A phase I study of 2-cyano-3, 12 dioxoolean-1, 9-dien-28-oic acid (CDDO) in advance solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14137-14137 ◽  
Author(s):  
B. Holkova ◽  
S. Kummar ◽  
P. Glauber ◽  
A. Chen ◽  
J. M. Strong ◽  
...  
Keyword(s):  
Dose Level ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Human Liver Tissue ◽  
Cohort Design ◽  
Starting Dose ◽  
Post Infusion ◽  
Dose Levels ◽  
Dose Limiting Toxicity

14137 Background: CDDO, a synthetic triterpenoid, induces apoptosis through intrinsic and extrinsic pathways, and as a ligand for the transcription factor PPAR-? that controls cellular differentiation and growth inhibition. Methods: CDDO was given as a 5 day continuous infusion every 28 days; starting dose 0.6 mg/m2/hr. Accelerated titration design used, 1 patient (pt)/cohort entered until a single pt has dose-limiting toxicity (DLT) or 2 pts exhibit grade (gr) = 2 toxicity during the first cycle. The study then converts to a standard 3–6 pt/cohort design. Maximum tolerated dose (MTD): Dose at which no more than 1/6 pts have DLT and the dose below which at least 2/6 patients have DLT. Objectives: Determine toxicity profile, pharmacokinetics (PK), and MTD of CDDO. PK were determined by LC-MS/MS analysis of plasma collected pre, during and post CDDO infusion. Results: 6 pts have been accrued thus far up to dose level 6. (19.2 mg/m2). Diagnoses: colon -3, sarcoma-1, bladder -1 and ovary-1. Median age: 52. DLT and MTD have not yet been achieved. Gr 1–2 toxicities have been acceptable: anemia, thrombocytopenia, decreased Na+, Mg++ and albumin, elevated Ca++, transaminases and bilirubin, and anorexia, fatigue and constipation. Gr 4 pulmonary emboli (unrelated to CDDO) was seen in one pt. PK: Steady state CDDO plasma concentrations (Css) in the first 3 dose levels increased linearly (see table ). Post infusion CDDO plasma concentrations decreased in a bi- exponential manner for the first three dose levels. Data indicate that < 1% of CDDO is excreted in the urine unchanged. No oxidative metabolism has been observed; however, we identified a CDDO glucuronide conjugate in urine and in human liver tissue incubations in vitro. Conclusions: The DLT and MTD have not been reached, and accelerated dose escalation continues. Since the CDDO Css appears to increase linearly with dose, we anticipate achieving 1 μM plasma levels at dose level 5 (9.6mg/m2/hr), the effective concentration in preclinical models. [Table: see text] No significant financial relationships to disclose.

Phase I study of a combination of recombinant interferon-alpha and recombinant interferon-gamma in cancer patients.

1986 ◽  
Vol 4 (11) ◽  
pp. 1677-1683 ◽  
Author(s):  
R Kurzrock ◽  
M G Rosenblum ◽  
J R Quesada ◽  
S A Sherwin ◽  
L M Itri ◽  
...  
Keyword(s):  
Interferon Gamma ◽  
Interferon Alpha ◽  
Maximum Tolerated Dose ◽  
Blood Levels ◽  
Recombinant Interferon ◽  
Starting Dose ◽  
The Individual ◽  
Dose Levels ◽  
Recombinant Interferon Alpha

Combinations of interferon-alpha and interferon-gamma demonstrate synergistic antiviral and anti-proliferative activity in vitro. Therefore, we initiated a clinical study of combination interferon therapy in humans. Eighteen patients with metastatic solid tumors received daily intramuscular (IM) injections of recombinant interferon-alpha-A (IFN alfa-2a, Roferon-A; Hoffman-LaRoche, Nutley, NJ) and recombinant IFN-gamma (rIFN-gamma) for 6 weeks. The dose levels were 0.5, 1.0, 2.0, and 5.0 X 10(6) U/m2/d of each interferon. A minimum of two patients were entered sequentially at each dose level. Fever, chills, fatigue, and a greater than or equal to 50% drop in granulocyte counts were observed at all doses. Severity of symptoms corresponded to increasing dose levels. In contrast to the tachyphylaxis to these symptoms that usually develops in patients treated with the individual interferons, many patients on this study experienced persistent fever and worsening fatigue over 6 weeks. The maximum tolerated dose was 1 X 10(6) U/m2/d of each interferon. One patient with renal-cell carcinoma achieved a partial remission (duration, 3 months). Enzyme-linked immunoassay analysis in all four patients for whom complete data were available revealed that peak blood levels of IFN alfa-2a on day 22 were about tenfold higher than on day 1. Because of the possibility of cumulative toxicity, the recommended starting dose for further studies is 0.5 X 10(6) U/m2/d of each interferon, with escalation to 1.0 X 10(6) U/m2/d after 1 month if tolerance is acceptable. Phase II investigations to explore the antitumor efficacy of this regimen are planned.

