A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

1991 ◽  
Vol 9 (2) ◽  
pp. 320-327 ◽  
Author(s):  
A D Elias ◽  
L J Ayash ◽  
J P Eder ◽  
C Wheeler ◽  
J Deary ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Renal Toxicity ◽  
Single Agent ◽  
Autologous Bone Marrow ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Autologous Bone ◽  
Dose Limiting Toxicity

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

High-dose ifosfamide with mesna uroprotection: a phase I study.

1990 ◽  
Vol 8 (1) ◽  
pp. 170-178 ◽  
Author(s):  
A D Elias ◽  
J P Eder ◽  
T Shea ◽  
C B Begg ◽  
E Frei ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Continuous Infusion ◽  
Dose Level ◽  
Phase I Study ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone ◽  
Dose Limiting Toxicity ◽  
Cns Toxicity

Phase II trials of ifosfamide have been performed with standard doses of 5 to 8 g/m2/course. In this phase I study, 29 patients were treated with a 4-day continuous infusion ifosfamide to determine the maximum-tolerated dose and the nonhematologic dose-limiting toxicity. Autologous bone marrow support was to have been used for the subsequent dose level if granulocytes were more than 500/microL for more than 14 days in two of two to five patients at a given dose level. Doses were escalated from 8 to 18 g/m2 ifosfamide. Mesna was given at an equivalent dose by continuous infusion for 5 days. At the 18 g/m2 dose level, dose-limiting renal insufficiency and a median of 11 days (range, 8 to 18 days) of granulocytopenia (less than 500/microL) were observed. Thus, autologous bone marrow reinfusion ws not used. The duration of myelosuppression, the frequency and severity of mucositis, and renal tubular acidosis were all dose-dependent. Mild to moderate CNS toxicity also appeared to be related to dose; however, severe CNS toxicity (transient confusion, hallucinations, and somnolence) was observed sporadically at both low- and high-dose levels. Transient hematuria (greater than 50 red blood cells [RBCs]/high power field) occurred once but did not affect treatment. There were nine responses (two complete) in 27 heavily pretreated assessable patients including seven responses in 20 patients with advanced refractory sarcoma. Ifosfamide with mesna uroprotection can undergo considerable dose escalation over the usual prescribed doses before nonhematologic dose-limiting toxicity is encountered. Ifosfamide has broad cytotoxicity against solid tumors and may prove to be an important addition to high-dose combination chemotherapy regimens.

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.

scholarly journals Phase I Trial of Intra-arterial Administration of Autologous Bone Marrow-Derived Mesenchymal Stem Cells in Patients with Multiple System Atrophy

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Seok Jong Chung ◽  
Tae Yong Lee ◽  
Yang Hyun Lee ◽  
KyoungWon Baik ◽  
Jin Ho Jung ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Multiple System Atrophy ◽  
Phase I ◽  
Dose Group ◽  
Low Dose ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone

Background. This study is aimed at investigating the safety and tolerability of the intra-arterial administration of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) in patients with multiple system atrophy- (MSA-) cerebellar type (MSA-C). Methods. This was a single-center, open-label phase I clinical trial in patients with MSA-C. A three-stage dose escalation scheme (low-dose, 3.0 × 10 5 cells/kg; medium-dose, 6.0 × 10 5 cells/kg; high-dose, 9.0 × 10 5 cells/kg) was applied to determine the maximum tolerated dose of intra-arterial administration of BM-MSCs based on the no-observed-adverse-effect level derived from the toxicity study. The occurrence of adverse events was evaluated 1 day before and 1, 14, and 28 days after BM-MSC therapy. Additionally, we assessed changes in the Unified MSA Rating Scale (UMSARS) score 3 months after BM-MSC treatment. Results. One serious adverse drug reaction (ADR) of leptomeningeal enhancement following the intra-arterial BM-MSC administration occurred in one patient in the low-dose group. The safety review of the Internal Monitoring Committee interpreted this as radiological evidence of the blood-brain barrier permeability for MSCs. No other ADRs were observed in the medium- or high-dose groups. In particular, no ischemic lesions on diffusion-weighted images were observed in any of the study participants. Additionally, the medium- and high-dose groups tended to show a slower increase in UMSARS scores than the low-dose group during the 3-month follow-up. Conclusion. The present study confirmed that a single intra-arterial administration of autologous BM-MSCs is a safe and promising neuroprotective strategy in patients with MSA-C.

