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Triple Negative Breast Neoplasms

Breast Diseases

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Tyrosine

This is an open-label, single arm, dose-escalation phase I-II study to determine the maximum tolerated dose (MTD) of temsirolimus with daily neratinib, and to determine the safety and efficacy of this combination when given to patients with advanced breast carcinoma. Patients with trastuzumab-refractory HER2-amplified disease or triple negative disease will be enrolled in both phases of this clinical trial.

28 day treatment cycle Phase 1

* Weekly intravenously (IV) on days 1, 8, 15, and 22
* Starting dose 8 mg IV weekly (dose level 1). Three patients initially enrolled in each cohort

Phase 2

* Dose escalation cohort - 8 mg IV weekly on Days 1, 8, 15, and 22, and then 15 mg IV weekly starting on Day 29
* HER2-amplified and Triple negative - 8 mg IV weekly on Days 1, 8, 15, and 22

28 day treatment cycle

• 240 mg orally daily

Puma Biotechnology

This is an open-label, single arm, multi-center, multi-national, adaptive design, dose-escalation Phase 1/2 study to determine the maximum tolerated dose (MTD) of temsirolimus with daily neratinib, and to determine the safety and efficacy of this combination when given to patients with advanced breast carcinoma, specifically trastuzumab-refractory HER2-amplified disease or triple-negative disease.

Phase I Design A standard, 3+3, dose escalation schedule to determine the MTD of temsirolimus in combination with neratinib with no intrapatient dose escalation and a starting dose of temsirolimus 8 mg administered intravenously (IV) weekly (dose level 1) and three patients enrolled in each cohort.

Phase II Design The phase II portion of this trial is comprised of three cohorts. Two of the cohorts utilized a Simon two-stage design to determine the sample size to assess the efficacy of temsirolimus when administered in combination with neratinib: HER2-amplified and triple negative breast cancer. The third cohort was a single stage design with HER2-amplified patients and dose escalation.

Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer

A Phase I/II Trial of Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer

ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

Defined as the proportion of patients who achieved objective response (CR or PR) or SD for at least 24 weeks per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study.

Clinical Benefit (CB) = CR + PR + SD \>= 24 weeks.

Measured from the time at which measurement criteria were first met for CR or PR (whichever status was recorded first), until the date of first recurrence, Progressive Disease (PD), or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR; Progressive Disease (PD), At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study, and/or the appearance of one or more new lesions.

Defined as time from date of enrollment until the first disease recurrence or progression or death due to any cause; censored at the last assessable evaluation or at the initiation of new anti-cancer therapy. Disease assessment is based on investigator tumor assessments. If no post-baseline tumor assessment then censored at enrollment date.

Defined as the time from enrollment to death due to any cause; censored at the date last known alive.

Puma Biotechnology, Inc.

Phase I, HER - Amplified (HER2-Positive) cohort

Phase 1

Phase 2 Triple -ve

Phase 2, HER2 - Amplified (HER2-Positive) cohort

Phase 2 HER2+

Phase 2, HER2 - Positive cohort with dose escalation

Phase 2 HER2+ Dose Esc

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Senior Director, Clinical Operations

Intent to Treat (ITT) population (all enrolled subjects) for the Phase II portion of the study. Per protocol, Phase I data was not included in efficacy analysis.

Objective Response Rate (ORR) (Phase II)

ITT population (all enrolled subjects) for the Phase II portion of the study. Per protocol, Phase I data was not included in efficacy analysis.

Clinical Benefit Rate (CBR)

Patients who were enrolled and responded in the Phase II portion of the study. Per protocol, Phase I data was not included in efficacy analysis.

Note, no subject in Phase II triple negative cohort had a response. Therefore, no participants were analyzed for DOR.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer	NCT01111825	Breast Cancer	Temsirolimus Neratinib	18 Years -	Puma Biotechnology, Inc.
Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer	NCT01111825	Breast Cancer	Temsirolimus Neratinib	18 Years -	Puma Biotechnology, Inc.

Spots Global Cancer Trial Database for invasive adenocarcinoma