Clinical trial NCT01827267: Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HER2-mutant Non-Small Cell Lung Cancer
Keywords: Lung cancer
Puma
neratinib
HKI-272
PB-272
Nerlynx
Lead sponsor: Puma Biotechnology, Inc.
Sponsor class: INDUSTRY
First posted: 2013-04-09
Enrollment: 62
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Secondary outcomes:
measure: Clinical Benefit Rate (CBR)
timeFrame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
measure: Duration of Response (DOR)
timeFrame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
measure: Progression Free Survival (PFS)
timeFrame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
measure: Overall Survival (OS)
timeFrame: From randomization to death or end of long term follow-up, assessed up to 31.8 months.
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Santa Monica
country: United States
facility: University of California Los Angeles
state: California
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Baltimore
country: United States
facility: Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Boston
country: United States
facility: Massachusettes General Hospital
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Center
state: New York
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University
state: Tennessee
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Grenoble
country: France
facility: CHU de Grenoble Hopital Albert Michallon
city: Lille
country: France
facility: CHRU de Lille - Hopital Calmette
city: Marseille
country: France
facility: Hopital Nord
city: Strasbourg
country: France
facility: Hopitaux universitaires de Strasbourg Nouvel Hopital Civil
city: Toulouse
country: France
facility: CHU de Toulous Hopital Larre
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Puma Biotechnology, Inc.
name: Clinical Development Senior Vice President
role: STUDY_DIRECTOR
References: