ASA404 or Placebo in Combination With Paclitaxel and Carboplatin as First-Line Treatment for Stage IIIb/IV Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine if adding ASA404 to standard chemotherapy makes the cancer treatment more effective in patients with advanced lung cancer.

Official Title
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A Phase III, Randomized, Double-Blind, Placebo-Controlled Multi-Center Study of ASA404 in Combination With Paclitaxel and Carboplatin as First-Line Treatment for Locally Advanced or Metastatic (Stage IIIb/IV) Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: ASA404
* Drug: Placebo
* Drug: carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed non-small cell carcinoma of the lung. (Histological or cytological specimens must be collected via surgical biopsy, brushing, washing or core needle aspiration of a defined lesion. Sputum cytology is not acceptable.) Newly diagnosed Stage IIIb disease (malignant pleural effusion or pericardial effusion that have been confirmed cytologically) or Stage IV disease No prior systemic antineoplastic treatment for Stage IIIb/IV non-small cell carcinoma of the lung (Prior neoadjuvant or adjuvant chemotherapy for earlier stage I/II NSCLC is allowed if 12 months or more prior to Baseline visit.) Age ≥ 18 years old WHO Performance Status of 0-1 Measurable or non-measurable disease per RECIST criteria (Post-text supplement 1) Lab values within the range, as defined below, within 2 weeks of randomization: Absolute neutrophils count (ANC) > 2.0 x 109/L Platelets ≥ 100 x109/L Hemoglobin ≥ 10 g/dL Serum creatinine ≤ 1.5 x ULN (≤ 120 micro mol/L) Serum bilirubin ≤ 1.5 x ULN (≤ 25 micro mol/L) Aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases) International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 x IULN (Sections 6.9.1 and 7.3.4.2) Electrolyte values (potassium, calcium, magnesium) within > 1 x LLN and < 1 x ULN. Patients with corrected electrolyte values are eligible. See Sections 6.8.1 and 7.3.4.3. Females of child-bearing potential must have negative serum pregnancy test (confirmation of negative urine pregnancy test within 72 hours prior to initial dosing). Life expectancy ≥ 12 weeks Written informed consent obtained according to local guidelines Exclusion Criteria: Patients having CNS metastases (Patients having any clinical signs of CNS metastases must have a CT or MRI of the brain performed to rule out CNS metastases in order to be eligible for study participation. Patients who have had brain metastases surgically removed or irradiated with no residual disease confirmed by imaging are allowed.). Patients with a history of another primary malignancy ≤ 5 years, with the exception of non-melanoma skin cancer or cervical cancer in situ. Radiotherapy ≤ 2 weeks prior to randomization. Patients must have recovered from all radiotherapy-related toxicities. Major surgery ≤ 4 weeks prior to randomization or minor surgery ≤ 2 weeks prior to randomization.(Major surgery is defined by the use of general anesthesia however, endoscopic examinations with diagnostic intent are not considered major surgery. Insertion of a vascular access device is exempt from this exclusion criteria. Patients must have recovered from all surgery-related complications. Concurrent use of other investigational agents and patients who have received investigational agents ≤ 4 weeks prior to randomization Prior exposure to Tumor-VDAs or other vascular targeting agents (anti-VEGF, anti-VEGF receptor agents, anti-EGFR agents [bevacizumab, cetuximab, etc.]) Pleural effusion that causes ≥ CTC grade 2 dyspnea Patients with systolic BP > 160 mm Hg and/or diastolic BP >90 mm Hg Patients with recent hemoptysis associated with NSCLC (> 1 teaspoon in a single episode within 4 weeks) Patients with any one of the following: Patients with long QT syndrome Patients with a Baseline 12-lead ECG QTc of > 450 msec per central evaluation Congestive heart failure (NY Heart Association class III or IV) Patients with a myocardial infarction within 12 months of study entry Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris History of labile hypertension or poor compliance with anti-hypertensive regimen History of a sustained ventricular tachycardia Any history of ventricular fibrillation or Torsades de Pointes Right bundle branch block and left anterior hemiblock (bifasicular block) Bradycardia defined as heart rate < 50 beats per minute Concomitant use of drugs with a risk of causing Torsades de Pointes (See Table 6-3) Known allergy or hypersensitivity to platinum-containing drugs, taxanes, other drugs formulated in Cremophor EL (polyoxyethylated castor oil) or any known excipients of these drugs. Peripheral sensory neuropathy with functional impairment (CTC grade 2 neuropathy, regardless of causality) Pregnant or breast feeding females • Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml) Women of child bearing potential or sexually active males, unwilling or unable to use the required highly effective method(s) of contraception for both sexes while receiving treatment and for at least 6 months after the discontinuation of study treatment. (Adequate forms of contraception include IUD, oral or depot contraceptive or the barrier method plus spermicide.) • Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions while taking paclitaxel and therefore are not considered effective contraceptive methods for this study when used as a single agent. Therefore, it is highly recommended that a concomitant barrier method be used with oral, implantable, or injectable contraceptives. The investigator shall counsel the patient accordingly. Women of childbearing potential must have a negative pregnancy test (serum or urine) 72 hours prior to administration of study treatment. For a list of substrates of human liver microsomal P450 enzymes, visit website (http://medicine.iupui.edu/flockhart/) Concurrent severe and/or uncontrolled medical disease (i.e. uncontrolled diabetes, chronic renal disease, chronic liver disease, confirmed diagnosis of HIV infection or active uncontrolled infection). Significant neurologic or psychiatric disorder which could compromise participation in the study Patient unwilling or unable to comply with the protocol Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASA404<br> | Drug: ASA404<br> <br> Drug: carboplatin<br> <br> Drug: Paclitaxel<br> <br> |
| Placebo Comparator: ASA40 Placebo<br> | Drug: Placebo<br> <br> Drug: carboplatin<br> <br> Drug: Paclitaxel<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate |  | Patients will be followed every six weeks for survival following treatment completion, discontinuation, or documented disease progression until either death or the data cut off date. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival of patients with squamous and non-squamous NSCLC |  | Patients will be followed every six weeks for survival following treatment completion, discontinuation, or documented disease progression until either death or the data cut off date. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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VDA, Tumor vascular disrupting agent, ASA404, non-small cell lung cancer, NSCLC