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

NCT01111825 | Completed Phase 1 Results FDA Drug

• 1 other identifier: 10-005
• Study Type: interventional
• Target: 99
• Locations: 6 countries
• Sites: 12

Brief Summary

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.

Conditions

Breast Cancer

Keywords

HKI-272 (NERATINIB); TEMSIROLIMUS (CCI-779); HER2-Amplified; Triple-negative; invasive adenocarcinoma; 10-005; Nerlynx; PB-272

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate (ORR) (Phase II)

  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.

  From enrollment date to first documented response, or last tumor assessment, assessed up to two years

Secondary Outcomes (4)

• Clinical Benefit Rate (CBR)

  From enrollment date to first documented response, or last tumor assessment, assessed up to two years

• Duration of Response (DOR)

  From first response to first PD or death, assessed up to two years.

• Progression-free Survival (PFS)

  From date of enrollment until the date of first documented progression, or date of death from any cause, whichever came first, assessed up to two years.

• Overall Survival (OS)

  From enrollment to date of death from any cause, or end of long term follow-up, assessed up to three years.

Study Arms (1)

Temsirolimus plus Neratinib

EXPERIMENTAL

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.

Drug: Temsirolimus; Drug: Neratinib

Interventions

Temsirolimus DRUG

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

Also known as: Torisel

Temsirolimus plus Neratinib

Neratinib DRUG

28 day treatment cycle • 240 mg orally daily

Also known as: Nerlynx

Temsirolimus plus Neratinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Phase I HER2-amplified Cohort
• HER2 overexpression and/or amplification as determined by immunohistochemistry (3+) or fluorescence in situ hybridisation (FISH) (≥2.0)
• Previously received trastuzumab as part of a regimen in the adjuvant or metastatic setting with evidence of progression. Washout period for trastuzumab of 14 days.
• May have previously received lapatinib as part of a regimen in the adjuvant or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
• Radiographic progression of disease while on treatment with trastuzumab or lapatinib as defined by RECIST 1.1 criteria.
• No restriction on prior chemotherapy regimens for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.
• Phase II HER2-amplified Cohort
• HER2 overexpression and/or amplification as determined by immunohistochemistry (3+) or FISH (≥2.0).
• Previously received trastuzumab as part of a regimen in the adjuvant or metastatic setting with evidence of progression. Washout period for trastuzumab of 14 days.
• May have previously received lapatinib as part of a regimen in the adjuvant or metastatic setting with evidence of progression of disease. Washout period for lapatinib of 14 days.
• Radiographic progression of disease while on treatment with trastuzumab as defined by RECIST 1.1 criteria.
• Phase II Triple-negative Cohort - As of 2/10/12, this cohort is closed to accrual
• Invasive adenocarcinoma negative for estrogen receptor (\<5%) and progesterone receptor (\<5%) expression and a lack of HER2 overexpression and/or amplification as determined by immunohistochemistry (\<3+) or FISH (\<2.0).
• Phase II HER2-Positive Cohort with dose escalation
• HER2 overexpression and/or amplification as determined by immunohistochemistry (IHC) (3+) or FISH (≥2.0).

You may not qualify if:

• Potential subjects will be excluded from enrollment into this study if they meet any of the following criteria:
• Patients receiving any concurrent anticancer therapy or investigational agents with the intention of treating breast cancer.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to neratinib or temsirolimus.
• Unable to consent to biopsy of metastatic disease or for whom a biopsy would be medically unsafe.
• Women who are pregnant or breast feeding.
• Life expectancy \<3 months.
• Completion of previous chemotherapy regimen \<3 weeks prior to the start of study treatment. Prior hormonal therapy must be discontinued prior to treatment start. Biologic therapy with bevacizumab for the treatment of metastatic disease must be discontinued ≥3 weeks from the start of protocol treatment.
• Concurrent radiotherapy is not permitted for disease progression on treatment on protocol, but might be allowed for pre-existing non-target lesions with approval from the principal investigator of the trial.
• Concurrent medical conditions which may increase the risk of toxicity, including ongoing or active infection, history of significant bleeding disorder unrelated to cancer (congenital bleeding disorders, acquired bleeding disorders within one year), HIV-positive or active hepatitis.
• History of clinically significant or uncontrolled cardiac disease, including congestive heart failure, angina, myocardial infarction, arrhythmia, and left ventricular ejection fraction less than 50% measured by a multigated blood pool imaging of the heart (MUGA scan) or an echocardiogram (ECHO).
• QT corrected interval \> 0.47 seconds.
• Patients with GI tract disease resulting in an inability to take oral medication, malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption, or uncontrolled inflammatory GI disease.
• History of an invasive second primary malignancy diagnosed within the previous 3 years, except for stage I endometrial or cervical carcinoma or prostate carcinoma treated surgically, and non-melanoma skin cancer.
• History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake.
• Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests and other study procedures are necessary to participation in this clinical trial.

Sponsors & Collaborators

• Puma Biotechnology, Inc.: lead

Study Sites (12)

Western Regional Medical Center, Inc.

Goodyear, Arizona, 85338, United States

Location

USC/Norris Comprehensive Cancer Center

Los Angeles, California, 90033, United States

Location

Memorial Sloan Kettering Cancer Center (MSKCC)

New York, New York, 10065, United States

Location

Weill Cornell Medical College - New York - Presbyterian Hospital

New York, New York, 10065, United States

Location

Roskilde Hospital

Roskilde, 4000, Denmark

Location

Institut Gustave Roussy

Villejuif, 94800, France

Location

UNIMED Medical Institute

Wan Chai, Hong Kong

Location

Hospital Universitario Sant Joan de Reus

Tarragona, Reus, 43204, Spain

Location

Hospital Universitario Vall d'Hebron

Barcelona, 08035, Spain

Location

Hospital Universitari Arnau de Vilanova de Lleida

Lleida, 25006, Spain

Location

Edinburgh Cancer Center, Western General Hospital

Edinburgh, EH4 2XU, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

London, SW3 6JJ, United Kingdom

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

temsirolimus; neratinib

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Senior Director, Clinical Operations
• Organization: Puma Biotechnology, Inc.

clinicaltrials@pumabiotechnology.com

+1 (424) 248-6500

Study Officials

• Puma Biotechnology

  Puma

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2010
• First Posted: April 28, 2010
• Study Start: April 1, 2010
• Primary Completion: July 1, 2016
• Study Completion: July 1, 2016
• Last Updated: September 26, 2018
• Results First Posted: November 7, 2017

Record last verified: 2018-08

Locations

ES (3); US (4); GB (2); DK (1); FR (1); HK (1)