Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01827267
Recruitment Status : Active, not recruiting
First Posted : April 9, 2013
Results First Posted : September 11, 2017
Last Update Posted : September 11, 2017
Information provided by (Responsible Party):
Puma Biotechnology, Inc.

Brief Summary:
This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter, multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy in patients with non-small cell lung cancer (NSCLC) who have documented somatic HER2 mutations.

Condition or disease Intervention/treatment Phase
HER2-mutant Non-Small Cell Lung Cancer Drug: neratinib Drug: temsirolimus Phase 2

Detailed Description:

This is a Phase 2, therapeutic-exploratory, adaptive design, open-label, multicenter, multinational study evaluating neratinib monotherapy and neratinib plus temsirolimus combination therapy in patients with NSCLC and documented somatic HER2 mutations. Patients randomized at study entry into 1 of 2 treatment arms:

  • Arm A: neratinib 240 mg orally once daily
  • Arm B: neratinib 240 mg orally once daily plus temsirolimus 8 mg once weekly by intravenous (IV) infusion

In the case of disease progression, patients initially assigned to neratinib monotherapy arm given option to add temsirolimus 8 mg IV once weekly.

Patients on combination therapy given option to dose-escalate temsirolimus to 15 mg/week at the end of first cycle of treatment, if well tolerated and at the physician's discretion. If neratinib 240 mg/day plus temsirolimus 15 mg/week dose not well tolerated, patient subsequently dose reduced back to neratinib 240 mg/day plus temsirolimus 8 mg/week.

Dosing continuous on nominal 3-week cycles until evidence of progressive disease, unacceptable toxicity, or patient withdrawal of consent.

Disease measured radiographically at baseline and every 6 weeks until disease progression or withdrawal from the study.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 62 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Neratinib and Neratinib Plus Temsirolimus in Patients With Non-Small Cell Lung Cancer Carrying Known HER2 Activating Mutations
Actual Study Start Date : July 1, 2013
Actual Primary Completion Date : September 20, 2016
Estimated Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer

Arm Intervention/treatment
Experimental: neratinib monotherapy
240 mg once daily with food, continuously in 21 day cycles
Drug: neratinib
Other Name: Nerlynx

Experimental: neratinib plus temsirolimus
240 mg neratinib plus 8 mg temsirolimus IV with optional dose escalation to 15 mg temsirolimus
Drug: neratinib
Other Name: Nerlynx

Drug: temsirolimus
Other Name: Torisel

Primary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: From randomization to disease progression or last tumor assessment ]
    ORR is defined as proportion of subjects who achieved confirmed complete response (CR) or partial response (PR) per RECIST v1.1. A complete or partial response must be confirmed no less than 4-weeks after the criteria for response are initially met.

Secondary Outcome Measures :
  1. Clinical Benefit Rate (CBR) [ Time Frame: From randomization to disease progression or death ]
    CBR is defined as the proportion of patients who achieved objective response (CR or PR) or SD for at least 12 weeks.

  2. Duration of Response (DOR) [ Time Frame: From first response to first PD or death ]
    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, PD, or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST (v1.1) criteria.

  3. Progression Free Survival (PFS) [ Time Frame: From randomization to disease progression or last tumor assessment ]
    Defined as time from date of randomization until the first disease recurrence or progression per RECIST V1.1 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.

  4. Overall Survival (OS) [ Time Frame: From randomization to death or end of long term follow-up ]
    Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria

  1. Aged ≥18 years at the time of signing the informed consent.
  2. Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic (stage IV).
  3. Documented somatic ErbB2 (HER2) activating mutation.
  4. Patients with anaplastic lymphoma kinase (ALK) translocations must have received crizotinib, except for cases of intolerable toxicity to crizotinib.
  5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
  6. Eastern Cooperative Oncology Group (ECOG) status <2.
  7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple -gated acquisition scan (MUGA) or echocardiogram (ECHO).
  8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive capacity (those who are biologically capable of having children) and for women less than 12 months after menopause.
  9. Men and women of childbearing potential must agree and commit to the use of a highly effective method of contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 3 months after the last dose of the investigational products.
  10. Provide written, informed consent to participate in the study and follow the study procedures.

Exclusion Criteria

  1. Previous treatment with any investigational agent ≤14 days prior to the initiation of investigational products.
  2. Previous treatment with any strong inhibitor and/or inducer of CYP3A4 enzyme or sensitive P-glycoprotein (P-gp) substrates ≤30 days prior to the initiation of investigational products.
  3. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.
  4. Major surgery <30 days of starting treatment.
  5. Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding inhaled steroids).
  6. Currently breast feeding.
  7. Symptomatic or unstable brain metastases.
  8. QTc interval >0.450 seconds for men and >0.470 seconds for women, or known history of QTc prolongation or Torsades de Pointes (TdP).
  9. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn's disease, malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline).
  10. Prior exposure to neratinib or mTOR inhibitor.
  11. Active infection or unexplained fever >38.5°C (101.3°F).
  12. Unable or unwilling to swallow tablets.
  13. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that would, in the Investigator's judgment, make the patient inappropriate for this study.
  14. Known hypersensitivity to any component of the investigational products.
  15. Unstable or uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.5%).
  16. Screening laboratory assessments outside the following limits: ANC <1000/μL (<1.0 x 109/L), Platelet count <75,000/μL (<75 x 109/L), Hemoglobin <8 g/dL, transfusions allowed, must be at least 7 days prior to baseline, Total bilirubin >1.5 x institutional upper limit of normal (ULN), AST and/or ALT 5 minutes, Creatinine clearance <50 mL/min.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01827267

United States, California
City of Hope
Duarte, California, United States, 91010
University of California Los Angeles
Santa Monica, California, United States, 94040
United States, Colorado
University of Colorado
Aurora, Colorado, United States, 80045
United States, Florida
Moffitt Cancer Center
Tampa, Florida, United States, 33612
United States, Maryland
Johns Hopkins
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
Massachusettes General Hospital
Boston, Massachusetts, United States, 02215
United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
United States, New York
Memorial Sloan-Kettering Cancer Center
New York, New York, United States, 10065
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, United States, 15232
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
United States, Texas
UT Southwestern Medical Center
Dallas, Texas, United States, 75390
MD Anderson Cancer Center
Houston, Texas, United States, 77030
CHU de Grenoble Hopital Albert Michallon
Grenoble, France, 38043
CHRU de Lille - Hopital Calmette
Lille, France, 59037
Hopital Nord
Marseille, France, 13915
Hopitaux universitaires de Strasbourg Nouvel Hopital Civil
Strasbourg, France, 167091
CHU de Toulous Hopital Larre
Toulouse, France, 30030
Institut Gustave Roussy
Villejuif, France, 94805
Sponsors and Collaborators
Puma Biotechnology, Inc.

Responsible Party: Puma Biotechnology, Inc. Identifier: NCT01827267     History of Changes
Other Study ID Numbers: PUMA-NER-4201
2012-004743-68 ( EudraCT Number )
First Posted: April 9, 2013    Key Record Dates
Results First Posted: September 11, 2017
Last Update Posted: September 11, 2017
Last Verified: August 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Puma Biotechnology, Inc.:
Lung cancer

Additional relevant MeSH terms:
Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antifungal Agents