Determination of the Maximum Tolerated Dose of Cyclophosphamide in Conjunction with High-Dose Etoposide and Carboplatin Followed by Autologous CD34+ Hematopoietic Rescue in Pediatric Patients with Recurrent/Refractory Solid Tumors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5462-5462
Author(s):  
Michelle P. Hudspeth ◽  
Barbara Duffy ◽  
Stephen Noga ◽  
Steven Goodman ◽  
Curt I. Civin ◽  
...  
Keyword(s):  
Continuous Infusion ◽  
Solid Tumors ◽  
Median Time ◽  
Pediatric Patients ◽  
Cardiac Toxicity ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Cyclophosphamide (Cy) is an alkylating agent utilized in almost all preparative regimens for hematopoietic stem cell transplantation, and in vitro sensitivity has been demonstrated with carboplatin and etoposide. Multiple previous studies have involved this combination of agents; however, they almost exclusively utilized a fixed dose of Cy and/or bolus administration. The potential fatal cardiac toxicity of Cy is likely related to high peak concentrations of active metabolites from bolus dosing. Additionally, some evidence exists that the increased metabolism of Cy with continuous infusion has a therapeutic benefit. The objective of this study was to determine the maximum tolerated dose (MTD) of continuous infusion Cy with fixed dose etoposide (2400 mg/m2) and carboplatin (2175 mg/m2) followed by autologous CD34+ hematopoietic rescue in pediatric patients with recurrent/refractory solid tumors. Twenty patients were enrolled, and fourteen patients completed therapy on study. The MTD of Cy was 60 mg/kg/24 hr by continuous 60 hr infusion on days -4 to -2 for a total dose of 150 mg/kg. Alopecia, stomatitis and nausea were the most common toxicities. The single episode of direct cardiac toxicity was reversible. Two Grade IV toxicities occurred, consisting of diarrhea in one patient and coma in another patient who recovered and remains a long-term survivor. All patients were evaluable for neutrophil engraftment, with a median time to ANC > 200/μl of 11 days (range 7–30 days). Thirteen of the fourteen patients were evaluable for platelet engraftment, with a median time to platelet count of 20,000/μl independent of transfusion of 21 days (range 11–72 days). Six out of the fourteen patients remain alive greater than five years after study completion. The MTD of Cy was lower than expected. These results suggest that autoinduction of Cy metabolism (repeated administration of Cy at 24 hour intervals leads to increased hepatic cytochrome enzymes) could be a primary factor in the determination of the MTD. Future studies should aim to further characterize the pharmacokinetics and effectiveness of continuous infusion Cy in pediatric patients.

A phase I-II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients.

1990 ◽  
Vol 8 (7) ◽  
pp. 1239-1245 ◽  
Author(s):  
J P Eder ◽  
A Elias ◽  
T C Shea ◽  
S M Schryber ◽  
B A Teicher ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Standard Dose ◽  
Autologous Bone Marrow Transplantation ◽  
Maximum Tolerated Dose ◽  
Cross Resistance ◽  
Testis Cancer ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Dose Therapy

The principles of dose-response and combination chemotherapy were basic to the design of the initial curative standard-dose treatment regimens for leukemias, lymphomas, and testis cancer. Agents were selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. A fourth principle in the design of curative regimens was to combine agents with different mechanisms of action to avoid cross-resistance. Based on these principles, combinations of the highest tolerated doses of active noncross-resistant agents are required to decrease the emergence of drug resistance and achieve optimum cytotoxicity. Hematopoietic stem-cell support provides a mechanism for significantly increasing the doses of active agents, a strategy that has resulted in the cure of 10% to 50% of selected patients with lymphoma who could not be cured with standard-dose therapy. The lack of sufficiently effective cytoreductive conditioning regimens remains the major impediment to improving the high-dose therapy of patients with solid tumors. In this study, 27 patients with solid tumors were treated with a combination of cyclophosphamide, thiotepa, and carboplatin (CTCb) in a phase I-II study. Severe mucositis and neurotoxicity were dose-limiting. The maximum-tolerated dose (MTD) of the combination was 6.0 g/m2 of cyclophosphamide, 500 mg/m2 of thiotepa, and 800 mg/m2 of carboplatin. There were two deaths (7%) of sepsis, and an overall response rate of 72% in refractory tumors (81% in breast cancer). CTCb is a combination with low morbidity and high cytoreductive efficacy designed to exploit the principles of curative cancer chemotherapy.