Gemcitabine (G) given as a prolonged infusion in patients (pts) with advanced solid tumors: A phase I study with intra-pt dose escalation (DE) and pharmacokinetic (PK) / pharmacodynamic (PD) analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12029-12029
Author(s):  
P. Soulié ◽  
D. Luet ◽  
S. Dupuis ◽  
M. Boisdron-Celle ◽  
V. Guérin-Meyer ◽  
...  
Keyword(s):  
Dose Level ◽  
Early Death ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Pharmacokinetic Data ◽  
Tumor Type ◽  
Fixed Dose Rate ◽  
Common Grade ◽  
Post Infusion ◽  
Dose Limiting Toxicity

12029 Background: Optimizing drug delivery based on pharmacokinetic data is an important research issue. Previous studies have demonstrated a pharmacological advantage for infusions of G with a fixed dose rate to maximize cellular accumulation of G active metabolite (GTP), despite high interindividual PK variability. Methods: To develop a PK-guided G dosing schedule, we conducted an intra-pt G DE trial to determine: (1) maximum tolerated dose level (MTD) and dose-limiting toxicity (DLT), (2) plasma G and peripheral mononuclear cell GTP post-infusion levels. G was administered over 150 min on day 1, 8 and 15, q4w. The initial dose level (DL) was 1000 mg/m2, escalated by 250 mg/m2 every cycle (cy) if no limiting toxicity occurred. Results: From 09/2003, 30 pts entered the study. Pts’ characteristics: 16 men/14 women; median age 66 years (49–81); tumor type: pancreas (10 pts), lung (7 pts), others (13 pts); prior chemotherapy (15 pts). A total of 109 cy were given (median: 3 cy/pt). Tolerance: Number of pts/DL: DL1 = 7 pts, DL2 = 5 pts, DL3 = 11 pts, DL4 = 5 pts, DL5 = 2 pts. Main reasons for stopping DE were: disease progression/early death (15 pts), DLT (4 pts), investigator’s decision (8 pts). DLT were: haematological (1 pt), asthenia (2 pts) and infection (1 pt). Most common grade (gr) 1–2/3–4 toxicities (% cy) included: nausea/vomiting (38%/2%), asthenia (56%/11%), neutropenia (29%/27%) and thrombocytopenia (42%/1%). Activity: 26 pts are evaluable (radiological assessment every 3 cycles) showing 5 partial response (2 unconfirmed), 7 stabilization and 14 progression. Conclusions: The main reason for DE failure was early progression, stressing the importance of an early individual dose adjustment. PK and PK/PD correlation analyses are ongoing to confirm our hypothesis. No significant financial relationships to disclose.

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.

Clinical development of namitecan (ST1968), a novel camptothecin derivative with high antitumor activity: Phase I clinical data

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2570-2570 ◽  
Author(s):  
D. Hess ◽  
S. Boehm ◽  
A. Delmonte ◽  
E. Gallerani ◽  
P. Barbieri ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Maximum Tolerated Dose ◽  
Water Soluble ◽  
Hematologic Toxicity ◽  
Cohort Design ◽  
Blood And Urine Samples ◽  
High Antitumor Activity ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

