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Phase 1b/2 Study of Carfilzomib, Carboplatin, and Etoposide in Patients With Previously Untreated Extensive Stage Small-cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01987232
Recruitment Status : Completed
First Posted : November 19, 2013
Results First Posted : August 28, 2017
Last Update Posted : August 28, 2017
Sponsor:
Information provided by (Responsible Party):
Amgen

Tracking Information
First Submitted Date  ICMJE November 6, 2013
First Posted Date  ICMJE November 19, 2013
Results First Submitted Date  ICMJE July 26, 2017
Results First Posted Date  ICMJE August 28, 2017
Last Update Posted Date August 28, 2017
Study Start Date  ICMJE November 5, 2013
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 26, 2017)
Number of Participants With Dose-limiting Toxicities [ Time Frame: First 21-day Cycle ]
The maximum tolerated dose (MTD) was defined as the highest dose level at which < 33% of participants experienced a dose-limiting toxicity (DLT) during the first 21-day cycle. Dose-limiting toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. A DLT was defined as:
  • A grade 3 or greater non-hematologic toxicity that was assessed as related to carfilzomib by the investigator except in the case of neuropathy. A grade 2 or higher neuropathy with pain was considered a DLT.
  • Grade 4 neutropenia: absolute neutrophil count (ANC) < 500 mm³, lasting ≥ 7 days despite granulocyte colony stimulating factor support, or any febrile (temperature > 38.3°C) neutropenia (ANC < 1000 mm³).
  • Thrombocytopenia of any grade associated with clinically significant bleeding or platelet/blood transfusion
  • Grade 4 fatigue lasting ≥ 7 days
  • Grade 3 nausea, vomiting or diarrhea lasting ≥ 7 days.
Original Primary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
  • Maximum Tolerated Dose (MTD) - Phase 1b [ Time Frame: First 21-day Cycle ]
    To determine the MTD of carfilzomib given in combination with standard dose carboplatin (target AUC = 5; IV) on Day 1 and etoposide (100 mg/m2; IV) on Days 1, 2, and 3 every 3 weeks as treatment for previously untreated Extensive-stage Small-cell Lung Cancer (ES-SCLC). The MTD is defined as the highest dose level at which < 33% of subjects experience a dose-limiting toxicity (DLT) during the first 21-day cycle.
  • Progression-free Survival (PFS) - Phase 2 [ Time Frame: 24 months after the first subject is randomized ]
    To evaluate the efficacy of carfilzomib with carboplatin and etoposide (carfilzomib combination arm) versus carboplatin and etoposide alone (control arm) in subjects with treatment-naïve ES-SCLC, as measured by progression-free survival (PFS).
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 26, 2017)
  • Number of Participants With Adverse Events (AEs) [ Time Frame: From first day of any study treatment (i.e., carfilzomib, carboplatin, or etoposide) up to 30 days after the last day of study treatment. The median overall duration of treatment was 16 weeks. ]
    The severity of each adverse event was assessed using the NCI-CTCAE Version 4.03 according to the following: Grade 1 - Mild: Asymptomatic or mild symptoms; intervention not indicated Grade 2 - Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3 - Severe: Medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Grade 4 - Life-threatening Grade 5 - Fatal. A serious AE is an AE that met one or more of the following criteria:
    • Death
    • Life-threatening
    • Required inpatient hospitalization or prolongation of an existing hospitalization
    • Resulted in persistent or significant disability/incapacity
    • A congenital anomaly/birth defect
    • Important medical events that required medical or surgical intervention to prevent one of the outcomes above.
  • Overall Survival (OS) - Phase 2 [ Time Frame: 30 months ]
    Overall Survival (OS) is defined as the time from randomization to the date of death. Overall survival was a specified secondary endpoint for the phase 2 portion of the study; since phase 2was not conducted, OS was not analyzed.
  • Maximum Plasma Concentration - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
  • Time of Maximum Plasma Concentration - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
  • Area Under Plasma Concentration-Time Curve - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2013)
  • Best Overall Response (BOR) - Phase 1b & Phase 2 [ Time Frame: 24 months after the first subject is randomized ]
    Best Overall Response (BOR) is defined as either confirmed complete response (CR) or partial response (PR) per RECIST Version 1.1.
  • Duration of Response (DOR) - Phase 1b & Phase 2 [ Time Frame: 24 months after the first subject is randomized ]
    Duration of Response (DOR) is defined as the time from first evidence of partial response (PR) or better to documented progressive disease (PD) or death due to any cause.
  • Overall Survival (OS) - Phase 2 [ Time Frame: 30 months after the first subject is randomized ]
    Overall Survival (OS) is defined as the time from randomization to the date of death.
  • Adverse Events - Phase 1b & Phase 2 [ Time Frame: 24 months after the first subject is randomized ]
    Number of patients that experience Adverse Events (AEs)
  • Maximum Plasma Concentration - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Maximum plasma concentration (Cmax, observed)
  • Time of Maximum Plasma Concentration - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Time of maximum plasma concentration (Tmax, observed)
  • Area Under Plasma Concentration-Time Curve - Phase 2 [ Time Frame: Cycle 1 Day 2 ]
    Area under the plasma concentration-time curve from time zero to time of last quantifiable concentration and to infinity (AUC0-last and AUC0-∞)
Current Other Pre-specified Outcome Measures
