Phase I study of rapamycin (R) in combination with CYP3A4 modifier, ketoconazole (K), in patients with advanced malignancies

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3061-3061
Author(s):  
E. E. Cohen ◽  
K. Moshier ◽  
F. Innocenti ◽  
M. Kocherginsky ◽  
L. House ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Advanced Malignancies ◽  
Starting Dose ◽  
Constant Dose ◽  
Cancer Types ◽  
Grade 3 ◽  
Elevated Transaminases ◽  
Dose Levels ◽  
Higher Doses ◽  
Experienced Grade

3061 Background: R is currently FDA approved for the treatment of renal allograft rejection but mTOR is a relevant target in several cancer types. K, a CYP3A4 inhibitor, increases the area under the concentration curve (AUC) of R and co-administration of R and K can overcome poor R bioavailability and decrease costs substantially. The aims of this study were to find the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of R administered weekly in combination with K and describe the pharmacokinetics (PK) of the combination in patients with advanced malignancies. Methods: R and K were administered concurrently to successive cohorts of patients. R starting dose was 1 mg once weekly and was escalated by 1 mg per dose level. K was administered at a constant dose of 200mg BID 1 day prior to each R dose then 200 mg QD on the next 3 consecutive days. Results: 34 subjects (median age 60 years) have been enrolled. The highest dose of R administered thus far was 5mg without DLT. Most frequent toxicities observed of any grade included hyperglycemia (41%), lymphopenia (35%), hyperlipidemia (35%), fatigue (29%), anemia (26%), anorexia (24%), and nausea (24%). Observed grade 3 toxicities included 2 patients with lymphopenia, 2 patients with elevated transaminases, and 1 patient each with emesis and hyperglycemia. One patient experienced grade 3 confusion likely due to a drug-drug interaction of K with concomitant psychotropic medications. PK analysis of the first 2 dose levels confirms that K significantly increases Cmax and AUC of R ( Table ). R Cmax (with K) averaged 22.5 (11.7) and 27.4 (7.9) (mean/SD) ng/ml at the 1 and 2 mg dose levels, respectively. R AUC (with K) averaged 408.9 (225.4) and 663.8 (201.8) (mean/SD) ng*h/ml at the 1 and 2 mg dose levels, respectively. Conclusions: Low dose weekly R plus K results in potentially efficacious concentrations, as demonstrated by classic mTOR inhibitor toxicity. Higher doses on this schedule without K are probably also feasible, but would have higher costs. [Table: see text] No significant financial relationships to disclose.

scholarly journals Genotype-Driven Phase I Study of Irinotecan Administered in Combination With Fluorouracil/Leucovorin in Patients With Metastatic Colorectal Cancer

2010 ◽  
Vol 28 (5) ◽  
pp. 866-871 ◽  
Author(s):  
Giuseppe Toffoli ◽  
Erika Cecchin ◽  
Giampiero Gasparini ◽  
Mario D'Andrea ◽  
Giuseppe Azzarello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Data ◽  
Patients With Cancer ◽  
Starting Dose ◽  
Common Grade ◽  
Grade 3 ◽  
Dose Levels ◽  
Higher Doses

