Cancer Patients Receiving Myelosuppressive Chemotherapy

NEUPOGEN® has been shown to be safe and effective in accelerating the recovery of neutrophil counts following a variety of chemotherapy regimens. In a phase 3 clinical trial in small cell lung cancer‚ patients received SC administration of NEUPOGEN® (4 to 8 mcg/kg/day‚ days 4 to 17) or placebo. In this study‚ the benefits of NEUPOGEN® therapy were shown to be prevention of infection as manifested by febrile neutropenia‚ decreased hospitalization‚ and decreased IV antibiotic usage. No difference in survival or disease progression was demonstrated.

In the phase 3‚ randomized‚ double-blind‚ placebo-controlled trial conducted in patients with small cell lung cancer‚ patients were randomized to receive NEUPOGEN® (n = 99) or placebo (n = 111) starting on day 4‚ after receiving standard dose chemotherapy with cyclophosphamide‚ doxorubicin‚ and etoposide. A total of 210 patients were evaluated for efficacy and 207 evaluated for safety. Treatment with NEUPOGEN® resulted in a clinically and statistically significant reduction in the incidence of infection‚ as manifested by febrile neutropenia; the incidence of at least one infection over all cycles of chemotherapy was 76% (84/111) for placebo-treated patients‚ versus 40% (40/99) for NEUPOGEN®-treated patients (p less than 0.001). The following secondary analyses were also performed. The requirements for in-patient hospitalization and antibiotic use were also significantly decreased during the first cycle of chemotherapy; incidence of hospitalization was 69% (77/111) for placebo-treated patients in cycle 1‚ versus 52% (51/99) for NEUPOGEN®-treated patients (p = 0.032). The incidence of IV antibiotic usage was 60% (67/111) for placebo-treated patients in cycle 1‚ versus 38% (38/99) for NEUPOGEN®-treated patients (p = 0.003). The incidence‚ severity‚ and duration of severe neutropenia (absolute neutrophil count [ANC] less than 500/mm3) following chemotherapy were all significantly reduced. The incidence of severe neutropenia in cycle 1 was 84% (83/99) for patients receiving NEUPOGEN® versus 96% (106/110) for patients receiving placebo (p = 0.004). Over all cycles‚ patients randomized to NEUPOGEN® had a 57% (286/500 cycles) rate of severe neutropenia versus 77% (416/543 cycles) for patients randomized to placebo. The median duration of severe neutropenia in cycle 1 was reduced from 6 days (range 0 to 10 days) for patients receiving placebo to 2 days (range 0 to 9 days) for patients receiving NEUPOGEN® (p less than 0.001). The mean duration of neutropenia in cycle 1 was 5.64 ± 2.27 days for patients receiving placebo versus 2.44 ± 1.90 days for patients receiving NEUPOGEN®. Over all cycles‚ the median duration of neutropenia was 3 days for patients randomized to placebo versus 1 day for patients randomized to NEUPOGEN®. The median severity of neutropenia (as measured by ANC nadir) was 72/mm3 (range 0/mm3 to 7912/mm3) in cycle 1 for patients receiving NEUPOGEN® versus 38/mm3 (range 0/mm3 to 9520/mm3) for patients receiving placebo (p = 0.012). The mean severity of neutropenia in cycle 1 was 496/mm3 ± 1382/mm3 for patients receiving NEUPOGEN® versus 204/mm3 ± 953/mm3 for patients receiving placebo. Over all cycles‚ the ANC nadir for patients randomized to NEUPOGEN® was 403/mm3‚ versus 161/mm3 for patients randomized to placebo. Administration of NEUPOGEN® resulted in an earlier ANC nadir following chemotherapy than was experienced by patients receiving placebo (day 10 vs day 12). NEUPOGEN® was well tolerated when given SC daily at doses of 4 to 8 mcg/kg for up to 14 consecutive days following each cycle of chemotherapy (see ADVERSE REACTIONS).

