High-dose ifosfamide: circumvention of resistance to standard-dose ifosfamide in advanced soft tissue sarcomas.

1995 ◽  
Vol 13 (7) ◽  
pp. 1600-1608 ◽  
Author(s):  
A Le Cesne ◽  
E Antoine ◽  
M Spielmann ◽  
T Le Chevalier ◽  
E Brain ◽  
...  

PURPOSE The study was designed to assess the toxicity and activity of high-dose ifosfamide (HDI) administered by continuous infusion at a dose of 4 g/m2/d over 3 days every 4 weeks in adult patients with advanced soft tissue sarcomas (ASTS) pretreated with doxorubicin and/or a standard-dose ifosfamide (SDI)-containing regimen. PATIENTS AND METHODS Between January 1991 and November 1993, 40 patients with progressive ASTS were entered onto the study. Twenty-eight patients had been pretreated with a multidrug regimen that contained SDI and were classified as follows: SDI-refractory (n = 21), SDI-resistant (n = 2), and indeterminate SDI-sensitive (n = 5). Patients were treated until progression or major toxicity. RESULTS One hundred forty-seven cycles of HDI were administered. Neutropenia was dose-limiting, with 100% of patients experiencing grade 3 to 4 toxicity and 12 admissions for febrile neutropenia (30% of patients). Neurotoxicity (17% of patients) was significantly associated with acute renal failure (n = 4) (P < .001), grade 4 thrombocytopenia (P < .01) and febrile neutropenia (P = .048). Chronic renal toxicity (n = 4) was significantly associated with retroperitoneal masses and/or prior nephrectomy (P = .008). Partial responses (PRs) were observed in 12 of 36 assessable patients (33%) and eight patients (22%) experienced disease stabilization. All but one response occurred in patients pretreated with SDI, with five PRs among SDI-refractory patients. Leiomyosarcomas appear resistant to HDI. The median response duration was 8 months (range, 6 to 13+) and the median overall survival time was 12 months. CONCLUSION The activity of HDI in these pretreated ASTS patients and the apparent circumvention of SDI resistance suggest a real dose-response relationship for ifosfamide and deserve further evaluation. Although toxic, this treatment appears feasible and manageable using routine clinical support. Since prophylaxis of ifosfamide-induced renal damage remains unknown, frequent monitoring of renal and tubular functions during therapy is highly recommended.

2000 ◽  
Vol 18 (14) ◽  
pp. 2676-2684 ◽  
Author(s):  
A. Le Cesne ◽  
I. Judson ◽  
D. Crowther ◽  
S. Rodenhuis ◽  
H.J. Keizer ◽  
...  

PURPOSE: This randomized multicenter study was designed to compare the activity of a high-dose doxorubicin-containing chemotherapy regimen with a conventional standard-dose regimen in adult patients with advanced soft tissue sarcomas (ASTS). PATIENTS AND METHODS: Between 1992 and 1995, 314 patients were randomized to receive a standard-dose regimen (arm A), containing doxorubicin (50 mg/m2 on day 1) and ifosfamide (5 g/m2 on day 1), or an intensified regimen (arm B), combining doxorubicin (75 mg/m2 on day 1), the same ifosfamide dose, and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF; sargramostim, 250 μg/m2 on days 3 to 16); all courses were repeated every 3 weeks. RESULTS: The median age of the 294 eligible patients was 50 years. They received a median of five chemotherapy cycles. The median dose and relative doxorubicin dose-intensity achieved were 245 mg and 97% in arm A and 360 mg and 99% in arm B, respectively. Thirty-eight percent and 23% of patients presented with leiomyosarcomas and liver metastases, respectively. Objective responses were observed in 31 (21%) of 147 assessable patients in arm A and in 31 (23.3%) of 133 in arm B (P = .65). No change was observed in 41.6% and 46.2% of patients in arm A and B, respectively. Progression-free survival (PFS) was significantly longer in the intensive arm (P = .03). The median duration of the time to progression was 19 weeks in the conventional arm and 29 weeks in the intensified arm. There was no difference in overall survival (P = .98) between the two therapeutic arms. Toxicities were manageable in both arms. A grade 3/4 neutropenia and infection occurred in 92% and 4.6% of patients in arm A, respectively, and in 90% and 16.6% in arm B, respectively. Grade 3/4 thrombocytopenia was more frequent in arm B. CONCLUSION: The use of rhGM-CSF allowed safe escalation of chemotherapy doses. Despite a 50% increase of the doxorubicin dose-intensity, the high-dose regimen failed to demonstrate any impact on survival in patients with ASTS. The low complete response rate, the high incidence of leiomyosarcomas, and liver metastases may in part explain these results. However, the lengthening of the PFS in the intensive arm, because of the quality of stable disease and inappropriate tumor evaluation policies that potentially lead to an underestimation of antitumor activity, does not definitively refute the use of a high-dose chemotherapy regimen in selected patients with ASTS.


