E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small Cell Lung Cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061873 |
E.1.2 | Term | Non-small cell lung cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective for Part A of the study is to confirm that the combination regimen of patritumab with erlotinib will improve PFS in HRG-high, EGFR-inhibitor–naïve, EGFR-wild type subjects with locally advanced or metastatic NSCLC who progressed on at least one prior systemic therapy.
The primary objective for Part B of the study is to determine if the combination regimen of patritumab with erlotinib will improve OS in EGFR-inhibitor–naïve subjects with locally advanced or metastatic, HRG-high, EGFR-wild type NSCLC who have progressed on at least one prior systemic therapy.
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E.2.2 | Secondary objectives of the trial |
Secondary objectives for Part A are:
- To evaluate overall survival (OS) and objective response rate (ORR)
- To further characterize the safety of patritumab in combination with erlotinib, including incidence of HAHA formation
- To refine the cut-off for HRG-high tumors that will be used to select subjects in Part B
- To evaluate the population pharmacokinetics of patritumab
Secondary objectives for Part B are:
- To evaluate OS in the pre-defined narrower subset of HRG-high subjects (the “extremely high-HRG” stratum) after the primary objective of Part B is achieved
- To evaluate PFS
- To further characterize the safety of patritumab in combination with erlotinib, including incidence of HAHA formation
- To evaluate population pharmacokinetics of patritumab
- To evaluate TTD on the LCS of the FACT-L and on the total FACT-L
- To evaluate ORR
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study:
1. Must be ≥ 20 years of age
2. Must have cytology or histologically confirmed NSCLC with either:
a) Metastatic disease (Stage IV) OR
b) Stage IIIB disease not amenable to surgery or curative intent.
Note: It is permissible to use either AJCC Version 6.0 or the AJCC Version 7.0 staging system. For sites that use AJCC Version 7.0, T4M0 patients with other ipsilateral nodules and N0-N2 are still eligible.
3. If tumor histology is adenocarcinoma, must have wild-type EGFR genotype as assessed by a validated assay that includes the exon 19 deletion and the exon 21 (L858R) substitution.
- Historical locally generated EGFR results may be acceptable if assay details are available. Historical EGFR test results for all subjects with adenocarcinoma must be provided to the Sponsor’s designee for confirmation prior to randomization. See Laboratory Manual for details.
- Archived tumor samples from patients without a verified historical result will be tested by the sponsor at the central testing lab. See Laboratory Manual for instructions on archived tumor sample submission.
4. Must have received one or two prior lines of systemic chemotherapy for advanced or metastatic disease
- One of the lines of therapy must be a platinum-doublet
- Must have received docetaxel OR have been judged by the physician as ineligible for docetaxel
- Patients who received only adjuvant systemic treatment will be eligible only if disease progression occurred <6 months after completion of adjuvant therapy.
- For patients who received adjuvant systemic therapy and subsequent systemic therapy for metastatic disease, the adjuvant treatment counts as a line of therapy only if disease progression occurred < 6 months after its completion.
- Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued without discontinuation after initiation of a treatment regimen.
5. Must have disease progression or recurrence documented by radiographic assessment following treatment after last chemotherapy or chemoradiation regimen (completed within the previous 12 months).
6. Must have available recent (before treatment start) or archival tumor specimen meeting these criteria:
- Part A subjects: Recent or archival tumor specimens must be determined by the central pathology laboratory to be HRG high or low using the validated IUO-1 assay. (Refer to the Laboratory Manual for details on specimen requirements). Subjects with undetermined HRG expression will be excluded.
- Part B subjects: Recent or archival tumor specimens must be HRG high as determined by the central pathology laboratory using IUO-2. (Refer to the Laboratory Manual for details on specimen requirements). Subjects with undetermined HRG expression will be excluded.
7. Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Version 1.1 for Part A; for Part B, must have measurable disease or non-measurable disease per RECIST
8. Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Must have adequate hematological function, as follows:
- ANC ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
10. Must have adequate renal function, as follows:
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 60 mL/min using the modified Cockroft-Gault equation
11. Must have adequate hepatic function, as follows:
- AST ≤ 2.5 x ULN (if liver metastases are present, < 5 x ULN)
- ALT ≤ 2.5 x ULN (if liver metastases are present, < 5 x ULN)
- Alkaline phosphatase ≤ 2.5 x ULN (if bone or liver metastases are present, < 5 x ULN)
- Bilirubin ≤ 1.5 x ULN
12. Must have adequate prothrombin time (PT) and partial thromboplastin time (PTT) ≤ 1.5 x ULN except for patients on coumarinderivative anticoagulants or other similar anticoagulant therapy, who must have an INR within the therapeutic range or if deemed appropriate by Investigator's clinical judgment.
