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.

Phase I Trial of Temozolomide Plus O6-Benzylguanine for Patients With Recurrent or Progressive Malignant Glioma

2005 ◽  
Vol 23 (28) ◽  
pp. 7178-7187 ◽  
Author(s):  
Jennifer A. Quinn ◽  
Annick Desjardins ◽  
Jon Weingart ◽  
Henry Brem ◽  
M. Eileen Dolan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
Malignant Glioma ◽  
Continuous Infusion ◽  
Plasma Concentrations ◽  
Maximum Tolerated Dose ◽  
Second Phase ◽  
Two Phase ◽  
Phase Clinical Trial ◽  
Dose Levels

Purpose We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. Patients and Methods For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. Results The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. Conclusion This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.

scholarly journals Tg.rasH2 Mice and not CByB6F1 Mice Should Be Used for 28-Day Dose Range Finding Studies Prior to 26-Week Tg.rasH2 Carcinogenicity Studies

2017 ◽  
Vol 36 (4) ◽  
pp. 287-292 ◽  
Author(s):  
Madhav G. Paranjpe ◽  
Jessica Belich ◽  
Tom J. Vidmar ◽  
Reem H. Elbekai ◽  
Marie McKeon ◽  
...  
Keyword(s):  
Selection Process ◽  
Dose Range ◽  
Maximum Tolerated Dose ◽  
High Dose ◽  
Dose Selection ◽  
Range Finding ◽  
Body Weights ◽  
Vehicle Test ◽  
High Doses ◽  
Dose Levels

Our recent retrospective analysis of data, collected from 29 Tg.rasH2 mouse carcinogenicity studies, determined how successful the strategy of choosing the high dose for the 26-week studies was based on the estimated maximum tolerated dose (EMTD) derived from earlier 28-day dose range finding (DRF) studies conducted in CByB6F1 mice. Our analysis demonstrated that the high doses applied at EMTD in the 26-week Tg.rasH2 studies failed to detect carcinogenic effects. To investigate why the dose selection process failed in the 26-week carcinogenicity studies, the initial body weights, terminal body weights, body weight gains, food consumption, and mortality from the first 4 weeks of 26-week studies with Tg.rasH2 mice were compared with 28-day DRF studies conducted with CByB6F1 mice. Both the 26-week and the earlier respective 28-day studies were conducted with the exact same vehicle, test article, and similar dose levels. The analysis of our results further emphasizes that the EMTD and subsequent lower doses, determined on the basis of the 28-day studies in CByB6F1 mice, may not be an accurate strategy for selecting appropriate dose levels for the 26-week carcinogenicity studies in Tg.rasH2 mice. Based on the analysis presented in this article, we propose that the Tg.rasH2 mice and not the CByB6F1 mice should be used in future DRF studies. The Tg.rasH2 mice demonstrate more toxicity than the CByB6F1 mice, possibly because of their smaller size compared to CByB6F1 mice. Also, the Tg.rasH2 males appear to be more sensitive than the female Tg.rasH2 mice.

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.

Phase I study of CPT-11 and etoposide in patients with refractory solid tumors.

1993 ◽  
Vol 11 (10) ◽  
pp. 2030-2035 ◽  
Author(s):  
A Karato ◽  
Y Sasaki ◽  
T Shinkai ◽  
K Eguchi ◽  
T Tamura ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Topoisomerase I ◽  
Phase Ii Trial ◽  
Supportive Therapy ◽  
Maximum Tolerated Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Small Cell Lung ◽  
Dose Levels ◽  
Stimulating Factor ◽  
Dose Limiting Toxicity

PURPOSE To determine the maximum-tolerated dose (MTD) and acceptable dose level of a cytotoxic regimen of CPT-11, a new camptothecin derivative, in combination with etoposide (VP-16) and to describe the principal toxicities associated with it. PATIENTS AND METHODS Patients with refractory solid tumors received VP-16 and CPT-11 daily for 3 consecutive days (days 1 through 3) every 3 or 4 weeks. Groups entered the trial at escalating CPT-11/VP-16 dose levels of 40/60, 60/60, 60/80, and 80/60 mg/m2. Thirty-four patients entered this study, of whom 33 were assessable for toxicity and 22 for therapeutic efficacy. RESULTS Granulocytopenia was so severe that this regimen required supportive therapy with recombinant human granulocyte colony-stimulating factor (G-CSF). The majority of the patients experienced a 5% weight loss and diarrhea was the dose-limiting toxicity. The MTDs were 60/80 and 80/60 mg/m2 administered on days 1 through 3. Five of seven previously untreated patients with non-small-cell lung cancer (NSCLC) achieved partial responses (PRs) to this therapy, as did two with NSCLC who had received prior chemotherapy, two with head and neck cancer, and one with an adenocarcinoma (primary tumor unknown). CONCLUSION The recommended dose of CPT-11/VP-16 for this regimen with G-CSF is 60/60 mg/m2 on days 1 through 3 every 3 to 4 weeks. We suggest that the combination of topoisomerase I and II inhibitors is likely to be an effective treatment strategy. The activity of this regimen against NSCLC is particularly encouraging and should be evaluated in a phase II trial.

PX-171–006: Phase Ib multicenter dose escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) and low-dose dexamethasone (loDex) in relapsed and refractory multiple myeloma (MM): Preliminary results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8541-8541
Author(s):  
R. Niesvizky ◽  
W. Bensinger ◽  
M. Vallone ◽  
A. Gutierrez ◽  
L. Kunkel
Keyword(s):  
Dose Escalation ◽  
Low Dose ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Dose Levels ◽  
Dose Limiting Toxicity

8541 Background: CFZ is a highly specific proteasome inhibitor with single agent activity in relapsed/refractory MM (ASH 2008). The purpose of this study is to evaluate the safety and activity of CFZ in combination with LEN and loDex. Methods: This phase Ib trial evaluates 4 dose levels (≥ 3 pts each) to define the maximum tolerated dose (MTD) of CFZ/LEN/loDex in relapsed/refractory MM pts who failed 1–3 prior therapies, including prior LEN or bortezomib (BTZ). CFZ IV 15- 20 mg/m2 (d1,2,8,9,15,16), LEN 10–20 mg po (d1–21) and loDex 40 mg po (d1, 8, 15, 22) in 28-day cycles (C). An additional 10–15 pts will be evaluated at the highest dose level reached. Dose limiting toxicity (DLT) has been defined as grade (G) ≥ 3 non- hematologic; G4 neutropenia for > 7d and/or neutropenic fever; G4 thrombocytopenia > 7d or G3-G4 thrombocytopenia in association with bleeding. Overall response (CR/sCR, VGPR/PR) is assessed by IWG criteria, with secondary assessment by modified EBMT criteria which includes MR. Results: 11 pts have been enrolled. 8/11 are evaluable for response and toxicity. Median prior lines of therapy was 2 (range 2–3). Prior therapies included DEX (8/8), BTZ (6/8), LEN (7/8), alkylators (6/8), anthracyclines (5/8), stem cell transplant (5/8), and thalidomide (1/8); 6/8 pts had received both LEN and BTZ. MTD has not yet been reached after the first 2 dose cohorts. No drug related SAEs or G3/4 treatment emergent AEs were reported. Responses to date with a median of 2 C (range 1–4) are shown below. Responses were rapid and occurred within the first 28-day cycle. Conclusions: CFZ/LEN/loDex in combination was well tolerated in the first 2 cohorts. There have been no myleosuppressive or renal DLTs. The combination has achieved early encouraging responses in pts who had failed both LEN and BTZ at doses well below the single agent MTD of either LEN or CFZ. Dose escalation is ongoing. Updated data will be presented at the meeting. [Table: see text] [Table: see text]

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.

Phase I and Pharmacokinetics Trial of ABI-007, a Novel Nanoparticle Formulation of Paclitaxel in Patients With Advanced Nonhematologic Malignancies

2005 ◽  
Vol 23 (31) ◽  
pp. 7785-7793 ◽  
Author(s):  
David W. Nyman ◽  
Kimberley J. Campbell ◽  
Evan Hersh ◽  
Kristen Long ◽  
Kelly Richardson ◽  
...  
Keyword(s):  
Castor Oil ◽  
Dose Range ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Endothelial Cell Surface ◽  
Pretreated Patients ◽  
Previously Treated ◽  
Albumin Receptor ◽  
Grade 3 ◽  
Dose Levels

Purpose ABI-007 is a novel solvent-free, albumin-bound, 130-nm particle formulation of paclitaxel designed to avoid solvent-related toxicities and to deliver paclitaxel to tumors via molecular pathways involving an endothelial cell-surface albumin receptor (gp60) and an albumin-binding protein expressed by tumor cells and secreted into the tumor interstitium (secreted protein acid rich in cysteine). This study determined the maximum-tolerated dose (MTD) of ABI-007 monotherapy administered weekly (three weekly doses, repeated every 4 weeks) and assessed the pharmacokinetics of paclitaxel administered as ABI-007. Patients and Methods Patients with advanced nonhematologic malignancies received ABI-007 without premedication at dose levels from 80 to 200 mg/m2 as a 30-minute intravenous infusion once a week for 3 weeks, followed by 1 week of rest (one cycle). Results Thirty-nine patients were treated with an average of five cycles of ABI-007; 33% of patients received ≥ six cycles of treatment. MTDs for heavily and lightly pretreated patients were 100 and 150 mg/m2, respectively; and the dose-limiting toxicities were grade 4 neutropenia and grade 3 peripheral neuropathy, respectively. Maximum paclitaxel concentration and area under the curve increased linearly with dose. Dose-dependent changes in plasma clearance did not occur. Partial responses were observed in five patients with breast, lung, and ovarian cancers, all of whom had previously been treated with paclitaxel containing polyoxyethylated castor oil in the formulation. Conclusion This study demonstrated that weekly ABI-007 can be administered at doses exceeding those typically used for paclitaxel containing polyoxyethylated castor oil. Pharmacokinetics were linear over the dose range studied. Antitumor responses occurred in patients previously treated with paclitaxel containing polyoxyethylated castor oil.

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.

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]

Novel phase I design for oncology research

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2517-2517
Author(s):  
L. Lupinacci ◽  
K. Anderson ◽  
L. Sun ◽  
Y. Tymofyeyev
Keyword(s):  
Phase I ◽  
Dose Range ◽  
Single Agent ◽  
Adaptive Method ◽  
Maximum Tolerated Dose ◽  
Target Dose ◽  
Regulatory Review ◽  
Stage Design ◽  
Oncology Research ◽  
Dose Levels

2517 Background: Phase I studies in oncology patients seek to identify a dose of a new investigational agent that is tolerable and has the potential to be effective. Toxicity data are the key to defining dose levels of the new agent that are acceptable for further study. Several Phase I designs are available to researchers. Some are practical and easy to implement. Others are complex but yield better information on the toxicity of studied doses. We sought a Phase I design that had a high probability of selecting a dose with acceptable toxicity, allowed adaptation based on observed dose-limiting toxicity (DLT) data and did not create considerable enrollment delays. Methods: We compared the 3+3 design, an algorithmically-determined adaptive method proposed by Ji, et al. (2007), and variations on Ji's design including a 2-stage design combining a 3+3 with a modified Ji design. We simulated Phase I trials with 6 dose levels and 12 dose response relationships and studied the properties of the designs including how often the dose with the target toxicity level was selected, the expected percentage of patients with a DLT and the expected sample size. We also implemented operational conventions on top of the preferred design to enhance the practicality and clinical usefulness of the design. Results: In general, the adaptive, Ji-based designs outperformed the 3+3, selecting the target dose up to 18% more often. The 2- stage and other Ji-based designs were comparable in most scenarios and performed the best when the target dose was among the middle doses in the dose range tested. When the target dose was the highest dose or higher than all of the doses tested, the 3+3 and 2-stage designs outperformed some of the other Ji-based designs. Conclusions: For single agent studies, we prefer a 2-stage design in which a 3+3 is implemented until a preliminary maximum tolerated dose (MTD) is identified. Then, a modified Ji design (target toxicity rate = 20%) is used to confirm the MTD and allow further dose refinement. While this design may underperform slightly compared with the complex continuous reassessment methods, this design is easier to implement and more intuitive to investigators and ethical and regulatory review boards. In addition, it maximizes enrollment continuity while ensuring appropriate patient safety. [Table: see text]

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