Phase I Clinical Trial of Oxaliplatin in Children and Adolescents With Refractory Solid Tumors

2007 ◽  
Vol 25 (16) ◽  
pp. 2274-2280 ◽  
Author(s):  
Sheri L. Spunt ◽  
Burgess B. Freeman ◽  
Catherine A. Billups ◽  
Valerie McPherson ◽  
Raja B. Khan ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Dose Intensity ◽  
Sensory Neuropathy ◽  
Maximum Tolerated Dose ◽  
Adverse Effect Profile ◽  
Fixed Dose ◽  
Hematologic Toxicity ◽  
Grade 3

Purpose To evaluate the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK), and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors and to determine whether carbamazepine reduces oxaliplatin-induced neurotoxicity. Patients and Methods Three regimens of oxaliplatin (given intravenously over 2 hours) were tested: regimen A (100 mg/m2, 130 mg/m2, or 160 mg/m2 every 3 weeks to determine the MTD of oxaliplatin); regimen B (to determine whether carbamazepine starting 24 hours before and ending 48 hours after oxaliplatin reduced the dose-limiting neurotoxicity and increased the MTD of regimen A); and regimen C (to evaluate the safety of a fixed dose two-thirds the MTD of regimen A given every 2 weeks [more frequent administration but comparable dose intensity]). Results Twenty-six patients were enrolled on regimens A (n = 11), B (n = 6), and C (n = 9). The DLT was grade 3 pharyngolaryngeal dysesthesia, sensory neuropathy, and ataxia at 160 mg/m2. The MTD was 130 mg/m2 every 3 weeks. At the MTD, the median clearance rate of ultrafiltrable platinum was 9.7 L/h/m2 (range, 6.5 to 15.5 L/h/m2). Addition of carbamazepine permitted dose escalation to 160 mg/m2 without DLT. DLT was not observed with a fixed dose of 85 mg/m2 given every 2 weeks. On all regimens, hematologic toxicity was mild. No significant nephrotoxicity, ototoxicity, or cumulative neurologic toxicity was observed. Conclusion The DLT, MTD, PK, and adverse effect profile of oxaliplatin in pediatric patients with refractory solid tumors are similar to those observed in adults. Carbamazepine may reduce the dose-limiting neurotoxicity of oxaliplatin.

scholarly journals High dose chemotherapy with autologous hematopoietic stem cell support for solid tumors other than breast cancer in adults

2006 ◽  
Vol 17 (10) ◽  
pp. 1479-1488 ◽  
Author(s):  
P. Pedrazzoli ◽  
J.A. Ledermann ◽  
J.-P. Lotz ◽  
S. Leyvraz ◽  
M. Aglietta ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Solid Tumors ◽  
Hematopoietic Stem Cell ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Stem Cell Support ◽  
Cell Support

scholarly journals Symptom Burden of Busulfan and Melphalan Versus Melphalan Alone for Multiple Myeloma

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 681-681
Author(s):  
Loretta A. Williams ◽  
Muzaffar H. Qazilbash ◽  
Qiuling Shi ◽  
Qaiser Bashir ◽  
Huei K. Lin ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Muscle Weakness ◽  
Symptom Severity ◽  
Conditioning Regimen ◽  
Symptom Burden ◽  
Phase Iii ◽  
Dry Mouth ◽  
Fixed Dose ◽  
High Dose ◽  
Hematopoietic Stem