Sarcoma ◽  
2006 ◽  
Vol 2006 ◽  
pp. 1-8 ◽  
Author(s):  
A. López-Pousa ◽  
J. Martín ◽  
J. Montalar ◽  
R. de las Peñas ◽  
J. García del Muro ◽  
...  

Background.To explore the tolerance and the activity of high-dose ifosfamide (IFOS) combined with doxorubicin (DXR) at 50 mg/m2every 4 weeks in patients with soft tissue sarcomas.Methods.DXR was given IV bolus and IFOS by continuous infusion at 2 g/m2/day. Initial IFOS dose (12 g/m2) was adjusted to 10, 13, or 14 g/m2according to toxicity.Results.Seventy patients received 277 cycles (median 3 cycles, range 1–10), 34% with IFOS dose increased, 30% decreased, and 48% delivered at 12 g/m2. Toxicity grade 4 occurred on granulocytes (67% of patients) or platelets (19%), 54% had febrile neutropenia, 31% grade 3/4 asthenia, and 26% abandoned the study due to toxicity. Three toxic deaths occurred. In 57 non-GIST patients objective activity was 45.6% (95% CI, 32 to 58%).Conclusion.At least 4 cycles were tolerated by 71% of patients, most receiving DXR 50 mg/m2plus IFOS 10–12 g/m2, with substantial toxicity.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7011-7011 ◽  
Author(s):  
Courtney Denton Dinardo ◽  
Anthony Selwyn Stein ◽  
Eytan M. Stein ◽  
Amir Tahmasb Fathi ◽  
Olga Frankfurt ◽  
...  

7011 Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC > 0.5×109/L and platelets > 50×109/L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.


1997 ◽  
Vol 15 (6) ◽  
pp. 2378-2384 ◽  
Author(s):  
S R Patel ◽  
S Vadhan-Raj ◽  
N Papadopolous ◽  
C Plager ◽  
M A Burgess ◽  
...  

PURPOSE To evaluate the efficacy and feasibility of high-dose ifosfamide (HDI) at a total dose of 14 g/m2 per cycle with mesna in combination with granulocyte colony-stimulating factor (G-CSF) in adult patients with sarcomas. PATIENTS AND METHODS Between July 1991 and February 1994, 74 patients with sarcomas (37 bone and 37 soft tissue) were treated on two simultaneous phase II studies that evaluated HDI given as a continuous infusion over 74 hours. G-CSF was started on day 5 at 5 microg/kg/d until recovery of granulocyte count. Additionally, between March 1993 and March 1994, 15 similar patients with previously treated bone or soft tissue sarcomas were treated on a pilot study in which the same total dose of ifosfamide was administered by a bolus schedule, along with mesna and G-CSF. Patients were treated until maximal response, and where possible, surgical resection of gross disease was performed. RESULTS Seventy-two patients from the phase II study using continuous infusion are assessable for response. Four complete responses (CRs) and 17 partial responses (PRs) were noted, for an overall response rate of 29% (95% confidence interval [CI], 19% to 39%). The response rate was 40% (95% CI, 24% to 56%) for bone sarcomas and 19% (95% CI, 6% to 32%) for soft tissue sarcomas. Fourteen patients from the pilot study that used a bolus schedule are assessable for response. One CR and seven PRs were noted, for an overall response rate of 57% (95% CI, 31% to 83%) and a response rate of 45% for soft tissue sarcomas. Two patients developed grade 3 to 4 renal toxicity, three developed grade 3 CNS toxicity, one had possible grade 3 cardiac toxicity, and two developed severe painful peripheral neuropathy. There were no treatment-related deaths. CONCLUSION HDI at 14 g/m2 with mesna and G-CSF is an active salvage regimen for patients with bone and soft tissue sarcomas. There is a definite positive dose-response curve, and bolus administration appears to be more active than continuous infusion.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9514-9514 ◽  
Author(s):  
Georgina V. Long ◽  
Caroline Robert ◽  
Marcus O. Butler ◽  
Felix Couture ◽  
Matteo S. Carlino ◽  
...  