PurposeWe aimed to identify the maximum-tolerated dose (MTD) of irinotecan in patients with cancer with UGT1A1*1/*1 and *1/*28 genotypes. We hypothesize that the patients without the *28/*28 genotype tolerate higher doses of irinotecan.Patients and MethodsPatients undergoing first-line treatment for metastatic colorectal cancer (CRC) eligible for treatment with irinotecan plus infusional fluorouracil/leucovorin (FOLFIRI) were screened for the UGT1A1*28/*28 genotype and excluded from the study. Fifty-nine white patients with either the *1/*1 or the *1/*28 genotype were eligible for dose escalation of irinotecan. The starting dose of biweekly irinotecan was 215 mg/m2for both genotype groups, whereas the dose of infusional fluorouracil was fixed. Pharmacokinetic data of irinotecan and metabolites were also obtained.ResultsThe dose of irinotecan was escalated to 370 mg/m2in patients with the *1/*28 genotype and to 420 mg/m2in those with the *1/*1 genotype. Dose-limiting toxicities (DLTs) were observed in two of four of *1/*28 patients at 370 mg/m2and in two of three of *1/*1 patients at 420 mg/m2. No DLTs were observed in 10 *1/*28 patients at 310 mg/m2and in 10 *1/*1 patients at 370 mg/m2; hence these dose levels were the MTD for each genotype group. The most common grade 3 to 4 toxicities were neutropenia and diarrhea. The pharmacokinetics of irinotecan and SN-38 exhibit linear kinetics.ConclusionThe recommended dose of 180 mg/m2for irinotecan in FOLFIRI is considerably lower than the dose that can be tolerated when patients with the UGT1A1*28/*28 genotype are excluded. Prospective genotype-driven studies should test the efficacy of higher irinotecan doses in the FOLFIRI schedule.

2-Chlorodeoxyadenosine dose escalation in nonhematologic malignancies.

1993 ◽  
Vol 11 (4) ◽  
pp. 671-678 ◽  
Author(s):  
A Saven ◽  
H Kawasaki ◽  
C J Carrera ◽  
T Waltz ◽  
B Copeland ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Intravenous Infusion ◽  
Hematologic Malignancies ◽  
Maximum Tolerated Dose ◽  
Malignant Astrocytoma ◽  
Dose Escalation Study ◽  
Tissue Samples ◽  
Grade 3 ◽  
Higher Doses ◽  
Experienced Grade

PURPOSE We performed a dose-escalation study of 2-chlorodeoxyadenosine (2-CdA) in solid tumors to determine the maximum-tolerated dose (MTD) and define its toxicity profile at higher doses. PATIENTS AND METHODS Twenty-one patients, seven with malignant astrocytoma, twelve with metastatic melanoma, and two with metastatic hypernephroma, were enrolled onto the study. Patients were entered onto cohorts that received 0.10, 0.15, or 0.20 mg/kg/d of 2-CdA by continuous intravenous infusion for 7 days every 28 days. 2-CdA levels were determined by radioimmunoassay. In tumor tissue samples, deoxycytidine kinase (dCK) levels were measured by both enzyme activity and immunoreactive protein analysis. RESULTS Of seven patients treated with 2-CdA at 0.1 mg/kg/d, one experienced grade 3 or 4 myelotoxicity. Of 11 patients treated at 0.15 mg/kg/d, four experienced myelotoxicity, two after a single course of 2-CdA. All three patients who received 2-CdA at 0.2 mg/kg/d experienced myelosuppression. Neurologic events occurred in two patients, both with malignant melanoma. Two of seven patients (28.6%) with astrocytomas obtained partial responses with a median duration of 8 months. 2-CdA penetrated the blood-brain barrier. An association was found between dCK levels as measured by enzymatic activity and immunoreactive proteins, but this did not correlate with 2-CdA tumor responsiveness. CONCLUSION The MTD for 2-CdA delivered as a 7-day intravenous infusion in patients with nonhematologic malignancies was determined to be 0.1 mg/kg/d, the same as the MTD for patients with hematologic malignancies. There was no clinical correlation with dCK expression and response to 2-CdA. The responses noted in patients with malignant astrocytoma warrant further phase II study.

