| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced squamous 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.1.3 | 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 estimate the clinical benefit of Gemcitabine and Carboplatin in combination with Apatorsen (OGX-427) compared to Gemcitabine and Carboplatin chemotherapy alone in patients previously untreated advanced squamous cell lung cancer |
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| E.2.2 | Secondary objectives of the trial |
1. Assess the clinical activity, by response rate (RECIST 1.1), clinical benefit rate, and duration of response of gemcitabine/carboplatin + Apatorsen compared to gemcitabine/carboplatin alone
2. Establish the safety and tolerability of gemcitabine/carboplatin + Apatorsen compared to gemcitabine/carboplatin alone
3. Evaluate drug exposure of gemcitabine/carboplatin + Apatorsen
4. Estimate the overall survival benefit of gemcitabine/carboplatin + Apatorsen compared to gemcitabine/carboplatin alone
5. Compare the differences in health-related quality of life (HRQL) and symptoms for patients by treatment assignment
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1 Written informed consent prior to admission to this study
2 Histologically confirmed squamous cell lung cancer; patients with adenosquamous or mixed histology are not eligible for this study
3 Stage IIIB disease that is unsuitable to radio-chemotherapy or Stage IV disease or recurrent NSCLC; recurrent disease must not be amenable to resection or radical radiotherapy with curative intent.
4 Patients must have:
• at least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements
OR
•lytic or mixed (lytic + sclerotic) bone lesions in the absence of measurable disease as defined above; NOTE: patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible
5. Willing to donate archival diagnostic tissue for translational research, if available.
6. Haematologic and biochemical indices within the ranges shown below. These measurements must be performed within one week prior to randomisation
• ANC ≥1.5 x 109/L;, platelet count ≥100 x 109/L,
• Serum creatinine < 1.5 times the upper limit of normal (ULN)
• Bilirubin level < 1.5 X ULN
• AST or ALT <3.0 X ULN or <5 X ULN in the presence of liver metastases
7. ECOG performance status 0-2
8. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who has had a hysterectomy, bilateral oophorectomy, bilateral tubular ligation or is post-menopausal (total cessation of menses for ≥ 1 year; if the patient is of childbearing potential, she must have a negative serum pregnancy test within 2 weeks prior to the first dose of study treatment, preferably as close to the first dose as possible, and agrees to use adequate contraception (for example, intrauterine device [IUD], birth control pills unless clinically contraindicated, or barrier device) beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product.Male patients must be surgically sterile or agree to use adequate contraception
9.Male or Female aged ≥18 years
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| E.4 | Principal exclusion criteria |
Patients meeting any of the following exclusion criteria are not to be enrolled in the study.
1. Symptomatic CNS involvement or CNS involvement requiring steroid therapy; patients with treated brain metastases that are asymptomatic and have been clinically stable for 1 month will be eligible for protocol participation
2. Previous systemic treatment for lung cancer (exception for patients with recurrent disease: adjuvant chemotherapy is allowed as long as this was finished at least 1 year prior to enrolment and did not contain gemcitabine)
3. Known tumour EGFR mutation, unless contraindication to EGFR-directed therapy
4. Known tumour ALK rearrangements, unless contraindication to Alk-directed therapy or Alk-directed therapy not available 1
5. Pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to NCI CTCAE
6. Significant cardiovascular disease, such as
•History of myocardial infarction, acute coronary syndromes (including unstable angina), or history of coronary angioplasty/stenting/bypass grafting within past 6 months.
• History of symptomatic congestive heart failure (CHF) New York Heart Association (NYHA) Classes III-IV or LVEF <50% by either ECHO or MUGA within past 6 months.
• Severe cardiac arrhythmia requiring medication or severe conduction abnormalities
• Poorly controlled hypertension (resting diastolic blood pressure >115 mmHg)
• Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy
7. Active second malignancy (except non-melanomatous skin cancer): active secondary malignancy is defined as a current need for cancer therapy or a high possibility (>30%) of recurrence during the study.
8. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry.
9. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that, in the investigator’s opinion, gives reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, may affect the interpretation of the results, render the patient at high risk from treatment complications or interferes with obtaining informed consent.
10. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
11.Pregnant or nursing women
12.Male or Female aged <18 years |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
The Primary outcome measure for the study is progression free survival (PFS).
PFS is defined as the time from randomisation to disease progression or relapse (as assessed by the site radiologist and/or investigator, using RECIST, Version 1.1) or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first. For patients who have not died or experienced disease progression at the end of study, PFS will be censored on the last date the patient was known to be progression free. |
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| E.5.2 | Secondary end point(s) |
secondary Efficacy Endpoints:
Objective response:
RECIST 1.1 criteria will be used to assess response. Objective response will be calculated in patients with measurable disease at baseline. Patients without measurable disease at baseline will not be included in this analysis. Patients without a post-baseline tumour assessment will be considered to be non-responders. An estimate of the objective response rate and 95% CIs (Blyth–Still–Casella) will be calculated for each treatment arm. CIs for the difference in tumour response rate will be calculated. The relative risk (treatment: control) will be reported along with the associated 95% confidence interval. Statistical inference will be evaluated using Chi-square statistic; the Fisher’s exact test may be used if the expected counts in some cells are small.
Change in tumour size at 12 weeks:
Change in tumour size at 12 weeks is based on RECIST measurements taken at baseline and at week 12. Tumour size is the sum of the diameters of the target lesions (TL) that have been selected at baseline. Baseline for RECIST is defined to be the last evaluable assessment prior to starting treatment. The change in tumour size will be assessed using the log (ratio) of the week 12 tumour size over the baseline tumour size for each patient
Clinical Benefit rate:
Clinical Benefit rate is defined as number of patients with complete or partial response or stable disease maintained ≥24 weeks (as assessed by the site radiologist and/or investigator, using RECIST1.1) divided by the number of patients in the analysis. Patients without a post-baseline tumour assessment will be considered to have no clinical benefit
Duration of Objective Response or Clinical Benefit:
For patients with an objective response, duration of objective response is defined as the time from initial complete or partial response to disease progression or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first.
For patients with a clinical benefit (objective response or stable disease maintained ≥24 weeks), duration of clinical benefit is defined as the time from randomisation to disease progression or death on study from any cause (defined as death within 30 days of the last study treatment), whichever occurs first
Overall Survival:
Overall survival is defined as the time from randomisation to death from any cause.
Proportion of patients without progressive disease at 12 and 24 weeks:
The proportion of patients without progressive disease at 12 and 24 weeks, respectively, is defined as the percentage of patients with a 12 or 24 week visit response of CR, PR or SD (as defined by RECIST 1.1) with no evidence of previous progression
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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 | 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 | 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 | 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 | 22 |
| 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 | No |
| 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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| For the purposes of Clinical Trial Authorisation (CTA) under the European Union Directive 2001/20/EC, the study is deemed to have ended 30 days after the last patient receives the last dose of the investigational medicinal product (IMP). For all other purposes, the study end date is deemed to be the date of last data capture. More specifically, end of recruitment is deemed to be when 111 patients have progressed and/or have died. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 2 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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