Abstract Background: High-dose melphalan 200 mg/m2 (Mel) is the standard for autologous hematopoietic stem cell transplantation (autoHSCT) for multiple myeloma. Retrospective analyses suggested that a combination of busulfan and melphalan (Bu-Mel) may be associated with a longer progression-free survival (PFS). A secondary aim of a randomized, phase III trial that compared the safety and efficacy of Bu-Mel vs Mel was to compare the symptom burden of the two regimens. Symptom burden is the combined impact of disease- and therapy-related symptoms on patient functional ability. Methods: Patients were randomized to Bu-Mel (Bu 130 mg/m2 daily for 4 days, either as a fixed dose or to target an average daily area under the curve of 5000 μmol-min, followed by 2 daily doses of Mel 70 mg/m)2or Mel (Mel 100 mg/m2 daily for 2 days). A subset of patients completed the 20 symptom severity and 6 interference items of MD Anderson Symptom Inventory for Multiple Myeloma (MDASI-MM) prior to the start of the treatment regimen and weekly for 4 weeks post autoHSCT. Symptoms and interference are rated on 0-10 scales (0 = none or no interference, 10 = worst imaginable or complete interference). Differences in individual symptom severity and interference between the two arms were assessed by t-tests and mixed modeling. Results: As previously reported, 204 (Bu-Mel: 104, Mel: 100) were enrolled between October 2011 and March 2017. At last evaluation, 52 (51%) and 49 (49%) patients achieved a CR (p=0.88), and 69 (68%) and 67 (67%) patients achieved a CR+nCR (p=0.88) in Bu-Mel and Mel arms, respectively. Median PFS was 64.7 months and 34.4 months (p=0.013) in Bu-Mel and Mel arms, respectively. There was no difference in OS between the two arms. One hundred sixty-five of the patients (Bu-Mel: 81, Mel: 84) completed at least one MDASI-MM assessment. Median ages at autoHSCT were 57.2 and 57.0 years in Bu-Mel and Mel groups, respectively (p=0.86). At baseline, t-tests showed significantly higher mean severity of constipation (1.80, standard deviation [SD] = 2.87 vs 0.98, SD = 1.94; p=0.036), muscle weakness (2.38, SD=2.49 vs 1.44, SD=1.87; p=0.034), diarrhea (1.45, SD=2.43 vs 0.60, SD=1.10; p=0.005), and global symptom interference (2.96, SD=2.81 vs 1.77, SD=2.00; p=0.003) in the Bu-Mel arm than the Mel arm. The Bu-Mel patients had a significantly higher mean severity of pain (5.67, SD=2.65 vs 3.17, SD=3.07; p=0.0043) and mouth sores (7.35, SD=2.41 vs 1.25, SD=2.22; p <0.0001) than the Mel patients 7 days post autoHSCT. Longitudinal analysis using mixed modeling showed that the Bu-Mel arm had a significantly higher mean severity of pain (ED = 1.102, p=0.003), drowsiness (ED = 0.674, p=0.040), dry mouth (ED = 0.904, p=0.009), constipation (ED = 0.695, p=0.006), muscle weakness (ED = 0.815, p=0.006), mouth sores (ED = 1.683, p <0.0001), rash (ED = 0.362, p=0.019), and interference with physical functions (general activity: ED = 1.015, p=0.010; working: ED=1.229, p=0.006; walking: ED=0.920, p=0.009) than the Mel arm during the 4 weeks following autoHSCT. Conclusions: Patients receiving Bu-Mel vs Mel prior to autoHSCT report some differences in symptom severity, with Bu-Mel patients experiencing more severe sore mouth, pain, and symptom interference with daily functioning. The greater intensity of the double-alkylating agent conditioning regimen of Bu-Mel likely led to these differences. The increased severity of drowsiness, dry mouth, constipation, and muscle weakness may be due to an increased need for opioids to control severe pain and mouth sores. The effect of significant differences in symptom severity and interference at baseline between these two groups, despite randomization, is not clear. However, the longer time to progression of myeloma with the Bu-Mel regimen may offset the greater symptom burden early post autoHSCT. Systematic measurement of symptom burden during clinical trials can provide useful information for clinicians and patients in evaluating the full impact of different treatment regimens and enhance treatment decision making and discussion between clinicians and patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Survival in Patients Who Underwent HLA-Haploidentical Stem Cell Transplantation in Two Centers in Colombia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-32
Author(s):  
Lisbeth Ramirez ◽  
Juan Manuel Herrera ◽  
Angela María Peña ◽  
Maria Luna-Gonzalez ◽  
Claudia Marcela Chalela ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Retrospective Study ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Median Time ◽  
Clinical Characteristics ◽  
High Dose ◽  
Post Transplantation ◽  
Hematopoietic Stem

