1217: FIXED-DOSE VS TITRATABLE STRATEGY FOR CISATRACURIUM CONTINUOUS INFUSION FOR VENTILATOR MANAGEMENT

856 Background: The FOLFOXIRI regimen (irinotecan, oxaliplatin, 5-fluorouracil and leucovorin) improves the response rate and overall survival compared to FOLFIRI in pts with metastatic colorectal cancer (mCRC), and addition of cetuximab to chemotherapy increases efficacy in pts with RAS wild-type mCRC. We conducted a phase 1 study of FOLFOXIRI plus cetuximab to determine the maximum-tolerated dose (MTD) and recommended dose (RD) and to assess its safety and efficacy in Japanese pts with RAS wild-type mCRC. Methods: Main eligibility criteria were: histologically confirmed colorectal adenocarcinoma; KRAS and NRAS wild-type status; measurable metastatic disease according to Response Evaluation Criteria in Solid Tumors version 1.1; age 20-74 years; Eastern Cooperative Oncology Group performance status 0 or 1. Pts with UDP-glucuronosyltransferase 1A1*6/*6, *28/*28 and *6/*28 genotypes were excluded. Pts received an escalating dose of intravenous irinotecan (100, 120, and 150 mg/m2 in the dose levels 0, 1, and 2, respectively) and a fixed dose of intravenous oxaliplatin (85 mg/m2), continuous infusion 5-fluorouracil (2400 mg/m2) plus l-leucovorin (200 mg/m2), and cetuximab (an initial dose of 400 mg/m2 followed by 250 mg/m2 per week). Results: A total of 9 Japanese pts were treated (3 and 9 in the dose levels 1 and 2, respectively). No patients experienced a dose-limiting toxicity (the MTD was not reached), and the dose level 2 (irinotecan 150 mg/m2) was established as the RD. With a median 8 cycles per patient, the most common grade 3 or 4 adverse events included neutropenia (44%), paronychia (22%), and acne-like rash (11%). No febrile neutropenia and treatment-related death were observed. Among 9 pts, 1 pt had complete response, 7 pts had partial response, and 1 pt had progressive disease, for an overall response rate of 89%. As of September 24, 2017, median progression free survival was 14.0 (95% CI 7.2-20.7) months. Conclusions: The combination of cetuximab and FOLFOXIRI has shown a favorable toxicity profile and promising antitumor activity in pts with RAS wild-type mCRC. Clinical trial information: UMIN000018217.

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Increasing dose of Continuous Infusion Ifosfamide and Fixed dose of Bolus Epirubicin in Soft Tissue Sarcomas. A Study of the Italian Group on Rare Tumors

Tumori Journal ◽

10.1177/030089169908500403 ◽

1999 ◽

Vol 85 (4) ◽

pp. 229-233 ◽

Cited By ~ 9

Author(s):

Sergio Frustaci ◽

Angela Buonadonna ◽

Antonella Romanini ◽

Alessandro Cornandone ◽

Maurizio Dalla Palma ◽

...

Keyword(s):

Soft Tissue ◽

Continuous Infusion ◽

Soft Tissue Sarcomas ◽

Fixed Dose ◽

Rare Tumors

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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 ◽

10.1182/blood.v108.11.5462.5462 ◽

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.

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Identification of an AUC of 7603 Umol∗Min/Hr Per Day X 4 Days as the Maximum Tolerated Dose (MTD) of IV Continuous Infusion (CI) Busulfan (BU) with Fixed Dose Fludarabine (FLU) in A Pharmacokinetically-Based Dose Phase I Study in Patients (PTS) with Hematologic Malignancies Undergoing Allogeneic Stem Cell Transplantation

Biology of Blood and Marrow Transplantation ◽

10.1016/j.bbmt.2008.12.304 ◽

2009 ◽

Vol 15 (2) ◽

pp. 99 ◽

Cited By ~ 2

Author(s):

W.A. Wood ◽

C.M. Walko ◽

K.V. Rao ◽

J. Whitley ◽

D.T. Moore ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Phase I ◽

Continuous Infusion ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Phase I Study ◽

Hematologic Malignancies ◽

Maximum Tolerated Dose ◽

Fixed Dose

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Phase I trial of continuous infusion carboplatin and etoposide in children with refractory acute leukemia: a Pediatric Oncology Group study.

