| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non small-cell lung cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non small-cell lung cancer (NSCLC): includes "non-small" cancer cell types in the lung such as epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. |
|
| 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 | 17.0 |
| 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) |
|
| 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 is to assess progression-free survival (PFS) in patients with Stage IV non-small cell lung cancer (NSCLC, based on American Joint Committee on Cancer [AJCC], Seventh Edition) not previously treated with chemotherapy for Stage IV disease, that are treated with chemotherapy combination with IMC-1121B versus chemotherapy alone. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to evaluate and compare the chemotherapy/IMC-1121B and chemotherapy arms with respect to:
• Radiographic objective response rate (ORR) determined by RECIST v1.1
• Disease control rate (DCR)
• Change in tumor size (CTS)
• Overall survival (OS)
• Duration of response
• Safety and toxicity profile |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The patient has histologically or cytologically confirmed NSCLC. Mixed NSCLC
tumors will be categorized by the predominant cell type. NSCLC tumors that are not
otherwise specified (NOS) with regard to histology or cannot be sub-classified as
squamous, adenocarcinoma, or large cell histology, will be categorized as nonsquamous. Primary or metastatic site may be used for histology. For squamous cell histology or for centrally located mediastinal masses (< 30 mm from the carina) identified by computed tomography scan (CT) or chest X-ray, the patient must undergo a magnetic resonance imaging (MRI) of the chest or I.V. contrast CT scan within 4 weeks of anticipated study entry, to exclude major airway or blood vessel invasion by cancer or intratumor cavitation.
2. The patient has Stage IV NSCLC disease at the time of study entry (based on the American Joint Committee on Cancer [AJCC], 7th ed).
3. The patient has measurable disease at the time of study entry as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).
4. The patient has resolution to Grade ≤ 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.03, of all clinically significant toxic effects of prior chemotherapy, surgery, radiotherapy, or hormonal therapy (with the exception of alopecia).
5. The patient has an Eastern Cooperative Oncology Group performance status (ECOG PS) score of 0-1.
6. The patient has adequate hematologic function as defined by an absolute neutrophil count (ANC) ≥ 1500/μL (≥ 1.5 × 10exp9/L), hemoglobin ≥ 9.5 g/dL (≥ 5.95 mmol/L), and a platelet count ≥ 100,000/μL (≥ 100 × 10exp9/L) obtained within 2 weeks prior to randomization.
7. The patient has adequate hepatic function as defined by a total bilirubin ≤ 1.5 mg/dL (25.7 μmol/L) (except for known Gilbert’s disease) and alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 5 x the upper limit of normal (ULN) in the presence of liver metastases or ≤ 2.5 x the ULN in the absence of liver metastases obtained, within 2 weeks prior to randomization.
The patient does not have:
- cirrhosis at a level of Child-Pugh B (or worse) or
- cirrhosis (any degree) and a history of hepatic encephalopathy or clinically
meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined
as ascites resulting from cirrhosis and requiring ongoing treatment with diuretics
and/or paracentesis.
8. The patient has adequate renal function as defined by calculated creatinine clearance (CrCl) ≥ 45 mL/min based on the original, weight-based Cockcroft and Gault formula, and urine dipstick or routine urinalysis for protein < 1+ (ie, either 0 or trace) obtained within 2 weeks prior to randomization. If urine dipstick is ≥ 1+, a 24-hour urine for protein must demonstrate < 500 mg of protein 24 hours to allow participation in the study.
9. The patient has adequate coagulation function as defined by international normalized ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above ULN if not receiving anticoagulation therapy. Patients on full-dose anticoagulation must be on a stable dose of oral anticoagulant or low molecular weight heparin, and if on warfarin must have therapeutic INR and have no active bleeding (14 days prior to randomization) or pathological condition that carries a high risk of bleeding (eg, tumor involving major vessels or known varices).
10. The patient, if sexually active, must be postmenopausal, surgically sterile, or using effective contraception (examples include condoms and spermicide; diaphragm and spermicide; an implanted hormonal contraceptive [eg, Implanon®]; injectable hormonal contraceptive; an intrauterine device or intrauterine system). The patient agrees to use adequate contraception during the study period and for 6 months after the last dose of any study medication.
11. Female patients of childbearing potential must have a negative serum pregnancy test within 7 days prior to randomization.
12. The patient is ≥ 18 years of age.
13. The patient has a life expectancy of ≥ 3 months.
14. The patient is able to provide informed written consent and is amenable to compliance with protocol schedules and testing. |
|
| E.4 | Principal exclusion criteria |
1. The patient’s tumor wholly or partially contains small cell lung cancer.
2. The patient has untreated central nervous system (CNS) metastases. Patients are eligible if they are clinically stable with regard to neurologic function, off all steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, stereotactic radiosurgery) ending at least 2 weeks prior to randomization, or after surgical resection performed at least 4 weeks prior to randomization.
3. 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.
4. The patient has received prior therapy with monoclonal antibodies, signal transduction inhibitors, or any therapies targeting VEGF or VEGFR.
5. The patient is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, radiotherapy, chemoembolization, or targeted therapy.