Phase I study of sorafenib in children with refractory solid tumors: A Children's Oncology Group Phase I Consortium trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 10012-10012 ◽  
Author(s):  
B. C. Widemann ◽  
E. Fox ◽  
P. C. Adamson ◽  
S. Baruchel ◽  
A. Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Maximum Tolerated Dose ◽  
Eligibility Criteria ◽  
Starting Dose ◽  
Hand Foot Syndrome ◽  
Normal Alt ◽  
Grade 3 ◽  
Dose Levels

10012 Background: Sorafenib, an oral multitargeted kinase inhibitor, is indicated for treatment of adults with refractory renal cell or hepatocelluar carcinoma. We performed a phase I trial to determine the toxicities, maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) of sorafenib in children with refractory solid tumors. Methods: Sorafenib was administered q12h for 28 consecutive day cycles. Cohorts of 3–12 patients were enrolled at 105, 130, 150, 200, and 250 mg/m2/dose dose levels. Results: 34 eligible pts [16M, median age 14.6 yrs, (range, 5–21)] with osteosarcoma (n = 8), rhabdomyosarcoma (n = 3), other sarcomas (n = 13), hepatoblastoma (n = 3), or other solid tumors (n = 7) received 1–22 cycles (median 2). Grade 3 dose-limiting toxicity (DLT) occurred in 4/6 pts at the starting dose (150 mg/m2) and included hypertension (n = 1), rash/urticaria (n = 1), back pain (n = 1), thrombocytopenia (n = 1) and ALT/AST (n = 1). No DLTs were observed at 105 (n = 6) or 130 (n = 3) mg/m2, and the dose was re-escalated to 150 mg/m2 with modified eligibility criteria (normal ALT) and revised guidelines for grading and management of hypertension. Gr 3 DLTs occurred in 1/6 pts (lipase) at 150 mg/m2 and 2/2 pts (hyponatremia, hand-foot syndrome) at 250 mg/m2. At 200 mg/m2 only 1/6 pts experienced DLT (gr 3 ALT). No objective responses were observed, but 2 pts had tumor shrinkage. Sorafenib AUC did not increase proportionally with dose - the mean AUC0–24h was similar at 150 mg/m2 (28±24 μg · h/mL, n = 9) and 200 mg/m2 (28±17 μg · h/mL, n = 4). Tmax was prolonged and variable (10±11 h, n = 19). Plasma VEGFR (n = 13) decreased from 9.9±1.6 ng/mL at baseline to 8.3±1.7 ng/mL by d 28 (p < 0.001). Conclusions: The MTD of sorafenib in children with solid tumors is 200 mg/m2, similar to the adult recommended dose (400 mg). No significant financial relationships to disclose.

Phase I Trial of the Novel Mammalian Target of Rapamycin Inhibitor Deforolimus (AP23573; MK-8669) Administered Intravenously Daily for 5 Days Every 2 Weeks to Patients With Advanced Malignancies

2008 ◽  
Vol 26 (3) ◽  
pp. 361-367 ◽  
Author(s):  
Monica M. Mita ◽  
Alain C. Mita ◽  
Quincy S. Chu ◽  
Eric K. Rowinsky ◽  
Gerald J. Fetterly ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Target Of Rapamycin ◽  
Phase Ii Trials ◽  
Solid Malignancies ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Dose Levels

Purpose This phase I trial was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of deforolimus (previously known as AP23573; MK-8669), a nonprodrug rapamycin analog, in patients with advanced solid malignancies. Patients and Methods Patients were treated using an accelerated titration design with sequential escalating flat doses of deforolimus administered as a 30-minute intravenous infusion once daily for 5 consecutive days every 2 weeks (QD×5) in a 28-day cycle. Safety, pharmacokinetic, pharmacodynamic, and tumor response assessments were performed. Results Thirty-two patients received at least one dose of deforolimus (3 to 28 mg/d). Three dose-limiting toxicity events of grade 3 mouth sores were reported. The maximum-tolerated dose (MTD) was 18.75 mg/d. Common treatment-related adverse events included reversible mouth sores and rash. Whole-blood clearance increased with dose. Pharmacodynamic analyses demonstrated mammalian target of rapamycin inhibition at all dose levels. Four patients (one each with non–small-cell lung cancer, mixed müllerian tumor [carcinosarcoma], renal cell carcinoma, and Ewing sarcoma) experienced confirmed partial responses, and three additional patients had minor tumor regressions. Conclusion The MTD of this phase I trial using an accelerated titration design was determined to be 18.75 mg/d. Deforolimus was well tolerated and showed encouraging antitumor activity across a broad range of malignancies when administered intravenously on the QD×5 schedule. On the basis of these overall results, a dose of 12.5 mg/d is being evaluated in phase II trials.

