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

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.

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) 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.

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.

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.

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.

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.

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 (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.