| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-small cell lung cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Non small cell lung cancer |
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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 | 14.1 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029521 |
| E.1.2 | Term | Non-small cell lung cancer stage IIIB |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 determine the progression free survival (PFS) of
maintenance OSI-906 plus erlotinib (Arm A), or erlotinib and placebo (Arm B) in patients with nonprogression following four cycles of first-line platinum-based chemotherapy for advanced NSCLC in the overall population.
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are to evaluate:
- EGFR mutation positive and EGFR mutation negative subsets;
- PFS in the squamous and non-squamous subsets;
- Disease control (DCR);
- Response upgrade rate (RUR);
- Best overall response rate (ORR);
- Duration of response;
- Overall survival (OS);
- Safety profile of OSI-906/erlotinib combination;
- Pharmacokinetic (PK) profile of OSI-906/erlotinib combination;
- Tissue analysis looking at protein expression – including the relationship between E-cadherin and Vimentin expression and clinical outcomes (PFS and OS);
- Exploratory biomarkers and correlations with treatment outcome. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologically confirmed locally advanced or metastatic stage IIIB or IV NSCLC;
2. Have experienced CR, PR or SD following completion of 4 cycles of first-line platinum-based chemotherapy and are not progressing at time of entry into study (prior completed first-line combination bevacizumab therapy is permitted however, current use of maintenance bevacizumab is not permitted);
3. A maximum interval of 28 days between the last day of the treatment cycle and
randomization;
4. Patient has recovered from prior chemotherapy-related toxicity to ≤ grade 2;
5. EGFR mutation status must be confirmed for participation in the study. EGFR analysis can be performed either by central or local laboratory. If analysis is done locally, verifiable documentation confirming the EGFR mutation status must be submitted for review and approval by APGD prior to randomization. If no local result is available, formalin-fixed, paraffin-embedded archival tissue representative of the tumor or in the absence of archival tissue, a fresh tumor tissue sample of sufficient size to perform EGFR mutation analysis must be submitted centrally. Results of the central analysis must be available prior to randomization. Additionally, subjects should provide tissue blocks centrally for biomarker analysis whenever possible. Ideal tissue requirement: block with ≥5 mm2 tumor area sufficient to provide four 4-micron, and five 10-micron sections;
6. Measurable disease (for those patients with SD or PR following 4 cycles of first-line
platinum based chemotherapy) according to RECIST (version 1.1);
7. Age ≥ 18 years;
8. ECOG PS 0 – 1 (Appendix 13-2);
9. Previous adjuvant or neo-adjuvant treatment is permitted;
10. Must be able to take oral medication;
11. Fasting glucose ≤ 150 mg/dL (8.3 mmol/L). Concurrent use of non-insulinotropic
antihyperglycemic therapy is permitted if the dose has been stable for ≥ 4 weeks at the time of randomization;
12. Adequate hematopoietic, hepatic, and renal function defined as follows:
• Neutrophil count ≥ 1.5 x 109/L;
• Platelet count ≥ 100 x 109/L;
• Bilirubin ≤ 1.5 x ULN;
• AST and ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if patient has documented liver metastases;
• Serum creatinine ≤ 1.5 x ULN
• Potassium, magnesium and calcium within normal limits (supplementation and retesting is permitted).
13. Female patient must be either:
• Of non child bearing potential:
- post-menopausal (defined as at least 1 year without any menses) prior toScreening, or
- documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening)
• Or, if of childbearing potential:
- must have a negative urine pregnancy test at Screening, and
- must use two forms of birth control (one of which must be a barrier method) starting at Screening and throughout the study period and for 180 days after final study drug administration
• Acceptable forms include:
- Established use of oral, injected or implanted hormonal methods of contraception
- Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- Barrier methods of contraception: Condon OR Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;
14. Female patient must not be breastfeeding at Screening or during the study period and for
180 days after final study drug administration;
15. Female patient must not donate ova starting at Screening and throughout the study period
and for 180 days after final study drug administration;
16. Male patient and their female spouse/partners who are of childbearing potential must be
using highly effective contraception consisting of two forms of birth control (one of which
must be a barrier method) starting at Screening and continue throughout the study period
and for 180 days after final study drug administration
• Acceptable forms include:
- Established use of oral, injected or implanted hormonal methods of contraception
- Placement of an intrauterine device (IUD) or intrauterine system (IUS)
- Barrier methods of contraception including a condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository;
17. Male patient must not donate sperm starting at Screening and throughout the study period
and for at least 180 days after final study drug administration;
18. Prior radiation therapy is permitted provided patients have recovered from acute toxic
effects of radiotherapy prior to randomization. A minimum of 28 days must have elapsed
between the end of radiotherapy and randomization;
19. Prior surgery is permitted provided that the surgery was performed ≥ 21 days prior to
randomization and adequate wound healing has occurred prior to randomization; and
