| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV Non-Small Cell Lung Cancer (NSCLC; including patients with pleural effusion who were previously classified as Stage IIIB) |
| IV stádiumú , nem kissejtes tüdőrákos (NSCLC) betegek, (beleértve azokat az előzőleg IIIB stádiumba sorolt betegeket is, akiknél pleurális folyadékgyülem van). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Stage IV Non-Small Cell Lung Cancer |
| IV stádiumú , nem kissejtes tüdőrákos betegek. |
|
| 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) |
|
| 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 |
In Part 1, the primary objective is to examine the safety and tolerability of ISIS 183750 in combination with carboplatin and paclitaxel and to determine the ISIS 183750 dose for evaluation in Part 2.
In Part 2, the primary objective is to estimate the overall survival of patients with Stage IV NSCLC treated with ISIS 183750 in combination with carboplatin and paclitaxel. |
|
| E.2.2 | Secondary objectives of the trial |
In Part 1,
To characterize the plasma and urine PK parameters
To explore anticancer effects of ISIS 183750 in combination with carboplatin and paclitaxel
In Part 2,
To determine the percent changes of tumor size from baseline to the end of the 2nd treatment cycle and from
baseline to the end of the 4th treatment cycle
To determine the objective tumor response rate (RECIST 1.1)
To explore the time-to-event efficacy measures
To determine the 7-day plasma trough levels of ISIS 183750
To determine the safety and tolerability of ISIS 183750 in combination with carboplatin and paclitaxel. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients with Stage IV NSCLC are eligible to be included in the study only if they meet all of the following
criteria:
1. Provide written informed consent prior to screening.
2. Male or female patients, age ≥ 18 years.
3. Histologically or cytologically confirmed diagnosis of NSCLC.
4. Stage IV disease (including patients with pleural effusion who were previously classified as Stage IIIB).
5. All of the following if patient has had prior radiation therapy:
a. Lesion(s) used for determination of response were not previously irradiated or have increased in size since the
completion of radiotherapy
b. The patient has recovered from any acute effects of the radiotherapy
c. Radiotherapy was completed at least 4 weeks prior to Screening.
6. Part 1: Have at least non-measurable evaluable disease (e.g., lesions which are smaller than the minimum size
required for measurability; other non-measurable lesions such as bone metastases, malignant pleural effusion)
Part 2: Have measurable disease, defined as at least 1 lesion that can be accurately measured in at least 1
dimension (longest diameter to be recorded) as ≥ 10 mm on cross-sectional imaging (where the CT slice
thickness is no greater than 5 mm) or at least 20 mm by standard techniques; positron emissions tomography
[PET] and ultrasound are not permitted methods for tumor measurements under this protocol. Consult RECIST
1.1 guidance for additional information (Appendix 5 and Eisenhauer et al., 2009)
7. Performance status of 0 or 1 on the ECOG Performance Status Scale.
8. Have an estimated life expectancy of at least 12 weeks.
9. Adequate organ function within 14 days prior to first study dose (ISIS 183750 or carboplatin/paclitaxel,
whichever occurs first) including the following:
a. Absolute neutrophil count (ANC)≥ 1.5 x 109/L
b. Platelet count ≥100 x 109/L
c. Hemoglobin ≥9 g/dL (≥5.6 mmol/L). Patients may receive packed RBC transfusion to achieve this level at the discretion of the investigator.
d. Total bilirubin < 1.5 x upper limit of normal (ULN) unless elevated secondary to conditions such as Gilbert’s
Disease
e. Aspartate aminotransferase (AST) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases)
f. Alanine aminotransferase (ALT) < 3 x ULN (< 5 x ULN in the presence of hepatic metastases)
g. Alkaline phosphatase < 3.0 x ULN
h. Calculated creatinine clearance ≥ 60 mL/min per Cockcroft and Gault formula (see Appendix 7)
i.Serum albumin ≥3.0 g/dL
10. Satisfy one of the following:
a. Females: non-pregnant and non-lactating; surgically sterile, post-menopausal, or patient or partner compliant
with a reliable contraceptive regimen, as determined by Investigator, for 4 weeks prior to Screening. Patients of
reproductive potential must test negative for pregnancy at Screen and must agree to use a reliable method of birth control during the study and for the 10 weeks following the last dose of ISIS 183750.
b. Males: surgically sterile or patient or partner must agree to use a reliable contraceptive method, as determined by the Investigator during the study and for the 10 weeks following the last dose of ISIS 183750.
