Phase III, randomized, double-blind, placebo-controlled, multicenter study of lipegfilgrastim in patients with non-small cell lung cancer receiving myelosuppressive therapy

This phase III, multinational, multicenter, double-blind, randomized, placebo-controlled
study (controlled-trials.com identifier ISRCTN55761467) was designed to demonstrate
superiority of a fixed 6-mg dose of lipegfilgrastim (XM22, Lonquex; Teva Pharmaceuticals
Ltd, Petach Tikva, Israel) versus placebo in patients with NSCLC. The study was conducted
in eight European countries (Belarus, Bosnia-Herzegovina, Bulgaria, Poland, Romania,
Russia, Serbia, Ukraine) and included four phases: screening and randomization, double-blind
treatment (chemotherapy cycles 1–4), end-of-study (or withdrawal) visit, and antibody
follow-up. The study design followed the European Medicines Agency’s guidelines for
a confirmatory study (EMEA 2007]). Everyone involved in the conduct of the study was blinded to study medications.

Patients

Eligible patients were men and women aged ?18 years of any ethnic origin with a diagnosis
of stage IIIb/IV NSCLC, documented histologically or cytologically, and a life expectancy
of at least 4 months. Patients had to be chemotherapy naive, eligible to receive four
cycles of cisplatin and etoposide as myelosuppressive chemotherapy (i.e., baseline
ANC ?1.5 × 10
⁹
/L and platelets ?100 × 10
⁹
/L), have an ECOG PS ?2, and have adequate hepatic, cardiac, and renal function. Women
of childbearing potential had to use an effective method of contraception.

Because this was a placebo-controlled study, patients with an individual high risk
of developing FN (i.e., ?20%) with regard to the cisplatin and etoposide chemotherapy
were excluded from the study. Potential individual high risk factors were patient
age 65 years, low ECOG PS, poor nutritional status, and liver, kidney, or cardiovascular
disease. Risk factors were considered together to determine a patient’s risk of developing
FN, and therefore having only one risk factor did not automatically result in exclusion
from the study. Other exclusion criteria included previous exposure to any G-CSF within
6 months before randomization, treatment with systemically active antibiotics within
72 h before chemotherapy, chronic use of oral corticosteroids, prior radiation therapy
within 4 weeks of randomization, prior bone marrow or stem cell transplantation, or
concomitant malignancy (other than in situ melanoma, skin cancer, or cervical carcinoma)
within the preceding 5 years. Women who were pregnant or breastfeeding were excluded.

Study design and treatment

All patients received chemotherapy with cisplatin and etoposide and were randomized
(2:1) to receive lipegfilgrastim or placebo. Randomization was performed by Biostatistics
Merckle GmbH through an interactive voice response system, using a block size of 2
and stratified by country. Patients received up to four 21-day chemotherapy cycles.
On day 1 of each cycle, patients received cisplatin 80 mg/m
²
intravenously (IV), with etoposide 120 mg/m
²
IV administered on days 1, 2, and 3. Patients had to have an ANC ?1.5 × 10
⁹
/L and platelet count of ?100 × 10
⁹
/L to begin the next full-dose cycle. A dose delay of up to 2 weeks was acceptable.
Absolute neutrophil counts were determined at local or regional laboratories rather
than a central laboratory, for logistical reasons; all other laboratory measures were
determined by two central laboratories. In addition, the patient’s overall condition
had to allow further chemotherapy treatment as determined by the treating investigator.
Generally, any chemotherapy-related toxicity had to have resolved to at least grade
1 toxicity prior to continuation of chemotherapy.

Patients received one dose of lipegfilgrastim 6 mg or placebo SC on day 4 of each
chemotherapy cycle, approximately 24 h after the last chemotherapy infusion and after
blood sampling to determine ANC and body temperature. The lipegfilgrastim 6-mg dose
was chosen based on findings from a phase II dose-finding study in breast cancer patients
that demonstrated neutrophil support that was at least equivalent to the standard
6.0-mg fixed dose of pegfilgrastim. Patients who developed FN in any cycle were not
discontinued except by investigator decision; instead, they received open-label prophylactic
treatment with lipegfilgrastim in subsequent cycles, regardless of treatment group.

