Interim results from eleven patients treated with sargramostim and nine patients receiving placebo showed that the mean changes of the MMSE score, Activities of Daily Living, and Delayed Word Recall score showed improvement in the sargramostim group, as compared with the placebo group by repeated measures mixed model analysis and/or permutation T-tests (p<0.05). These differences became non-significant by the follow-up visits   .
A randomised, double-blind, placebo-controlled trial investigated the prophylactic efficacy of sargramostim in reducing the incidence of nosocomial infections in very low birth weight neonates. 264 low birth weight infants were randomly assigned to placebo (n = 130) or recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) 8 µg/kg/day administered IV over 2h daily for 7 days then every other day for 21 days. There was no significant difference in the incidence of confirmed nosocomial infections in the neonates treated with GM-CSF vs placebo (54/134 [40%] vs 51/130 [39%]). In addition, there was no significant difference in the mean number of confirmed infections per infant between the placebo and GM-CSF groups. However, the absolute neutrophil and eosinophil counts were significantly elevated in the treated vs placebo groups on days 7, 21 and 28 post-therapy. The authors concluded that GM-CSFalone did not reduce the incidence of nosocomial infection in very low birth weight infants and that future studies should consider combination therapy such as GM-CSF + polyclonal or monoclonal immunoglobulins  .
Acute myelogenous leukaemia
In a double-blind, randomised, placebo-controlled study, sargramostim (250 µg/m2 administered by continuous IV infusion over 4h) was effective and well tolerated in patients with acute myelogenous leukaemia after both induction and consolidation therapy. 60% of patients in the sargramostim group achieved complete remission, compared with 44% in the placebo group. In addition, the median time for neutrophil recovery to 500/µl and 1,000/µl was significantly reduced to 13 days in the sargramostim group, compared with 17 days in the placebo group. Overall, treatment-related toxicity was reduced in the sargramostim group  .
When GM-CSF was used during induction chemotherapy in patients with acute myeloid leukaemia, it was shown to prevent infections, and saved costs associated with hospitalisation, laboratory tests, pharmacy services, blood products, diagnostic radiology, supplies, respiratory services and electrocardiograms. This retrospective analysis was based on data from the ECOG trial in which 88 patients were randomised to receive either GM-CSF 250 microg/m2/day given IV over 4h or placebo. The frequency of grade 4-5 infections was significantly lower in patients receiving GM-CSF than in placebo recipients (9.6 vs 36.2%, respectively). Furthermore, GM-CSF recipients had fewer grade 3-5 infections (52 vs 70%)  .
Interim results from the PROGRESS trial, an open label study of sargramostim in combination with an agressive colon cancer chemotherapeutic regimen, indicate that sargramostim helped to reduce the toxic effects associated with chemotherapy. Sargramostim was administered to 51 patients with metastatic colorectal cancer in an attempt to improve disease control with the Irinotecan (I), 5-Fluorouracil (F), and Leucovorin (L) regimen by decreasing therapy related toxicities, maintaining the shortened cycle schedule, and improving drug dose delivery. Patients received either a weekly (125 mg/m2 I, 500 mg/m2 F, 20 mg/m2 L) or biweekly combination of chemotherapy followed by sargramostim (250 µg/m2) on days 2-6 or 4-13 respectively. The biweekly chemotherapeutic regimen included: 180 mg/m2 I, 1000 mg/m2 F, 200 mg/m2 L administered on Day 1 and 400 mg/m2 F bolus, followed by 600 mg/m2 F infusion over 22 hours; 200 mg/m2 L on Day 2. Of the 33 evaluable patients, 27 had liver involvement, eight had lung involvement, and 11 had received prior F therapy. No disease progression was observed in 24 patients (73%, p=0.041), nine had progressed (27%), and five had died (15%). Mean dose intensity reached 81% of the planned I and F doses  .
In 39 patients with indolent non-Hodgkin's lymphoma, combination treatment with sargramostin and rituximab resulted in 36% of patients achieving a complete response (CR) and on overall response rate of 79%. In 14 patients antibody dependent cell cytotoxicity (ADCC) was measured post therapy and a greater, median, incremental ADCC activity in patients who had achieved a complete response (16%) than in those who had partial responses (6%)  .
in a phase II trial involving 45 patients with melanoma who had undergone surgery, disease-free survival, and overall survival at 21 months, was acheived in 60% and 64% of patients, respectively. Each patient received two years of therapy, in the first year patients received cycles of subcutaneous sargramostim followed by interleukin-2, in the second year patients received sargramostim alone unless resected recurrence was experienced  . Additional data from this trial showed that the median overall survival was 65 months and median recurrence-free survival was 5.6 months  .
In a phase II trial in patients with malignant melanoma, among 245 patients, the addition of sargramostim led to longer survival (median 17.5 vs 12.7 months)  .
the efficacy of sargramostim alone or in combination with monoclonal antibody (MAb) R-24 was investigated in a phase Ib study in 20 patients with malignant melanoma. Sargramostim (150 mg/m2/day) was administered SC od, on days 1-21 and MAb R-24 (10 or 50 mg/m2/day) was administered by continuous IV infusion on days 8-15. Six patients received sargramostim only. One course of treatment was administered to each patient. There were no partial responders, 2 patients had stable disease and 1 had no response in the sargramostim-only group. Of 14 evaluable patients who received sargramostim + MAb R-24, there were 2 partial responders, 3 patients had stable disease and 3 had no response. Both partial responders received sargramostim + MAb R-24 10 mg/m2/day, 1 of whom had a response duration of 2 months and the other patient was withdrawn from the study on day 14 with grade 4 toxicity  .
Sargramostim significantly increased the 1-year survival rate when administered to 30 patients with malignant melanoma following surgery. Patients receiving sargramostim had a median survival of > 20.6 months, compared with 11.2 months in a matched historical control group  .
In a trial in 35 patients with advanced prostate cancer, sargramostim (250 µg/m2/day) was administered SC on days 1-14 q4w (cohort 1, n = 22) or days 1-14 then 3/week (cohort 2, n = 13). The median overall survival duration was 15.8 months. Ten patients in cohort 1 had oscillating prostate-specific antigen (PSA) levels. The median maximal PSA decrease in this cohort was 37% and 5 patients had a > 50% decline in PSA levels on ≥ 1 occasion. The median response duration was 3.5 months. In cohort 2, only 1 patient did not have a decrease in PSA. Two patients had oscillating PSA levels. The median PSA decrease was 32.4%, but only 1 patient had a decrease of > 50% that was sustained for > 6 weeks. PSA levels in this patient declined from 77 ng/ml at baseline to 0.1 ng/ml and an improvement in a bone scan was evident, a response that was sustained for > 14 months  .
In a phase II trial of yeast-derived recombinant sargramostim as monotherapy in patients with advanced sarcomas, no objective responses were seen and patient accrual was stopped. The treatment cycle consisted of sargramostim 250 µg/m2 administered SC for 14 consecutive days followed by a rest period of 7 days between cycles. 15 patients were enrolled in the trial, of whom 14 had metastatic disease. The best response was 2 patients with stable disease lasting for ≥ 6 cycles  .
Small cell lung cancer
230 patients with limited-stage small cell lung cancer received chemotherapy and radiotherapy with or without sargramostim, which was administered on days 4-18 of each of 6 cycles. Those that received sargramostim had a lower complete response rate (36%) compared to those that did not (44%), but the difference was not significant. There was no significant difference in survival between the 2 groups  .
Bone marrow disorders
A total of 128 patients undergoing autologous bone marrow transplantation were enrolled in a randomised, double-blind, placebo controlled trial in order to evaluate the effects of sargramostim 250 µg/m2/day intravenously over 2h for 21 days after transplantation. Results from this study demonstrated that sargramostim accelerated the recovery of neutrophilis 7 days earlier than placebo and that in the sargramostim arm fewer infections were observed. A significant reduction in the number of days of administration of intravenous antibiotics was also observed when compared with the placebo group (24 vs 27 days). After 100 days from the transplantation, no difference was noted in the survival rate  .
Sargramostim was as effective as filgrastim in the treatment of chemotherapy-induced neutropenia according to results from a randomised trial. The results indicated that it may be clinically feasible to discontinue these agents when patients attain an absolute neutrophil count (ANC) of ≥ 1500/µl. There was no significant between-group difference in the mean number of days to reach an ANC of 500/µl, while the mean number of days to reach an ANC of 1000 and 1500/µl were slightly, but significantly, lower among filgrastim compared with sargramostim recipients. In about half the patients, ANC values did not change 48h after stopping growth factor therapy. The patients had developed an ANC of < 500/µl within 4 weeks of administration of chemotherapy and were randomised to receive SC sargramostim 250 µg/m2/day (n = 79), or SC filgrastim 5 µg/kg/day (102), until their ANC reached ≥ 1500/µl  .
Morbidity and mortality after chemotherapy is frequently caused by pancytopenia. Withdrawal of granulocyte-macrophage colony-stimulating factor (priming) induces haematopoietic stem-cell arrest. Therefore, administration of granulocyte-macrophage colony-stimulating factor prior to chemotherapy may decrease the severity and duration of pancytopenia by protecting haematopoietic stem cells from chemotherapy-induced cytotoxicity. In keeping with this hypothesis, sargramostim appeared to protect haematopoietic progenitor cells from cytotoxicity associated with chemotherapy in women with early-stage breast cancer. In this double-blind cross-over study, patients (n = 20) receiving 4 courses of cyclophosphamide and doxorubicin were randomised to receive priming with sargramostim or placebo on days 5 to 1 before each course. On day 16, patients had a higher mean neutrophil count and a lower proportion exhibited severe neutropenia (< 500/µl). The times to neutrophil and platelet nadirs were significantly shorter after priming compared with before  .
the phase III N.O.V.E.L 4 study, evaluating sargramostim in patients with moderate-to-severly active Crohn's disease, failed to meet its primary endpoints. in this double-blind study, 286 patients were randomised to receive, via subcutaneous injection, sargramostim 6µg/kg/day, or placebo, for eight weeks. Response was defined as a Crohn's Disease Activity Index (CDAI) decrease of ≥ 100 points, and remission as a CDAI score of ≤ 150 points. No significant differences were seen between treatment with sargramostim and placebo, with respect to the primary enpoints of response and/or remission at eight weeks; remission rates for sargramostim- and placebo-treated patients were 22.3% and 22.6%, respectively. Response rates were 41.1% and 33.3%, respectively. However, a trend towards treatment benefit was demonstrated in the trial and a secondary composite remission/response analysis showed sargramostim to be numerically better than placebo   .
results from the phase II, double-blind, N.O.V.E.L 2 study, investigating sargramostim in patients with active corticosteroid-dependent Crohn's disease, demonstrated that the drug was signifacntly more effective than placebo for induction of steroid-free clinical remission. Patients (n = 129) requiring 10-40mg of prednisone or equivalent, were randomised to receive, via subcutaneous injection, sargramostim 6µg/kg/day, or placebo, for 12-22 weeks depending on baseline corticosteroid dose. The primary endpoint was achieved, with sargramostim treatment being significantly more effective at inducing corticosteroid-free clinical remission (CDAI ≤ 150) four weeks after steroid withdrawl  .
A 20-22% improvement in total IBDQ (inflammatory bowel disease questionnaire) from baseline was reported for patients receiving sargramostim, versus 7-13% for placebo. In concurrence with this, 12- 20% improvements in the Physical Component Summary score were also reported for patients receiving treatment  .
In the multicentre, double-blind, phase II, N.O.V.E.L. 1 (New Opportunities to Verify Evolving Logic in Crohn's disease) study, 124 patients with moderately to severely active Crohn′s disease were randomised to receive sargramostim or placebo for 57 days. 48% of patients treated with sargramostim had a decrease of the Crohn's disease activity index (CDAI) of more than 100 points, and 40% of patients achieved clinical remission by the end of the study (CDAI less than or equal to 150), versus 26% and 19% of the placebo-treated patients, respectively (p=0.013 and p=0.014, respectively). 54% of patients treated with sargramostim achieved a CDAI decrease of more than 70 points, versus 44% of placebo-treated patients (p=0.275). These results were achieved without the use of steroids and/or immunosuppressants. The proportion of patients achieving CDAI response (70 and 100 points) and remission were significantly different from placebo at day 29. Significant differences between the sargramostim and placebo groups were observed in the time to 100 point response (30 days vs. not reached, p=0.003) and remission (56 days vs. not reached, p=0.004)   .
In the above phase II study, patients who responded at the end of treatment (57 days) were followed for up to six months. In the 30-day follow-up period, 42% of patients treated with sargramostim showed a significantly sustained improvement in clinical response compared to placebo recipients (21%). While, 33% of patients treated with sargramostim achieved significant clinical remission compared to placebo recipients (14%). In sargramostim treated patients, the Median time to loss of ≥70 points in the CDAI and ≥100 points was 10 weeks and 8 weeks, respectively. The median time to loss of remission (CDAI score > 150) was 8 weeks, while the median time to disease relapse (CDAI > 220) after remission induction was 10 weeks. Response was maintained beyond six-month follow-up in 15% of patients   .
Interim data from the N.O.V.E.L. 5 trial (n = 60) demonstrated that sargramostim 6 µg/kg/day treatment for up to 6 cycles induced response and remission among patients with moderately-to-severely active Crohn's disease. Median reduction in CDAI score after one cycle was 172 with 53% of patients achieving a 100 point response and 40% of patients achieving remission (CDAI ≤ 150). Response and remission rates were similar to those established in previous studies  .
Results from a phase I/II trial in paediatric patients (6-16yrs) with active Crohn's disease showed a remission/response rate of 83% (15/18 patients)  .
in a dose-escalating, pilot study, 15 patients with moderate-to-severe idiopathic Crohn's disease treated withsargramostim (4, 6 or 8 µg/kg/day) showed a significant decrease in disease symptoms over the eight-week course of therapy, as measured by the Crohn's disease activity index (CDAI). At 8-weeks, the mean CDAI significantly decreased by 190 points from baseline. A total of 75%, 85% and 75% of patients in the GM-CSF 4, 6 and 8 µg/kg/day treatment groups, respectively, responded to therapy. In total, 12 patients achieved a clinical response to therapy and 8 achieved clinical remission  .
Sargramostim had therapeutic benefit as adjunctive treatment of refractory oropharyngeal candidiasis in patients with AIDS. In 3 case reports, patients who had failed therapy with azoles (fluconazole or itraconazole) or amphotericin B were treated daily with sargramostim and either fluconazole or amphotericin B for 14 days. Clinical resolution of candidiasis had occurred in all 3 patients by day 14; however, despite continuation of the anti-fungal therapy, relapse of disease occurred in all 3 patients within 2 weeks of discontinuation of sargramostim therapy  .
In a prospective, open-label phase II trial, sargramostim therapy caused improvement in > 50% of patients with pulmonary alveolar proteinosis. Twenty-five patients with pulmonary alveolar proteinosis and circulating antibody to granulocyte macrophage colony stimulating factor (GM-CSF) received a starting dose of sargramostim 250 mg/day that was rapidly increased to a maximum of 18 µg/kg/day. Treatment duration was 12 weeks (n = 5) and ≥ 24 weeks (n = 18); 21 patients completed the trial. The mean duration of follow-up (post-therapy) was 39 months. There was radiographic and A-a (alveolar to arterial) gradient improvement in 13 patients. In patients responding to sargramostim therapy, the A-a gradient decreased from 36.2mm Hg (baseline) to 17.9mm Hg at follow-up; in non-responders, it increased from 40.1mm Hg (baseline) to 49.3mm Hg at follow-up. Prior to the trial, 21/25 patients had received whole lung lavage; during the trial, 14 patients remained free of whole lung lavage, but 11 required it for an average of two sessions  .
