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

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

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.

Study Overview

• Status: Terminated
• Conditions: Carcinoma, Small Cell
• Intervention / Treatment: Drug: Cisplatin; Drug: Pomalidomide; Drug: Etoposide

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose (MTD)	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.)	Cycle 1 (21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose Limiting Toxicities (DLTs) During the MTD Phase	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.	Cycles 1 - 6 (21-day cycles)
Tumor Response Rate According to Response Evaluation Criteria in Solid Tumors (RECIST)	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.	Cycles 1 -6 (21-day cycles)
Duration of Response	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.	From first Partial Response (PR) or Complete Response (CR) to disease progression (maximum of 19.4 weeks)
Overall Survival	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.	From enrollment through study termination (approximately 35 months)
Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the MTD (Combination Treatment) Phase	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.	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).
Number of Participants With Treatment Emergent Adverse Events (TEAEs) During the Recovery Period or Maintenance (Monotherapy) Phase	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.	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).

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Ulf Jungnelius, MD, Celgene Corporation

Publications and helpful links

General Publications

• 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. Erratum In: J Thorac Oncol. 2019 Aug;14(8):1484.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2008
• Primary Completion (Actual): November 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: September 27, 2007
• First Submitted That Met QC Criteria: September 27, 2007
• First Posted (Estimate): October 1, 2007

Study Record Updates

• Last Update Posted (Actual): November 19, 2019
• Last Update Submitted That Met QC Criteria: November 6, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Carcinoma; Neoplasms, Glandular and Epithelial; Carcinoma, Small Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Etoposide; Etoposide phosphate; Cisplatin; Pomalidomide
• Other Study ID Numbers: CC-4047-SCLC-002