Several other phase 1/2 studies‚ which did not directly measure the incidence of infection‚ but which did measure increases in neutrophils‚ support the efficacy of NEUPOGEN®. The regimens are presented to provide some background on the clinical experience with NEUPOGEN®. No claim regarding the safety or efficacy of the chemotherapy regimens is made. The effects of NEUPOGEN® on tumor growth or on the anti-tumor activity of the chemotherapy were not assessed. The doses of NEUPOGEN® used in these studies are considerably greater than those found to be effective in the phase 3 study described above. Such phase 1/2 studies are summarized in the following table.

  
* NEU® doses were those that accelerated neutrophil production. Doses which provided no additional acceleration beyond that achieved at the next lower dose are not reported.   
† Lowest dose(s) tested in the study.  
‡ Patients received doxorubicin at either 75‚ 100‚ 125‚ or 150 mg/m2.   
§ Cycles 2‚6 = cyclophosphamide 150 mg/m2 x 7 and etoposide 280 mg/m2 x 3.  
Cycle 4 = cisplatin 90 mg/m2 x 1 and etoposide 280 mg/m2 x 3.  
  
Patients With Acute Myeloid Leukemia Receiving Induction or Consolidation Chemotherapy

In a randomized, double-blind‚ placebo-controlled‚ multi-center‚ phase 3 clinical trial‚ 521 patients (median age 54‚ range 16 to 89 years) were treated for de novo acute myeloid leukemia (AML). Following a standard induction chemotherapy regimen comprising daunorubicin, cytosine arabinoside, and etoposide15 (DAV 3+7+5), patients received either NEUPOGEN® at 5 mcg/kg/day or placebo, SC, from 24 hours after the last dose of chemotherapy until neutrophil recovery (ANC 1000/mm3 for 3 consecutive days or 10,000/mm3 for 1 day) or for a maximum of 35 days.

Treatment with NEUPOGEN® significantly reduced the median time to ANC recovery and the median duration of fever, antibiotic use, and hospitalization following induction chemotherapy. In the NEUPOGEN®-treated group‚ the median time from initiation of chemotherapy to ANC recovery (ANC greater than or equal to 500/mm3) was 20 days (vs 25 days in the control group, p = 0.0001), the median duration of fever was reduced by 1.5 days (p = 0.009), and there were statistically significant reductions in the durations of IV antibiotic use and hospitalization. During consolidation therapy (DAV 2+5+5), patients treated with NEUPOGEN® also experienced significant reductions in the incidence of severe neutropenia, time to neutrophil recovery, the incidence and duration of fever, and the durations of IV antibiotic use and hospitalization. Patients treated with a further course of standard (DAV 2+5+5) or high-dose cytosine arabinoside consolidation also experienced significant reductions in the duration of neutropenia.

There were no statistically significant differences between NEUPOGEN® and placebo groups in complete remission rate (69% NEUPOGEN® vs 68% placebo, p = 0.77), disease-free survival (median 342 days NEUPOGEN® [n = 178], 322 days placebo [n = 177], p = 0.99), time to progression of all randomized patients (median 165 days NEUPOGEN®, 186 days placebo, p = 0.87), or overall survival (median 380 days NEUPOGEN®, 425 days placebo, p = 0.83).

Cancer Patients Receiving Bone Marrow Transplant

In two separate randomized‚ controlled trials‚ patients with Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL) were treated with myeloablative chemotherapy and autologous bone marrow transplantation (ABMT). In one study (n = 54)‚ NEUPOGEN® was administered at doses of 10 or 30 mcg/kg/day; a third treatment group in this study received no NEUPOGEN®. A statistically significant reduction in the median number of days of severe neutropenia (ANC less than 500/mm3) occurred in the NEUPOGEN®-treated group versus the control group (23 days in the control group‚ 11 days in the 10 mcg/kg/day group‚ and 14 days in the 30 mcg/kg/day group [11 days in the combined treatment groups‚ p = 0.004]). In the second study (n = 44‚ 43 patients evaluable)‚ NEUPOGEN® was administered at doses of 10 or 20 mcg/kg/day; a third treatment group in this study received no NEUPOGEN®. A statistically significant reduction in the median number of days of severe neutropenia occurred in the NEUPOGEN®-treated group versus the control group (21.5 days in the control group and 10 days in both treatment groups‚ p less than 0.001). The number of days of febrile neutropenia was also reduced significantly in this study (13.5 days in the control group‚ 5 days in the 10 mcg/kg/day group‚ and 5.5 days in the 20 mcg/kg/day group [5 days in the combined treatment groups‚ p less than 0.0001]). Reductions in the number of days of hospitalization and antibiotic use were also seen‚ although these reductions were not statistically significant. There were no effects on red blood cell or platelet levels.

In a randomized‚ placebo-controlled trial‚ 70 patients with myeloid and nonmyeloid malignancies were treated with myeloablative therapy and allogeneic bone marrow transplant followed by 300 mcg/m2/day of a Filgrastim product. A statistically significant reduction in the median number of days of severe neutropenia occurred in the treated group versus the control group (19 days in the control group and 15 days in the treatment group‚ p less than 0.001) and time to recovery of ANC to greater than or equal to 500/mm3 (21 days in the control group and 16 days in the treatment group‚ p less than 0.001).

In three nonrandomized studies (n = 119)‚ patients received ABMT and treatment with NEUPOGEN®. One study (n = 45) involved patients with breast cancer and malignant melanoma. A second study (n = 39) involved patients with HD. The third study (n = 35) involved patients with NHL‚ acute lymphoblastic leukemia (ALL)‚ and germ cell tumor. In these studies‚ the recovery of the ANC to greater than or equal to 500/mm3 ranged from a median of 11.5 to 13 days.

None of the conditioning regimens used in the ABMT studies included radiation therapy.

While these studies were not designed to compare survival‚ this information was collected and evaluated. The overall survival and disease progression of patients receiving NEUPOGEN® in these studies were similar to those observed in the respective control groups and to historical data.

Peripheral Blood Progenitor Cell Collection and Therapy in Cancer Patients

All patients in the Amgen-sponsored trials received a similar mobilization/collection regimen: NEUPOGEN® was administered for 6 to 7 days‚ with an apheresis procedure on days 5‚ 6, and 7 (except for a limited number of patients receiving apheresis on days 4‚ 6, and 8). In a non-Amgen-sponsored study‚ patients underwent mobilization to a target number of mononuclear cells (MNC)‚ with apheresis starting on day 5. There are no data on the mobilization of peripheral blood progenitor cells (PBPC) after days 4 to 5 that are not confounded by leukapheresis.

Mobilization: Mobilization of PBPC was studied in 50 heavily pretreated patients (median number of prior cycles = 9.5) with NHL‚ HD, or ALL (Amgen study 1). CFU-GM was used as the marker for engraftable PBPC. The median CFU-GM level on each day of mobilization was determined from the data available (CFU-GM assays were not obtained on all patients on each day of mobilization). These data are presented below.

The data from Amgen study 1 were supported by data from Amgen study 2 in which 22 pretreated breast cancer patients (median number of prior cycles = 3) were studied. Both the CFU-GM and CD34+ cells reached a maximum on day 5 at greater than 10-fold over baseline and then remained elevated with leukapheresis.

* n/a = not available  
  
  


In three studies of patients with prior exposure to chemotherapy‚ the median CFU-GM yield in the leukapheresis product ranged from 20.9 to 32.7 x 104/kg body weight (n = 105). In two of these studies where CD34+ yields in the leukapheresis product were also determined‚ the median CD34+ yields were 3.11 and 2.80 x 106/kg, respectively (n = 56). In an additional study of 18 chemotherapy-naive patients‚ the median CFU-GM yield was 123.4 x 104/kg.

Engraftment: Engraftment following NEUPOGEN®-mobilized PBPC is summarized for 101 patients in the following table. In all studies, a Cox regression model showed that the total number of CFU-GM and/or CD34+ cells collected was a significant predictor of time to platelet recovery.

In a randomized, unblinded study of patients with HD or NHL undergoing myeloablative chemotherapy (Amgen study 3)‚ 27 patients received NEUPOGEN®-mobilized PBPC followed by NEUPOGEN® and 31 patients received ABMT followed by NEUPOGEN®. Patients randomized to the NEUPOGEN®-mobilized PBPC group compared to the ABMT group had significantly fewer days of platelet transfusions (median 6 vs 10 days)‚ a significantly shorter time to a sustained platelet count greater than 20‚000/mm3 (median 16 vs 23 days)‚ a significantly shorter time to recovery of a sustained ANC greater than or equal to 500/mm3 (median 11 vs 14 days)‚ significantly fewer days of red blood cell transfusions (median 2 vs 3 days) and a significantly shorter duration of posttransplant hospitalization.

* n/a = not available  
  
  


Three of the 101 patients (3%) did not achieve the criteria for engraftment as defined by a platelet count greater than or equal to 20‚000/mm3 by day 28. In clinical trials of NEUPOGEN® for the mobilization of PBPC‚ NEUPOGEN® was administered to patients at 5 to 24 mcg/kg/day after reinfusion of the collected cells until a sustainable ANC (greater than or equal to 500/mm3) was reached. The rate of engraftment of these cells in the absence of NEUPOGEN® posttransplantation has not been studied.

Patients With Severe Chronic Neutropenia

Severe chronic neutropenia (SCN) (idiopathic‚ cyclic‚ and congenital) is characterized by a selective decrease in the number of circulating neutrophils and an enhanced susceptibility to bacterial infections.

The daily administration of NEUPOGEN® has been shown to be safe and effective in causing a sustained increase in the neutrophil count and a decrease in infectious morbidity in children and adults with the clinical syndrome of SCN.16 In the phase 3 trial‚ summarized in the following table‚ daily treatment with NEUPOGEN® resulted in significant beneficial changes in the incidence and duration of infection‚ fever‚ antibiotic use‚ and oropharyngeal ulcers. In this trial‚ 120 patients with a median age of 12 years (range 1 to 76 years) were treated.

* Incidence values were calculated for each patient‚ and are defined as the total number of events experienced divided by the number of 28-day periods of exposure (on-study). Median incidence values were then reported for each patient group.  
† Control patients were observed for a 4-month period.  
  


The incidence for each of these 5 clinical parameters was lower in the NEUPOGEN® arm compared to the control arm for cohorts in each of the 3 major diagnostic categories. All 3 diagnostic groups showed favorable trends in favor of treatment. An analysis of variance showed no significant interaction between treatment and diagnosis‚ suggesting that efficacy did not differ substantially in the different diseases. Although NEUPOGEN® substantially reduced neutropenia in all patient groups‚ in patients with cyclic neutropenia‚ cycling persisted but the period of neutropenia was shortened to 1 day.

As a result of the lower incidence and duration of infections‚ there was also a lower number of episodes of hospitalization (28 hospitalizations in 62 patients in the treated group vs 44 hospitalizations in 60 patients in the control group over a 4-month period [p = 0.0034]). Patients treated with NEUPOGEN® also reported a lower number of episodes of diarrhea‚ nausea‚ fatigue‚ and sore throat.

In the phase 3 trial‚ untreated patients had a median ANC of 210/mm3 (range 0 to 1550/mm3). NEUPOGEN® therapy was adjusted to maintain the median ANC between 1500 and 10‚000/mm3. Overall‚ the response to NEUPOGEN® was observed in 1 to 2 weeks. The median ANC after 5 months of NEUPOGEN® therapy for all patients was 7460/mm3 (range 30 to 30‚880/mm3). NEUPOGEN® dosing requirements were generally higher for patients with congenital neutropenia (2.3 to 40 mcg/kg/day) than for patients with idiopathic (0.6 to 11.5 mcg/kg/day) or cyclic (0.5 to 6 mcg/kg/day) neutropenia.