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

• ClinicalTrials.gov Identifier: NCT00397046
• Recruitment Status: Completed
• First Posted: November 8, 2006
• Results First Posted: February 19, 2018
• Last Update Posted: September 14, 2018
• Sponsor: Puma Biotechnology, Inc.
• Information provided by (Responsible Party): Puma Biotechnology, Inc.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Tumors	Drug: neratinib	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: This was an open-label, phase 1, ascending single and multiple oral dose study of neratinib administered to subjects with advanced solid tumors. Each subject participated in only 1 dose group and received a single dose of neratinib. This was followed by a 1-week observation period, and the subject then received neratinib administered as a continual oral daily dose for up to 6 months (6 cycles). Daily dose administration could continue beyond 6 cycles at the same dose level after consultation with the sponsor if neratinib was well tolerated and there was no evidence of progressive disease.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Ascending and Multiple Dose Study of the Safety, Tolerability, and Pharmacokinetics of HKI-272 Administered Orally to Japanese Subjects With Advanced Solid Tumors
• Actual Study Start Date: November 2006
• Actual Primary Completion Date: March 2009
• Actual Study Completion Date: March 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Dose Limiting Toxicity (DLT) [ Time Frame: First dose date through 21 days ]
   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.
2. Maximum Tolerated Dose (MTD) [ Time Frame: First dose date through 21 days ]
   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.

Secondary Outcome Measures :

1. Objective Response Rate (ORR) [ Time Frame: From first dose date to disease progression or last tumor assessment, up to 9.2 months ]
   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.
2. Clinical Benefit Rate [ Time Frame: From first dose date to progression/death or last assessment, up to 9.2 months. ]
   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.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

Japan

The Cancer Institute Hospital of Japanese Foundation for Cancer Research

Koto, Tokyo, Japan, 135-8550

Shizuoka Cancer Center

Shizuoka, Japan, 1411-8777

Sponsors and Collaborators

Puma Biotechnology, Inc.

Investigators

• Study Director: Puma; Biotechnology

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT00397046
• Other Study ID Numbers: 3144A1-104
• First Posted: November 8, 2006
• Results First Posted: February 19, 2018
• Last Update Posted: September 14, 2018
• Last Verified: August 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:

Advanced Malignant Solid Tumors; HKI-272; Neratinib; Nerlynx

Additional relevant MeSH terms:

Neoplasms