11. The patient is willing and able to comply with the study visit schedule and procedures, and has geographical proximity (Investigator’s discretion) that allows follow-up specified by the protocol.
12. For Part 1: have discontinued all prior chemotherapies, biological therapies, and other investigational
therapies for cancer for at least 4 weeks (6 weeks for mitomycin-C or nitrosoureas) prior to study treatment and
recovered from the acute effects of therapy. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
1. Part 1: More than 2 prior chemotherapy or biological therapy regimens (approved or experimental) for
NSCLC, not counting adjuvant and neoadjuvant treatment. A regimen is defined as two or more consecutive
cycles of treatment.
Part 2: Any prior chemotherapy or biological therapy (approved or experimental) for NSCLC including adjuvant
and neoadjuvant treatments
2. Treatment with another investigational drug, biological agent, or device within 4 weeks (6 weeks for biological
agents) before Screening or 5 half-lives of study agent, whichever is longer
3. Patients with treated or untreated parenchymal brain metastases or leptomeningeal disease. Brain imaging is
required for symptomatic patients to rule out brain metastases, but is not required in asymptomatic patients.
4. Patients with known pericardial effusion
5. Have active infection or serious concomitant systemic disorder (for example, heart failure) incompatible with
the study (at the discretion of the Investigator)
6. Presence or history of malignancy other than NSCLC, carcinoma in situ of the cervix, or non-melanoma skin
cancer. In the case of other malignancies, patients may be considered for participation if the prior malignancies
were diagnosed and definitively treated at least five years previously with no subsequent evidence of recurrence.
7. Presence of an underlying disease state associated with active bleeding
8. Ongoing therapy with oral or parenteral anticoagulants (e.g., heparin, warfarin/coumadin). Low-dose
anticoagulants for maintenance of catheter patency and low dose aspirin (≤ 325 mg/day) and nonsteroidal
antiinflammatory
agents are not exclusionary.
9. Concurrent treatment with other anticancer drugs
10. Pre-existing peripheral neuropathy Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE)
Grade 2
10. Known history of HIV, HCV, or chronic HBV infection
11. Previous treatment with a therapeutic antisense oligonucleotide or siRNA
12. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device
13. Have any other medical conditions that in the opinion of the Investigator, would make the patient unsuitable for enrollment, or could interfere with the patient participating in or completing the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The time-to-event endpoints (overall survival, progression free survival, time to tumor progression, time to and duration of objective tumor response) will be estimated using Kaplan-Meier method. |
|
| E.5.2 | Secondary end point(s) |
•Progression-free survival
•Percent survival at 1-year
•Time to objective tumor progression
•Duration of objective tumor response for responding patients (measured from the time measurement criteria are first met for CR/PR until the first date that recurrent or progressive disease is objectively documented)
•Time to objective tumor response
•Percent objective tumor response (i.e., partial + complete response + stable disease) as best response
•Percent changes of tumor size from baseline to the end of the 2nd and from baseline to the end of the 4th treatment cycle
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The time-to-event endpoints (overall survival, progression free survival, time to tumor progression, time to and duration of objective tumor response) will be estimated using Kaplan-Meier method. Objective tumor response rate will be analyzed using chi-square tests or the Fisher’s |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | 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 |
| Part2: carboplatin and paclitaxel compared to carboplatin and paclitaxel plus ISIS 183750 |
|
| 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 | 10 |
| 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 |
| Russian Federation |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 18 |
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