scholarly journals EPCT-11. PHASE 1 STUDY OF FLUVASTATIN-CELECOXIB COMBINATION IN CHILDREN WITH RELAPSING/REFRACTORY OPTICO-CHIASMATIC LOW-GRADE GLIOMA OR HIGH-GRADE GLIOMAS (FLUVABREX): FINAL RESULTS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii305-iii306
Author(s):  
Nicolas Andrew ◽  
Arthur Sterin ◽  
Caroline Solas ◽  
Marie-Cécile Le Deley ◽  
Alicia Probst ◽  
...  
Keyword(s):  
Phase I ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Low Grade ◽  
High Grade ◽  
Phase 2 Study ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Levels

Abstract BACKGROUND Preclinical data support the activity of celecoxib and fluvastatin in high grade (HGG) and low grade gliomas (LGG). A Phase I study was designed to evaluate this combination in children with refractory/relapsed glioma. AIM: To assess the safety, pharmacokinetics (PK), maximum tolerated dose, Recommended Dose for Phase II (RDP2). METHOD: Multicenter phase I trial, including patients aged 6 to 21 year old. Fluvastatin starting dose was 2 mg/kg/day, 14/28 days, with fixed dose of celecoxib (200–800 mg /day). Four dose levels of fluvastatin (2, 4, 6, 8 mg/kg/day) were evaluated. A Continual Reassessment Method was used for dose escalation. Dose-limiting toxicities (DLT) were determined on the 1st cycle. PK samples were obtained at D1 and D14 of cycle 1, pre-dose of cycle 2. RESULTS 20 patients were enrolled with a median age of 12 years (5.9–19). They previously received a median of 3 (1–7) lines of treatment. Ten patients were treated for LGG and 10 for HGG, receiving a median of 3.5 cycles (1–21). Patients with LGG received a median of 9 cycles (1–21). Among the 17 patients evaluable for DLT, 2 DLTs were reported: 1 grade 3 maculo-papular rash (4 mg/kg), and 1 grade 4 increase of CPK (6 mg/kg). The RP2D of fluvastatin is 6 mg/kg/day. CONCLUSION In children with refractory/relapsed glioma, the RDP2 of fluvastatin associated with celecoxib is 6 mg/kg/day. This combination is well tolerated encouraging a phase 2 study in LGG.

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 study of gemcitabine (GEM) and premetrexed (ptx) in the treatment of advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12025-12025
Author(s):  
A. Kalykaki ◽  
S. Agelaki ◽  
K. Kalbakis ◽  
A. Kotsakis ◽  
N. Kentepozidis ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Study ◽  
Median Number ◽  
Phase Ii Studies ◽  
Advanced Malignancies ◽  
Wide Range ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Levels

