Trial Outcomes & Findings for A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer (NCT NCT00398567)

Last Updated: 2018-07-24

Results Overview

16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

45 participants

Primary outcome timeframe

From first dose date to progression status (PD or death) at 16-week

Results posted on

2018-07-24

Participant Flow

Participant milestones

Participant milestones
Measure	Neratinib 160mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Neratinib 240mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Part 2 - Expanded MTD Cohort All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Overall Study STARTED	4	4	37
Overall Study COMPLETED	0	0	3
Overall Study NOT COMPLETED	4	4	34

Reasons for withdrawal

Reasons for withdrawal
Measure	Neratinib 160mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Neratinib 240mg + Trastuzumab All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Part 2 - Expanded MTD Cohort All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Overall Study Disease Progression	3	4	27
Overall Study Withdrawal by Subject	1	0	4
Overall Study Adverse Event	0	0	2
Overall Study Protocol Violation	0	0	1

Baseline Characteristics

A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Neratinib 160 mg + Trastuzumab n=4 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Neratinib 240 mg + Trastuzumab n=4 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Part 2 - Expanded MTD Cohort n=37 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Total n=45 Participants Total of all reporting groups
Age, Continuous	52.5 years STANDARD_DEVIATION 10.1 • n=5 Participants	61.0 years STANDARD_DEVIATION 12.8 • n=7 Participants	50.5 years STANDARD_DEVIATION 13.0 • n=5 Participants	51.6 years STANDARD_DEVIATION 12.9 • n=4 Participants
Sex: Female, Male Female	4 Participants n=5 Participants	4 Participants n=7 Participants	37 Participants n=5 Participants	45 Participants n=4 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	21 Participants n=5 Participants	21 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) White	3 Participants n=5 Participants	3 Participants n=7 Participants	15 Participants n=5 Participants	21 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants

PRIMARY outcome

Timeframe: From first dose date to progression status (PD or death) at 16-week

Population: The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.

16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=28 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
16-week Progression-free Survival (PFS) Rate	44.8 percentage of population Interval 25.9 to 62.1

SECONDARY outcome

Timeframe: From first dose date to progression or last tumor assessment, up to five and a half years.

Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=28 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Objective Response Rate (ORR)	28.6 percentage of participants Interval 13.2 to 48.7

SECONDARY outcome

Timeframe: From start date of response to first PD, assessed up to five and half years after the first subject was randomized

Population: The subjects who had a complete response or partial response.

Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=8 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Duration of Response (DOR)	44.2 weeks Interval 24.1 to Insufficient number of participants with events.

SECONDARY outcome

Timeframe: From first dose date to progression or death, assessed up to five and half years.

Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=28 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Progression Free Survival (PFS)	15.9 weeks Interval 15.1 to 31.3

SECONDARY outcome

Timeframe: From first dose date to progression or last tumor assessment, assessed up to five and half years.

The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) \>=24 weeks.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=28 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Clinical Benefit Rate (CBR)	35.7 percentage of participants Interval 18.6 to 55.9

SECONDARY outcome

Timeframe: Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22.

Population: Subjects for whom complete blood samples at day 22 were available.

Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=33 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Area Under the Curve of Neratinib Concentration	1110 ng*hr/mL Standard Deviation 430

SECONDARY outcome

Timeframe: Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6

Population: Subjects for whom complete blood samples at day 22 were available.

Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer.

Outcome measures

Outcome measures
Measure	Part 2 - Expanded MTD Cohort n=27 Participants All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab.	21.22 hr Standard Deviation 10.16

Adverse Events

Neratinib 160 mg + Trastuzumab

Serious events: 1 serious events

Other events: 4 other events

Deaths: 0 deaths

Neratinib 240 mg + Trastuzumab

Serious events: 0 serious events

Other events: 4 other events

Deaths: 0 deaths

Part 2 - Expanded MTD Cohort

Serious events: 9 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Senior Director, Clinical Operations

Puma Biotechnology, Inc

Phone: +1 424 248 6500

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Neratinib 160 mg + Trastuzumab n=4 participants at risk All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Neratinib 240 mg + Trastuzumab n=4 participants at risk All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Part 2 - Expanded MTD Cohort n=37 participants at risk All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Ear and labyrinth disorders Vertigo	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Abdominal adhesions	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Abdominal distension	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Abdominal pain	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	5.4% 2/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Diarrhoea	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Nausea	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Gastrointestinal disorders Vomiting	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
General disorders Disease progression	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Infections and infestations Influenza	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Infections and infestations Nasopharyngitis	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Nervous system disorders Ataxia	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Respiratory, thoracic and mediastinal disorders Dyspnoea	25.0% 1/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.
Skin and subcutaneous tissue disorders Angioedema	0.00% 0/4 • From first dose date through last dose date + 28 days.	0.00% 0/4 • From first dose date through last dose date + 28 days.	2.7% 1/37 • From first dose date through last dose date + 28 days.