A Phase I/II Study to Determine the Maximum Tolerated Dose (MTD) and Safety of CC-4047 (Pomalidomide) Administered in Conjunction With Cisplatin and Etoposide

Study Description

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Brief Summary:

The purpose of this study is to determine the maximum tolerated dose and safety of CC-4047 (pomalidomide) given in combination with cisplatin and etoposide in patients with extensive disease small cell lung cancer.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Small Cell	Drug: Pomalidomide; Drug: Cisplatin; Drug: Etoposide	Phase 1; Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	22 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Multicenter, Phase I/IIA, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose and To Evaluate the Safety Profile of CC-4047 Administered in Combination With Cisplatin and Etoposide in Patients With Extensive Disease Small Cell Lung Cancer
Study Start Date :	February 2008
Actual Primary Completion Date :	November 2010
Actual Study Completion Date :	December 2010

Arms and Interventions

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Arm

Intervention/treatment

Experimental: Dose-finding arm: Pomalidomide + Cisplatin + Etoposide; Oral pomalidomide 1 mg - 5 mg daily (QD) for 14 consecutive days of a 21-day cycle, in combination with intravenous (IV) cisplatin 25 mg/m^2 and IV etoposide 100 mg/m^2 on Days 1, 2 and 3 of each cycle during the dose-finding phase (Treatment and Extension Periods; 6 cycles in total). Dose escalation followed a standard phase 1 3+3 design. Participants continuing took only their pomalidomide dose (monotherapy) for an additional 3-week Recovery Period (14 days of consecutive dosing followed by 7 days of no study medication). Participants continuing took oral pomalidomide 5 mg QD as monotherapy for 14 consecutive days of each 21-day cycle until disease progression in the Maintenance Phase.

Drug: Pomalidomide; Other Names: CC-4047; Pomalyst Drug: Cisplatin; Other Names: Cisplatinum; CDDP; Platin Drug: Etoposide; Other Names: Etoposide phosphate; VP-16; Etopophos

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) [ Time Frame: Cycle 1 (21 days) ]
   The MTD was defined as the highest dose level at which no more than 1 in 6 participants experienced a dose-limiting toxicity (DLT) during the first 21-day cycle of treatment. The MTD Phase included the Treatment period (Cycle 1: Identification of the MTD) and the Extension period (Cycles 2 to 6: Confirmation of Safety of the MTD). (See Secondary Outcome Measure 2 for data on DLTs.)

Secondary Outcome Measures :

1. Number of Participants With Dose Limiting Toxicities (DLTs) During the MTD Phase [ Time Frame: Cycles 1 - 6 (21-day cycles) ]
   For the purposes of determining the MTD (see Primary Outcome Measure), a DLT was defined as any 1 or more of the following: inability to deliver all 3 doses of cisplatin and etoposide due to toxicity; inability to deliver 14 consecutive days of daily pomalidomide dosing because the participant did not tolerate the medication due to any of the following: ≥ grade 3 non-hematological toxicity (excluding alopecia) occurring before Day 14 of pomalidomide dosing; febrile neutropenia (absolute neutrophil count [ANC] <1,000/µL and fever >101ºF, core temperature); grade 4 neutropenia of ≥7 days duration with onset on or before Day 14 of pomalidomide dosing; platelet count <25,000/µL occurring before Day 14 of pomalidomide dosing. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), Version 4.0, grades: 1=mild, 2=moderate, 3=severe, 4=life threatening, 5=death.
2. Tumor Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Cycles 1 -6 (21-day cycles) ]
   Investigator's best assessment of response based on RECIST criteria during the MTD phase. For target lesions: Complete Response (CR)=Disappearance of all target lesions; Partial Response (PR)=≥30% decrease in sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD; Progressed Disease (PD)=≥20% increase in sum of LD of target lesions taking as reference the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesions; Stable Disease (SD)=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD since treatment started. For non-target lesions: CR= Disappearance of all non-target lesions and normalization of tumor marker level; Incomplete Response/SD=Persistence of ≥1 non-target lesions and/or maintenance of tumor marker level above normal limits; PD=Appearance of ≥1 new lesions; unequivocal progression of existing non-target lesions.
3. Duration of Response [ Time Frame: From first Partial Response (PR) or Complete Response (CR) to disease progression (maximum of 19.4 weeks) ]
   Duration of Response was calculated from first Partial Response (PR) or Complete Response (CR) to disease progression. Duration of response was censored at the last date that the participant was known to be progression-free for: 1) participants who had not progressed at the time of analysis; 2) participants who had been removed from the treatment phase prior to documentation of progression.
4. Overall Survival [ Time Frame: From enrollment through study termination (approximately 35 months) ]
   Overall Survival was defined as time (in weeks) from enrollment to death. The median is based on Kaplan-Meier estimate, with 95% confidence intervals about the median overall survival. Overall survival was censored at the last time participant was known to be alive for those who were alive at time of analysis.
5. Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the MTD (Combination Treatment) Phase [ Time Frame: Cycles 1-6 (21-day cycles). Median (full range) duration of exposure (in weeks) to pomalidomide (MTD Phase): 1 mg, 17.9 (1.0, 20.3); 3 mg, 17.0 (16.9, 22.0); 4 mg, 14.0 (0.7, 22.0); 5 mg, 13.0 (2.0, 22.1). Cisplatin and etoposide: 15.3 (0.4, 20.6). ]
   Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. Serious adverse event (SAE) = any AE which: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. TEAE = any AE occurring or worsening on or after the first treatment with any study drug. Related = suspected by investigator to be related to study treatment. National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE], Version 4.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death.
6. Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Recovery Period or Maintenance (Monotherapy) Phase [ Time Frame: Cycle 7 to discontinuation (21-day cycles). Median (full range) duration of exposure (in weeks) to pomalidomide during Maintenance Phase was 5.0 (1.1, 36.0). ]
   Adverse event (AE) = any noxious, unintended, or untoward medical occurrence occurring at any dose that may appear or worsen in a participant during the course of a study, including new intercurrent illness, worsening concomitant illness, injury, or any concomitant impairment of participant's health, including laboratory test values, regardless of etiology. TEAE = any AE occurring or worsening on or after the first treatment with any study drug. 'Related' = suspected by investigator to be related to study treatment. National Cancer Institute [NCI] Common Toxicity Criteria for Adverse Events [CTCAE], Version 4.0, grades: 1 = mild, 2 = moderate, 3 = severe, 4 = life threatening, 5 = death.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• signature of informed consent
• Age >= 18
• histologically or cytologically confirmed small cell lung cancer (SCLC)
• extensive stage SCLC
• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2
• brain metastases that are asymptomatic and do not require steroid control
• females of child bearing potential must use two forms of birth control

