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

1994 ◽  
Vol 12 (9) ◽  
pp. 1969-1973 ◽  
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.

A UGT1A1 genotype-directed phase I study of irinotecan (CPT-11) combined with fixed dose of capecitabine in patients with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2554-2554
Author(s):  
T. Kim ◽  
S. Sym ◽  
S. Lee ◽  
M. Ryu ◽  
J. Lee ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Common Polymorphism ◽  
Level I ◽  
Grade Iii ◽  
Ugt1a1 Genotype

2554 Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study. [Table: see text] No significant financial relationships to disclose.

scholarly journals Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1146-1151
Author(s):  
HM Kantarjian ◽  
M Beran ◽  
A Ellis ◽  
L Zwelling ◽  
S O'Brien ◽  
...  
Keyword(s):  
Partial Response ◽  
Acute Leukemia ◽  
Phase I ◽  
Continuous Infusion ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Dose Limiting Toxicity ◽  
Severe Mucositis

The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Phase I study of recombinant leukocyte A human interferon combined with BCNU in selected patients with advanced cancer.

1986 ◽  
Vol 4 (3) ◽  
pp. 408-413 ◽  
Author(s):  
E T Creagan ◽  
J S Kovach ◽  
H J Long ◽  
R L Richardson
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Phase I Trial ◽  
Outpatient Setting ◽  
Small Sample ◽  
Human Interferon ◽  
Recombinant Interferon ◽  
Life Threatening ◽  
Cytotoxic Therapies ◽  
Small Sample Sizes

Interferons manifest diverse immunomodulatory and antiproliferative characteristics. Since their spectrum of toxicities includes primarily fatigue and anorexia rather than the myelosuppression concomitant with cytotoxic therapies, it is conceptually appealing to combine both modalities. We conducted a phase I trial among 18 patients using the combination of leukocyte A recombinant interferon (IFN-rA) and BCNU. The intramuscular (IM) IFN-rA dose for the initial 12 patients was 12 X 10(6) U/m2 three times a week for an anticipated duration of 12 weeks. Among these patients, we escalated the monthly intravenous (IV) BCNU dose from 50 mg/m2 to 150 mg/m2. Six subsequent patients received IFN-rA 12 X 10(6) U/m2, days 1 to 3, and BCNU 150 mg IV on day 3 of each monthly cycle. Dose-limiting toxicities from both regimens were fatigue and myelosuppression. We recognize the limitation of small sample sizes. Nevertheless, in the absence of a significant number of life-threatening toxicities, it appears that near maximal doses of BCNU and concomitant IFN-rA can be administered with safety in an outpatient setting.

A phase I trial of bexarotene and docetaxel in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13085-13085
Author(s):  
M. J. Pishvaian ◽  
K. Firozvi ◽  
J. J. Hwang ◽  
J. L. Marshall ◽  
P. Ramzi ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Trial ◽  
Performance Status ◽  
Fixed Dose ◽  
Ecog Performance Status ◽  
Radiation Recall ◽  
Serum Triglycerides ◽  
Experienced Grade ◽  
Grade Iii

