measures

Outcome Measure	Time Frame
To determine the PK profile of KW-2450, lapatinib, and letrozole when administered together	1 year (or until PD)

Collaborators and Investigators

• Sponsor: Kyowa Kirin Co., Ltd.
• Collaborators: Kyowa Hakko Kirin Pharma, Inc.
• Investigators: Study Director: Michael Kurman, MD, Kyowa Hakko Kirin Pharma, Inc.

Publications and helpful links

General Publications

• Dickson MA, P. LoRusso P, E. A. Sausville EA, Rao N, Kobayashi E, Kurman MR, Akinaga S, Schwartz GK. Open-label, sequential, ascending, multi-dose, phase I study of KW-2450 as monotherapy in subjects with previously treated advanced solid tumors. J Clin Oncol 29: 2011 (suppl; abstr 3078)

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): December 1, 2012
• Study Completion (Actual): December 1, 2012

Study Registration Dates

• First Submitted: September 8, 2010
• First Submitted That Met QC Criteria: September 9, 2010
• First Posted (Estimated): September 10, 2010

Study Record Updates

• Last Update Posted (Actual): April 25, 2024
• Last Update Submitted That Met QC Criteria: April 23, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: advanced or metastatic breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Protein Kinase Inhibitors; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Tyrosine Kinase Inhibitors; Letrozole; Lapatinib
• Other Study ID Numbers: 2450-US-002