13. If female, must be either postmenopausal (no menstrual period for a minimum of 12 months), surgically sterile, or if of childbearing potential, must have a negative urine or serum pregnancy test upon entry into this study; and must be willing to use maximally effective birth control during the period of therapy and contraception for 6 months following the last investigational drug dose
14. If male, must be surgically sterile or willing to use a double-barrier contraception method upon enrollment, during the course of the study, and for 6 months following the last investigational drug dose
15. Must have provided informed consent for study participation (see Section 1.5.2) |
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E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the study:
1. Lung adenocarcinoma with an ALK gene rearrangement. Test results for all subjects with adenocarcinoma must be provided to the Sponsor’s designee for confirmation prior to randomization. Refer to the Laboratory Manual for further details on sample and testing requirements.
a. Historical locally generated results may be acceptable if assay details are available. Historical ALK test results for all subjects with adenocarcinoma must be provided to the Sponsor’s designee for confirmation prior to randomization. See Laboratory Manual for details.
b. Archived tumor samples from patients without a verified historical result will be tested by the sponsor at the central testing lab. See laboratory manual for instructions on archived tumor sample submission.
2. Left ventricular ejection fraction (LVEF) < 45%
3. Prior EGFR-targeted regimen, anti-HER2, anti-HER3, or anti-HER4 therapy
4. History of other malignancies, except adequately treated non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
5. History of corneal disease
6. History of interstitial lung disease (ILD)
7. Clinically active brain metastases, defined as untreated symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms. Subjects with treated brain metastases that are no longer symptomatic and require no treatment with steroids may be included in the study if they have recovered from the acute toxic effect of radiotherapy and have no evidence of disease progression on imaging studies (MRI/CT scan). A minimum of 4 weeks (2 weeks for subjects with brain lesion amenable to stereotactic radiosurgery) must have elapsed between the end of radiotherapy and study enrollment.
8. Uncontrolled hypertension (diastolic > 100 mmHg or systolic > 140 mmHg). It is permissible for the subject to receive treatment with antihypertensive medication to maintain blood pressure within required parameters.
9. Clinically significant ECG changes that obscure the ability to assess the RR, PR, QT, QTc, and QRS intervals.
10. Clinically significant (in the opinion of the Investigator) ascites or pleural effusion requiring chronic medical intervention
11. Myocardial infarction within 1 year before enrollment, symptomatic congestive heart failure (New York Heart Association > Class II), unstable angina, or unstable cardiac arrhythmia requiring medication
12. Treatment with anticancer therapy, antibody-based therapy, retinoid therapy, or hormonal therapy within 4 weeks before study drug treatment; treatment with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or treatment with small molecule TKIs within 2 weeks before study drug treatment
Prior and concurrent use of hormone replacement therapy is permitted.
13. Therapeutic radiation therapy or major surgery within 4 weeks before study drug treatment; or palliative radiation within 2 weeks before study drug treatment. No target lesion should be selected within the previously irradiated field unless there was progression at that lesion following radiation.
14. Participation in clinical drug trials within 4 weeks (2 weeks for small molecule TKIs) before study drug treatment, or current participation in other investigational procedures
15. Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Subjects should be tested for HIV prior to randomization if required by local regulations or ethics committee.
16. History of hypersensitivity to any of the study drugs or to any excipients.
17. Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism or excretion of the study drug; or impair the assessment of study results.
18. Psychological, social, familial, or geographical factors that would interfere with study participation or follow-up.
19. Pregnant or nursing women. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part A primary efficacy endpoint: PFS
Part B primary efficacy endpoint: OS
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Part A secondary efficacy endpoints: OS; ORR.
Part B secondary efficacy endpoints: PFS; TTD on the LCS; TTD on the total FACT-L; ORR
Safety Endpoints: (Part A and Part B)
- Frequency and severity of treatment-emergent AEs
- Incidence of human anti-human antibody (HAHA) formation
Population Pharmacokinetic (PK) Endpoints (Part A and Part B):
- Serum patritumab concentrations
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 106 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
Brazil |
Canada |
European Union |
Israel |
Japan |
Korea, Republic of |
Russian Federation |
Serbia |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |