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

NCT ID: NCT01827267

Last Updated: 2018-07-03

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 62 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-01
• Study Completion Date: 2017-10-06

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.

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.

Conditions

HER2-mutant Non-Small Cell Lung Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

neratinib monotherapy

240 mg once daily with food, continuously in 21 day cycles

Group Type: EXPERIMENTAL

neratinib

Intervention Type: DRUG

neratinib plus temsirolimus

240 mg neratinib plus 8 mg temsirolimus IV with optional dose escalation to 15 mg temsirolimus

Group Type: EXPERIMENTAL

neratinib

Intervention Type: DRUG

temsirolimus

Intervention Type: DRUG

Interventions

neratinib

Intervention Type: DRUG

temsirolimus

Intervention Type: DRUG

Other Intervention Names

Nerlynx; Torisel

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Puma Biotechnology, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Clinical Development Senior Vice President

Role: STUDY_DIRECTOR

Puma Biotechnology, Inc.

Locations

City of Hope

Duarte, California, United States

University of California Los Angeles

Santa Monica, California, United States

University of Colorado

Aurora, Colorado, United States

Moffitt Cancer Center

Tampa, Florida, United States

Johns Hopkins

Baltimore, Maryland, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

Dana Farber Cancer Institute

Boston, Massachusetts, United States

Massachusettes General Hospital

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Memorial Sloan-Kettering Cancer Center

New York, New York, United States

Ohio State University

Columbus, Ohio, United States

University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, United States

Vanderbilt University

Nashville, Tennessee, United States

UT Southwestern Medical Center

Dallas, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

CHU de Grenoble Hopital Albert Michallon

Grenoble, , France

CHRU de Lille - Hopital Calmette

Lille, , France

Hopital Nord

Marseille, , France

Hopitaux universitaires de Strasbourg Nouvel Hopital Civil

Strasbourg, , France

CHU de Toulous Hopital Larre

Toulouse, , France

Institut Gustave Roussy

Villejuif, , France

Countries

United States; France

Other Identifiers

2012-004743-68

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PUMA-NER-4201

Identifier Type: -

Identifier Source: org_study_id