E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-Small Cell Lung Cancer stage IV |
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E.1.1.1 | Medical condition in easily understood language |
metastatic 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 | 19.1 |
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 |
To evaluate if the combination regimen of custirsen and docetaxel improves the Overall Survival (OS) of patients with advanced or metastatic (Stage IV) NSCLC who have received one prior line of platinum-based systemic anticancer therapy. |
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E.2.2 | Secondary objectives of the trial |
Efficacy:
1.To compare Progression Free Survival (PFS) between patients receiving docetaxel with or without custirsen.
2.To compare Objective Response Rate (ORR) between patients receiving docetaxel with or without custirsen.
3.To compare Duration of Objective Response between patients receiving docetaxel with or without custirsen
4.To compare Disease Control Rate (DCR) between patients receiving docetaxel with or without custirsen
5.To compare Duration of Disease Control (DC), between patients receiving docetaxel with or without custirsen.
Safety:
To assess the safety profile of custirsen in combination with docetaxel.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Patients must have a histologically or cytologically confirmed, unresectable, advanced or metastatic (Stage IV per American Joint Committee on Cancer 7th edition of tumor, nodes and metastases classification of malignant tumors [TNM] staging) NSCLC
2.Males or females ≥ 18 years of age at screening.
3.Life expectancy of > 12 weeks from screening, according to the Investigator's assessment.
4.Patients must have received one prior line of platinum-based systemic anticancer therapy for advanced (stage IIIB) or metastatic (stage IV) NSCLC. Prior maintenance therapy is allowed and will be considered as the same line of therapy when continued at the end of a treatment regimen. (Note: prior platinum-based therapy in the neoadjuvant or adjuvant setting for early-stage disease is allowed.)
5.Patients must have documented radiological disease progression either during or after the first-line therapy.
6.Patients must have at least one measurable lesion per RECIST 1.1 criteria.
7.ECOG PS of 0 or 1 at screening.
8.Have adequate bone marrow, renal and liver functions at screening as defined below:
-Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
-Platelet count ≥ 100 x 109/L
-Hemoglobin ≥ 9 g/dL
-Serum creatinine ≤ 1.5 x upper limit of normal (ULN)
-Total Bilirubin≤1.0 x ULN (unless elevated secondary to benign conditions such as Gilbert’s disease)
-Aspartate transaminase (AST) and alanine transaminase (ALT)≤1.5 x ULN
9.Resolution of any toxic effects of prior therapy to Grade ≤1 according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 4.0 (exception of alopecia and ≤ Grade 2 peripheral neuropathy).
10.Females of child-bearing potential must have negative serum pregnancy test within 72 hours before randomization.
11.Women of child-bearing potential will practice a highly effective method of birth control during and for 3 months after the chemotherapy/custirsen last dose. Men of reproductive potential who are not surgically sterile must agree to abstain from sexual activity or use medically accepted and highly effective method of contaception during and for 6 months after chemotherapy/custirsen last dose.
12.Patients must be willing and able to give written informed consent prior to any protocol-specific procedures being performed and comply with the protocol requirements for the duration of the study
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E.4 | Principal exclusion criteria |
1.Patients treated with any systemic anti-cancer therapy for NSCLC within 21 days prior to randomization (6 weeks for bevacizumab).
2.Radiotherapy ≤ 2 weeks prior to randomization. Patients must have recovered from all radiotherapy-related toxicities.
3.Major surgical procedure within 4 weeks prior to randomization. Patient must have recovered from all surgery-related complications.
4.Patients with known central nervous system (CNS) metastases (Patients with any clinical signs of CNS metastases must have a CT or MRI of the brain to rule out CNS metastases in order to be eligible for participation in the study. Patients who have had brain metastases treated with radiotherapy or surgically removed with no residual disease confirmed by imaging should be clinically stable and off corticosteroid treatment at least 3 weeks prior to randomization).
5.Patients with current diagnosis or a history of another active primary malignancy (except in situ carcinoma of the cervix, adequately treated non-melanomatous skin cancers, clinically localized prostate cancer, superficial bladder cancer or other malignancy treated at least 5 years previously with no evidence of recurrence).
6.Severe or unstable medical conditions such as heart failure, ischemic heart disease, uncontrolled hypertension, uncontrolled diabetes mellitus, psychiatric condition, as well as an ongoing cardiac arrhythmia requiring medication (≥ Grade 2, according to NCI CTCAE v4.0) or any other significant or unstable concurrent medical illness that in the opinion of the Investigator would preclude protocol therapy.
7.A history of events such as myocardial infarction, cerebrovascular accident (CVA) or acute hepatitis within 3 months of randomization or treatment of a major active infection within one month of randomization, or any other significant event that in the opinion of the Investigator would preclude protocol therapy.
8.Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device. Concomitant participation in observational studies is acceptable.
9.Female patients who are breastfeeding.
10.Patients previously treated with docetaxel for NSCLC or with known severe hypersensitivity to taxane therapies. (Note: Prior use of paclitaxel is allowed).
11. Patients with known and documented EGFR mutation who have not received and EGFR inhibitor. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint and variable for the study is OS, defined as the time from date of randomization to the date of death from any cause. |
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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) |
-Progression Free Survival (PFS)
-Objective Response Rate (ORR)
-Duration of Objective Response
-Disease Control Rate (DCR)
-Duration of Disease Control
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-PFS, defined as the time from the date of randomization to the first objective documented progression per RECISTv1.1 or death due to any cause,whichever occurs first.
-OR is defined as achieving a best overall response of CR or PR,as defined using RECISTv1.1.
-Duration of OR is defined as time from first occurrence of CR or PR (whichever is first recorded) until date of the first documented disease progression or death, whichever occurs first.
-DC is defined as achieving a best overall response of CR, PR or SD.
-Duration of DC is defined as the time from randomization to the date of the first documented disease progression or death, whichever occurs first. |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
To compare the arms with respect to Quality of Life (QoL) parameters Functional Assessment of Cancer Therapy – Lung (FACT-L) and Euro Quality of Life – 5D (EQ-5D) |
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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 | No |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Docetaxel 75 mg/m2 IV on Day 1 of every 21-day cycle |
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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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
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 |
Germany |
Hungary |
Israel |
Italy |
Korea, Republic of |
New Zealand |
Poland |
Russian Federation |
Singapore |
Spain |
Taiwan |
Thailand |
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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2 formal interim analyses are planned for stopping the trial early based on inadequate evidence of clin. benefit or futility:see stop criteria pg11-protocol.If study continues final efficacy analysis is planned after 850death events.All pts who discont.study treatm. will be followed to collect further anticancer treatment and survival information until death,loss to follow-up,withdrawal of consent,or up to 12months after end of treatment visit for last patient on the study,whichever comes first. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |