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

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Puma Biotechnology, Inc.
Sponsor:
Information provided by (Responsible Party):
Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier:
NCT01111825
First received: April 22, 2010
Last updated: October 21, 2014
Last verified: October 2014
  Purpose

The purpose of this study is to test the safety and benefit of two new drugs for the treatment of breast cancer. The patient is eligible for the study because their breast cancer has grown in spite of standard treatment. The two drugs tested in the study, Neratinib and Temsirolimus, will be given together. Also, this study will help the investigators learn why therapy directed against HER2 sometimes stops working.


Condition Intervention Phase
Breast Cancer
Drug: Temsirolimus plus Neratinib
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer

Resource links provided by NLM:


Further study details as provided by Puma Biotechnology, Inc.:

Primary Outcome Measures:
  • To determine the maximum tolerated dose of weekly IV temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy (phase I) [ Time Frame: day 1 ] [ Designated as safety issue: Yes ]
  • To estimate the efficacy [overall response rate (ORR) = complete response (CR) and partial response (PR)](phase II) [ Time Frame: CT evaluation after 8 weeks ] [ Designated as safety issue: No ]
  • To determine the maximum tolerated dose of weekly IV temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy (phase I) [ Time Frame: day 8 ] [ Designated as safety issue: Yes ]
  • To determine the maximum tolerated dose of weekly IV temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy (phase I) [ Time Frame: day 15 ] [ Designated as safety issue: Yes ]
  • To determine the maximum tolerated dose of weekly IV temsirolimus when administered in combination with a fixed dose of daily oral neratinib therapy (phase I) [ Time Frame: day 22 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine the safety and tolerability of temsirolimus when administered in combination with neratinib. [ Time Frame: Each cycle, days 1 and 15 ] [ Designated as safety issue: Yes ]
  • To estimate secondary efficacy endpoints of this combination including progression free survival (PFS) and duration of response. [ Time Frame: 8 weeks or approximately after every two cycles of therapy for the first 6 cycles, then assessment will take place q12 weeks thereafter. ] [ Designated as safety issue: No ]
  • To determine the expression level of HER2 and p95-HER2 in the metastatic tissue samples and correlate this with response to the temsirolimus-neratinib combination in HER2-amplified tumors. [ Time Frame: once at the time of biopsy ] [ Designated as safety issue: No ]
  • To assess abnormalities in the PI3K-PTEN-AKT-mTOR pathway through the analysis of expression of PTEN and upstream molecular targets IGF1-R, EGFR, and HER3 and mutational activation of PI3K in the metastatic tumor samples. [ Time Frame: optional at the end of study ] [ Designated as safety issue: No ]
  • To determine if the addition of neratinib affects the exposure and half-life of temsirolimus and its active metabolite, sirolimus. [ Time Frame: Pre, post, 1, 2, 4, 24, 72, 168 hrs after Temsirolimus ] [ Designated as safety issue: No ]

Estimated Enrollment: 65
Study Start Date: April 2010
Estimated Study Completion Date: December 2015
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Temsirolimus plus Neratinib
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 plus Neratinib

A treatment cycle will consist of 28 days, according to the following schedule:

  • Neratinib PO once daily with food, preferably in the morning
  • Weekly temsirolimus given MTD dose from phase I IV (8mg) intravenously on days 1, 8, 15, and 22 Phase I Design A standard, 3+3, dose escalation schedule will be used. Between 6 and 12 patients will likely be necessary to determine the MTD of temsirolimus in combination with neratinib. There will be no intrapatient dose escalation. The starting dose of temsirolimus is 8 mg administered intravenously weekly (dose level 1). Three patients will initially be enrolled in each cohort.

Detailed Description:

Phase I Design

A standard, 3+3, dose escalation schedule will be used. Between 6 and 12 patients will likely be necessary to determine the MTD of temsirolimus in combination with neratinib. There will be no intrapatient dose escalation. The starting dose of temsirolimus is 8 mg administered intravenously weekly (dose level 1). Three patients will initially be enrolled in each cohort. The Phase I portion is closed to enrollment.

Phase II Design

The phase II portion of this trial will be comprised of two cohorts—HER2-amplified and triple negative breast cancer—each of which has a Simon two-stage design to determine the efficacy of temsirolimus when administered in combination with neratinib. Both pathologic subtypes of patients will be studied separately though accrual will be simultaneous. Response (RECIST criteria) will be assessed every 8 weeks (every 2 cycles) after the start of therapy. As of 2/10/12, the Triple-negative cohort is closed to accrual. The HER2- amplified cohort will continue to enroll as planned up to a total of 34 patients.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Phase I 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 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.
  • Prior therapy inclusion:
  • No more than four prior chemotherapy regimens allowed for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.

Phase I Triple-negative Cohort

  • 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).
  • 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 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).
  • Prior therapy inclusion:
  • No more than four prior chemotherapy regimens allowed for advanced stage disease. No restriction for prior hormonal therapy. No concurrent use of endocrine therapy is permitted.