13085 Background: Retinoids have been used to treat a wide variety of malignancies. Bexarotene is a synthetic retinoid that binds preferentially to the RXR subclass of retinoid receptors. In the initial phase I trial of bexarotene, a subset of patients with non-small cell lung cancer (NSCLC) had prolonged stabilization of disease and survival. In vitro evidence suggests that the effects of retinoids may be enhanced when used in conjunction with taxanes. This is a phase I trial designed to determine the maximum tolerated dose of docetaxel in combination with a fixed dose of bexarotene. Methods: Patients with pathologically confirmed solid tumors for whom no standard therapies exist, who have an ECOG performance status ≤2, adequate organ function and normal serum triglycerides were eligible. Each cycle was 4 weeks long. Oral bexarotene was given at 400 mg/m2 daily. Docetaxel was given weekly for 3 out of 4 weeks at two dose levels, 25 or 30 mg/m2, for up to 6 cycles. For patients exhibiting disease stabilization or response, treatment with bexarotene was continued until disease progression. Restaging studies were performed after every 2 cycles. Results: To date 10 patients have been enrolled, half of whom had NSCLC - 7 male, mean age = 61 (range 37–73), 100% PS = 0 or 1. 29 cycles were completed (range 1 to 8). 7 patients have been treated at 25 mg/m2 and 3 at 30 mg/m2 of docetaxel. Hypothyroidism, hypertriglyceridemia, and fatigue were common but generally mild. Two patients experienced grade III fatigue, and 1 each experienced grade III hypertriglyceridemia, neutropenia, and cough. There were no grade IV toxicities. Two patients were taken off study because of non-fatal radiation recall pneumonitis that was controlled with steroids. In this heavily pretreated population, of 8 patients assessable for response, 5 had stable disease for at least 2 cycles. One patient with NSCLC had a partial response that persisted for 6 cycles. Conclusions: Bexarotene and docetaxel (at a minimum of 25 mg/m2) can be safely coadministered. Care should be taken in patients who have been previously irradiated. Enrolment and dose escalation for the phase I trial is still ongoing. A phase II trial of the combination as second line therapy in NSCLC is planned. [Table: see text]

scholarly journals Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia

Blood ◽  
1993 ◽  
Vol 81 (5) ◽  
pp. 1146-1151 ◽  
Author(s):  
HM Kantarjian ◽  
M Beran ◽  
A Ellis ◽  
L Zwelling ◽  
S O'Brien ◽  
...  
Keyword(s):  
Partial Response ◽  
Acute Leukemia ◽  
Phase I ◽  
Continuous Infusion ◽  
Phase I Study ◽  
Topoisomerase I ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Dose Limiting Toxicity ◽  
Severe Mucositis

Abstract The purpose of this study was to define, in a phase I study in leukemia, the maximally tolerated dose (MTD), major toxicities, and possible antitumor activity of Topotecan, a new topoisomerase I (topo I) inhibitor. Topotecan was delivered by a 5-day continuous infusion every 3 to 4 weeks to patients with refractory or relapsed acute leukemia, at doses ranging from 3.5 mg/m2 to 18 mg/m2 per course. Twenty-seven patients were treated, including 17 patients with acute myelogenous or undifferentiated leukemia, 7 with acute lymphocytic leukemia, and 3 with chronic myelogenous leukemia in blastic phase. Severe mucositis was the dose-limiting toxicity occurring in two of five patients treated with Topotecan 11.8 mg/m2 per course; a third patient had prolonged myelosuppression. At the MTD of 10 mg/m2 per course, 1 of 12 patients had severe mucositis and 5 had mild-to- moderate mucositis. Nausea, vomiting, diarrhea, and prolonged myelosuppression were uncommon. Three patients (11%) achieved a complete response, two (7%) had a partial response, and one (4%) had a hematologic improvement. The overall complete plus partial response rate was 19%, and 24% in acute myelogenous or undifferentiated leukemia. A novel in vitro assay that quantifies Topotecan-stabilized topo I-DNA complexes in patient samples was used, which demonstrated heterogeneity in the ability of Topotecan to interact with topo I, the intracellular target of Topotecan. This phase I study defined the MTD of Topotecan to be 10 mg/m2 by continuous infusion over 5 days every 3 to 4 weeks in patients with refractory or relapsed acute leukemia. Severe mucositis was the dose-limiting toxicity. Future studies will define the precise activity of Topotecan in different leukemia subsets, its efficacy in combination with other antileukemic drugs, and correlations between Topotecan-induced topo I-DNA complex formation and individual patient response to Topotecan.