2570 Background: Namitecan is a new water-soluble camptothecin analogue which showed high antitumor activity in preclinical models. Aim of this trial was to determine safety, PK profile and activity in adult patients with advanced solid tumors. Methods: The dose escalation started at 2.5 mg i.v. on days 1 and 8 of a 21 day cycle (D1, D8 Q21D) and increased according to 3+3 cohort design depending on the observed toxicity. Dose limiting toxicity (DLT) definitions were: ANC <0.5x109/L for >5 days; PLT ≥ Grade 3 (CTC V3); grade ≥2 liver/renal toxicity not recovered by D22; any non-hematologic toxicity ≥ Grade 3; D8 dose skipping due to toxicity. Maximum tolerated dose (MTD) and recommended dose (RD) were the primary end-points. Blood and urine samples were collected at cycle 1 for PK evaluation. Results: 31 pts (11 endometrial ca., 5 CRC, 5 ovarian ca., 2 NSCLC, 8 other) have been included, with 6 dose levels evaluated (2.5; 5; 10; 15; 17.5 and 20 mg). 17.5 mg was introduced later when 2/7 DLTs at 20 mg were observed (ANC G4>5days, one with D8 skipping). At 17.5mg 2/4 pts experienced DLTs (ANC G4; D8 skipped). Uncomplicated neutropenia and thrombocytopenia were the most relevant G3/4 hematological toxicities. Other toxicities were mild or moderate asthenia, fatigue and alopecia. The MTD was defined at 17.5 mg and the RD was 15 mg. Stable disease ≥ 6 cycles was recorded in 6 pts (2 stable diseases ≥ 10 cycles). PK was linear and data suggest an entero-hepatic recirculation. No metabolites were found in plasma and the product resulted poorly excreted into urine. Conclusions: The MTD and RD of D1, D8 Q21D schedule have been identified. The study will continue with the evaluation of MTD and RD of a single administration per cycle (D1 Q21D), to optimize the schedule of treatment. [Table: see text]

Phase I study of paclitaxel in patients with recurrent malignant glioma: a North American Brain Tumor Consortium report.

1998 ◽  
Vol 16 (6) ◽  
pp. 2188-2194 ◽  
Author(s):  
S M Chang ◽  
J G Kuhn ◽  
J Rizzo ◽  
H I Robins ◽  
S C Schold ◽  
...  
Keyword(s):  
Malignant Glioma ◽  
Phase Ii Study ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Recurrent Malignant Glioma ◽  
Starting Dose ◽  
Dose Levels ◽  
Higher Doses ◽  
Dose Limiting Toxicity ◽  
Unacceptable Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) of paclitaxel administered as a 3-hour infusion in patients with recurrent malignant glioma. PATIENTS AND METHODS Patients were stratified by starting dose of paclitaxel and concurrent anticonvulsant (AC) use and were treated in cohorts of three patients. The starting dose was 240 mg/m2 administered intravenously with escalations of 30 mg/m2 until the MTD was established. Pharmacokinetic data were obtained for each patient for the first infusion. Tumor response was assessed at 6-week intervals and treatment was continued until documented tumor progression, unacceptable toxicity, or a total of 12 paclitaxel infusions. RESULTS From April 1995 to December 1996, 34 patients were treated; 27 patients in the AC group and seven patients in the non-AC group. The MTD for patients who received ACs was established at 360 mg/m2 and the dose-limiting toxicity (DLT) was central neurotoxicity, characterized as transient encephalopathy and seizures. In contrast, the MTD for patients who did not receive ACs was 240 mg/m2, and myelosuppression, gastrointestinal toxicity, and fatigue were the DLTs. Pharmacokinetic data confirmed that the plasma drug levels and clearance rates were similar for patients in both groups at the respective dose levels that produced DLTs. CONCLUSION The pharmacokinetics of paclitaxel are altered by ACs, and significantly larger doses of the drug can be administered to patients with brain tumors on AC therapy. The toxicity profile is different for patients on AC therapy treated at these higher doses. A phase II study has been initiated that uses a dose of 330 mg/m2 for patients on AC therapy and 210 mg/m2 for patients not on AC therapy.

Phase I and Pharmacokinetic Study of Two Different Schedules of Oxaliplatin, Irinotecan, Fluorouracil, and Leucovorin in Patients With Solid Tumors

2003 ◽  
Vol 21 (20) ◽  
pp. 3761-3769 ◽  
Author(s):  
Matthew P. Goetz ◽  
Charles Erlichman ◽  
Anthony J. Windebank ◽  
Joel M. Reid ◽  
Jeffrey A. Sloan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Weekly Schedule ◽  
Total Platinum ◽  
Starting Dose ◽  
Platinum Accumulation ◽  
Dose Levels ◽  
Dose Limiting Toxicity

Purpose: We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics. Patients and Methods: Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD. Results: Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P = .048), but objective neurotoxicity was not seen. Conclusion: The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.

