| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-squamous advanced Non-Small-Cell Lung-Cancer (Stage IV) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10025077 |
| E.1.2 | Term | Lung carcinoma stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To determine the activity of a first-line treatment related to Thymidylate Synthetase (TS) Expression in patients with non-squamous advanced Non-Small Cell Lung Cancer. The main efficacy parameter is the progression free survival (PFS). |
|
| E.2.2 | Secondary objectives of the trial |
- Overall survival
- Quality of life
- Response rate
- Explorative subgroup analyses (for example: LDH-level, gender, age, performance status, histology, smoking history)
- Molecular investigations
- Analysis of prognostic and predictive value of TS-Expression |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histological confirmed Non-Small-Cell lung cancer
2. Tumor stage IV (UICC 7th Version)
3. The following histological tumor types are eligible:
- Adenocarcinoma (including adenocarcinomas with bronchioloalveolar differentiation)
- Large Cell carcinoma without neuroendocrine differentiation
- Mixed Cell Carcinoma without small cell fraction and without predominant squamous cell fraction
- undifferentiated non-small-cell-carcinoma
4. No previous chemotherapy for stage IV NSCLC
5. Adjuvant or neoadjuvant chemotherapy for NSCLC must be
completed at least one year prior to study enrolment (from end of chemotherapy)
6. No previous treatment with Pemetrexed or Bevacizumab
7. Patients with prior radiation therapy may be eligible for this study if they meet the following guidelines:
- Previous radiation therapy is allowed to <25% of the bone marrow (Cristy and Eckerman 1987), but should have been limited and must not have included whole pelvis radiation
- Patients must have recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia)
- Prior thoracic radiotherapy must be completed 30 days before study enrollment
- Lesions that have been radiated cannot be included as sites of measurable disease unless clear tumor progression has been
documented in these lesions since the end of radiation therapy
- Palliative extrathoracic radiotherapy to preexisting lesions may continue on study; however, these lesions may not be included as sites of measurable disease.
8. At least 4 weeks since last major surgery
9. Age ≥ 18 and ≤ 70 years
10. ECOG ≤ 1
11. Adequate hematological laboratory parameters:
- Hemoglobin ≥ 9 g/dl
- Neutrophils ≥ 1.500 μl
- WBC ≥ 3.000 μl
- Platelets ≥ 100.000 μl
12. Adequate hepatic laboratory parameters:
- Total Bilirubin ≤ 1,5 x ULN
- Alkaline phosphatase ≤ 3 x ULN
- AST(GOT) < 2,5 ULN in patients without liver metastasis < 5 x ULN in patients with liver metastasis ULN = (upper limit of normal)
- ALT(GPT) < 2,5 ULN in patients without liver metastasis < 5 x ULN in patients with liver metastasis ULN = (upper limit of normal)
13. Adequate renal laboratory parameters:
- Creatinine Clearance > 50 ml/min
- Urine dipstick for proteinuria < 2+
Patientients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate <1 g of protein in 24 hours
14. Normal cardiac function defined by New York Heart Association – NYHA Class I and Class II
15. Electrocardiogram without significant signs of cardiac arrhythmias
16. Provision of informed consent according to local regulatory requirements prior to any protocol specific treatment
18. Measurable lesion according to RECIST 1.1
19. Negative pregnancy test for women of childbearing potential unless they are postmenopausal at baseline.(Postmenopausal women must have been amenorrheic at least for 12 months to be considered of non childbearing potential)
20. Women of child bearing potential and men to be willing to use an acceptable method to avoid pregnancy at least one month before study start. Examples: oral contraceptives (sole application of oral contraceptives is not sufficient), diaphragm pessary, intrauterine device (spiral), condom plus diaphragm pessary plus spermicide |
|
| E.4 | Principal exclusion criteria |
1. Histological confirmed predominant squamous cell carcinoma
2. Presence of activating EGFR mutations in exons 18-21
3. Pregnancy or lactation period
4. Have known central nervous system disease, other than stable, treated brain metastasis. Stable, treated brain metastasis is defined as metastasis having no evidence of progression or
hemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and posttreatment brain imaging. Patients should be off corticosteroids for 1 week at the time of the post-treatment brain CT/MRI. Anticonvulsants are allowed. Treatment for brain metastases may
include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician, and must have been completed > 28 days prior to Day 1 of Cycle 1. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 8 weeks prior to Day 1 of Cycle 1 will be excluded
5. Evidence of tumor invading or abutting major blood vessels
6. Presence of a tracheobronchial fistula
7. History of abdominal fistula or fistulisation of urogenital tract,
gastrointestinal perforation or intra-abdominal abscess, inflammatory bowel disease, or diverticulitis within 6 months prior to study start
8. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of a CIS of the cervix, nonmelanomatous skin cancer, stable chronic lymphatic leukaemia,
non-muscle invasive bladder cancer or surgically treated or irradiated prostate cancer with no signs of recurrence for one year. Patients with other malignancies curatively treated and free of disease for at least 5 years will be discussed with the Principal Investigator before inclusion
9. Treatment with an investigational new drug, currently or within the last 28 days, and/or participation in another clinical trial, currently or during the last 12 weeks, and/or previous participation in this study.
