A Study Of The Safety And Tolerability Of HKI-272 Administered Orally To Japanese Subjects With Advanced Solid Tumors

An Ascending and Multiple Dose Study of the Safety, Tolerability, and Pharmacokinetics of HKI-272 Administered Orally to Japanese Subjects With Advanced Solid Tumors

The purpose of this study is to assess the tolerability and safety of HKI-272, and to determine the maximum dose that can safety be given. The secondary purpose of this study is to determine how the body uses and gets rid of HKI-272 and to assess whether HKI-272 is effective for the treatment of advanced solid tumors.

Study Overview

• Status: Completed
• Conditions: Tumors
• Intervention / Treatment: Drug: neratinib

Detailed Description

This is a phase 1 open-label sequential-group study of ascending single and multiple oral doses administered to subjects with advanced solid tumors. Each subject will participate in only 1 dose group and will receive a single dose of test article, followed by a 1-week observation period, and then will receive the test article administered once-daily by mouth in cycles consisting of 28 days. Subjects will be enrolled in groups of 3 to 6. Adverse events and dose-limiting toxicities will be assessed from the first single dose.

• Study Type: Interventional
• Enrollment (Actual): 21
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Shizuoka, Japan, 1411-8777
    • Shizuoka Cancer Center
  • Tokyo
    • Koto, Tokyo, Japan, 135-8550
      • The Cancer Institute Hospital of Japanese Foundation for Cancer Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria

1. Diagnosis of metastatic or advanced cancer that has failed standard effective therapy
2. Life expectancy of at least 12 weeks and adequate performance status
3. Adequate bone marrow, kidney and liver function
4. Willingness of male and female subjects who are not surgically sterile or post-menopausal to use adequate methods of birth control

Exclusion Criteria

1. Any anticancer chemotherapy, radiotherapy immunotherapy or investigational agents within 4 weeks of first dose of HKI-272
2. Inadequate cardiac function
3. Surgery within 2 weeks of first dose of HKI-272
4. Active central nervous system metastases (i.e., symptomatic, required use of corticosteroids and/or progressive growth)
5. Significant gastrointestinal disorder with diarrhea as a major symptom
6. Pregnant or breast feeding women

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Neratinib 80 mg	Drug: neratinib; HKI-272
Experimental: Neratinib 160 mg	Drug: neratinib; HKI-272
Experimental: Neratinib 240 mg	Drug: neratinib; HKI-272
Experimental: Neratinib 320 mg	Drug: neratinib; HKI-272

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity (DLT)	DLT was defined as any drug-related nonhematologic grade 3 or any grade 4 adverse event (AE) according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, except the grade 3 nausea, vomiting, diarrhea, or rash, unless the subject was receiving appropriate medical therapy. Additional DLTs included the following: grade 2 or 3 diarrhea lasting 2 or more days for which the subject was receiving medical therapy or that was associated with fever or dehydration.	First dose date through 21 days
Maximum Tolerated Dose (MTD)	MTD is defined as the prior dose level of the dose level which has >=2 of 3 to 6 subjects that experience a neratinib-related DLT during 21 days from first dose date. A DLT is defined as any HKI-272-related nonhematologic grade 3 or any grade 4 AE according to the Common Terminology Criteria for Adverse Events version 3.0 except: Grade 3 nausea, vomiting, diarrhea, or rash unless subject was receiving appropriate medical therapy.	First dose date through 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective Response Rate (ORR)	ORR is defined as the proportion of subjects who had either a complete response (CR) or partial response (PR), according to a modified Response Evaluation Criteria in Solid Tumors (RECIST). The modified RECIST is defined as CR: Disappearance of all target lesions, PR: At least a 30% decrease in the sum of the Longest Diameters (LDs) of target lesions, taking as reference the baseline sum LDs. Response required confirmation.	From first dose date to disease progression or last tumor assessment, up to 9.2 months
Clinical Benefit Rate	Subjects with confirmed Complete Response (CR) or confirmed Partial Response (PR), or Stable Disease (SD) >= 24 weeks, according to a modified Response Evaluation Criteria in Solid Tumors (RECIST). SD is defined as SD in target lesions and a non-progressive disease (PD) in nontarget lesions; A PR is defined as either a PR in target lesions and a non-PD in nontarget lesions, or a CR in target lesions and an incomplete response or SD in nontarget lesions; and a CR is defined as a CR in target lesions and a CR in nontarget lesions.	From first dose date to progression/death or last assessment, up to 9.2 months.

Collaborators and Investigators

• Sponsor: Puma Biotechnology, Inc.

Publications and helpful links

General Publications

• Ito Y, Suenaga M, Hatake K, Takahashi S, Yokoyama M, Onozawa Y, Yamazaki K, Hironaka S, Hashigami K, Hasegawa H, Takenaka N, Boku N. Safety, efficacy and pharmacokinetics of neratinib (HKI-272) in Japanese patients with advanced solid tumors: a Phase 1 dose-escalation study. Jpn J Clin Oncol. 2012 Apr;42(4):278-86. doi: 10.1093/jjco/hys012. Epub 2012 Feb 27.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2006
• Primary Completion (Actual): March 1, 2009
• Study Completion (Actual): March 1, 2009

Study Registration Dates

• First Submitted: November 7, 2006
• First Submitted That Met QC Criteria: November 7, 2006
• First Posted (Estimate): November 8, 2006

Study Record Updates

• Last Update Posted (Actual): September 14, 2018
• Last Update Submitted That Met QC Criteria: August 15, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: Neratinib; HKI-272; Nerlynx; Advanced Malignant Solid Tumors
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: 3144A1-104

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No