A Multinational, Randomized, Open-Label Study of Custirsen In Patients With Advanced or Metastatic (Stage IV) Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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The primary objective of the study is to compare overall survival of patients randomized to receiving custirsen in combination with docetaxel (Arm A) with patients randomized to receive docetaxel alone (Arm B).

Official Title
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A Multinational, Randomized, Open-Label Phase III Study of Custirsen (TV-1011/OGX-011) In Combination With Docetaxel Versus Docetaxel As A Second-Line Treatment In Patients With Advanced or Metastatic (Stage IV) Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Custirsen
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histologically or cytologically confirmed, unresectable, advanced or metastatic (Stage IV per AJCC 7th edition TNM staging) NSCLC Males or females ≥ 18 years of age at screening. Life expectancy of > 12 weeks from screening, according to the investigator's assessment. Patients must have received one prior line of platinum-based systemic anticancer therapy for advanced or metastatic 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. Patients must have documented radiological disease progression either during or after the first-line therapy. Patients must have at least one measurable lesion per RECIST 1.1 criteria. ECOG performance status of 0 or 1 at screening. Have adequate values, 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) AST and ALT ≤ 1.5 x ULN Resolution of any toxic effects of prior therapy to Grade ≤1 according to NCI CTCAE, version 4.0 (exception of alopecia and ≤ Grade 2 peripheral neuropathy). Females of child-bearing potential must have negative serum pregnancy test within 72 hours before randomization. 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 contraception during and for 6 months after the chemotherapy/custirsen last dose. 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. Exclusion Criteria: Patients treated with any systemic anti-cancer therapy for NSCLC within 21 days prior to randomization (6 weeks for Bevacizumab). Radiotherapy ≤ 2 weeks prior to randomization. Patients must have recovered from all radiotherapy-related toxicities. Major surgical procedure within 4 weeks prior to randomization. Patient must have recovered from all surgery-related complications. Patients with known 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; patients should be clinically stable and off corticosteroid treatment at least 3 weeks prior to randomization). 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). 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. A history of events such as myocardial infarction, cerebrovascular accident 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. Planned concomitant participation in another clinical trial of an experimental agent, vaccine, or device. Concomitant participation in observational studies is acceptable. Female patients who are breastfeeding. Patients previously treated with docetaxel for NSCLC or with known severe hypersensitivity to taxane therapies. Patients with known and documented EGFR mutation who have not received an EGFR inhibitor.

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Custirsen + Docetaxel<br>Custirsen: Three loading doses of custirsen 640mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle Docetaxel: 75 mg/m2 IV over 1 hour on Day 1 of every 21-day cycle | Drug: Custirsen<br>* Custirsen: Three loading doses of custirsen 640 mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle<br>* Other names: TV-1011;Drug: Docetaxel<br>* Docetaxel: 75 mg/m2 IV over 1 hour on Day 1 of every 21-day cycle<br>|
| Active Comparator: Docetaxel<br>Docetaxel: 75 mg/m2 IV over 1 hour on Day 1 of every 21-day cycle Continue treatment until disease progression, unacceptable toxicity, withdrawal of consent or protocol specified parameters to stop treatment. | Drug: Docetaxel<br>* Docetaxel: 75 mg/m2 IV over 1 hour on Day 1 of every 21-day cycle<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Primary endpoint and variable for the study is overall survival (OS), defined as the time from date of randomization to the date of death from any cause. | 60 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival per RECIST v1.1 | Progression Free Survival: time from date of randomization to first objective documented progression per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurs first. Tumor lesions measured in at least one dimension with minimum size of 10 mm by CT scan, 10 mm caliper by clinical exam. Malignant lymph nodes must be >15 mm in short axis when assessed by CT scan. All measurable lesions up to a maximum of 2 lesions per organ and 5 in total representative of all involved organs should be identified as target lesions and measured and recorded. | 60 months | 
| Objective Response Rate as defined by RECIST v1.1. | Objective Response (OR) is defined as achieving a best overall response of complete response (CR) or partial response (PR), as defined using RECIST v1.1. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | 60 months | 
| Duration of Disease Control | The Duration of Disease Control is defined as the time from randomization to the date of the first documented disease progression (taking as reference for progressive disease the smallest measurements recorded on study) or death, whichever occurs first. | 60 months | 
| Adverse events | Adverse events and concomitant medications will be collected throughout the study up to 28 days after the last dose of study treatment. Medical history will be assessed, mutation status will be collected, if available, and an electrocardiogram will be performed at screening. Physical examination, vital signs, and laboratory evaluations will be conducted at screening and throughout the study. | 60 months | 
| Duration of Objective Response | The evaluation of overall response at each assessment is a composite of target lesion response, non-target lesion response, presence of new lesions. | 60 months | 
| Disease Control Rate | The disease control rate will be calculated as the total number of patients in each group with best overall response of CR, PR or Stable Disease (SD) divided by the total number of randomized patients in the group and will be compared similarly as Objective Response Rate (ORR.) | 60 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metastatic, Stage IV, Advanced, lung cancer