HER2-mutant Non-Small Cell Lung CancerPhase 2NCT01827267
Neratinib With and Without Temsirolimus for Patients With HER2 Activating Mutations in Non-Small Cell Lung Cancer
A Phase 2 study testing neratinib and temsirolimus in people with HER2-mutant Non-Small Cell Lung Cancer, run by Puma Biotechnology, Inc. at 21 sites in 2 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HER2-mutant Non-Small Cell Lung Cancer
- What is being tested?
- neratinib and temsirolimus
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 62 participants
- Where
- 21 sitesin 2 countries
- Study dates
- 1 Jul 2013to 6 Oct 2017
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Aged ≥18 years at the time of signing the informed consent.
- Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic (stage IV).
- Documented somatic ErbB2 (HER2) activating mutation.
- Patients with anaplastic lymphoma kinase (ALK) translocations must have received crizotinib, except for cases of intolerable toxicity to crizotinib.
- At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
- Eastern Cooperative Oncology Group (ECOG) status <2.
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- Left ventricular ejection fraction (LVEF) ≥50% measured by multiple -gated acquisition scan (MUGA) or echocardiogram (ECHO).
- 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.
- 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.
- Provide written, informed consent to participate in the study and follow the study procedures.
Who cannot join
- Previous treatment with any investigational agent ≤14 days prior to the initiation of investigational products.
- 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.
- 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.
- Major surgery <30 days of starting treatment.
- Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding inhaled steroids).
- Currently breast feeding.
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- Symptomatic or unstable brain metastases.
- QTc interval >0.450 seconds for men and >0.470 seconds for women, or known history of QTc prolongation or Torsades de Pointes (TdP).
- 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).
- Prior exposure to neratinib or mTOR inhibitor.
- Active infection or unexplained fever >38.5°C (101.3°F).
- Unable or unwilling to swallow tablets.
- 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.
- Known hypersensitivity to any component of the investigational products.
- Unstable or uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >6.5%).
- 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.
Trial locations and contacts
21 sites in 2 countries.
21 sites in 2 countries
United States15 sites
University of Colorado
Aurora, Colorado, 80045
Johns Hopkins
Baltimore, Maryland, 21231
Beth Israel Deaconess Medical Center
Boston, Massachusetts, 02215
Dana Farber Cancer Institute
Boston, Massachusetts, 02215
Massachusettes General Hospital
Boston, Massachusetts, 02215
Ohio State University
Columbus, Ohio, 43210
UT Southwestern Medical Center
Dallas, Texas, 75390
City of Hope
Duarte, California, 91010
MD Anderson Cancer Center
Houston, Texas, 77030
Vanderbilt University
Nashville, Tennessee, 37232
Memorial Sloan-Kettering Cancer Center
New York, New York, 10065
University of Pittsburgh Cancer Institute
Pittsburgh, Pennsylvania, 15232
University of California Los Angeles
Santa Monica, California, 94040
Washington University School of Medicine
St Louis, Missouri, 63110
Moffitt Cancer Center
Tampa, Florida, 33612
France6 sites
CHU de Grenoble Hopital Albert Michallon
Grenoble, 38043
CHRU de Lille - Hopital Calmette
Lille, 59037
Hopital Nord
Marseille, 13915
Hopitaux universitaires de Strasbourg Nouvel Hopital Civil
Strasbourg, 167091
CHU de Toulous Hopital Larre
Toulouse, 30030
Institut Gustave Roussy
Villejuif, 94805
About this study
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
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.
Read the 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
- Being tested
- neratinib, temsirolimus
- Keywords
- Lung cancer, Puma, neratinib, HKI-272, PB-272, Nerlynx
- Medical subject headings
- Lung Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
neratinibDrug
Also called Nerlynx
temsirolimusDrug
Also called Torisel
| Study group | Role | What they receive |
|---|---|---|
| neratinib monotherapy | Experimental | 240 mg once daily with food, continuously in 21 day cycles Receives: Drug: neratinib |
| neratinib plus temsirolimus | Experimental | 240 mg neratinib plus 8 mg temsirolimus IV with optional dose escalation to 15 mg temsirolimus Receives: Drug: neratinib; Drug: temsirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rate (ORR)
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.
Measured: 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 (4)
Clinical Benefit Rate (CBR)
CBR is defined as the proportion of patients who achieved objective response (CR or PR) or stable disease (SD) for at least 12 weeks.
Measured: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Duration of Response (DOR)
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, progressive disease (PD), or death was objectively documented, taking as a reference for PD the smallest measurements recorded since enrollment, per RECIST (v1.1) criteria.
Measured: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Progression Free Survival (PFS)
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.
Measured: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Overall Survival (OS)
Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive.
