Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Rare Diseases

Lung Neoplasms

Small Cell Lung Carcinoma

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

Antineoplastic Agents

All Drugs and Chemicals

Antiemetics

Gastrointestinal Agents

Etoposide

Cisplatin

Etoposide phosphate

Enzyme Inhibitors

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.

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.

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.

Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles

Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles

Placebo

ZD6474 100mg oral daily to be continued for the duration of the study.

ZD6474

Nasser Hanna, M.D.

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.

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.

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

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

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.

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.

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.

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).

AstraZeneca

Hoosier Cancer Research Network

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.

Cisplatin: Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles

Etoposide: Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles

Placebo: Matched placebo oral daily

Arm A: ZD6474 Matched Placebo

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.

Cisplatin: Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles

Etoposide: Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles

ZD6474: ZD6474 100mg oral daily to be continued for the duration of the study.

Arm B: ZD6474

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.

Cisplatin: Cisplatin 60 mg/m2 IV day 1 every 21 days for a total of 4 cycles

Etoposide: Etoposide 120 mg/m2 IV days 1, 2, and 3 every 21 days for a total of 4 cycles

ZD6474: ZD6474 100mg oral daily to be continued for the duration of the study.

Safety Lead-In

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Eastern Cooperative Oncology Group Score

0 Fully active, able to carry on all pre-disease performance without restriction

1. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work
2. Ambulatory and capable of all selfcare but unable to carry out any work activities; up and about more than 50% of waking hours
3. Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours
4. Completely disabled; cannot carry on any selfcare; totally confined to bed or chair
5. Dead

ECOG Performance Status

Present

Absent

Liver Metastases

Brain Metastases

Carboplatin

Platinum Therapy

Subjects 18 years of age or older at time of consent, ECOG Performance Status of 0-1 14 days prior to registration, and histological or cytological proof of chemotherapy naive extensive small cell cancers or neuroendocrine cancers that are high grade or poorly differentiated.

The primary object analysis was under powered. The sample size calculation determined 34 subjects per arm, however the actual primary objective analysis was based on 31 subjects per arm.

Georgia Gould

A one-sided log rank test with an overall sample size of 68 subjects (of which 34 are in arm A and 34 are in arm B) achieves 80% power at a 0.10 significance level to detect a difference of 3 months in PFS between 4 month median PFS and 7 month median PFS.

Two participants from Arm A and Two Participants from Arm B were inevaluable for the time to disease progression analysis. (Reasons inevaluable include: toxicity and withdrawal of consent)

Time to Disease Progression - Median Time to Progression and Log-Rank Test

Grade 3/4 Hematologic Toxicity

Grade 3/4 Non-Hematologic Toxicity

Arm B: ZD6474 + Safety Lead-In

The participants from the safety run-in cohort were combined with the participants from ARM B for analysis of safety.

Percentage of Participants With Grade 3/4 Hematologic and Non-Hematologic Toxicities

12 participants are excluded due to missing data.

Measure the Response Rate (CR + PR) in Each Arm

12 participants were not analyzed due to missing data.

Measure Disease Control Rate (CR + PR+ SD) in Each Arm

Measure Overall Survival for Each Arm

Data was not collected for safety lead-in participants and these participants were not included in the analysis.

Survival Analysis VEGF SNP rs699947

Survival Analysis VEGF SNP rs3025039

Survival Analysis VEGF SNP rs2019063

Survival Analysis VEGF SNP rs1570360

Survival Analysis VEGF SNP rs833061

Response Analysis VEGF rs699947

Response Analysis VEGF SNP rs3025039

Response Analysis VEGF SNP rs2019063

Response Analysis VEGF SNP rs1570360

Response Analysis VEGF SNP rs833061

This data was not collected for the safety lead-in participants.

Assess VEGF Polymorphisms and Correlate Subject Response

Overall Study

Irinotecan

Sunitinib

Topoisomerase I Inhibitors

Angiogenesis Inhibitors

Growth Inhibitors

Protein Kinase Inhibitors

Patients in the study will receive the following for the duration of the study: irinotecan 60 mg/m2 intravenously on Days 1, 8, and 15 and carboplatin AUC=4 on Day 1. The study will consist of 28-day cycles, to a maximum of 6 cycles of therapy with irinotecan and carboplatin. After treatment with irinotecan and carboplatin, sunitinib will be given alone as maintenance therapy in all patients who have achieved study entry hematologic criteria and who do not have progressive disease or severe toxicity. During sunitinib maintenance therapy, patients will receive sunitinib at 25 mg orally daily. Sunitinib maintenance therapy will continue until progressive disease or irreversible toxicity occurs.

Re-staging will be performed every 2 cycles (every 8 weeks) during the study.

irinotecan 60 mg/m2 intravenously (IV) on Days 1, 8, and 15

irinotecan

sunitinib 25 mg orally (PO) daily after initial chemotherapy

sunitinib

David R Spigel, M.D.

This proposed Phase II trial will investigate the combination of irinotecan and carboplatin followed by sunitinib in the first-line treatment of patients with extensive-stage SCLC.

Irinotecan/platinum regimens are emerging as standard treatments for patients with extensive-stage disease. The irinotecan/carboplatin doses that will be used in this study have been used in two previous Phase II SCLC trials, and were found to be extremely well tolerated (Thompson et al. 2005; Spigel et al. 2007). Adding a novel, minimally toxic agent to this regimen may further enhance efficacy in this patient population without contributing to toxicity. This trial will evaluate the use of sunitinib following 6 cycles of treatment with chemotherapy in the treatment of SCLC.

The trial will be performed under the leadership of SCRI, a community-based, multi-center, clinical trial organization.

Irinotecan, Carboplatin, and Sunitinib in First Line Extensive-Stage Small Cell Lung Cancer

Phase II Study of Irinotecan, Carboplatin, and Sunitinib in the First Line Treatment of Extensive-Stage Small Cell Lung Cancer

Objective benefit is defined as substantial (30% or greater) shrinkage in tumor volume per RECIST 1.0.

Time To Progression (TTP) was defined as the interval between the start date of treatment and the date of occurrence of progressive disease

Overall survival was defined as the interval between the date of study entry until the date of death.

The toxicity assessments were made according to the common terminology criteria for adverse events (CTCAE version 3.0) of the National Cancer Institute. Number of participants with Grade 1 to 5 adverse events are reported here.

Pfizer

SCRI Development Innovations, LLC

Patients in the study will receive the following for the duration of the study: irinotecan 60 mg/m2 intravenously on Days 1, 8, and 15 and carboplatin AUC=4 on Day 1. The study will consist of 28-day cycles, to a maximum of 6 cycles of therapy with irinotecan and carboplatin. After treatment with irinotecan and carboplatin, sunitinib will be given alone as maintenance therapy in all patients who have achieved study entry hematologic criteria and who do not have progressive disease or severe toxicity. During sunitinib maintenance therapy, patients will receive sunitinib at 25 mg orally daily. Sunitinib maintenance therapy will continue until progressive disease or irreversible toxicity occurs.

Intervention

Patients receive irinotecan 60mg/m2 IV on days 1, 8, and 15 and carboplatin AUC=4 on day 1 of each 28-day cycle. After completion of 6 cycles, patients receive only sunitinib 25 mg daily by mouth.

Irinotecan, Carboplatin, Sunitinib

Age, Categorical

Dr. David Spigel

The original study design administered sunitinib concurrently with irinotecan/carboplatin. After the first three patients enrolled experienced severe myelosuppression, the treatment plan was modified to delay sunitinib until after completion of combination therapy. Only patients treated under the revised plan are included in the results analysis.

One-year Survival, The Percentage of Patients Who Are Alive One Year After Completing Protocol Treatment

Overall Response Rate (ORR), the Percentage of Patients Who Experience an Objective Benefit From Treatment

Time to Progression

Median Overall Survival

Toxicity was evaluated in all patients who received at least 1 dose of therapy. The original study design administered sunitinib concurrently with irinotecan/carboplatin. After the first three patients enrolled experienced severe myelosuppression, the treatment plan was modified to delay sunitinib until after completion of combination therapy. Only patients treated under the revised plan are included in the results analysis.