Introduction: Allogeneic hematopoietic stem cell transplantation (HCT) is a potentially curative treatment for several malignant and non-malignant hematological diseases. However, sometimes it is challenging to find human leukocyte antigen (HLA)-matched related or unrelated donors, especially in minority populations such as Hispanics. Transplantation of T cell replete HLA haploidentical graft (HaploHCT) followed by a high dose post-transplantation cyclophosphamide (PTCy) to eradicate alloreactive T cells is an option for populations with low donor availability. HaploHCT has emerged as an effective and safe strategy in this population (Luznik L et al. BBMT 2008), but data in Hispanics is scarce. Objective: The aim of our study was to describe the clinical characteristics and assess overall survival at 100 days, 1- and 3-years of patients who underwent haploHCT in two Colombian reference centers. Methods: An observational retrospective study was conducted at two tertiary referral centers in Colombia. Patients who underwent haploHCT at Clinica FOSCAL and Centro Medico Imbanaco between January 2013 and January 2020 were selected. Demographic and clinical characteristics where analyzed using descriptive statistics. The Kaplan-Meier method was used to assess overall survival (OS) rates and the log-rank test was used to compare survival rates between groups. All data were analyzed using R statistical software®. Results: Seventy-six patients were included. Mean age at transplantation was 34 years (range 18-60). Forty-two (57.89%) patients were female. Average body mass index was 19.86kg/m2. The majority of patients (57%) had a pre-transplantation ECOG performance status of 2. The most common indication for haploHCT was acute lymphoblastic leukemia (55.26%), followed by acute myeloid leukemia (23.64%). A sibling was the donor in 69.74% of the cases. Forty-seven (61.84%) patients were ABO-matched group. Peripheral blood stem cells were the graft source in 96% of the patients. The average number of infused CD34+ cells was 11.15 x 106/kg. Fludarabine-melphalan was the most commonly used conditioning regimen (57%), followed by fludarabine-busulfan-thiotepa (39%). Graft-versus-host disease (GVHD) prophylaxis consisted of PTCy (50 mg/kg/day) on days 3 and 4 after HCT and a calcineurin inhibitor plus mycophenolate mofetil from day 5 to day 35 post-HCT. Median time to neutrophil engraftment (neutrophils > 0,5x109/L) was 15 days (range 10-33), while platelet engraftment, defined as as the second day of unsupported platelet count of ≥20 × 109, occurred at a median time of 13 days (range 5-38) post-transplantation. On day 28 post-HSCT, 93.4% of the patients had achieved 100% chimerism. OS was 91% (95%CI 84-97.5) at 100 days, 81% (95%CI 72-90) at 1-year, and 77% (95%CI 68-88) at 3-years after HaploHCT. C onclusion: The results of our haploHCT retrospective study in a Hispanic population are comparable to several other cohorts that have reported similar outcomes of haploHCT compared to HLA-matched HCT. The OS rates reported in our study suggest that haploHCT is a viable option in patients without an HLA-matched related or unrelated donor available, especially in populations with lower rates of suitable donors. Acknowledgements: We deeply thank Gonzalo Gutiérrez García, M.D. for his leadership and guidance implementing the haploHCT program in Clinica FOSCAL. Disclosures Peña: Roche: Honoraria. Salazar:Janssen: Honoraria; Novartis: Honoraria. Sandoval-Sus:MorphoSys US: Consultancy; Janssen: Consultancy; Massive Bio: Consultancy; Celgene: Speakers Bureau. Sossa:Novo: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Roche: Honoraria.

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

1992 ◽  
Vol 10 (11) ◽  
pp. 1712-1722 ◽  
Author(s):  
W H Wilson ◽  
V Jain ◽  
G Bryant ◽  
K H Cowan ◽  
C Carter ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Solid Tumors ◽  
Autologous Bone Marrow ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Autologous Bone ◽  
Hodgkin's Lymphomas ◽  
Phase I And Ii

PURPOSE High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Phase I study of topotecan in combination with cyclophosphamide in pediatric patients with malignant solid tumors: a Pediatric Oncology Group Study.

1998 ◽  
Vol 16 (3) ◽  
pp. 945-952 ◽  
Author(s):  
R L Saylors ◽  
C F Stewart ◽  
W C Zamboni ◽  
D A Wall ◽  
B Bell ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Pediatric Patients ◽  
Wilms Tumor ◽  
Systemic Exposure ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Phase Ii Trials ◽  
Pediatric Solid Tumors ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and dose-limiting toxicity of topotecan when combined with cyclophosphamide in pediatric patients with recurrent or refractory malignant solid tumors. PATIENTS AND METHODS A total of 33 patients received cyclophosphamide (250 mg/m2/dose) followed by topotecan in escalating doses (0.6 to 0.75 mg/m2/dose), each given as a 30-minute infusion daily for 5 days. A total of 154 fully assessable treatment courses were given to these patients. RESULTS Neutropenia was the dose-limiting toxicity of the therapy at both topotecan dose levels. The addition of filgrastim allowed escalation of the topotecan dose to the 0.75-mg/m2 level with acceptable neutropenia. Other significant toxicities were anemia and thrombocytopenia. Nonhematopoietic toxicity of grades > or = 3 was not observed. Responses were reported in patients with Wilms' tumor (one complete response [CR], one partial response [PR]), neuroblastoma (one CR, one PR), rhabdomyosarcoma (one PR), and osteosarcoma (one PR). Pharmacokinetic studies indicate that cyclophosphamide administered on the schedule used in this study did not alter topotecan disposition on day 5. As with previous studies, a pharmacodynamic relation between systemic exposure and myelosuppression was noted. CONCLUSION The combination of topotecan and cyclophosphamide shows activity in a wide variety of pediatric solid tumors and can be given with acceptable hematopoietic toxicity with the use of filgrastim support. We recommend that pediatric phase II trials use cyclophosphamide 250 mg/m2 followed by topotecan 0.75 mg/m2 daily for 5 days with filgrastim for amelioration of neutropenia.

Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.

1995 ◽  
Vol 13 (5) ◽  
pp. 1089-1095 ◽  
Author(s):  
W P Vaughan ◽  
E Kris ◽  
J Vose ◽  
P J Bierman ◽  
P Gwilt ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
Rank Test ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Rescue

PURPOSE A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.

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