Measured: From randomization to death or end of long term follow-up, assessed up to 31.8 months.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Apr 2013 (estimated)
- Study start1 Jul 2013
- Primary completion20 Sep 2016
- Study completion6 Oct 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HER2-mutant Non-Small Cell Lung CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 62 participants (actual)
Sponsor and investigators
- Lead sponsor
- Puma Biotechnology, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Clinical Development Senior Vice President, Study director, Puma Biotechnology, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01827267
- Sponsor's protocol ID
- PUMA-NER-4201
- Other IDs
- 2012-004743-68
- Status last verified
- May 2018
- First submitted
- 1 Apr 2013
- Last updated
- 3 Jul 2018
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Li BT, Gandhi L, Ravichandran V, Besse B, Mazieres J, Shapiro GI, Boni V, Waqar SN, Park H, Quinn DI, Martinez A, Stemmer SM, Cortot AB, Barlesi F, Quoix E, Burkard ME, Selcuklu SD, Hunt C, Donoghue MTA, Kris MG, Bebchuk J, Eli LD, McCulloch L, Solit DB, Janne PA. Efficacy of Neratinib-Based Therapy in ERBB2-Mutant Lung Adenocarcinomas: Findings From 2 International Phase 2 Studies. Clin Lung Cancer. 2026 Mar;27(2):214-226.e5. doi: 10.1016/j.cllc.2025.09.009. Epub 2025 Oct 1.
PubMed 41193346
Study at a glance
From the registry record, last updated by the sponsor on 3 Jul 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT01827267
- Acronym / sponsor ID
- PUMA-NER-4201
- Conditions
- HER2-mutant Non-Small Cell Lung Cancer
- Keywords
- Lung cancer, Puma, neratinib, HKI-272, PB-272, Nerlynx
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 62 participants (actual)
- Lead sponsor
- Puma Biotechnology, Inc.Industry (pharma, biotech, devices)
- Study start
- 1 Jul 2013 (actual)
- Primary completion
- 20 Sep 2016 (actual)
- Study completion
- 6 Oct 2017 (actual)
- First posted
- 9 Apr 2013 (estimated)
- Results
- Posted 11 Sep 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| neratinib monotherapy | Experimental | Drug: neratinib240 mg once daily with food, continuously in 21 day cycles |
| neratinib plus temsirolimus | Experimental | Drug: neratinib, Drug: temsirolimus240 mg neratinib plus 8 mg temsirolimus IV with optional dose escalation to 15 mg temsirolimus |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (10 listed)
- Aged ≥18 years at the time of signing the informed consent.
- Histologically confirmed diagnosis of NSCLC, advanced (stage IIIB) or metastatic (stage IV).
- Documented somatic ErbB2 (HER2) activating mutation.
- Patients with anaplastic lymphoma kinase (ALK) translocations must have received crizotinib, except for cases of intolerable toxicity to crizotinib.
- At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).
Key exclusion criteria (16 listed)
- Previous treatment with any investigational agent ≤14 days prior to the initiation of investigational products.
- 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.
- 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.
- Major surgery <30 days of starting treatment.
- Chronic steroid use (prednisone >12.5 mg/day or dexamethasone >2 mg/day, excluding inhaled steroids).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| neratinibAlso: Nerlynx | Drug | neratinib monotherapy, neratinib plus temsirolimus |
| temsirolimusAlso: Torisel | Drug | neratinib plus temsirolimus |
Primary outcome
Objective Response Rate (ORR)
Time frame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
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.
4 secondary outcomes
Clinical Benefit Rate (CBR)
Time frame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Duration of Response (DOR)
Time frame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Progression Free Survival (PFS)
Time frame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.
Overall Survival (OS)
Time frame: From randomization to death or end of long term follow-up, assessed up to 31.8 months.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Jul 2018.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 41193346Li BT, Gandhi L, Ravichandran V, Besse B, Mazieres J, Shapiro GI, Boni V, Waqar SN, Park H, Quinn DI, Martinez A, Stemmer SM, Cortot AB, Barlesi F, Quoix E, Burkard ME, Selcuklu SD, Hunt C, Donoghue MTA, Kris MG, Bebchuk J, Eli LD, McCulloch L, Solit DB, Janne PA. Efficacy of Neratinib-Based Therapy in ERBB2-Mutant Lung Adenocarcinomas: Findings From 2 International Phase 2 Studies. Clin Lung Cancer. 2026 Mar;27(2):214-226.e5. doi: 10.1016/j.cllc.2025.09.009. Epub 2025 Oct 1.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Clinical Development Senior Vice President study director
Puma Biotechnology, Inc.
21 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing neratinib and temsirolimus in people with HER2-mutant Non-Small Cell Lung Cancer, run by Puma Biotechnology, Inc. at 21 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 10 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 3 Jul 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 21 sites in United States, France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Sep 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Objective Response Rate (ORR) (time frame: From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01827267, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jul 2018; AzTrials last refreshed its copy on 6 Nov 2026.