Efficacy assessments

The primary efficacy measure was the incidence of FN in cycle 1. Febrile neutropenia
was defined as an oral body temperature 38.5°C for at least 1 h (two consecutive
same-day measurements, ?60 min apart) with severe neutropenia (ANC 0.5 × 10
⁹
/L) on the day before, same day, or day after the elevated temperature readings; neutropenic
sepsis (sepsis with ANC 0.5 × 10
⁹
/L); or serious or life-threatening neutropenic infection (infection with ANC 0.5 × 10
⁹
/L).

Secondary efficacy measures included the incidence of FN in cycles 2, 3, and 4 and
across all cycles; incidence and DSN (defined as grade 4 neutropenia with ANC 0.5 × 10
⁹
/L); incidence and duration of very severe neutropenia (ANC 0.1 × 10
⁹
/L); depth of ANC nadir (lowest ANC in each cycle); time to ANC nadir (defined as
time from chemotherapy administration until occurrence of ANC nadir); time to ANC
recovery (defined as time from chemotherapy administration until ANC increased to
?2.0 × 10
⁹
/L after nadir); and time to ANC recovery from ANC nadir (defined as the difference
in days between day of ANC nadir to first day with ANC ?1.5 × 10
⁹
/L).

Blood samples to determine ANC were obtained daily until day 15, or longer, of each
cycle, until ANC ?2.0 × 10
⁹
/L was reached. A blood sample was taken on day 4 of each cycle, before administration
of study medication. Body temperature was measured orally at least twice daily (morning
and evening) until day 15, or longer, of each cycle, until ANC ?2.0 × 10
⁹
/L was reached.

Other secondary efficacy measures, including hospitalizations, use of IV antibiotics,
delivered versus scheduled chemotherapy, chemotherapy dose modifications (reductions,
omissions, delays), quality of life, and the incidence of patients requiring prophylactic
open-label treatment, as well as pharmacokinetic properties were assessed but are
not reported here.

Safety assessments

Safety was assessed using reported treatment-emergent AEs data, including intercurrent
illnesses and clinically abnormal laboratory values; AEs were recorded until 3 weeks
after the last injection of study medication. Adverse events were summarized by seriousness,
severity, and investigator-assessed relationship to study medication. A serious AE
was one that was life-threatening or resulted in death, required hospitalization or
prolongation of hospitalization, or resulted in a persistent or significant disability
or incapacity that required medical or surgical intervention. Investigators assessed
AEs as probably, possibly, unlikely, or not related to the study medication or chemotherapy
regimen, or as not classifiable. For laboratory values, all AEs of grade 3 and higher
were documented. The AEs were assessed on days 1 and 7 of each chemotherapy cycle.
Safety samples (hematology and clinical chemistry) were taken on day 15. Other safety
assessments, including physical examination and vital signs, were performed within
24 h before chemotherapy administration on day 1 and on days 7 and 15 of each chemotherapy
cycle.

Statistical analysis

The planned sample size was 375 patients from approximately 90 centers in nine countries,
based on the assumption that the incidence of FN would be in the range of 7% to 10%
in the placebo group and, at most, 1% in the lipegfilgrastim group. For a statistical
test with a two-sided significance level ? of 5%, a required power of at least 80%,
and a sampling rate of 2:1 (lipegfilgrastim:placebo), sample size requirements were
250 patients in the lipegfilgrastim group and 125 patients in the placebo group. As
the actual incidence of FN in the placebo group was expected to be closer to 10%,
a power of at least 90% was expected.

For the primary efficacy measure (incidence of FN in cycle 1), a 95% CI for the OR
(placebo/lipegfilgrastim) was calculated to assess the relative efficacy of lipegfilgrastim
versus placebo. For secondary efficacy measures, no adjustment for Type I error was
applied, so all secondary analyses should be interpreted as exploratory. When applicable,
for secondary efficacy measures for which regression analyses were planned, statistical
models with the same explanatory variables as in the analysis of the primary measures
were estimated. Demographic and baseline characteristics, AEs, and other safety assessments
were presented as descriptive statistics (continuous variables) or frequency tables
(categorical variables).

The intent-to-treat population, which included all patients randomized at baseline,
was also the efficacy population. The safety population included all randomized patients
who received at least one dose or partial dose of study medication.