Phase II Trial of Clofarabine in Combination with Topotecan, Vinorelbine, and Thiotepa (TVTC) in Pediatric Patients with Refractory or Relapsed Acute Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1514-1514
Author(s):  
Neerav Shukla ◽  
Rachel Kobos ◽  
Thomas M. Renaud ◽  
Laurel Steinherz ◽  
Peter G Steinherz
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Acute Leukemia ◽  
Phase I ◽  
Cell Transplantation ◽  
Phase Ii ◽  
Phase I Study ◽  
Phase Ii Trial ◽  
Myelogenous Leukemia ◽  
Significant Activity

Abstract Abstract 1514 Background: Outcomes for children with relapsed/refractory acute leukemia remain dismal. Clofarabine has been approved for the treatment of relapsed acute lymphoblastic leukemia (ALL). However activity in pediatric acute myelogenous leukemia (AML), and optimal combination chemotherapy regimens have yet to be established. We previously reported a 36% complete remission (CR) rate with gemcitabine in combination with topotecan, vinorelbine, and thiotepa (TVTG) in relapsed/refractory pediatric acute leukemias. In an effort to improve on the outcomes of TVTG, we substituted clofarabine for the gemcitabine to create the TVTC protocol. Methods: Following completion of a phase I study, a phase II trial of TVTC was conducted. Patients with relapsed/refractory ALL or AML were eligible. Patients were treated at the maximum tolerated dose (MTD) as determined from the preceding phase I study: clofarabine 40mg/m2/day IV × 5 days, topotecan 1mg/m2/day IV continuous infusion × 5 days, vinorelbine 20mg/m2/week IV × 3, and thiotepa 15mg/m2/day IV × 1 day. The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). 17 patients were enrolled. The median age was 10 years (8 months – 24 years). 12 patients had AML, 4 had pre-B ALL, and 1 had biphenotypic leukemia. 13 patients had relapsed disease, and 4 had refractory disease. 2 of the 17 patients were inevaluable for response; one patient was enrolled with minimal residual disease positivity of leukemia, and one patient is currently undergoing therapy. Results: Of the 15 patients evaluable for response, the ORR was 73% (10 CR, 1 CRp). Among the 11 responders, 10 (91%) proceeded to stem cell transplantation. Of the 4 non-responders, 2 patients had no detectable leukemia in their follow-up marrow samples, but failed to have count recovery. The other 2 patients were refractory to therapy. 16 of the 17 patients were evaluable for overall survival (OS), as one patient is currently undergoing therapy. The OS of the 16 evaluable patients is 53%, with a median OS time of 16.2 months (1.5 – 57.7 months). The most common grade 3 or higher toxicities included febrile neutropenia (69%), transient transaminase elevation (50%), and catheter-related infection (44%). One of the patients died from cardiac arrest 45 days after beginning TVTC. There were no cases of VOD. Conclusion: TVTC demonstrates significant activity in patients with relapsed/refractory acute leukemia. Infectious complications occurred at similar rates to previously reported clofarabine combination studies. The activity seen in relapsed/refractory AML patients was very encouraging, with 8 of 11 (73%) evaluable patients achieving a CR/CRp. Given the high response and stem cell transplantation rates in relapsed AML patients on this study, patients with high risk de novo AML may benefit from incorporation of TVTC therapy into their treatment regimens. This regimen warrants further exploration in a larger cohort of relapsed leukemia patients. Disclosures: Off Label Use: Use of Clofarabine for patients with AML. Steinherz:Genzyme: Research Funding.

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

2003 ◽  
Vol 21 (16) ◽  
pp. 3092-3097 ◽  
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.

CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi70
Author(s):  
Bakhtiar Yamini ◽  
Seán Lyne ◽  
Riley Driscoll ◽  
Giovanna Bernal ◽  
Longtao Wu ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Phase I Study ◽  
Objective Response ◽  
Controlled Study ◽  
Current Phase ◽  
Newly Diagnosed ◽  
Biomarker Analysis ◽  
Secondary Endpoints ◽  
Grade Iii

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

Sign in / Sign up

Export Citation Format

Share Document