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

Phase 1b/2, Multicenter, Open-label Study of Carfilzomib, Carboplatin, and Etoposide in Subjects With Previously Untreated Extensive-stage Small-cell Lung Cancer

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).

Study Overview

• Status: Completed
• Conditions: Extensive-Stage Small-Cell Lung Cancer
• Intervention / Treatment: Drug: Carfilzomib; Drug: Carboplatin; Drug: Etoposide

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada
      • Juravinski Cancer Centre
• Russian Federation
  • Arkhangelsk, Russian Federation
    • State Budgetary Healthcare Institution of Arkhangelsk Region "Arkhangelsk Clinical Oncological Dispensary"
  • Moscow, Russian Federation
    • Federal State Budgetary Scientific Institution "N.N. Blokhin Russian Cancer Research Center"
  • St. Petersburg, Russian Federation
    • State Budgetary Educational Inslitution of Higher Professional Education "First St. Petersburg I.P.Pavlov State Medical University"
  • Yaroslavl, Russian Federation
    • State Budgetary Healthcare Institution of Yaroslavl Region "Regional Clinical Oncological Hospital"
  • Kursk
    • Kislino, Kursk, Russian Federation
      • Regional Budgetary Healthcare Institution "Kursk Regional Clinical Oncology Dispensary"
• United States
  • Connecticut
    • New Haven, Connecticut, United States
      • Yale University, Yale Cancer Center
  • Florida
    • Gainesville, Florida, United States
      • UF Health Davis Cancer Pavilion and Shands Med Plaza
  • Indiana
    • Goshen, Indiana, United States
      • Goshen Center for Cancer Care
    • Lafayette, Indiana, United States
      • Horizon Oncology Research, Inc.
    • Muncie, Indiana, United States
      • Indiana University Health Ball Memorial Hospital
  • Kentucky
    • Lexington, Kentucky, United States
      • Baptist Health Lexington Clinical Research Center
  • Maryland
    • Frederick, Maryland, United States
      • Frederick Memorial Hospital
  • New Jersey
    • Hackensack, New Jersey, United States
      • John Theurer Cancer Center At Hackensack UMC
  • North Carolina
    • Charlotte, North Carolina, United States
      • Levine Cancer Institute
    • Winston-Salem, North Carolina, United States
      • Wake Forest Baptist Health
  • Texas
    • Houston, Texas, United States
      • The University of Texas MD Anderson Cancer 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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Drug: Carfilzomib; Administered by intravenous infusion.; Other Names: PR-171; Kyprolis®; PR171; Drug: Carboplatin; Administered by intravenous infusion.; Drug: Etoposide; Administered by intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Dose-limiting Toxicities	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.	First 21-day Cycle

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs)	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.	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.
Overall Survival (OS) - Phase 2	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.	30 months
Maximum Plasma Concentration - Phase 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.	Cycle 1 Day 2
Time of Maximum Plasma Concentration - Phase 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.	Cycle 1 Day 2
Area Under Plasma Concentration-Time Curve - Phase 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.	Cycle 1 Day 2

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival	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.	From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.
Overall Response Rate	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.	From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.
Duration of Response	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.	From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.

Collaborators and Investigators

• Sponsor: Amgen

Study record dates

Study Major Dates

• Study Start: November 5, 2013
• Primary Completion (Actual): August 1, 2016
• Study Completion (Actual): May 4, 2017

Study Registration Dates

• First Submitted: November 6, 2013
• First Submitted That Met QC Criteria: November 12, 2013
• First Posted (Estimate): November 19, 2013

Study Record Updates

• Last Update Posted (Actual): August 28, 2017
• Last Update Submitted That Met QC Criteria: July 26, 2017
• Last Verified: July 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Carboplatin; Etoposide
• Other Study ID Numbers: CFZ004; 2013-002597-44 (EudraCT Number); 20130399 (Other Identifier: Amgen Inc.)