What is ASA404?
ASA404, a flavone-8-acetic acid analogue, is a novel Tumor-Vascular Disrupting Agent (Tumor-VDA) that acts on established tumor vasculature. By inducing apoptosis of tumor vascular endothelial cells and cytokine production, ASA404 causes disruption of tumor blood vessels, inhibition of tumor blood flow and extensive tumor necrosis.
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What is the rationale for using ASA404 in combination with docetaxel for lung cancer treatment?
ASA404 plus docetaxel has the potential to improve the secondline treatment of patients with advanced non-small cell lung cancer (NSCLC). Docetaxel alone has been demonstrated to increase overall survival in patients with advanced NSCLC following first-line platinum-based therapy and is approved worldwide for this indication. The antitumor effect of ASA404 has been shown to increase synergistically when combined with taxanes. It is thought that synergistic tumor cell killing occurs as ASA404 acts on poorly perfused regions of the tumor that are inaccessible to other chemotherapeutic agents. This and the lack of overlapping toxicities with ASA404 and docetaxel make a compelling case for combination cancer treatment.
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What is the rationale for testing ASA404 treatment in patients with NSCLC?
Although several novel drugs have been introduced recently, there is still an unmet need for a more effective second-line treatment for NSCLC. ASA404 has a unique mode of action and has shown synergistic activity in combination with taxanes. In a phase lb/ll trial of ASA404 for the first-line treatment of patients with stage IIIb or stage IV NSCLC, presented at the 2006 EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, the addition of ASA404 to paclitaxel and carboplatin increased median survival by 5.2 months.
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What is the primary objective of the ATTRACT-2 clinical trial?
The primary objective of the ATTRACT-2 clinical trial is to compare the overall survival of patients receiving ASA404 or placebo in combination with docetaxel for second-line treatment of stage IIIb/IV NSCLC.
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What are the secondary objectives of ATTRACT-2?
The secondary objectives of the ATTRACT-2 clinical trial are to compare Progression-Free Survival (PFS) and the Overall Response Rate (ORR) between patients receiving ASA404 or placebo in combination with docetaxel.
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Are there other objectives of this study?
ATTRACT-2 has a number of other objectives including:
- To determine time to response (Complete Response [CR] or Partial Response [PR] for responders only) and duration of response (CR or PR for responders only) between NSCLC patients receiving ASA404 or placebo in combination with docetaxel.
- To assess the safety of ASA404 in combination with docetaxel.
- To determine population pharmacokinetics and factors influencing systemic exposure to ASA404.
- To assess the quality of life of lung cancer patients receiving ASA404 or placebo in combination with docetaxel.
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Who is eligible for the ATTRACT-2 clinical trial?
Adult patients, 18 years of age or older, with locally advanced or metastatic (stage IIIb/IV) NSCLC who have progressed while on or following first-line systemic chemotherapy are eligible.
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What is the time commitment for patients participating in ATTRACT-2?
A treatment cycle is 21 days. Study treatment with docetaxel will be administered for a maximum of six cycles. Once these six cycles have been completed, patients may continue to receive ASA404 or placebo as maintenance treatment for NSCLC until disease progression, unacceptable toxicity, or withdrawal of consent. Patients will be followed every six weeks (two cycles) for survival following treatment completion, discontinuation or documented disease progression until either death or the data cutoff date.
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What happens if a patient discontinues the study or withdraws consent?
Patients who discontinue the study treatment for reasons other than documented disease progression will continue to have tumor assessments performed every six weeks until documented disease progression or the start of a new chemotherapy. Patients who withdraw consent and do not wish to have radiological assessments will be followed for survival every six weeks.
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Can study participants receive supportive therapies during the study?
Therapies considered as supportive care, including granulocyte colony stimulating factor, palliative radiation and bisphosphonates for bone metastasis are acceptable for patients participating in this study.
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Are there any therapies that should not be administered concomitantly while patients are participating in this study?
The use of drugs that pose a potential risk of prolonging the QT interval and/or inducing Torsades de Pointes ventricular arrhythmia should be avoided throughout this study. If the use of these medications is deemed medically necessary by the investigator, study treatment should be discontinued and the patient followed radiologically every six weeks for RECIST until documented disease progression and then for overall survival. However, the investigator is encouraged to contact the Novartis medical monitor and discuss all treatment options for patients prior to discontinuation of study treatment.
As ASA404 is known to cause an increase of serotonin levels in the blood, the investigator must exercise caution and refrain from administering any other drugs that are known or suspected to raise serotonin levels, particularly antidepressants, due to the risk of “serotonin syndrome.” In addition, the investigator must exercise caution and refrain from administering nitrates and alpha blockers as they may cause symptomatic hypotension due to known phosphodiesterase pharmacological activity of ASA404.
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How is the cancer treatment administered?
All patients will receive a one-hour IV infusion of 75 mg/m2 of docetaxel followed by a 20-minute IV infusion of ASA404 1800 mg/m2 or placebo on day one of every cycle.
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What side effects might patients experience as a result of the treatment?
Information about side effects seen with study treatment can be found in the informed consent document.
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In case of adverse events, are dose reductions or treatment delays allowed?
ASA404 must be administered on the same day as docetaxel. If a cycle delay is recommended for one therapy (either docetaxel or study drug), the remaining therapy must also be delayed until the toxicity resolves or returns to its baseline value.
Any dose reduction or dose delay of the study drug is based upon the severity of toxicity, as graded by National Cancer Institute Clinical Toxicity Criteria (NCI-CTCAE, version 3.0). Once a dose has been reduced during a treatment cycle, re-escalation will not be permitted during any subsequent cycles.
Patients requiring >1 dose reduction or a delay in study treatment >3 weeks will be discontinued from study treatment. If study treatment is stopped due to toxicity attributed specifically to docetaxel, the patient may continue to receive ASA404 as maintenance treatment.
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How will efficacy of the cancer treatment regimens be evaluated?
The primary efficacy endpoint, OS (Overall Survival), will be calculated based on the date of randomization and the date of death or last date of contact. PFS, ORR, time to response and duration of response will be documented per RECIST guidelines.
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Is there a cost to my patients to participate in ATTRACT-2?
No. All procedures that are required as part of the study and that are not standard of care will be covered.
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Where is the ATTRACT-2 clinical trial being conducted?
This trial is being conducted at a large number of sites throughout the United States and worldwide. For a list of participating countries, please visit www.attractstudy.com or call 1-800-340-6843.*
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How many patients will be treated in ATTRACT-2?
The planned accrual for ATTRACT-2 is 900 NSCLC patients.
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How can I enroll patients in ATTRACT-2?
For further information or to enroll patients in this clinical study, please visit www.attractstudy.com or call 1-800-340-6843.*
* For countries outside the United States, please contact your local Novartis representative for more information.
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