Tumors
Conditions
Keywords
Advanced Malignant Solid Tumors, HKI-272, Neratinib, Nerlynx
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.
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.
Interventions
DRUGneratinib
HKI-272
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) | 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. |
| Maximum Tolerated Dose (MTD) | 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
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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. |
| Clinical Benefit Rate | 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. |
Countries
Japan
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib 80 mg Neratinib 80 mg qd | 3 |
| Neratinib 160 mg Neratinib 160 mg qd | 3 |
| Neratinib 240 mg Neratinib 240 mg qd | 10 |
| Neratinib 320 mg Neratinib 320 mg qd | 5 |
| Total | 21 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Disease Progression | 3 | 3 | 10 | 5 |
Baseline characteristics
| Characteristic | Neratinib 160 mg | Neratinib 240 mg | Neratinib 80 mg | Neratinib 320 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 5 Participants | 0 Participants | 2 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 5 Participants | 3 Participants | 3 Participants | 14 Participants |
| Age, Continuous | 48.33 years STANDARD_DEVIATION 5.13 | 62.50 years STANDARD_DEVIATION 10.19 | 53.67 years STANDARD_DEVIATION 9.5 | 59.40 years STANDARD_DEVIATION 7.64 | 58.48 years STANDARD_DEVIATION 9.86 |
| Race/Ethnicity, Customized Japanese | 3 Participants | 10 Participants | 3 Participants | 5 Participants | 21 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 8 Participants |
| Sex: Female, Male Male | 1 Participants | 8 Participants | 2 Participants | 2 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 10 / 10 | 5 / 5 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 4 / 10 | 2 / 5 |
Outcome results
Primary
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.
Time frame: First dose date through 21 days
Population: All subjects who received at least one dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neratinib 80 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 160 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 240 mg | Dose Limiting Toxicity (DLT) | 0 Participants |
| Neratinib 320 mg | Dose Limiting Toxicity (DLT) | 2 Participants |
Primary
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.
Time frame: First dose date through 21 days
Population: All subjects who received at least one dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 80 mg | Maximum Tolerated Dose (MTD) | 240 mg |
Secondary
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.
Time frame: From first dose date to progression/death or last assessment, up to 9.2 months.
Population: Subjects who received at least 14 days of continual dose administration of drug and who had undergone at least 1 follow-up tumor assessment were considered evaluable for efficacy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 80 mg | Clinical Benefit Rate | 0 percentage of participants |
| Neratinib 160 mg | Clinical Benefit Rate | 0 percentage of participants |
| Neratinib 240 mg | Clinical Benefit Rate | 30.0 percentage of participants |
| Neratinib 320 mg | Clinical Benefit Rate | 40.0 percentage of participants |
Secondary
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.
Time frame: From first dose date to disease progression or last tumor assessment, up to 9.2 months
Population: Subjects who received at least 14 days of continual dose administration of drug and who had undergone at least 1 follow-up tumor assessment were considered evaluable for efficacy
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Neratinib 80 mg | Objective Response Rate (ORR) | 0 percentage of participants |
| Neratinib 160 mg | Objective Response Rate (ORR) | 0 percentage of participants |
| Neratinib 240 mg | Objective Response Rate (ORR) | 10.0 percentage of participants |
| Neratinib 320 mg | Objective Response Rate (ORR) | 20.0 percentage of participants |