12025 Background: GEM has activity against a wide range of tumors and ptx is a multitargeted antifolate agent with activity in mesothelioma and non small lung cancer (NSCLC). A phase I study of a combination of GEM plus ptx for advanced malignancies was conducted. Methods: Patients with advanced malignancies were enrolled in this accelerated dose escalation trial. Both patients with or without prior chemotherapy were also eligible. They were treated with Gem followed by ptx on days 1 and 15 every 4 weeks. The starting dose was GEM 1250 mg/m2 and ptx 300 mg/m2. The dose of each drug was escalated alternately by 250 mg for GEM and 50 mg for ptx at each dose level. Results: A total of 41 patients (9 female/32 males) with median age of 60 years were enrolled at 6 dose levels. A total of 93 cycles were conducted with a median number of 2 cycles/pt. 35 patients were assessable for efficacy and all courses were assessable for toxicity. Grade 3/4 neutropenia was observed in 8 cycles whereas grade 3 /4 anemia and grade 3/4 thrombocytopenia in 3 and 2 cycles respectively. Grade 3 febrile neutropenia occurred in 1 cycle. Other ≥ grade 3 non-hematological toxicities were observed in only 3 cycles [grade 3/4 asthenia: in 2 cy; grade 3 edema: in 1 cy). The MTD was 1750 mg/m2 for GEM and 450 mg/m2 for ptx. Dose limiting toxicities were grade IV neutropenia, grade III thrombocytopenia and febrile neutropenia. Two partial responses (1 patient with ovarian cancer and 1 with NSCLC) were observed and stable disease in 4. Conclusions: The recommended doses for further phase II studies are GEM (1750 mg/m2) followed by ptx (450 mg/m2) biweekly. No significant financial relationships to disclose.

A phase I study of SDX-102 for the treatment of patients with MTAP-deficient recurrent malignant gliomas

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2063-2063
Author(s):  
S. Phuphanich ◽  
M. Chamberlain ◽  
T. Mikkelsen ◽  
X. Ye ◽  
S. A. Grossman ◽  
...  
Keyword(s):  
Dose Escalation ◽  
De Novo ◽  
Malignant Gliomas ◽  
Maximum Tolerated Dose ◽  
Purine Biosynthesis ◽  
Starting Dose ◽  
Chemotherapy Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Rate Limiting

2063 Background: De novo purine biosynthesis entails two metabolic pathways of which one pathway is frequently impaired in cancer due to gene deletion of the rate limiting enzyme, methythioadenosine phosphorylase (MTAP). In MTAP-deficient cancers, SDX-102 inhibits purine biosynthesis by blocking the remaining synthetic pathway. This study was to determine the maximum tolerated dose (MTD), toxicity and pharmacokinetic activity of SDX-102 in the treatment of recurrent MTAP-deficient malignant gliomas. Methods: Eligible patients had recurrent supratentorial MTAP-deficient malignant gliomas treated previously with surgery, radiation and = 2 regimens of chemotherapy. Dose escalation was conducted separately for patients taking enzyme inducing anti-seizure drugs (EIASD+) and for those not (EIASD-). The starting dose in both groups was 80 mg/m2/day continuous infusion for 5 days every 3 weeks, cycle length was 3 weeks. Dose escalation was in a stepwise fashion in cohorts of three patients, up to a maximum dose of 125 mg/m2/day. Results: 118 patients were screened of which 39 (33%) had MTAP-deficient tumors. 21 patients (14 males/7 females) were enrolled between 9/17/04 and 3/17/06. Median age was 50 years (23–76); median KPS was 90 (60–100); 16 patients (76%) had GBM. Two dose levels of SDX-102 were tested in the EIASD+ group: 80 mg/m2/day (n=4) and 100 mg/m2/day (n=3), 3/3 dose limiting toxicity (DLT) were noted with grade 3 mucositis at 100 mg/m2/day , so in the EIASD+ group the MTD was 80 mg/m2/day. Three dose levels were tested in the EIASD- group: 80 mg/m2/day (n=4), 100 mg/m2/day (n=7), 1/3 patients had DLT (Grade 4 mucositis) at 100 mg/m2/day and the cohort was expanded for additional 3 patients without DLT noted; and 125 mg/m2/day (n=3) amongst whom no DLT was observed. No MTD was determined in the EIASD- group because the MTAP assay became unavailable through the sponsor. There were a range of 1–14 cycles administered in this patient population. Conclusions: SDX-102 infusion is safe and feasible in patients with recurrent MTAP-deficient malignant gliomas. The MTD in EIASD+ patients is 80 mg/m2/day. The EIASD-group MTD has not been determined however the highest dose tested is 125 mg/m2/day. No significant financial relationships to disclose.

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.

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