71 patients with chronic hepatitis C virus (HCV) infections were treated with sargramostim (n = 19) or interferon α-2b alone (n = 25) or with sargramostim (n = 27) for 6 months. Treatment with interferon α-2b alone and with sargramostim resulted in biochemical responses in 54.2% and 31.8% of patients, respectively, with sustained biochemical responses reported in 1 patient each from these 2 groups. 13 patients receiving interferon α-2b monotherapy and 18 who also received sargramostim were viraemic at 3 months. Mean HCV RNA titre was significantly reduced, relative to baseline, with decreases of 10% for patients receiving interferon α-2b alone and 14% of those also receiving sargramostim  .
No biochemical or virological responses occurred in patients given sargramostim (65, 125 or 250 µg/m2) monotherapy, and mean HCV RNA levels were not significantly reduced, relative to baseline, by any sargramostim dose used  .
In a phase III study conducted in Brazil, 105 AIDS patients (CD4 cell count < 300 cells/mm3) received either sargramostim (125 µg/m2) or placebo, SC twice weekly, in combination with zidovudine monotherapy or combination nucleoside analogue therapy including zidovudine. At the end of 6 months, median viral load was reduced -0.60 log10 in the sargramostim group compared with -0.07 log10 in the placebo group. Decreases of ≥ 1 log10 copies/ml occurred in 20/53 (38%) sargramostim recipients vs 9/51 (17%) patients in the placebo group. Viral load was reduced to < 500 copies/ml at ≥ 2 evaluations in 11% of the sargramostim group, compared with 2% of the placebo group. Mean increases in CD4+ cell count for sargramostim recipients after 1, 3 and 6 months were 57, 64 and 35 cells/µl, respectively. In the placebo group, CD4+ cell count increased by 22 and 12 cells/µl after 1 and 6 months, respectively, but decreased by 2 cells/µl at month 3. The difference between the placebo and sargramostim goups was only statistically significant at 3 months. 80% of sargramostim recipients and 59% of the placebo group had increases in CD4+ cell count of ≥ 30%; this difference was statistically significant. Significantly fewer sargramostim recipients had new mutations at 6 months (50% vs 80% for placebo)  .
Sargramostim demonstrated beneficial effects in patients with advanced HIV infection according to the results of a phase III study conducted in Canada and the USA. In this multicentre study, 309 such patients were randomised to receive SC sargramostim 250µg (n = 155) or placebo, 3 times weekly for 24 weeks. After 1 month, sargramostim recipients had increases from baseline in total lymphocyte and CD4 cell counts. A significantly greater proportion of sargramostim, compared with placebo, recipients maintained undetectable viral loads. Compared with placebo recipients, sargramostim recipients had a significantly lower incidence of infections or death; the median time to first infection or death was also significantly longer. At week 24, increases in CD4+ cell counts, relative to baseline, had occurred in 31% of sargramostim recipients, but none of the placebo group. Among patients with baseline CD4+ counts of 50-100 cells/µl, increases occurred in 52% given sargramostim, compared with 6% of those given placebo. HIV RNA level was < 400 copies/ml at baseline and at week 24 in significantly more patients in the sargramostim group (83% vs 54%)   .
Results from a study in 20 patients with HIV indicated that treatment with SC sargramostim (250µg 3/week) in addition to indinavir- or ritonavir-containing antiretroviral therapy was significantly more effective than treatment with the antiretroviral regimens + placebo. Median maximum decreases in HIV RNA levels, relative to baseline, were 0.40 log10copies/ml for the sargramostim group, compared with 0.33 log10copies/ml for placebo recipients; decreases of ≥ 0.5 log10copies/ml occurred at ≥ 2 time points in the study in 5/10 and 1/10 patients in the sargramostim and placebo groups, respectively. Mean maximal increase in CD4 cell count was 129.6 cells/µl with sargramostim, compared with 57 cells/µl with placebo, and increases of ≥ 30% over baseline occurred in 7 and 3 patients in the sargramostim and placebo groups, respectively  .