20. Patients must provide written (signed) informed consent to participate in the study and for use of tumor tissues.
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| E.4 | Principal exclusion criteria |
1. Prior exposure to agents directed at the HER axis (e.g., erlotinib, gefitinib, cetuximab, and trastuzumab);
2. Malignancies other than NSCLC within past 3 years (exceptions if curatively treated: basal or squamous cell carcinoma of skin; locally advanced prostate cancer; ductal carcinoma in situ of breast; in situ cervical carcinoma; and superficial bladder cancer);
3. Type 1 diabetes mellitus or Type 2 diabetes mellitus currently requiring insulinotropic or insulin therapy;
4. Prior IGF-1R inhibitor therapy;
5. Participated in any interventional clinical study or has been treated with any investigational drugs within 30 days or 5 half lives whichever is longer, prior to the initiation of Screening or during the course of the study;
6. Concurrent use of maintenance bevacizumab;
7. History of poorly controlled gastrointestinal disorders that could affect the absorption of study drug (e.g., Crohn’s disease, ulcerative colitis, etc);
8. History (within last 180 days) of significant cardiovascular disease unless the disease is
well-controlled. Significant cardiac disease includes second/third degree heart block;
clinically significant ischemic heart disease; superior vena cava (SVC) syndrome; poorly
controlled hypertension; congestive heart failure of New York Heart Association (NYHA) Class II or worse (slight limitation of physical activity; comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea);
9. History of arrhythmia (multifocal premature ventricular contractions [PVCs], bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) that is symptomatic or requires treatment (≥ grade 3), left bundle branch block (LBBB), or asymptomatic sustained ventricular tachycardia are not allowed. Patients with atrial fibrillation controlled by medication are not excluded;
10. Mean QTcF interval ≥ 450 msec based on independent central reviewer analysis of
screening visit ECGs;
11. Use of drugs that have a known risk of causing Torsades de Pointes (TdP) (‘Torsades List’on www.azcert.org/medical-pros/drug-lists/bycategory.cfm, see Appendix 13-3) are
prohibited within 14 days prior to randomization;
12. Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine. Other less potent CYP1A2 inhibitors/inducers are not excluded;
13. Use of potent CYP3A4 inhibitor such as ketoconazole, clarithromycin, atazanavir,
indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin,
troleandomycin (TAO), or voriconazole;
14. Use of proton pump inhibitors such as omeprazole. H2-receptor antagonists such as
ranitidine are not excluded;
15. History of cerebrovascular accident (CVA) within 180 days prior to randomization or that resulted in ongoing neurologic instability;
16. Active infection, serious underlying medical condition (including any type of active seizure disorder within 12 months prior to randomization), or serious chronic illness that would impair the ability of the patient to receive study drug;
17. History of any psychiatric or neurologic condition that might impair the patient’s ability to understand or to comply with the requirements of the study or to provide informed consent;
18. Pregnant or breast-feeding females;
19. Symptomatic brain metastases that are not stable, require steroids, are potentially
life-threatening, or that have required radiation and/or other related treatment (e.g., antiepileptic medication) within 21 days prior to randomization; and/or
20. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drug.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable is PFS.
The secondary efficacy variables include: OS, DCR, best ORR, RUR, and duration of response.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy variable is PFS based on RECIST.
Assessments are done every 6 wks pre-dose on D1 of every TP unless otherwise stated and at the post-treatment visit.
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|
| E.5.2 | Secondary end point(s) |
The secondary efficacy variables include: OS, DCR, best ORR, RUR, and duration of response.
AEs are monitored continuously;
Laboratory and physical examination (pre-dose on Day 1 of every timepoint unless specified otherwise and timepoint 1, Day 8 and 15)
and ECGs (pre-dose on Day 1 of every timepoint unless otherwise specified and timepoint 1, Day 1 and 8, 2-4 hrs postdose, and at the post-treatment visit).
PK samples are taken at timepoint 1, 2, 3 (pre-dose and 4 hrs post-dose) and at the post-treatment visit.
Exploratory marker samples are taken at timepoint 1, Day 1 pre-dose and 4 hrs post-dose) pre-dose Day 1, timepoint 2-5 and at the post-dose visit.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Assessments are conducted every 6 weeks pre-dose on D1 of every TP unless otherwise stated and at the post-treatment visit |
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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 | 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 | 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 | 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | Information not present in EudraCT |
| 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 |
| Brazil |
| Canada |
| Korea, Republic of |
| Russian Federation |
| United States |
|
| 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 study will be deemed as the date of the last visit of the last patient participating in the clinical 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 | 2 |
| 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 | 2 |
| 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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