HER2-mutant Non-Small Cell Lung Cancer
Conditions
Keywords
Lung cancer, Puma, neratinib, HKI-272, PB-272, Nerlynx
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.
Interventions
DRUGneratinib
DRUGtemsirolimus
Sponsors
Puma Biotechnology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Clinical Benefit Rate (CBR) | From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included. | CBR is defined as the proportion of patients who achieved objective response (CR or PR) or stable disease (SD) for at least 12 weeks. |
| Duration of Response (DOR) | From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included. | 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. |
| Progression Free Survival (PFS) | From randomization to last tumor assessment, assessed up to 116.5 weeks. For the Neratinib arm, only tumor assessments prior to crossover were included. | 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. |
| Overall Survival (OS) | From randomization to death or end of long term follow-up, assessed up to 31.8 months. | Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive. |
Countries
France, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Neratinib Neratinib 240 mg | 17 |
| Neratinib+Temsirolimus Neratinib 240 mg + Temsirolimus 15 mg. | 43 |
| Total | 60 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not receive study drug | 1 | 1 |
| Overall Study | Disease Progression | 1 | 1 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Sponsor Discontinued Study | 2 | 8 |
| Overall Study | Still on study | 0 | 2 |
Baseline characteristics
| Characteristic | Neratinib | Neratinib+Temsirolimus | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 7 Participants | 24 Participants | 31 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 19 Participants | 29 Participants |
| Age, Continuous | 62.24 years STANDARD_DEVIATION 8.88 | 63.44 years STANDARD_DEVIATION 12.72 | 63.10 years STANDARD_DEVIATION 11.7 |
| Sex: Female, Male Female | 9 Participants | 32 Participants | 41 Participants |
| Sex: Female, Male Male | 8 Participants | 11 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 17 / 17 | 43 / 43 | 10 / 11 |
| serious Total, serious adverse events | 7 / 17 | 16 / 43 | 7 / 11 |
Outcome results
Primary
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.
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.
Population: All subjects who received at least 1 dose of drug
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neratinib | Objective Response Rate (ORR) | 0 Participants |
| Neratinib+Temsirolimus | Objective Response Rate (ORR) | 6 Participants |
Secondary
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.
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.
Population: All subjects who received at least one dose.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Neratinib | Clinical Benefit Rate (CBR) | 6 Participants |
| Neratinib+Temsirolimus | Clinical Benefit Rate (CBR) | 21 Participants |
Secondary
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.
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.
Population: All subjects who received at least 1 dose of drug and had either complete or partial response.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Neratinib | Duration of Response (DOR) | Less than 3 months | 0 Participants |
| Neratinib | Duration of Response (DOR) | 3 to less than 6 months | 0 Participants |
| Neratinib | Duration of Response (DOR) | 6 to less than 12 months | 0 Participants |
| Neratinib | Duration of Response (DOR) | Greater than 12 months | 0 Participants |
| Neratinib+Temsirolimus | Duration of Response (DOR) | Greater than 12 months | 2 Participants |
| Neratinib+Temsirolimus | Duration of Response (DOR) | Less than 3 months | 2 Participants |
| Neratinib+Temsirolimus | Duration of Response (DOR) | 6 to less than 12 months | 0 Participants |
| Neratinib+Temsirolimus | Duration of Response (DOR) | 3 to less than 6 months | 2 Participants |
Secondary
Overall Survival (OS)
Defined as the time (month) from randomization to death due to any cause; censored at the date last known alive.
Time frame: From randomization to death or end of long term follow-up, assessed up to 31.8 months.
Population: All subjects who received at least 1 dose of drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Overall Survival (OS) | 10.0 months |
| Neratinib+Temsirolimus | Overall Survival (OS) | 15.1 months |
Secondary
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.
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.
Population: All subjects who received at least 1 dose of drug
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neratinib | Progression Free Survival (PFS) | 2.9 months |
| Neratinib+Temsirolimus | Progression Free Survival (PFS) | 4.0 months |