Number of Participants Experiencing Treatment Related Toxicity

Carcinoma, Small Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Patients received vinflunine 320 mg/m2 every 21 days as a 15- to 20-minute infusion.

320mg/m2 every 21 days as a 15-20 minute infusion

Vinflunine

David R. Spigel, MD

This clinical trial involves the administration of the chemotherapeutic medication vinflunine. Vinflunine is not approved by the FDA and is experimental in the treatment of extensive small cell lung cancer. The purpose of this research trial is to study the effectiveness of vinflunine in patients with relapsed extensive small cell lung cancer, evaluate the toxicity, and evaluate how long the response to this drug lasts.

Eligible patients will receive vinflunine as a 15-20 minute intravenous (IV)infusion once every three weeks (21 days). This three week treatment period is called a cycle. Patients whose cancer has not grown or if it has decreased in size may receive up to 6 cycles of vinflunine. Evaluation will be conducted every other cycle.

Vinflunine in the Treatment of Patients With Relapsed Extensive Small Cell Lung Cancer

A Phase II Trial of VInflunine in the Treatment of Patients With Relapsed Extensive Small Cell Lung Cancer

Overall response rate is the percentage of patients with complete response or partial response per RECIST v.1 Criteria. Complete response (CR) = Disappearance of all target lesions, disappearance of all nontarget lesions for at least 4 weeks. Partial Response (PR) = At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameters. The final response criteria assigned represented the best response obtained during treatment.

The Response Duration was calculated from time of initial measured response to date of first observation of progressive disease.

Overall survival was measured from the date of study entry until the date of death.

Progression free survival was defined as the interval between the start date of treatment and the date of occurrence of progressive disease or death.

Bristol-Myers Squibb

Age Continuous

John Hainsworth, MD

All patients were assessed for response. Only patients with objective response were analyzed for response duration.

Duration of Response, the Length of Time, in Months, That Protocol Treatment Produced an Objective Improvement in Patients' Disease

All patients were assessed for overall survival.

Overall Survival (OS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Death

All patients were assessed for progression free survival.

Progression Free Survival (PFS), the Length of Time, in Months, That Patients Were Alive From Their First Date of Protocol Treatment Until Worsening of Their Disease

Topotecan

Topotecan 6mg/m2 IV weekly x 6 consecutive weeks followed by a 2 week break.

This proposed phase II trial will investigate weekly topotecan at a higher dose than was used in the previous trials in an attempt to achieve improved response rates and disease control without added toxicity. To help ameliorate the fatigue, planned rest weeks will be incorporated into the schedule. This trial will be the first clinical trial to evaluate a higher dose of weekly topotecan in the treatment of extensive-stage SCLC.

All patients will receive weekly topotecan.

Topotecan 6mg/m2 IV weekly x 6 consecutive weeks followed by a 2 week break. Cycles are repeated every 8 weeks, for 3 cycles. Restaging studies will be performed every cycle (or 8 weeks.)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cisplatin + Etoposide +/- Concurrent ZD6474 in Previously Untreated Extensive Stage Small Cell Lung Cancer	NCT00613626	Small Cell Lung...	Cisplatin Etoposide Placebo ZD6474	18 Years -	Hoosier Cancer Research Network
Irinotecan, Carboplatin, and Sunitinib in First Line Extensive-Stage Small Cell Lung Cancer	NCT00695292	Small Cell Lung...	irinotecan Carboplatin sunitinib	18 Years -	SCRI Development Innovations, LLC
Vinflunine in the Treatment of Patients With Relapsed Extensive Small Cell Lung Cancer	NCT00284154	Carcinoma, Smal... Lung Cancer	Vinflunine	18 Years -	SCRI Development Innovations, LLC
Irinotecan, Carboplatin, and Sunitinib in First Line Extensive-Stage Small Cell Lung Cancer	NCT00695292	Small Cell Lung...	irinotecan Carboplatin sunitinib	18 Years -	SCRI Development Innovations, LLC
Higher Dose Weekly Topotecan In The Treatment Of Patients With Extensive Stage Small-Cell Lung Cancer	NCT00294190	Small Cell Lung... Carcinoma, Smal...	Topotecan	18 Years -	SCRI Development Innovations, LLC

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