A phase Ⅰ open-label dose-escalation study of AL2846 in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16210-e16210
Author(s):  
Rui Liu ◽  
Ting Deng ◽  
Ming Bai ◽  
Le Zhang ◽  
Tao Ning ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Dose Level ◽  
Standard Dose ◽  
Locally Advanced ◽  
Maximum Tolerated Dose ◽  
Ductal Adenocarcinoma ◽  
Efficacy Evaluation ◽  
Dose Escalation Study ◽  
Grade 3 ◽  
Dose Levels

e16210 Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 10%. Overexpression of c-Met is associated with the poor prognosis in patients with PDAC and it was noted that phosphorylation of c-Met is increased in gemcitabine-resistant PDAC. AL2846 is an oral c-Met inhibitor, which targets multiple receptor tyrosine kinases (RTK’s) primarily including c-Met, VEGFR1, KIT, Axl and RET. The combination of AL2846 with chemotherapy may improve the clinical efficacy of PDAC. Based on these consideration, a phase Ⅰ clinical trial was initiated to determine the maximum tolerated dose (MTD) of AL2846 in combination with gemcitabine in patients with advanced PDAC and to clarify the potential anti-tumor activity. Methods: Patients with untreated locally advanced or metastatic PDAC were enrolled to receive oral AL2846 once daily in a fasted state in combination with gemcitabine intravenous infusion over 30 min on days 1, 8, and 15 every 28 days. The starting dose level is AL2846 40 mg and gemcitabine 1000 mg/m2. Primary endpoint was the maximum tolerated dose (MTD), defined as the highest dose level at which ≤33 % of patients incurred a dose-limiting toxicity (DLT), and RP2D. Secondary endpoints included response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: As of January 1, 2021, a total of 15 patients with PDAC were enrolled and received 4 dose-levels of AL2846 (40 mg: n = 1; 60 mg: n = 6; 90 mg: n = 3; 120 mg: n = 5) treatment. DLTs occurred in 1 patient who experienced grade 3 abnormal liver function. The most common grade 3 or above drug-related adverse events were neutropenia (n = 7, 46.7%), thrombocytopenia (n = 5, 33.3%), leukopenia (n = 4, 26.7%), GGT increased (n = 4, 26.7%), hyperbilirubinemia (n = 3, 20.0%) and alkaline phosphatase increased (n = 3, 20.0%). Among the 15 patients available for efficacy evaluation, 1 patient (6.6%) achieved partial response who was at the dose levels of 90mg. There were 4 patients whose PFS was more than 5 months. Although there were no more than 2 DLT events, we chose 90 and 120 mg as the target dose for RP2D according to the dose reduction and proportion of gemcitabine. Conclusions: The RP2D of AL2846 in combination with standard dose of gemcitabine were 90 and 120 mg QD continuously. The results demonstrated that AL2846 in combination with gemcitabine was well tolerated at doses up to 120 mg. Further clinical studies about the efficacy of AL2846 in pancreatic cancer are in progress. Clinical trial information: CTR20201021.

Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer.

1998 ◽  
Vol 16 (4) ◽  
pp. 1450-1457 ◽  
Author(s):  
R L Schilsky ◽  
J Hohneker ◽  
M J Ratain ◽  
L Janisch ◽  
L Smetzer ◽  
...  
Keyword(s):  
Washout Period ◽  
Mononuclear Cells ◽  
Dihydropyrimidine Dehydrogenase ◽  
Maximum Tolerated Dose ◽  
Peripheral Blood Mononuclear ◽  
Period 2 ◽  
Daily Schedule ◽  
Starting Dose ◽  
Dose Levels

