Cisplatin + Etoposide +/- Concurrent ZD6474 in Previously Untreated Extensive Stage Small Cell Lung Cancer

Study Overview
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Brief Summary
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At this point in the treatment of extensive stage SCLC, we have reached a plateau in survival with conventional chemotherapy and newer regimens are greatly needed. It has been noted that patients with increased VEGF levels have a poorer prognosis. Anti-angiogenic agents hold significant promise in the treatment of patients with extensive stage SCLC. ZD6474, a new inhibitor of the VEGFR-2, has shown favorable action in NSCLC.

Detailed Description
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OUTLINE: This is a multi-center study. Arm A: Cisplatin 60mg/m2 Day 1 + Etoposide 120mg/m2 Day 1,2,3 + Placebo oral daily given continuously for the duration of the study Arm B: Cisplatin 60mg/m2 Day 1 + Etoposide 120mg/m2 Day 1,2,3 + ZD6474 100mg oral daily given continuously for the duration of the study For both arms, PE and toxicity evaluation prior to each cycle and disease assessment by imaging every 2 cycles. Patients with non-PD and acceptable toxicity will continue protocol therapy; patients with progressive disease or excessive toxicity will be taken off treatment. Cycles will be repeated every 21 days up to a total of 4 cycles. ECOG Performance Status of 0 or 1 Life Expectancy: Not specified Hematopoietic: Platelets > 100K/mm3 Absolute neutrophil count (ANC) > 1.5K/mm3 Hepatic: Bilirubin < 1.5 x ULN Aspartate aminotransferase (AST) < 2.5 x ULN or < 5 x ULN if judged by the investigator to be related to liver metastases Alkaline phosphatase < 2.5 x ULN or < 5 x ULN if judged by the investigator to be related to liver metastases Renal: Serum creatinine < 1.5 x ULN or Calculated creatinine clearance of > 45 cc/min using the Cockcroft-Gault formula Cardiovascular: No clinically significant cardiac event such as myocardial infarction; New York Heart Association (NYHA) classification of heart disease >2 (see SPM) within 3 months prior to registration for protocol therapy No presence of cardiac disease that, in the opinion of the Investigator, increases the risk of ventricular arrhythmia. No history of arrhythmia (multifocal premature ventricular contractions (PVCs), bigeminy, trigeminy, ventricular tachycardia, or uncontrolled atrial fibrillation) which is symptomatic or requires treatment (CTCAE grade 3) or asymptomatic sustained ventricular tachycardia. Atrial fibrillation, controlled on medication is permitted.

Official Title
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A Randomized Double Blind Phase II Trial of Cisplatin Plus Etoposide With/Without Concurrent ZD6474 in Patients With Previously Untreated Extensive Stage Small Cell Lung Cancer: Hoosier Oncology Group LUN06-113

Conditions
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Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Etoposide
* Drug: Placebo
* Drug: ZD6474


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological proof of chemotherapy-naïve, extensive, small cell lung cancer. Measurable disease according to RECIST and obtained by imaging within 28 days prior to being registered for protocol therapy. Written informed consent and HIPAA authorization for release of personal health information. Age 18 years or older at the time of consent. Potassium ≥4.0 mmol/L and <5.5mmol/L (supplementation is allowed). Calcium within normal range (supplementation is allowed). Magnesium within normal range (supplementation is allowed). Exclusion Criteria: No prior EGFR inhibitor or antiangiogenic agent allowed. No prior hormonal therapy. No symptomatic brain metastasis. No clinically significant infections as judged by the treating investigator. No evidence of severe or uncontrolled other systemic disease or any concurrent condition which in the Investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol. No previous history of QTc prolongation as a result of medication that required discontinuation of that medication. No congenital long QT syndrome or known 1st degree relative with unexplained sudden death under 40 years of age. No presence of left bundle branch block (LBBB.) No QTc with Bazett's correction that is unmeasurable, or ≥480 msec on screening ECG obtained within 7 days prior to registration for protocol therapy. If a subject has QTc ≥480 msec on screening ECG, the screen ECG may be repeated twice (at least 24 hours apart). The average QTc from the three screening ECGs must be <480 msec in order for the subject to be eligible for the study. No concomitant (within 14 days prior to registration for and during protocol therapy) medication associated with Torsades de Pointes or cause QTc prolongation, is allowed. Medications that prolong QT, but are not strictly associated with Torsades, are allowed if medically necessary and will require increased ECG and electrolyte monitoring. No uncontrolled hypertension (systolic blood pressure greater than 160 mm Hg or diastolic blood pressure greater than 100 mm Hg). No currently active diarrhea that may affect the ability to absorb ZD6474. No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason < grade 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 5 years. Major surgery must be completed greater than 28 days prior to registration for protocol therapy and healed surgical incision is required. No concomitant (within 14 days prior to registration for and during protocol therapy) medications that are potent inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital and St. John's Wort) of CYP3A4 function. Females of childbearing potential and males must be willing to use an effective method of contraception (hormonal or barrier method of birth control; abstinence) from the time consent is signed until 8 weeks after treatment discontinuation. Females of childbearing potential must have a negative pregnancy test within 7 days prior to being registered for protocol therapy. Females must not be breastfeeding.