Journal of Clinical Oncology ◽

10.1200/jco.1994.12.9.1969 ◽

1994 ◽

Vol 12 (9) ◽

pp. 1969-1973 ◽

Cited By ~ 3

Author(s):

P D Sadowitz ◽

R Dubowy ◽

A Souid ◽

B H Pollock ◽

H Weinstein ◽

...

Keyword(s):

Acute Leukemia ◽

Phase I ◽

Continuous Infusion ◽

Phase I Study ◽

Phase I Trial ◽

Phase Ii Trial ◽

Fixed Dose ◽

Life Threatening ◽

Pediatric Oncology Group ◽

Grade Iii

PURPOSE The purpose of this phase I study was to determine the toxicities and response to continuous infusion carboplatin in combination with a fixed dose of etoposide (VP-16) in children with refractory acute leukemia. PATIENTS AND METHODS From January 1989 to February 1992, 20 patients received 28 courses of treatment. Each course of treatment consisted of a 1-hour intravenous (IV) infusion of VP-16 100 mg/m2/d for 5 days, followed by a 23-hour IV infusion of carboplatin each day. The initial, total 5-day dose of carboplatin (1,000 mg/m2) was escalated by 250- to 375-mg increments to a final, total dose of 1,875 mg/m2 over 5 days. RESULTS Significant marrow suppression was observed in all patients, with prolonged marrow aplasia at the 1,875-mg/m2 dose level. Grade III diarrhea occurred in three patients; 10 patients experienced life-threatening infection and three had severe thrombocytopenic bleeding. Major marrow responses (two complete remissions and two partial remissions) occurred in four patients (20%). CONCLUSION In view of the apparent antileukemic efficacy and minimal extramedullary toxicity, carboplatin deserves further study in a phase II trial.

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Phase I Trial of Preoperative Concurrent Doxorubicin and Radiation Therapy, Surgical Resection, and Intraoperative Electron-Beam Radiation Therapy for Patients With Localized Retroperitoneal Sarcoma

Journal of Clinical Oncology ◽

10.1200/jco.2003.01.143 ◽

2003 ◽

Vol 21 (16) ◽

pp. 3092-3097 ◽

Cited By ~ 106

Author(s):

Peter W.T. Pisters ◽

Matthew T. Ballo ◽

Mark J. Fenstermacher ◽

Barry W. Feig ◽

Kelly K. Hunt ◽

...

Keyword(s):

Radiation Therapy ◽

Electron Beam ◽

Phase I ◽

Continuous Infusion ◽

Surgical Resection ◽

Phase I Trial ◽

External Beam Radiation ◽

Fixed Dose ◽

External Beam ◽

Beam Radiation

Purpose: The primary objective of this phase I trial was to define the maximum-tolerated dose of external-beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by surgical resection and electron-beam intraoperative radiation therapy (EB-IORT) for patients with localized, potentially resectable retroperitoneal sarcomas (RPS). Patients and Methods: Thirty-five patients with radiographically resectable primary or recurrent intermediate- or high-grade RPS were treated. Doxorubicin was administered each week for 4 or 5 weeks as an initial bolus (4 mg/m2) followed by a 4-day continuous infusion (4 mg/m2/d). Concurrent radiation therapy was administered in escalating doses of 18.0, 30.6, 36.0, 41.4, 46.8, or 50.4 Gy in 1.8-Gy fractions. Radiographic restaging was performed 4 to 8 weeks after chemoradiation, and patients with localized disease underwent surgical resection with EB-IORT (15 Gy). Results: Chemoradiation was completed as outpatient therapy in 31 patients (89%); four patients required hospital admission during chemoradiation or in the postchemoradiation preoperative period. At the highest radiation dose of 50.4 Gy, two (18%) of 11 patients had grade 3 or 4 nausea. Twenty-nine patients (83%) underwent laparotomy; six patients had interval disease progression and did not undergo surgery. Grossly complete resection (R0 or R1) was performed in 26 (90%) of 29 patients who had surgery. EB-IORT was feasible and successfully administered to 22 patients who had R0 or R1 resections. Conclusion: Preoperative chemoradiation, surgical resection, and EB-IORT are feasible for patients with RPS. Preoperative external-beam radiation can be administered to a total dose of 50.4 Gy with continuous-infusion doxorubicin.

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