scholarly journals 157P Survey of the onset of the dose limiting toxicity in oncology phase I trial: How long should we assess the toxicity profiles in the era of molecular targeted drug development?

2016 ◽  
Vol 27 ◽  
pp. ix49
Author(s):  
N. Kobayashi ◽  
N. Yamamoto
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Phase I Trial ◽  
Molecular Targeted Drug ◽  
Targeted Drug ◽  
Dose Limiting Toxicity

scholarly journals A Bayesian dose-finding design for outcomes evaluated with uncertainty

2021 ◽  
pp. 174077452110015
Author(s):  
Matthew J Schipper ◽  
Ying Yuan ◽  
Jeremy MG Taylor ◽  
Randall K Ten Haken ◽  
Christina Tsien ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Data Augmentation ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Continual Reassessment Method ◽  
Number Of Patients ◽  
Continual Reassessment ◽  
Partially Observed ◽  
Dose Limiting Toxicity

Introduction: In some phase I trial settings, there is uncertainty in assessing whether a given patient meets the criteria for dose-limiting toxicity. Methods: We present a design which accommodates dose-limiting toxicity outcomes that are assessed with uncertainty for some patients. Our approach could be utilized in many available phase I trial designs, but we focus on the continual reassessment method due to its popularity. We assume that for some patients, instead of the usual binary dose-limiting toxicity outcome, we observe a physician-assessed probability of dose-limiting toxicity specific to a given patient. Data augmentation is used to estimate the posterior probabilities of dose-limiting toxicity at each dose level based on both the fully observed and partially observed patient outcomes. A simulation study is used to assess the performance of the design relative to using the continual reassessment method on the true dose-limiting toxicity outcomes (available in simulation setting only) and relative to simple thresholding approaches. Results: Among the designs utilizing the partially observed outcomes, our proposed design has the best overall performance in terms of probability of selecting correct maximum tolerated dose and number of patients treated at the maximum tolerated dose. Conclusion: Incorporating uncertainty in dose-limiting toxicity assessment can improve the performance of the continual reassessment method design.

scholarly journals Focused Ultrasound Hyperthermia for Targeted Drug Release from Thermosensitive Liposomes: Results from a Phase I Trial

Radiology ◽  
2019 ◽  
Vol 291 (1) ◽  
pp. 232-238 ◽  
Author(s):  
Michael D. Gray ◽  
Paul C. Lyon ◽  
Christophoros Mannaris ◽  
Lisa K. Folkes ◽  
Michael Stratford ◽  
...  
Keyword(s):  
Drug Release ◽  
Phase I ◽  
Phase I Trial ◽  
Focused Ultrasound ◽  
Thermosensitive Liposomes ◽  
Targeted Drug ◽  
Ultrasound Hyperthermia

Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial in patients with advanced hematological malignancies

1995 ◽  
Vol 36 (3) ◽  
pp. 204-210 ◽  
Author(s):  
Richard A. Larson ◽  
Robert B. Geller ◽  
Linda Janisch ◽  
John Milton ◽  
Louise B. Grochow ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Hematological Malignancies ◽  
Dose Limiting Toxicity

Phase I Trial Examining Addition of Gemcitabine to CHOP in Intermediate Grade NHL.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4765-4765
Author(s):  
John L. Reagan ◽  
James N. Butera ◽  
Alan G. Rosmarin ◽  
Ahmed Nadeem ◽  
Fred J. Schiffman ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Trial ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Chop Chemotherapy ◽  
Intermediate Grade ◽  
Chemotherapeutic Regimen ◽  
Grade 3 ◽  
Dose Limiting Toxicity

Abstract Abstract 4765 BACKGROUND Gemcitabine induces a 20% response as single agent therapy in patients with relapsed or refractory NHL. We report phase I findings of gemcitabine in combination with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. The protocol was modified during enrollment to include rituximab in CD 20+ lymphomas. METHODS Patients received CHOP plus gemcitabine at 500 mg/m2 (Cohort 1) or 750 mg/m2 (Cohort 2) on days 1,4 of each 21 day cycle. Accrual was suspended once each cohort was filled. Dose escalation occurred after all patients in the cohort were determined to not have a dose limiting toxicity. RESULTS Between 4/02 and 5/04 10 patients were enrolled and completed the study treatment (6 in cohort 1, 4 in cohort 2). In Cohort 1, grade 3 toxicities included neutropenia, anemia, neuropathy, and constipation. Grade 4 toxicities were febrile neutropenia, and thrombocytopenia. In Cohort 2, grade 3 toxicities included neutropenia, thrombocytopenia, mucositis, anemia and intestinal obstruction. Grade 4 toxicities included febrile neutropenia, neutropenia, and thrombocytopenia. One patient developed MDS 36 months after chemotherapy. Three of four patients in Cohort 2 developed dose limiting toxicities (mucositis and thrombocytopenia) requiring dose reduction of gemcitabine after cycle 1. Overall, the survival rate at 2.5 years was 71%. CONCLUSIONS This Phase I trial concludes that gemcitabine 500mg/m2 on days 1 and 4 of each 21 day cycle is the maximum tolerated dose when combined with standard CHOP chemotherapy with G-CSF support for intermediate grade NHL. Response rates are encouraging for this novel chemotherapeutic regimen. Disclosures: Off Label Use: Gemcitabine was added to standard CHOP chemotherapy in this trial.. Sikov:Eli Lilly: Honoraria.

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.

Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial.

1995 ◽  
Vol 13 (1) ◽  
pp. 227-232 ◽  
Author(s):  
R Whittington ◽  
D Neuberg ◽  
W J Tester ◽  
A B Benson ◽  
D G Haller
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Phase I Trial ◽  
Eastern Cooperative Oncology Group ◽  
Maximum Tolerated Dose ◽  
Survival Duration ◽  
Local Progression ◽  
Daily Dose ◽  
Dose Limiting Toxicity ◽  
Group Trial

PURPOSE The purpose of this study was to determine the maximum-tolerated dose (MTD) of fluorouracil (5-FU) administered as a protracted intravenous (IV) infusion with concurrent radiation in patients with pancreaticobiliary carcinoma. METHODS Twenty-five patients with recurrent, residual, or unresectable carcinoma of the pancreas or biliary tract were treated on a phase I trial of protracted IV infusions of 5-FU, beginning at 200 mg/m2/d, concurrent with radiation therapy (59.4 Gy in 33 fractions over 6 to 7 weeks). Chemotherapy began on the first day of radiation and continued through the entire course of treatment. After each cohort of five patients had been treated and observed, the daily dose was escalated in 25-mg/m2 increments until dose-limiting toxicity was encountered. An additional cohort of five patients was treated at the MTD. Clinical examination and computed tomography (CT) were used to evaluate response and patterns of progression. RESULTS The MTD of 5-FU was 250 mg/m2/d. The dose-limiting toxicity was oral mucositis. The median survival duration of all patients treated was 11.9 months and the 2-year survival rate was 19%. Eleven of 25 patients remain free of local progression and four patients are without evidence of progression at 18+, 18+, 34+, and 44+ months following treatment. CONCLUSION Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system.

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results.

1998 ◽  
Vol 16 (6) ◽  
pp. 2202-2212 ◽  
Author(s):  
D D Bigner ◽  
M T Brown ◽  
A H Friedman ◽  
R E Coleman ◽  
G Akabani ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Phase I ◽  
Phase I Trial ◽  
Hematologic Toxicity ◽  
Metastatic Brain Tumors ◽  
Tumor Patients ◽  
Iodine 131 ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.

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