PURPOSE To determine the highest dose of fluorouracil (5-FU) that could be safely administered with Eniluracil (776C85; Glaxo Wellcome Inc, Research Triangle Park, NC), an inactivator of dihydropyrimidine dehydrogenase (DPD), on a daily schedule for 5 days, and to define the toxicities of the combination and the pharmacokinetics of 5-FU when administered with 776C85. PATIENTS AND METHODS Patients with advanced solid tumors refractory to standard therapy were enrolled at two institutions. The study consisted of three periods designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of 776C85 alone (period 1); the effects of 776C85 on the pharmacokinetics of 5-FU (period 2); and the maximum-tolerated dose (MTD) of 5-FU, with or without leucovorin, that could be safely administered with 776C85 (period 3). Cohorts of at least three patients each received oral 776C85 alone at doses of 3.7 mg/m2/d, 18.5 mg/m2/d and 0.74 mg/m2/d. After a 14-day washout period, each patient then received 776C85 daily for 3 days, with a single intravenous (i.v.) bolus dose of 5-FU 10 mg/m2 on day 2. After a second washout period, patients were treated with 776C85 daily for 7 days and 5-FU i.v. bolus on days 2 through 6. The starting dose of 5-FU 10 mg/m2/d was escalated until the MTD was determined. After determination of the MTD of 5-FU given with 776C85, oral leucovorin 50 mg/d on days 2 through 6 was added to determine the MTD of 5-FU with leucovorin in the presence of 776C85. Near the completion of the study, additional cohorts of patients were treated with 776C85 at 50 mg/d and oral 5-FU with or without leucovorin. RESULTS Sixty-five patients were enrolled onto the study and 60 were assessable for toxicity and response. Bone marrow suppression was the primary and dose-limiting toxicity of this regimen. Other toxicities included diarrhea, mucositis, anemia, anorexia, nausea, vomiting, and fatigue. 776C85 suppressed DPD activity in peripheral-blood mononuclear cells (PBMCs) by at least 90% for at least 24 hours at all dose levels tested. In the presence of 776C85, 5-FU half-life was prolonged, clearance was reduced, and the drug displayed linear pharmacokinetics. Recommended doses for further testing on a daily for 5-day schedule are 776C85 10 mg/d with i.v. 5-FU 25 mg/m2/d; 776C85 10 mg/d with i.v. 5-FU 20 mg/m2/d plus leucovorin 50 mg/d; 776C85 50 mg/d with 5-FU given orally at 15 mg/m2/d with leucovorin at 50 mg/d. CONCLUSION 5-FU can be safely administered with 776C85; however, the MTDs are considerably lower than those conventionally used, caused, at least in part, by marked alterations in 5-FU plasma pharmacokinetics.

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 spirogermanium given daily.

1983 ◽  
Vol 1 (5) ◽  
pp. 331-336 ◽  
Author(s):  
S S Legha ◽  
J A Ajani ◽  
G P Bodey
Keyword(s):  
Continuous Infusion ◽  
Tumor Regression ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
Optimum Dose ◽  
Second Phase ◽  
Clinical Effects ◽  
Third Phase ◽  
Dose Levels ◽  
Dose Limiting Toxicity

Spirogermanium, an azaspirane compound, has recently had limited clinical trials using a schedule of intravenous injection one to three times every week. The observation of clinical antitumor activity and lack of myelosuppression prompted us to investigate further the clinical effects of spirogermanium administered on various schedules. A total of 52 patients with advanced metastatic tumors refractory to standard therapy were treated with spirogermanium. Three different schedules of drug administration were evaluated. Initially, a short daily IV infusion for 5 days every week was evaluated, starting with a dose of 30 mg/m2/day. A total of 22 patients received 69 courses with a dose range of 30-120 mg/m2/day for 5 days every week. The maximum tolerated dose was 100 mg/m2/day IV over 1 hr and 120 mg/m2 over 2-3 hr. In the second phase of the study, 12 patients received 41 courses of spirogermanium as a 24-hr continuous infusion for 5 days/wk at a dose of 150-375 mg/m2/day. The maximum tolerated dose was 200 mg/m2/day for 5 days. In the third phase of the study, 18 patients received spirogermanium as a continuous infusion daily for a median of 30 days (range 6-77 days) in a dose range of 100-200 mg/m2/day. The maximum tolerated dose was 150 mg/m2/day. Of the 44 assessable patients, 3 demonstrated a partial response and 3 had minor tumor regression; all responses occurred in lymphoma patients. The dose-limiting toxicity of spirogermanium was neurologic; other side effects consisted of mild anorexia, nausea and vomiting, and possible lung toxicity. There was no clear evidence of cumulative toxicity despite daily administration of spirogermanium. Our data suggest that spirogermanium can be administered daily by several different schedules, and the optimum dose depends on the infusion time and the duration of therapy. The delivery of drug by continuous infusion permitted administration of twofold higher dose levels compared to the standard IV schedules used in previous studies.

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