Phase I study of oral etoposide in children with refractory solid tumors.

1994 ◽  
Vol 12 (7) ◽  
pp. 1452-1457 ◽  
Author(s):  
P Mathew ◽  
R C Ribeiro ◽  
D Sonnichsen ◽  
M Relling ◽  
C Pratt ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Plasma Concentrations ◽  
Rest Period ◽  
Maximum Tolerated Dose ◽  
Oral Etoposide ◽  
Daily Dose ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and plasma concentrations of orally administered etoposide (VP-16) in pediatric oncology patients. PATIENTS AND METHODS In a phase I study, 20 children with refractory solid tumors received oral VP-16 (the intravenous preparation diluted with sodium chloride) three times daily for 21 days. Daily dose levels studied were 50 mg/m2 (n = 5), 60 mg/m2 (n = 7), and 75 mg/m2 (n = 8). VP-16 concentrations were measured in blood samples collected on days 1, 7, 14, and 21. RESULTS Grade 3 to 4 thrombocytopenia and/or neutropenia causing interruption of the 21-day course or persisting for more than 7 days after the last day of chemotherapy was seen at all dose levels, but was not dose-limiting. One patient treated at the 50-mg/m2 daily dose died of sepsis. At the 75-mg/m2 dose level, diarrhea was dose-limiting. Estimated plasma VP-16 concentrations were greater than 1 micrograms/mL for median periods of 9.4, 15.4, and 13.5 hours per day at daily doses of 50, 60, and 75 mg/m2, respectively. Responses were observed in seven of 14 patients who received at least one additional course of etoposide after a rest period of 7 days. There was one complete and two objective responses. Four patients were considered to have stable disease. CONCLUSION The intravenous preparation of VP-16 administered orally appears to be well tolerated by heavily pretreated pediatric patients. On the three-times daily, 21-day schedule, a daily dose of 75 mg/m2 exceeds the MTD, with diarrhea as the dose-limiting toxicity. The recommended dose for oral etoposide is 60 mg/m2/d administered every 8 hours.

Cefixime Allows Greater Dose Escalation of Oral Irinotecan: A Phase I Study in Pediatric Patients With Refractory Solid Tumors

2006 ◽  
Vol 24 (4) ◽  
pp. 563-570 ◽  
Author(s):  
Wayne L. Furman ◽  
Kristine R. Crews ◽  
Catherine Billups ◽  
Jianrong Wu ◽  
Amar J. Gajjar ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase I Study ◽  
Area Under The Curve ◽  
Systemic Exposure ◽  
Maximum Tolerated Dose ◽  
Severe Diarrhea ◽  
Dose Limiting Toxicity

PurposeIrinotecan is active against a variety of malignancies; however, severe diarrhea limits its usefulness. In our phase I study, the intravenous formulation of irinotecan was administered orally daily for 5 days for 2 consecutive weeks (repeated every 21 days) to children with refractory solid tumors. Our objectives were to determine the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of oral irinotecan and to evaluate whether coadministration of cefixime (8 mg/kg/d beginning 5 days before irinotecan and continuing throughout the course) ameliorates irinotecan-induced diarrhea.Patients and MethodsIn separate cohorts, irinotecan doses were escalated from 15 to 45 mg/m2/d without cefixime and then from 45 to 60 and 75 mg/m2/d with cefixime.ResultsWithout cefixime, diarrhea was dose limiting at irinotecan 45 mg/m2/d. Myelotoxicity was not significant at any dose. The MTD was 40 mg/m2/d without cefixime but 60 mg/m2/d with cefixime. Systemic exposure to SN-38 at the MTD was significantly higher with cefixime than without cefixime (mean SN-38 area under the curve: 19.5 ng×h/mL; standard deviation [SD], 6.8 ng × h/mL v 10.4 ng × h/mL; SD, 4.3 ng × h/mL, respectively; P = .030).ConclusionCefixime administered with oral irinotecan is well tolerated in children and allows greater dose escalation of irinotecan. Because diarrhea is a major adverse effect of both intravenous and oral irinotecan, further evaluation of the use of cefixime to ameliorate this adverse effect is warranted.

scholarly journals Phase I Study of Rivoceranib, a Selective VEGFR-2 Angiogenesis Inhibitor, Administered Daily in Patients With Advanced Solid Tumors

2021 ◽  
Author(s):  
Yoon-Koo Kang ◽  
Min-Hee Ryu ◽  
Yong Sang Hong ◽  
Chang-Min Choi ◽  
Tae Won Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Safety Profile ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Potential Clinical Benefit ◽  
Dose Levels

Abstract Rivoceranib is a highly potent and selective inhibitor of VEGFR-2 and subsequent angiogenesis through this receptor signaling pathway. This phase I study was the first global study with rivoceranib outside of China in Korean and Caucasian patients and was designed to determine the safety profile (including maximum tolerated dose), pharmacokinetics, and efficacy in patients with advanced solid tumors. Thirty-one adult patients with advanced malignant solid tumors were enrolled to investigate 6 dose levels of rivoceranib. Twenty-five patients were initially enrolled to 5 dose levels of rivoceranib from 81 to 685 mg and an additional 6 patients were later enrolled in a supplemental study to evaluate the 805 mg dose level. Rivoceranib was very well tolerated. At the 805 mg dose level, 2 dose-limiting toxicities were observed but the 685 mg dose was well tolerated over multiple cycles of therapy. The maximum tolerated dose for rivoceranib was 685 mg (equivalent to 850 mg rivoceranib mesylate) and recommended for further study in patients with advanced solid tumors. The most common adverse events were hypertension (all grades %/≥G3%: 58/29), nausea (42/0), diarrhea (39/0), anorexia (32/3), and fatigue (29/6). Rivoceranib pharmacokinetics were proportional across all dose levels but interpatient variability was high. Of the 31 patients enrolled, 21 were evaluable for efficacy. In this evaluable group, partial response was recorded in 5 patients, stable disease in 10, and disease progression in 6. Results indicate the potential clinical benefit of daily rivoceranib in patients with advanced malignant solid tumors with a tolerable safety profile.Trial registration: NCT01497704 (ClinicalTrials.gov) registered on December 22, 2011 and NCT02711969 (ClinicalTrials.gov) registered on March 17, 2016.

Chronic daily administration of oral etoposide--a phase I trial.

1989 ◽  
Vol 7 (3) ◽  
pp. 396-401 ◽  
Author(s):  
J D Hainsworth ◽  
D H Johnson ◽  
S R Frazier ◽  
F A Greco
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Combination Regimen ◽  
Oral Etoposide ◽  
Phase Ii Studies ◽  
Level Of Activity ◽  
Wbc Count ◽  
Dose Limiting Toxicity

In this phase I study, we administered etoposide (VP-16) orally for 21 consecutive days to patients with advanced refractory cancers. All patients had received previous chemotherapy, and 50% of patients had received more than one combination regimen. When given for 21 consecutive days, the maximum-tolerated dose of oral VP-16 was 50 mg/m2/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 21 and 28. In most patients, blood counts had recovered sufficiently by day 35 to begin another 3-week course. WBC count nadirs of less than 1,000/microL occurred in four of 20 courses at this dose, and three patients required hospitalization for treatment of neutropenia and fever. Alopecia occurred in most patients; gastrointestinal (GI) and other toxicities were uncommon. Five of 16 patients with measurable tumor had partial responses of 3 to 4 months duration. Four of these five patients had malignancies that are usually unresponsive to VP-16 when administered by previously investigated schedules. This method of VP-16 administration is well tolerated, convenient, and may optimize antitumor efficacy by exploiting the schedule dependency of this drug. Phase II studies are necessary to define the level of activity of this schedule of VP-16.

Phase I study of the HSP90 inhibitor AUY922 in combination with capecitabine as treatment for patients with advanced solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3564-3564
Author(s):  
Shubham Pant ◽  
Lowell L. Hart ◽  
Johanna C. Bendell ◽  
Jeffrey R. Infante ◽  
Suzanne Fields Jones ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase I Study ◽  
Standard Dose ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Hsp90 Inhibition ◽  
Grade 3 ◽  
Dose Levels

3564 Background: Heat shock protein 90 (HSP90) is a molecular chaperone involved in the maintenance and function of client proteins, many of which are integral to key oncogenic processes. AUY922 is a competitive inhibitor of HSP90. Preclinical evidence suggests potential synergy between HSP90 inhibition and fluorouracil. This phase I study was designed to determine the maximum tolerated dose (MTD) of AUY922 in combination with standard dose of capecitabine as treatment for patients with advanced solid tumors. Methods: Pts with refractory solid tumors received AUY922 with capecitabine in a standard 3+3 dose escalation. Dose levels were capecitabine 1000mg/m2 PO BID d 1-14 of 21-day cycles, with escalating doses of AUY922 IV days 1, 8, and 15; the 6th dose level combined the MTD of AUY922 with capecitabine 1250mg/m2. Dose-limiting toxicities (DLTs), safety, and efficacy were evaluated. Results: 23 pts were treated at 6 dose levels: 22mg/m2 (n = 3); 28mg/m2 (n = 3); 40mg/m2 (n = 3); 55mg/m2 (n = 5); 70mg/m2 (n = 3); 70mg/m2 with capecitabine 1250mg/m2 (n= 6). No DLTs were observed until the 6th dose level (grade 3 diarrhea). Related adverse events (% grade 1/2; % grade 3/4) included: diarrhea (43%; 17%), fatigue (30%; 13%), nausea (39%; 0), hand-foot skin reaction (30%; 5%), anorexia (30%; 4%), vomiting (30%; 0), and darkening vision (26%; 0). Vision darkening, a class effect of HSP90 inhibitors, was reversible with drug hold and retreatment was possible. Two pts (9%) had hematologic G 3/4 events of neutropenia. Of the 19 pts evaluable for response, partial response was noted in 4 patients (colorectal, 2; breast, 1; stomach, 1); 2 had progressed on prior fluorouracil, and remained on treatment for 13-35 wks. Stable disease was noted in 8 pts (35% [colorectal, 5; pancreas, 2; breast, 1]) with a median duration of 25.5 wks (range: 11-44+). All 5 colorectal pts were refractory to 5-FU. Conclusions: The addition of AUY922 to standard dose capecitabine was well-tolerated at doses of up to 70mg/m2. Preliminary efficacy is encouraging, particularly as seen in pts previously resistant to fluorouracil, and warrants further investigation of this regimen. Clinical trial information: NCT01226732.

Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

2005 ◽  
Vol 23 (30) ◽  
pp. 7646-7653 ◽  
Author(s):  
Katherine E. Warren ◽  
Alberta A. Aikin ◽  
Madeleine Libucha ◽  
Brigitte C. Widemann ◽  
Elizabeth Fox ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pediatric Patients ◽  
Maximum Tolerated Dose ◽  
Biologically Active ◽  
Conventional Dose ◽  
Daily Schedule ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Active Dose

Purpose This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. Patients and Methods Patients ≤ 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. Results Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. Conclusion The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Final results of a phase I study of TH-302, a hypoxia-activated cytotoxic prodrug (HAP)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2573-2573 ◽  
Author(s):  
J. C. Bendell ◽  
G. J. Weiss ◽  
J. R. Infante ◽  
E. G. Chiorean ◽  
M. Borad ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Skin Lesions ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Isophosphoramide Mustard ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity ◽  
Skin Mucosa

2573 Background: TH-302 is a 2-nitroimidazole prodrug of the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM). TH-302 is essentially inactive under normoxia but in severe hypoxia and in the presence of certain reductases, it is reduced and Br-IPM is released. Methods: Eligible patients (pts) had ECOG ≤1, advanced or metastatic solid tumors, evaluable by RECIST, and acceptable hematologic, liver and renal function. A modified accelerated titration design was used. TH-302 was administered intravenously over 30–60 minutes on Day 1, 8 and 15 of a 28-day cycle. CT scans were obtained after every 2 cycles. Detailed pharmacokinetic sampling was performed on Days 1 and 15. The primary objectives of this study were to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twenty-nine pts enrolled at 3 sites at 9 dose levels from 7.5–670 mg/m2. Median age: 64y. 20 male/9 female. ECOG 0/1: 16/13. Primary tumor: prostate (8), colorectal (8), lung (5) other (8). Two of 5 pts at 670 mg/m2 had DLT: Herpes simplex perianal/rectal ulcers and dehydration due to mucositis. Reversible skin and mucosal adverse events (AE) occurred in 12 of 15 (80%) pts at ≥480 mg/m2 including grade 3 events in 3 pts. The most common TH-302-related AEs were nausea, skin lesions, vomiting and fatigue. Hematologic toxicity was mild and limited: two pts with grade 1 and one pt with grade 2 neutropenia and five pts with grade 1 thrombocytopenia. Five pts had grade 3 and one grade 4 lymphopenia. Four pts have enrolled at an intermediate dose of 575 mg/m2 with no DLT so this is likely the MTD and is well above the predicted biologic effective dose of 100 mg/m2. One pt with SCLC treated at 480 mg/m2 and one with melanoma treated at 670 mg/m2 had unconfirmed partial responses; 12 pts had stable disease (6 continuing after 4 or more cycles), 7 had PD, 4 were unevaluable and 4 are too early to assess. Cmax and AUC for TH-302 and Br-IPM increased linearly with no accumulation at Day 15. Conclusions: Weekly TH-302 has remarkably little hematologic toxicity. Skin and mucosal AEs have developed at the higher dose levels. Skin/mucosa are known to have hypoxic regions. TH-302 is the first HAP to demonstrate tumor responses in Phase I. The MTD is likely 575 mg/m2. Studies in combination with chemotherapy are ongoing. [Table: see text]

Phase I study of weekly oral docetaxel (ModraDoc001) plus ritonavir in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2550-2550 ◽  
Author(s):  
Serena Marchetti ◽  
Frederik Stuurman ◽  
Stijn Koolen ◽  
Johannes Moes ◽  
Jeroen Hendrikx ◽  
...  
Keyword(s):  
Oral Administration ◽  
Solid Tumors ◽  
Phase I Study ◽  
Oral Formulation ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