 (submitted: July 26, 2017)
  • Progression-free Survival [ Time Frame: From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks. ]
    Progression-free survival (PFS) was specified as a primary endpoint for the phase 2 portion of the study. Since phase 2 did not proceed PFS was analyzed in phase 1b participants on an exploratory basis. PFS was defined as the time from the start of treatment to documented disease progression or death due to any cause, whichever occurred first. Disease progression was determined by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, defined as at least a 20% increase in the size of target lesions (absolute increase ≥ 5 mm), unequivocal progression of existing non-target lesions, or any new lesions. Median PFS was calculated using Kaplan-Meier methods. Participants with no baseline disease assessments, who started a new anticancer therapy before documentation of PD or death, with death or PD immediately after more than 1 consecutively missed disease assessment visit or alive without documentation of PD before the data cutoff date were censored.
  • Overall Response Rate [ Time Frame: From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks. ]
    The overall response rate (ORR) was defined as the percentage of participants for whom the best overall confirmed response was either complete response (CR) or partial response (PR) assessed by the investigator according to RECIST v1.1 criteria. CR: Disappearance of all target and non-target lesions, no new lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker levels above normal limits.
  • Duration of Response [ Time Frame: From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks. ]
    Duration of response (DOR) was calculated for participants who achieved a confirmed CR or PR. defined as the time from first evidence of confirmed PR/CR to disease progression or death due to any cause. Median DOR was calculated using Kaplan-Meier methods. Participants with no baseline disease assessments, who started a new anticancer therapy before documentation of PD or death, with death or PD immediately after more than 1 consecutively missed disease assessment visit or alive without documentation of PD before the data cutoff date were censored. DOR was originally specified as a secondary endpoint for the phase 2 portion of the study. Since phase 2 did not proceed, DOR was analyzed in phase 1b participants on an exploratory basis.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 1b/2 Study of Carfilzomib, Carboplatin, and Etoposide in Patients With Previously Untreated Extensive Stage Small-cell Lung Cancer
Official Title  ICMJE Phase 1b/2, Multicenter, Open-label Study of Carfilzomib, Carboplatin, and Etoposide in Subjects With Previously Untreated Extensive-stage Small-cell Lung Cancer
Brief Summary The purpose of this study is to determine the maximum tolerated dose and assess the safety, tolerability and activity of carfilzomib given in combination with carboplatin and etoposide as initial therapy for patients with extensive-stage small-cell lung cancer (ES SCLC).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Extensive-Stage Small-Cell Lung Cancer
Intervention  ICMJE
  • Drug: Carfilzomib
    Administered by intravenous infusion.
    Other Names:
    • PR-171
    • PR171
    • Kyprolis®
  • Drug: Carboplatin
    Administered by intravenous infusion.
  • Drug: Etoposide
    Administered by intravenous infusion.
Study Arms  ICMJE Experimental: Carfilzomib Combination
Participants received carfilzomib on days 2, 3, 9, and 10 of each 21-day cycle as per the dose escalation schema, carboplatin at a target area under the curve (AUC) of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
Interventions:
  • Drug: Carfilzomib
  • Drug: Carboplatin
  • Drug: Etoposide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 21, 2016)
32
Original Estimated Enrollment  ICMJE
 (submitted: November 12, 2013)
150
Actual Study Completion Date  ICMJE May 4, 2017
Actual Primary Completion Date August 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  1. Histologically or cytologically confirmed diagnosis of extensive-stage small-cell lung cancer (ES-SCLC) with measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1; ES-SCLC is defined as: small-cell lung cancer (SCLC) that has spread beyond one hemithorax and regional lymph nodes on the same side (e.g., supraclavicular) to the contralateral hemithorax, lymph nodes, or more distant locations in the body
  2. Subjects with asymptomatic brain metastases or other central nervous system (CNS) disease at screening/diagnosis are eligible
  3. Males and females ≥ 18 years of age
  4. Eastern Cooperative Oncology Group (ECOG) performance status 0-1

Key Exclusion Criteria:

  1. Previous systemic therapy to treat small-cell lung cancer (SCLC). Subjects with recurrent or progressive limited-stage SCLC after previous systemic treatment are not eligible for study participation.
  2. Whole brain or focal radiation therapy within 14 days prior to Cycle 1 Day 1 (C1D1) for Phase 1b or prior to randomization for Phase 2
  3. Congestive heart failure (New York Heart Association [NYHA] class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction within 6 months prior to prior to C1D1 for Phase 1b or prior to randomization for Phase 2
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Russian Federation,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01987232
Other Study ID Numbers  ICMJE CFZ004
2013-002597-44 ( EudraCT Number )
20130399 ( Other Identifier: Amgen Inc. )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Amgen
Study Sponsor  ICMJE Amgen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: MD Amgen
PRS Account Amgen
Verification Date July 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP