E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced nonsquamous non small cell lung cancer |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
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 of this study is to evaluate the overall survival (OS) in patients with Stage IV nonsquamous NSCLC (per the AJCC Staging Manual, Seventh Edition) treated with IMC-11F8 plus pemetrexed-cisplatin chemotherapy (Arm A) versus pemetrexed-cisplatin chemotherapy alone (Arm B) in the first-line metastatic setting. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate progression-free survival (PFS) in each arm;
• To evaluate the objective response rate (ORR) in each arm;
• To evaluate the time to treatment failure (TTF) in each arm;
• To evaluate the safety profile of IMC-11F8 in combination with pemetrexed-cisplatin chemotherapy;
• To evaluate the pharmacokinetics (PK) of IMC-11F8 (Arm A only);
• To determine the immunogenicity of IMC-11F8 (Arm A only);
• To evaluate Health Status; and
• To evaluate the relationship between EGFR protein expression (as measured by immunohistochemistry [IHC]) and efficacy. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The patient has histologically or cytologically confirmed nonsquamous
(adenocarcinoma/large cell or other) NSCLC.
2. The patient has Stage IV disease (per the AJCC Staging Manual,
Seventh Edition[43]; please see Appendix) at the time of study entry.
3. Measurable or nonmeasurable disease at the time of study entry as
defined by the Response Evaluation Criteria in Solid Tumors (RECIST
1.0)[44] (patients with only truly
nonmeasurable disease are not eligible).
4. The patient is ≥ 18 years of age.
5. The patient has resolution to Grade ≤ 1 by the National Cancer
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),
Version 3.0, of all clinically significant toxic effects of prior
chemotherapy, surgery, radiotherapy, or hormonal therapy (with the
exception of alopecia).
6. The patient has an Eastern Cooperative Oncology Group performance
status (ECOG PS) score of 0-2.
7. The patient has adequate hepatic function as defined by a total
bilirubin ≤ 1.5 x the upper limit of normal (ULN), and aspartate
transaminase (AST) and alanine ransaminase (ALT) ≤ 5.0 x the ULN in
the presence of liver metastases or ≤ 2.5 x the ULN in the absence of
liver metastases.
8. The patient has adequate renal function, defined by serum creatinine
≤ 1.2 x the ULN or calculated creatinine clearance > 50 mL/minute.
9. The patient has adequate hematologic function, as evidenced by white
blood cell count ≥ 3000/μL, an absolute neutrophil cell count (ANC) ≥
1500/μL, hemoglobin ≥ 9.5 g/dL, and platelets ≥ 100,000/μL.
10. The patient, if female, is surgically sterile, postmenopausal, or
compliant with a highly effective contraceptive method (failure rate <
1%) during and for 6 months after the treatment period (oral hormonal
contraception alone is not considered highly effective
and must be used in combination with a barrier method). If male, the
patient is surgically sterile or compliant with a highly effective
contraceptive regimen during and for
6 months after the treatment period.
11. Female patients of childbearing potential must have a negative
serum pregnancy test within 7 days prior to randomization.
12. The patient is able to provide informed written consent and is
amenable to compliance with protocol schedules and testing.
13. The patient has archived tumor tissue available for analysis of EGFR
protein expression (by IHC), and other defined biomarkers, depending
on tissue availability; minimum of four slides, paraffin-embedded tissue,
required. |
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E.4 | Principal exclusion criteria |
1. The patient has squamous NSCLC.
2. The patient has received prior anticancer therapy with monoclonal
antibodies, signal transduction inhibitors, or any therapies targeting the
EGFR, vascular endothelial growth factor (VEGF), or VEGF receptor.
3. The patient has received previous chemotherapy for advanced NSCLC
(patients who have received adjuvant chemotherapy are eligible if the
last administration of the prior adjuvant regimen occurred at least 1 year
prior to randomization).
4. The patient has undergone major surgery or received any
investigational therapy in the 4 weeks prior to randomization.
5. The patient has undergone chest irradiation within 12 weeks prior to
randomization (except palliative irradiation of bone lesions, which is
allowed).
6. The patient has brain metastases that are symptomatic or require
ongoing treatment with steroids or anticonvulsants. Patients who have
undergone previous radiotherapy for brain metastases, who are now
nonsymptomatic and no longer require treatment with steroids or
anticonvulsants, are eligible.
7. The patient has superior vena cava syndrome contraindicating
hydration.
8. The patient has current clinically-relevant coronary artery disease or
uncontrolled congestive heart failure (New York Heart Association III or
IV).
9. The patient has experienced myocardial infarction within 6 months prior to randomization.
10. The patient has an ongoing or active infection (requiring antibiotics),
including active tuberculosis or known infection with the human
immunodeficiency virus.
11. The patient has a history of significant neurological or psychiatric
disorders, including dementia, seizures, or bipolar disorder, potentially
precluding protocol compliance.
12. The patient has any NCI-CTCAE Version 3.0 Grade ≥ 2 peripheral
neuropathy.
13. The patient has significant third space fluid retention, requiring
repeated drainage.
14. The patient has any other serious uncontrolled medical disorders or
psychological conditions that would, in the opinion of the investigator,
limit the patient's ability to
complete the study or sign an informed consent document.
15. The patient has a known allergy / history of hypersensitivity reaction
to any of the treatment components, including any ingredient used in the
formulation of IMC-11F8, or any other contraindication to one of the
administered treatments.
16. The patient is pregnant or breastfeeding.
17. The patient has a known history of drug abuse.
18. The patient has a concurrent active malignancy other than
adequately-treated basal cell carcinoma of the skin or preinvasive
carcinoma of the cervix. A patient with previous
history of malignancy other than NSCLC is eligible, provided that he/she
has been free of disease for ≥ 3 years. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (defined as the time from randomization to death from any cause). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The final efficacy analysis will be performed when at least 474 deaths are observed. |
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E.5.2 | Secondary end point(s) |
• Progression-free survival (PFS)
• Objective response rate (ORR)
• Time to treatment failure (TTF)
• Safety endpoints (occurrence of at least one adverse event within a subject, vital sign parameters, laboratory parameters)
• Health Status (EQ-5D Index Score and VAS-Score, LCSS Index Score)
• PK parameters
• Immunogenicity (development of antibodies against IMC-11F8)
• EGFR protein expression (as measured by immunohistochemistry) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Assessment for response, according to RECIST 1.0, will be performed every 6 weeks (± 3 days).
Blood for determination of serum concentrations of IMC-11F8 will be drawn prior to the first infusion on Day 1 of Cycles 1, 2, 3, 4, 5, and 6 from patients in Arm A only.
Immunogenicity will be assessed based on serum drawn prior to the initial IMC-11F8 infusion on Day 1 of Cycles 1, 3, and 5 (Arm A only). An additional sample will be collected approximately 30 days following the last dose of IMC-11F8. Samples will also be obtained in the setting of an infusion reaction. |
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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 | Yes |
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 | No |
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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard of care treatment with pemetrexed and cisplatin |
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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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 141 |
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 |
Austria |
Belgium |
Brazil |
Canada |
France |
Germany |
Greece |
Hungary |
India |
Italy |
Poland |
Portugal |
Romania |
Russian Federation |
Serbia |
Slovakia |
South Africa |
Spain |
United Kingdom |
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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The end of the trial will be defined as the point at which no patient is receiving study therapy, all patients have completed the 30-day safety follow up evaluation subsequent to last dose, and analysis of the primary endpoint can be performed. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |