| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Recurrent or Advanced Non-Small Cell Lung Cancer with Non-Squamous Histology |
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| E.1.1.1 | Medical condition in easily understood language |
Non-small Cell Lung Cancer (NSCLC)
|
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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 | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| 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 |
| The primary objective is to compare the Progression free survival (PFS) of CT-322 versus bevacizumab in combination with carboplatin and paclitaxel in chemonaive subjects with recurrent or advanced non-squamous NSCLC. |
|
| E.2.2 | Secondary objectives of the trial |
• To compare overall survival (OS) between the two treatment arms
• To compare the objective tumor response rate (ORR) between the two treatment arms
• To evaluate the safety in the CT-322 plus carboplatin and paclitaxel arm
Exploratory objectives:
• To estimate the duration of response and time to response in each of the two treatment arms
• To evaluate the pharmacokinetics of CT-322 and paclitaxel when administered in combination.
• To explore the relationship between change in tumor size at 6 weeks and Progression-Free Survival.
• An exploratory assessment of predictive and pharmacodynamic markers of CT-322 or bevacizumab administered in combination with carboplatin and paclitaxel will be performed by analyzing pre- and post-treatment specimens, including whole blood, serum or plasma and possibly tumor biopsies. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
PK sub-study:
Approximately 14 subjects in each arm will have additional blood samples collected to measure CT-322 plasma concentration as listed in Table 6.5.1.2 (in addition to the blood samples specified in table 6.5.1.1).
See protocol section 6.5.2 Paclitaxel Pharmacokinetic Sample Collection and Handling
For both sub-studies, a separate patient Informed Consent Form is to be signed.
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| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Target Population
a) Histologically or cytologically confirmed, stage IIIB (malignant pleural effusion), stage IV or recurrent NSCLC;
b) Measurable disease by RECIST guidelines, with at least 1 target lesion outside any previous radiotherapy field (also see Section 6.4.1);
c) ECOG performance status < 1 (see Appendix 2);
d) Life expectancy of at least 3 months;
e) Accessible for treatment and follow-up. Subjects enrolled in this trial must be treated at the participating center(s).
f) Willing to give a whole blood sample for the study of proteins and genetic polymorphisms in genes related to the VEGFR signaling pathway.
3) Age and Sex
a) Men and women, ages >18 years.
Men and women of childbearing potential (WOCBP) participating to this trial must be using an adequate method of contraception to avoid pregnancy throughout the study [and for up to 6 weeks after the last dose of investigational product] in such a manner that the risk of pregnancy is minimized (see Protocol Section 7.6). |
|
| E.4 | Principal exclusion criteria |
1) Sex and Reproductive Status
a) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period [and for up to 6 weeks after the last dose of investigational product]
b) Women who are pregnant or breastfeeding
c) Women with a positive pregnancy test on enrollment or prior to investigational product administration
d) Sexually active fertile men not using effective birth control if their partners are WOCBP.
2) Target Disease Exceptions
a) Evidence of predominantly squamous-cell histology
b) Symptomatic brain metastasis not stabilized with medical treatment (patients who have received radiotherapy for their brain metastasis prior to the systemic treatment for the NSCLC will be eligible)
3) Medical History and Concurrent Diseases
a) At the time of randomization less than 28 days elapsed following major surgery or radiotherapy (less than 7 days elapsed following minor surgery or focal/palliative RT)
b) Excessive risk of bleeding such as history of clinically significant bleeding diathesis or coagulopathy including platelet function disorder (eg, known hemophilia or von Willebrand disease) or acquired bleeding disorder within 12 months (eg, acquired anti-factor VIII antibodies)
c) Gross hemoptysis (≥ 1/2 teaspoon (or ≥2.5 ml) of red blood
d) Subjects receiving anticoagulation, however low doses of aspirin (≤ 325 mg) are permitted
e) Thrombotic or embolic cerebrovascular accident including transient ischemic attacks within the past 12 months
f) Uncontrolled hypertension (defined as systolic blood pressure >150 mmHg or diastolic > 90 mmHg, measured repeatedly at ≥2 visits despite adequate treatment with ≥ 2 antihypertensive drugs)
g) Clinically significant cardiovascular disease, including (but not limited to) the following:
i) Myocardial infarction within the past 6 months
ii) Unstable angina
iii) New York Heart Association class II-IV congestive heart failure (see Appendix 3)
iv) Serious cardiac arrhythmia (eg ventricular arrhythmia, high-grade atrioventricular block), not controlled by medication or requiring medication which might interfere with regularity of study treatment
v) Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) as measured by 2-dimensional echocardiogram (ECHO) or cardiac MUGA scan (MUGA)
h) History of visceral fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
i) Serious non-healing wound, active peptic ulcer, non-healing bone fracture, or bleeding skin metastases
j) Known glomerulonephritis or other protein-wasting glomerulopathy
k) Active clinically significant infection(> Grade 2) requiring the use of antimicrobial agents, or that would otherwise, in the opinion of the investigator, interfere with the ability the subject to participate
l) Any concurrent malignancy other than non-melanoma skin cancer, or carcinoma/dysplasia in-situ of the cervix or bladder. Subjects with a history of previous malignancies but without evidence of disease for 4 years and for which no additional therapy is required or anticipated will be allowed to enter the trial.
m) Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent
n) Any serious uncontrolled medical disorder that, in the opinion of the investigator, would impair the ability of the subject to receive study therapy.
o) Known HIV positive.
4) Physical and Laboratory Test Findings
a) Hematology:
i) Hemoglobin <9.0 g/dL, Absolute Neutrophil Count <1500 cells/mm³,
Platelets <100,000 cells/mm³
b) Chemistry:
i) Serum creatinine >1.5 mg/dL
ii) Calculated creatinine clearance (CrCl) <50 mL/min (using Cockcroft and Gault formula - see Appendix 4)
iii) urine protein/creatinine ratio (UPCR) > 1
iv) Serum total bilirubin >1.5 times the institutional upper limit of normal (ULN), unless due to Gilbert’s disease
v) ALT or AST >2.5 times the institutional ULN (>5 times ULN for subjects with documented liver metastases)
vi) Serum amylase or lipase >1.5 times the ULN (at least one of these tests must be performed)
5) Allergies and Adverse Drug Reactions
a) Known hypersensitivity to any of the investigational products or excipients, including Cremophor EL®
6) Prohibited Treatments and/or Therapies
a) Any prior antineoplastic systemic therapy for Stage IIIb/IV or recurrent NSCLC. Subjects must not initiate any concurrent antineoplastic therapy while on study.
7) Other Exclusion Criteria
a) Prisoners or subjects who are involuntarily incarcerated
b) Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival based on tumor assessments (CT scans/MRI) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time Frame: every 6 weeks until documented progressive disease , death or initiation of subsequent therapy for NSCLC
|
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| E.5.2 | Secondary end point(s) |
Overall survival (OS) between 2 arms [ Time Frame: every 12 weeks ]
Objective tumor response rate (ORR) between 2 arms [ Time Frame: every 6 weeks ]
Safety in the CT-322 plus carboplatin and paclitaxel arm [ Time Frame: weekly ] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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 |
| Immunogenicity testing, change in tumor size analysis |
|
| 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 11 |
| 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 |
| Brazil |
| France |
| Italy |
| Russian Federation |
| South Africa |
| United Kingdom |
| 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
|
| The study will end when all subjects are off treatment. |
|
| 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 | 2 |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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