Exclusion Criteria:

• pregnant or lactating females
• prior use of cytotoxic chemotherapy
• surgery within 14 days of study
• radiation within 14 days of study
• prior therapy with CC-4047 (pomalidomide), lenalidomide or thalidomide
• concurrent use or anticipated use of anti-cancer agents
• absolute neutrophil count (ANC) < 1500/mm^3
• platelets < 100 x 10^3/µL
• serum creatinine >2.5 mg/dL
• serum glutamic oxaloacetic transaminase (SGOT) or serum glutamic pyruvic transaminase (SGPT) > 3.0 x upper limit of normal (ULN)
• serum total bilirubin > 1.8 mg/dL
• uncontrolled hypercalcemia
• creatinine clearance <50 mL/min
• uncontrolled hypertension
• neuropathy >= grade 2
• body mass index (BMI) >= 40
• any other active invasive malignancy requiring treatment
• known chronic infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
• inability or unwillingness to comply with birth control requirements

Contacts and Locations

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Locations

United States, Ohio
Ireland Cancer Center, Case Western Reserve University, Division of Hematology/Oncology
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
Pennsylvania State University
Hershey, Pennsylvania, United States, 17033
United States, Texas
University of Texas Southwestern Medical Center
Dallas, Texas, United States, 75390
Canada, Ontario
Juranvinski Cancer Center - Medical Oncology
Hamilton, Ontario, Canada, L8V 5C2
Princess Margaret Hospital
Toronto, Ontario, Canada, M5G 2M9
Canada, Quebec
Mc Gill University - Department of Oncology - Clinical Research Program
Montreal, Quebec, Canada, H2W 1S6

Sponsors and Collaborators

Celgene Corporation

Investigators

Study Director:	Ulf Jungnelius, MD	Celgene Corporation

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications of Results:

Ellis PM, Jungnelius U, Zhang J, Fandi A, Beck R, Shepherd FA. A phase I study of pomalidomide (CC-4047) in combination with cisplatin and etoposide in patients with extensive-stage small-cell lung cancer. J Thorac Oncol. 2013 Apr;8(4):423-8. doi: 10.1097/JTO.0b013e318282707b.

Responsible Party:	Celgene Corporation
ClinicalTrials.gov Identifier:	NCT00537511 History of Changes
Other Study ID Numbers:	CC-4047-SCLC-002
First Posted:	October 1, 2007
Results First Posted:	April 17, 2013
Last Update Posted:	May 10, 2013
Last Verified:	May 2013

Additional relevant MeSH terms:

Carcinoma, Small Cell; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Etoposide phosphate; Pomalidomide; Cisplatin; Etoposide; Thalidomide; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors	Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Physiological Effects of Drugs; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Immunosuppressive Agents; Leprostatic Agents; Anti-Bacterial Agents; Anti-Infective Agents