6. The patient has received previous chemotherapy for Stage IV NSCLC (patients who have received adjuvant chemotherapy are eligible if the last administration of the prior adjuvant regimen occurred at least 6 months prior to randomization).
7. The patient has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
8. Regardless of tumor histology, the patient has radiographic evidence of intratumor
cavitation.
9. The patient has undergone chest irradiation within 12 weeks prior to randomization (except palliative irradiation of bone lesions, which is allowed; in the case of focal or palliative radiation treatment to bone, at least 7 days must have elapsed from last radiation treatment prior to randomization provided that 25% or less of total bone marrow had been irradiated).
10. The patient has an ongoing or active clinically significant infection (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 experienced clinically relevant coronary artery disease, myocardial infarction within 6 months prior to randomization, uncontrolled congestive heart failure, or symptomatic poorly controlled arrhythmia.
13. The patient has poorly-controlled hypertension (ie, blood pressure in abnormal range despite medical management).
14. The patient has superior vena cava syndrome contraindicating hydration.
15. The patient has clinically significant third space fluid collections; for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to Day 1 of Cycle 1.
16. The patient has experienced any Grade 3-4 gastrointestinal bleeding within 3 months prior to study entry.
17. The patient has uncontrolled thrombotic or hemorrhagic disorders.
18. The patient is receiving chronic daily treatment with aspirin (> 325 mg/day) or other known inhibitors of platelet function including, but not limited to clopidogrel.
19. Patients with a history of gross hemoptysis (defined as bright red blood or
≥ 1/2 teaspoon) within 2 months of entry into this trial.
20. The patient has had a serious nonhealing wound, ulcer, or bone fracture within 28 days prior to randomization.
21. The patient has peripheral neuropathy ≥ Grade 2 (NCI-CTCAE v 4.03).
22. The patient has undergone major surgery within 28 days prior the first dose of study medication, or subcutaneous venous access device placement within 7 days prior to randomization. Furthermore, any patients with postoperative bleeding complications or wound complications from a surgical procedures performed in the last 2 months will be excluded.
23. The patient has an elective or a planned major surgery to be performed during the course of the trial.
24. The patient is pregnant or lactating.
25. 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.
26. The patient has a known allergy / history of hypersensitivity reaction to any of the treatment components.
27. The patient has a known history of drug abuse. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
*Progression-free Survival:
Progression-free survival is defined as the time from the randomization to the first evidence of objective progression as defined by RECIST v1.1, or death from any cause, whichever is first.
Efficacy endpoint - imaging; tumor measurements/disease response assessment; survival information |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- Imaging (CTs or MRI scans): pretreatment; every 6 weeks until disease progression or discontinuation of toxicity; follow-up approx. every 3 months for up to 2 years
- Tumor measurements/disease response assessment:pretreatment; every 6 weeks until disease progression or discontinuation of toxicity; follow-up approx. every 3 months for up to 2 years
- Survival information: follow-up approx. every 3 months for up to 2 years after treatment discontinuation |
|
| E.5.2 | Secondary end point(s) |
* Objective Response Rate (ORR): is the proportion of all patients with PR or CR according to RECIST v 1.1 from the start of the treatment until disease progression/recurrence.
* Disease Control Rate (DCR): is defined as the proportion of randomized patients achieving a best overall response of CR, PR, or SD.
*Overall Survival (OS)
defined as the time from randomization to the date of death from any cause.
* Change in tumor size
defined as the log ratio of tumor size at 6 weeks to tumor size at baseline.
*Duration of Response:
measured from the time measurement criteria are first met for CR/PR (whichever is first recorded) until the first date that the criteria for PD is met , or death.
*Pharmacokinetics
*Immunogenicity testing (IMC-1121B antibodies)/pharmacodynamic sampling |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
* Objective Response Rate (ORR) - by patient based on imaging assessments
* Disease Control Rate (DCR) - by patient based on imaging assessments
* Overall Survival (OS) - by patient - date of death from any cause
* Change in tumor size: 6 weeks from baseline
*Duration of Response - time from CR/PR (whichever is first recorded) until the first date that the criteria for PD is met or death by patient.
*Pharmacokinetics: standard PK parameters - 1, 2, 48, 120, 168, 336, and (504) hrs after infusion - depending on treatment group starting either in cycle 1 or in cycle 4.
*Immunogenicity testing (IMC-1121B antibodies)/pharmacodynamic sampling: prior to cycle 1, 3 and 5 and 30 days following the last dose. |
|
| 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 | Yes |
| 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 |
| Immunogenicity; Tumor Specimen Collection |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Stratified; treatment regimens compared within arms A and B and within arms C and D |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.3.1 | Comparator description |
| Combination of Pemetrexed/platinum-based CT in arms A,B; Gemcitabine/ platinum-based CT in arms C,D |
|
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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 |
| Belgium |
| Canada |
| Germany |
| Poland |
| United Kingdom |
|
| 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
|
| The end of trial occurs after study completion and after the last patient has discontinued study treatment and completed the 30-day follow-up in the extension period (if applicable). The study will be considered complete after the final analysis of overall survival is performed and evaluated, as determined by the Sponsor. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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