10. History or presence of a mental disease or condition such as to interfere with the patient's ability to understand the requirements of the study and the intake of study medication according to study protocol.
11. Patients with any clinically significant disease that in the opinion of the investigator is likely to put the patient at risk or to interfere with the evaluation of the patient's safety and of the study outcome. This includes, but is not limited to:
- Immediate need for therapeutic intervention
- Clinically significant cardiac disease or myocardial infarction within the last 6 months
12. Have a history of hypertension, unless hypertension is well controlled upon study entry and the patient is on a stable regimen of antihypertensive therapy. Patients should not have any prior history of hypertensive crisis or hypertensive encephalopathy.
13. Non healing wound, ulcer or bone fracture
14. Fresh thrombosis under full dose therapy with anticoagulants
15. History of thrombotic disorders within the last 6 months prior to entry
16. Current or recent full-dose oral or parenteral anticoagulants, or thrombolytic agents for therapeutic purposes
17. Prophylactic use of anticoagulants is allowed; international normalized ratio should be <1.5 at study enrollment.
18. Current or recent use of ASS – Dosage > 325 mg/day
19. Current or recent use of Plavix/Clopidogrel, at doses >75 mg/d, dipyramidole, ticlopidine, cilostazol
20. Hemorrhagic diathesis, Hemophilia A, Hemophilia B
21. Implantation of a central vein catheter within 24 h prior to application of study medication
22. Have a history of gross hemoptysis <3 months prior to enrollment or history or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding
23. Peritoneal carcinomatosis
24. Pleural effusion with the need of therapeutic pleurodesis
25. Ascites with the need of intervention
26. Any other uncontrolled infection
27. Organ allograft
28. Hardness of hearing that interferes with daily life
30. Sensory Neuropathy > Grade 1 (CTCAE Version 4.0)
31. Alcohol and drug abuse
32. Known hypersensitivity to any of the study drugs
33. Have a history of a serious reaction to a monoclonal antibody. Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible
34. Have received a recent or are receiving concurrent yellow fever vaccination
35. Have had major surgery, open biopsy, or significant traumatic injury within 28 days prior to study enrollment, or anticipate the need for major surgical procedure during the course of the study
36. Patients with creatinine clearance 50-79 ml/min must be able to interrupt NSAIDs 2 days before, the day of, and 2 days following administration of pemetrexed
37. Are unable or unwilling to take folic acid, vitamin B12 supplementation, or corticosteroids |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| PFS will be calculated from the date of start of treatment (cycle 1, day 1) to the date of first progression, death or date of last contact. |
|
| E.5.2 | Secondary end point(s) |
- Quality of life
- Response rate
- Explorative subgroup analyses
- Molecular investigations |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Screening, day 1, day 84 and end of treatment (quality of life questionnaire)
- Total study duration |
|
| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | No |
| 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 | No |
| 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 | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Stratification according to the Thymidylate Synthetase (TS) expression level. |
|
| 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 |
| Stratum A (low TS expression) and Stratum B (high TS expression) |
|
| 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 | 20 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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