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 |
| --- | --- |
| Placebo Comparator: Arm A: ZD6474 Matched Placebo<br>Subjects will receive cisplatin 60 mg/m2 IV day 1 plus etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles plus ZD6474 matched placebo oral daily to be continued for the duration of the study. Prophylactic antiemetics will be given at the discretion of the treating investigator. | Drug: Cisplatin<br>* Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles<br>Drug: Etoposide<br>* Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles<br>Drug: Placebo<br>* Matched placebo oral daily<br>|
| Active Comparator: Arm B: ZD6474<br>Subjects will receive cisplatin 60 mg/m2 IV day 1 plus etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles plus ZD6474 100mg oral daily to be continued for the duration of the study. Prophylactic antiemetics will be given at the discretion of the treating investigator. | Drug: Cisplatin<br>* Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles<br>Drug: Etoposide<br>* Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles<br>Drug: ZD6474<br>* ZD6474 100mg oral daily to be continued for the duration of the study.<br>|
| Experimental: Safety Lead-In<br>Subjects will receive cisplatin 60 mg/m2 IV day 1 plus etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles plus ZD6474 100mg oral daily to be continued for the duration of the study. Prophylactic antiemetics will be given at the discretion of the treating investigator. The safety lead-in will be conducted to determine the safety of the combination of ZD6474 and cisplation + etopiside. If this combination is found to be unsafe, no patients will be randomized in the Phase II portion of the trial. If the combination is deemed safe according to the protocol, participants from the safety lead-in cohort will not be included in the efficacy analysis. | Drug: Cisplatin<br>* Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles<br>Drug: Etoposide<br>* Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles<br>Drug: ZD6474<br>* ZD6474 100mg oral daily to be continued for the duration of the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Disease Progression - Median Time to Progression and Log-Rank Test | Kaplan-Meier analysis comparing arm A to arm B. Median time to progression and log-rank test. Safety lead-in participants are not included in this analysis per protocol. | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grade 3/4 Hematologic and Non-Hematologic Toxicities | Percentage of participants who experienced grade 3/4 hematologic and non-hematologic toxicities. Participants from Arm A were compared to subjects from Arm B + Safety Lead-In. | 6 weeks (2 Cycles) | 
| Measure the Response Rate (CR + PR) in Each Arm | Response assessments completed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST Therasse et al., 2000). Complete Response (CR) is defined as: Disappearance of all target lesions. Partial Response (PR) is defined as: >=30% decrease in the sum of the longest diameter of target lesions. | 24 months | 
| Measure Disease Control Rate (CR + PR+ SD) in Each Arm | Response assessments completed per Response Evaluation Criteria In Solid Tumors Criteria (RECIST Therasse et al., 2000). Complete Response (CR) is defined as: Disappearance of all target lesions. Partial Response (PR) is defined as: >=30% decrease in the sum of the longest diameter of target lesions. Stable Disease (SD) is defined as: neither a partial response or progressive disease ( >=20% increase in the sum of the longest diameter of the target lesions). | 24 months | 
| Measure Overall Survival for Each Arm |  | 24 months | 
| Assess VEGF Polymorphisms and Correlate Subject Response |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Extensive Stage, Untreated