9514 Background: KEYNOTE-029 cohort 1B showed substantial efficacy for standard-dose pembro + 4 doses of ipi 1 mg/kg with lower rate of grade 3-5 toxicity than reported for standard-dose nivolumab + ipi in patients (pts) with advanced melanoma. In KEYNOTE-029 cohort 1C, we assessed the toxicity and antitumor activity of standard-dose pembro plus 2 alternate ipi doses (NCT02089685). Methods: Eligible pts with previously untreated stage III/IV melanoma, ECOG PS 0-1, and no active CNS metastases were randomized 1:1 to pembro 200 mg Q3W for 24 mo + 4 doses of ipi 50 mg Q6W (arm A) or pembro 200 mg Q3W for 24 mo + 4 doses of ipi 100 mg Q12W (arm B). Primary endpoints were the grade 3-5 treatment-related AE (TRAE) rate and ORR (RECIST v1.1, central review). With 50 pts per arm and compared with other anti–PD-1 + ipi regimens, a grade 3-5 TRAE rate ≤26% would suggest a meaningful reduction in toxicity and an ORR ≥48% would suggest no decrease in efficacy. Data cutoff date was Jul 17, 2018, and will be updated. Results: 102 pts were randomized: 51 to each arm. Median age was 63.5 y, 70% were male, 15% had ECOG PS 1, 34% had BRAF mutation, and 30% had elevated LDH at baseline. With 9.4 mo median follow-up, 69% of pts in arm A and 71% in arm B remained on treatment. All pts in arm A and 96.1% in arm B had ≥1 TRAE; grade 3-5 TRAE rates were 22% in arm A and 33% in arm B. 1 pt had a grade 5 TRAE (autoimmune myocarditis; arm A). ORR was 49% (95% CI 35-63) in arm A, including 7 CRs and 18 PRs, and 53% (95% CI 39-67) in arm B, including 6 CRs and 21 PRs. An additional 16 pts in each arm had SD or non-CR/non-PD, leading to a DCR of 80% and 84%, respectively. Median response duration was not reached in either arm (range 1.4+ to 9.6+ in arm A, 1.4+ to 9.8+ in arm B). Updated data based on longer follow-up will be presented. Conclusions: Standard-dose pembro + ipi 50 mg Q6W and standard-dose pembro + ipi 100 mg Q12W showed robust antitumor activity in this initial analysis. Both regimens appeared to have a lower rate of grade 3-5 TRAEs than previously observed. Longer follow-up and randomized studies are needed to confirm that these regimens reduce toxicity without compromising efficacy compared with other anti–PD-1 and ipi combinations. Clinical trial information: NCT02089685.


2005 ◽  
Vol 23 (1) ◽  
pp. 105-112 ◽  
Author(s):  
Francis P. Worden ◽  
Jeremy M.G. Taylor ◽  
Janet S. Biermann ◽  
Vernon K. Sondak ◽  
Kirstin M. Leu ◽  
...  

Purpose The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. Patients and Methods Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m2 and either SD ifosfamide (1.5 g/m2/d, days 1 through 4) or HD ifosfamide (3.0 g/m2, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. Results The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. Conclusion When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.


2002 ◽  
Vol 20 (5) ◽  
pp. 1329-1334 ◽  
Author(s):  
Massimo Lopez ◽  
Patrizia Vici ◽  
Luigi Di Lauro ◽  
Silvia Carpano

PURPOSE: To evaluate the maximum-tolerated dose and the clinical efficacy of epirubicin in patients with advanced soft tissue sarcoma. PATIENTS AND METHODS: Sixty-one patients were treated at three different epirubicin dose levels: 140 mg/m2 (six patients), 160 mg/m2 (52 patients), and 180 mg/m2 (three patients). Cycles were repeated every 3 weeks for a maximum of eight cycles. The first two dose levels proved to be feasible and safe without dose-limiting toxicity (DLT). Because the first three patients entering the third dose level experienced DLT, subsequent patients received the next lower dose level. RESULTS: The overall response rate was 44% (95% confidence interval, ± 12%), with six complete (10%) and 21 partial (34%) responses. Responses seemed related to epirubicin dose level, because the response rate was 17%, 44%, and 100% for the three dose levels (χ2 test for trend, P = .02). Median response duration, median time to progression, and median overall survival were 10, 8, and 15 months, respectively. Myelosuppression was the most frequent side effect, with grade 3 or 4 neutropenia occurring in 79% of the patients; 31% of patients were febrile. Nonhematologic toxicity was mainly grades 1 and 2. The mean epirubicin dose-intensity was 49 mg/m2 per week. CONCLUSION: The third epirubicin dose level (180 mg/m2) was the maximum-tolerated dose. The recommended drug dose for clinical use is 160 mg/m2 every 3 weeks with hematopoietic support. Single high-dose epirubicin is effective as first-line treatment and should be preferentially used whenever a high response rate is important to allow the resection of an otherwise unresectable disease or whenever it might result in a significant symptomatic benefit.