Inclusion Criteria for ALL subjects (HER2-Amplified and Triple-negative)

  • Patients with a diagnosis of invasive adenocarcinoma of the breast confirmed by histology or cytology at MSKCC.
  • Metastatic disease that is or has been pathologically documented.
  • At least one measurable metastatic lesion according to RECIST 1.1 criteria. Ascites, pleural effusions, and bone metastases are not considered measurable. Minimum indicator lesion size ≥ 10 mm by helical CT or ≥ 20 mm by conventional techniques.
  • Pathological nodes must be ≥ 15 mm by the short axis to be considered measurable.
  • Age ≥ 18, as no dosing or adverse event data are currently available on the use of neratinib or temsirolimus in patients <18 years of age, children are excluded from this study.
  • Able and willing to consent for biopsy of metastatic breast cancer prior to treatment. Consent to preservation of frozen and fixed samples of tumor cores for evaluation. (HER2-amplified patients who have previously provided samples of metastatic breast cancer as part of IRB #06-163 will be exempt).
  • Consent to evaluation of primary tumor biopsy specimen.
  • Patients must be willing to discontinue sex hormonal therapy, e.g., birth control pills, hormonal replacement therapy, prior to enrollment. Women of childbearing potential must consent to effective contraception while on treatment and for a period thereafter.
  • Negative serum HCG pregnancy test for premenopausal women of reproductive capacity and for women less than 12 months after menopause.
  • Asymptomatic, central nervous system metastases are permitted if patients remain clinically stable after discontinuation of steroids and anticonvulsants for 3 months.
  • Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2.
  • Patients must have normal organ and marrow function: AST/ALT ≤2.5x institutional upper limit of normal except for patients with liver metastases. For patients with liver metastases, AST/ALT/Alkaline phosphatase ≤5.0x institutional upper limit of normal. Total bilirubin within institutional limits except for patients with liver metastases. For patients with liver metastases, total bilirubin ≤1.5x institutional upper limit of normal. Creatinine clearance within normal limits or ≥ 60mL/min, PT and PTT ≤1.5x institutional upper limit of normal except for patients on Coumadin or low molecular weight heparin, leukocytes ≥3,000/μl, absolute neutrophil count ≥1,000/μl, and platelets ≥75,000/μl
  • Able to swallow and retain oral medication.

Exclusion Criteria:

  • 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).
  • QTc 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01111825

Contacts
Contact: Puma Clinical Operations 424-248-6500 ClinicalTrials@pumabiotechnology.com

Locations
United States, Arizona
Cancer Treatment Centers of America Active, not recruiting
Goodyear, Arizona, United States, 85338
United States, California
Kenneth Norris Comprehensive Cancer Center (University of Southern California) Active, not recruiting
Los Angeles, California, United States, 90033
Los Angeles County, University of Southern California (LAC+USC) Active, not recruiting
Los Angeles, California, United States, 90033
United States, New York
Memorial Sloan Kettering Cancer Center Active, not recruiting
New York, New York, United States, 10065
Weill Cornell Breast Center Active, not recruiting
New York, New York, United States, 10065
Denmark
Roskilde Hospital Recruiting
Ringsted, Denmark, DK-4100
France
Institut Gustave Roussy Active, not recruiting
Villejuif, France, 94800
Hong Kong
UNIMED Medical Institute Active, not recruiting
Wanchai, Hong Kong
Spain
Hospital Universitari Sant Joan de Reus Active, not recruiting
Tarragona, Reus, Spain, 43204
Hospital Universitario Vall d'Hebron Active, not recruiting
Barcelona, Spain, 08035
Hospital Universitari Arnau de Vilanova de Lleida Active, not recruiting
Lleida, Spain, 25198
United Kingdom
University of Edinburgh, Western General Hospital Active, not recruiting
Edinburgh, United Kingdom, EH1 3EG
The Royal Marsden NHS Foundation Trust Active, not recruiting
London, United Kingdom, SW3 6JJ
Sponsors and Collaborators
Puma Biotechnology, Inc.
Investigators
Study Director: Puma Biotechnology Puma
  More Information

No publications provided

Responsible Party: Puma Biotechnology, Inc.
ClinicalTrials.gov Identifier: NCT01111825     History of Changes
Other Study ID Numbers: 10-005
Study First Received: April 22, 2010
Last Updated: October 21, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Puma Biotechnology, Inc.:
HKI-272 (NERATINIB)
TEMSIROLIMUS (CCI-779)
HER2-Amplified
Triple-negative
invasive adenocarcinoma
10-005

Additional relevant MeSH terms:
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms
Neoplasms by Site
Everolimus
Sirolimus
Breast Diseases
Skin Diseases
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents
Antineoplastic Agents
Immunologic Factors
Immunosuppressive Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014