2550 Background: ModraDoc001 is a novel oral formulation containing docetaxel as a solid dispersion. Oral administration of docetaxel is feasible in combination with the CYP3A4 inhibitor ritonavir. Objectives were to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of weekly oral docetaxel (as ModraDoc001) in combination with ritonavir. Methods: Patients with advanced solid tumors, WHO PS ≤ 2, no concomitant use of MDR or CYP3A modulating drugs, adequate bone marrow (ANC ≥ 1.5x109 /L), liver (bilirubin ≤ 1.5xULN, ALAT/ASAT ≤ 2.5xULN) and renal function (creatinine ≤ 1.5xULN or clearance ≥ 50 ml/min) were eligible. Docetaxel (ModraDoc001 10mg capsule) and ritonavir (Norvir 100mg) were simultaneously given once weekly in a ‘3+3 cohort’ dose escalation design. MTD was defined as the highest dose resulting in <1/6 probability of causing a dose limiting toxicity in the first 4 weeks of treatment. This cohort was expanded with 6 patients. PK was determined on days 1 and 8. Results: 40 patients (25 male, 35 evaluable for safety) were enrolled in 6 dose levels (30/100, 40/100, 60/100, 80/100, 60/200 and 80/200 mg docetaxel/ritonavir). Common treatment related adverse events in the 4 highest dose levels were diarrhea (68%), nausea (62%) and fatigue (62%), mostly CTC grade 1-2 (80%, 95% and 73% respectively). Five patients experienced a DLT (grade 3 diarrhea (4), elevated ASAT/ALAT (1), grade 4 dehydration and grade 3 mucositis (1), grade 3 fatigue (2)). The MTD was 60 mg/200 mg docetaxel/ritonavir. Partial remission was seen in 4 patients (CUP, NSCLC, gastric and mamma ca) and sustained stable disease in 15 patients (6x NSCLC). Both drugs were rapidly absorbed after oral administration. Mean Tmax was 2.0 hours (CV=73%) for docetaxel. Cmax and AUC of docetaxel increased less than proportionally with dose to 162 ng/ml (CV= 67%) and 1615 ng/ml*hr (CV= 81%), respectively, in 15 patients at the MTD. Conclusions: At the MTD (once weekly 60 mg docetaxel and 200 mg ritonavir) ModraDoc001 is safe, well tolerated and shows encouraging antitumor activity. The exposure of docetaxel with this regimen is comparable to weekly intravenous administration of 35 mg/m2 docetaxel. Phase II studies in solid tumors are planned.

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Ying Cheng ◽  
Ying Liu ◽  
Jinhua Xu ◽  
Jing Zhu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Renal Cancer ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

Phase I and Pharmacokinetic Study of the Camptothecin Analog DX-8951f Administered as a 30-Minute Infusion Every 3 Weeks in Patients With Advanced Cancer

2000 ◽  
Vol 18 (23) ◽  
pp. 3986-3992 ◽  
Author(s):  
Valérie Boige ◽  
Eric Raymond ◽  
Sandrine Faivre ◽  
Michel Gatineau ◽  
Kathleen Meely ◽  
...  
Keyword(s):  
Phase I ◽  
Intravenous Infusion ◽  
Topoisomerase I ◽  
High Performance ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Analysis ◽  
Phase Ii Studies ◽  
Heavily Pretreated ◽  
Dose Limiting Toxicity

PURPOSE: DX-8951f is a totally synthetic derivative of camptothecin with greater cytotoxicity and more potent topoisomerase I inhibition than SN-38, topotecan, and camptothecin in preclinical studies. This phase I study aimed to describe the toxicity and to determine the maximum-tolerated dose (MTD) and pharmacokinetics of DX-8951f given as a 30-minute intravenous infusion every 3 weeks. PATIENTS AND METHODS: Twelve patients with refractory solid malignancies were treated with DX-8951f at dose levels ranging from 4 to 7.1 mg/m2. All but one patient had received previous chemotherapy, and eight patients were considered heavily pretreated. Total DX-8951f plasma concentrations were assayed using high-performance liquid chromatography. RESULTS: Thirty-six cycles of DX-8951f were administered. Neutropenia was the dose-limiting toxicity, and it was dose-related, reversible, and noncumulative. Other toxicities included nausea and vomiting, alopecia, asthenia, fever, and anemia. Grade 1 or 2 diarrhea was observed in seven patients but was transient and resolved without requiring treatment. Pharmacokinetic analysis showed that DX-8951f had a half-life of 7.15 hours and a clearance rate of 1.65 L/h·m2. The DX-8951f area under the plasma-concentration curve increased linearly with the dose. We defined the MTD of DX-8951f administered as a 30-minute intravenous infusion every 3 weeks as 7.1 mg/m2. CONCLUSION: The dose-limiting toxicity of DX-8951f is neutropenia. The recommended dose for phase II studies is 5.33 mg/m2 every 3 weeks in patients previously treated with chemotherapy.

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

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