1998 ◽  
Vol 16 (4) ◽  
pp. 1438-1443 ◽  
Author(s):  
P Reichardt ◽  
J Tilgner ◽  
P Hohenberger ◽  
B Dörken

PURPOSE To evaluate the feasibility and toxicity of the combination of full-dose epirubicin (EPI) and high-dose ifosfamide (IFO) with granulocyte colony-stimulating factor (G-CSF) support and to determine the clinical efficacy in terms of response and impact on survival. PATIENTS AND METHODS Forty-six consecutive, previously untreated patients with locally advanced or metastatic high-grade soft tissue sarcomas were treated with IFO 2.5 g/m2/d as a continuous infusion on days 1 to 5 and EPI 45 mg/m2/d as a continuous infusion on days 2 and 3 every 3 weeks. G-CSF 5 microg/kg/d subcutaneously (s.c.) was given on days 6 to 15 or until recovery of leukocytes after all cycles. Response evaluation was performed every two cycles and responding patients were treated with up to six cycles. All patients were evaluated for resectability of residual local or metastatic disease and underwent surgery if possible. RESULTS All patients experienced grade 3 or 4 myelosuppression. Other toxicities were mild. The overall response rate was 52%, with a complete remission (CR) rate of 22% after chemotherapy alone. Eight additional patients were rendered free of tumor (no evidence of disease [NED]) by surgical procedures. The median overall survival of all patients is 24 months. The CR/NED patients (39%) have a significantly superior survival time compared with all other patients. Thirteen of these 18 patients (72%) are alive, nine free of tumor, with a median follow-up time of 33 months. CONCLUSION This dose-intensive combination chemotherapy is toxic but feasible and produced a high number of partial remissions (PRs) and especially CRs, which resulted in prolonged survival.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5084-5084
Author(s):  
K. Oechsle ◽  
C. Bokemeyer ◽  
F. Honecker ◽  
F. Mayer ◽  
C. F. Waller ◽  
...  

5084 Background: Treatment of pts with cisplatin-refractory GCT remains a therapeutic challenge. The present phase II study investigates the toxicity and activity of triple combination of gemcitabine/oxaliplatin/paclitaxel (GOP) in pts with multiple relapse or cisplatin- refractory GCT. Patients and Methods: Between 04/03 - 10/06, 41 patients (pts) refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy plus autologous peripheral blood stem cell transplantation (PBSCT) received 800 mg/m2gemcitabine, 80 mg/m2 paclitaxel, both on days 1+8, and oxaliplatin 130 mg/m2 on day 1 of a three week cycle for at least 2 cycles. Treatment was continued until tumor progression or a maximum of 8 cycles. Results: Pts were pretreated with a median number of 2 previous lines of platin-based chemotherapy (range, 1 - 3) and 78 % had relapsed after either first- (39%) or second-line high-dose chemotherapy (39%) with PBSCT. Responses: 5% of the pts achieved a complete response (CR), 47% a partial response and 20% a disease stabilisation. 20% of the pts underwent a secondary complete tumor resection resulting in a total NED-rate of 22%. After a median follow up time of 5 months (mos) (0 - 20+) 17% of the pts are continuously disease-free with a median response duration of 8 mos (1–17+). Median progression free and overall survival was 3 mos (1–17+) and 6 mos (1–19+), respectively. Toxicity was acceptable. 51% of 150 cycles could be applied without dose modifications or delay. Leucocytopenia grade 3/4 was observed in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients. Grade 3/4 nonhematologic toxicities (diarrhoea, nausea and neurotoxicity) occurred in one patient each (2%). Conclusion: The triple combination chemotherapy with gemcitabine, oxaliplatin and paclitaxel is feasible and effective in patients with cisplatin-refractory or multiply relapsed germ cell tumors exhibiting an overall response rate of >50% and prolonged survival in about 20% of the pts. Despite a significant rate of grade 3/4 thrombocytopenia the overall toxicity profile is acceptable. No significant financial relationships to disclose.


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