A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support.

1989 ◽  
Vol 7 (5) ◽  
pp. 651-661 ◽  
Author(s):  
T C Shea ◽  
M Flaherty ◽  
A Elias ◽  
J P Eder ◽  
K Antman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Autologous Bone Marrow ◽  
Recurrent Ovarian Cancer ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
Systemic Clearance ◽  
Heavily Pretreated ◽  
Pretreated Patients ◽  
Autologous Bone

A series of 33 patients were treated with a four-day continuous infusion of carboplatin in a phase I study to determine the maximum-tolerated dose (MTD) of this agent when used with autologous bone marrow reinfusion. Doses were escalated from 375 to 2,400 mg/m2; autologous bone marrow reinfusion was added to the regimen at doses of 1,600 mg/m2 and above. The MTD was determined to be 2,000 mg/m2. Dose-limiting toxicity consisting of reversible hepatotoxicity, renal dysfunction, and moderate to severe ototoxicity was observed with a dose of 2,400 mg/m2. There were ten responses in 31 heavily pretreated patients, including six responses in 11 patients with recurrent ovarian cancer. Pharmacokinetic studies revealed a systemic clearance (Clss) of 4.5 L/m2/h. This value is consistent with clearances reported for carboplatin administered at lower doses and by different schedules. No evidence for saturation of systemic clearance at higher doses was observed. Carboplatin appears to be an active drug that can undergo considerable dose escalation when used in conjunction with autologous bone marrow support.

Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study

1991 ◽  
Vol 117 (S4) ◽  
pp. S208-S213 ◽  
Author(s):  
Anthony D. Elias ◽  
Lois J. Ayash ◽  
J. Paul Eder ◽  
Cathy Wheeler ◽  
Joan Deary ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Phase I Study ◽  
Autologous Bone Marrow ◽  
High Dose ◽  
Autologous Bone

scholarly journals Phase I trial with recombinant human interleukin-3 in patients with lymphoma undergoing autologous bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 82 (11) ◽  
pp. 3273-3278
Author(s):  
J Nemunaitis ◽  
FR Appelbaum ◽  
JW Singer ◽  
K Lilleby ◽  
S Wolff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Autologous Bone Marrow Transplantation ◽  
Autologous Bone Marrow ◽  
Maximum Tolerated Dose ◽  
Marrow Transplant ◽  
Cell Recovery ◽  
Dose Escalation Study ◽  
Interleukin 3 ◽  
Autologous Bone

Recombinant human interleukin-3 (rhIL-3) was administered to 30 patients undergoing autologous bone marrow transplant (ABMT) for treatment of lymphoma. In this phase I dose escalation study, rhIL-3 was administered from day 0 to 20 after ABMT by 2-hour intravenous infusion at dose levels of 1, 2, 5, and 10 micrograms/kg/d. Seventeen patients did not complete therapy with rhIL-3. Eleven requested early discontinuation for malaise, confusion, transplant complications, or rapid engraftment and were removed from the study, whereas six patients developed grade III toxicity, including fever (three patients), or headache (three patients) possibly attributable to rhIL3. Other common toxicities included diarrhea, rigors, mucositis, and rash. The maximum tolerated dose of rhIL-3 was 2 micrograms/kg/d. No evidence of earlier hematopoietic cell recovery was observed compared with similar historical patients treated with recombinant human granulocyte- macrophage colony-stimulating factor. Future trials will be needed to determine alternate schedules of administration of rhIL-3 or the use of rhIL-3 in combination or in sequence with other growth factors.

Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

1994 ◽  
Vol 12 (1) ◽  
pp. 176-183 ◽  
Author(s):  
P J Stiff ◽  
R S McKenzie ◽  
D S Alberts ◽  
J A Sosman ◽  
J R Dolan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Ovarian Carcinoma ◽  
Rapid Development ◽  
Autologous Bone Marrow ◽  
High Response Rate ◽  
High Dose ◽  
Platinum Resistant ◽  
Autologous Bone

PURPOSE To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. PATIENTS AND METHODS A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. RESULTS We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. CONCLUSION This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

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