Evaluation of statistical designs of phase I/II clinical trials for cancer patients published in 2005

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14077-14077
Author(s):  
N. Houede ◽  
A. Kramar ◽  
X. Paoletti
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Escalation ◽  
Objective Response ◽  
Biological Marker ◽  
Statistical Design ◽  
Phase Ii Trials ◽  
Dose Levels

14077 Background: Phase I trials determine the maximal safe dose that could be used in phase II trials. Designs are based on the assumption that efficacy and toxicity increase with dose. Phase I/II trials determine the safety, dosage levels, and response rate. This review addresses statistical issues of phase I/II studies designs. Methods: We reviewed phase I/II clinical trials for cancer patients published in 2005. The main criteria were: type of treatment, statistical design, endpoints, expected efficacy and toxicity, one- or two-steps designs, dose levels, definition of Dose Limiting Toxicity and recommended dose, objective response, survival, patient selection and follow-up. Results: 41 phase I/II trials were found. All but one, targeted a specific type of tumor. 14 studies included combined cytotoxic therapies. 21 studies included a cytotoxic agent combined with a targeted therapy (12) or with radiations (9). Others used monochemotherapy, immunotherapy, vaccine or gene therapy. 23 studies were a two steps design, i.e. a phase I followed by a phase II trial, and used a classical Fibonacci escalation dose model. All others used a one-step design evaluating efficacy and toxicity concomitantly. Among them, 3 had a Fibonacci-like design with a desescalation model and 4 had a randomization to different dose levels. In 1 trial, dose escalation was performed in the same patient. In the 10 remaining studies, 1 evaluated only one dose level and was improperly presented as a phase I/II study, and 9 did not describe any statistical design. DLT was described in only 27 trials. Also, recommended doses for further trials were only provided in 30 studies. Efficacy was evaluated with clinical or radiological response for 34 studies, biological marker was evaluated in 5 cases and time to progression in 2 cases. Conclusion: Most of the phase I/II trials published in 2005 used a classical two steps design with an adapted Fibonacci dose escalation. None of them used new designs such as continual reassessment method (CRM), which have the advantage to incorporate data during the course of the trial, leading to optimization of the study in terms of cost and speed. Methodological progresses are necessary to address issues related to multiple endpoints and to help clinicians to feel comfortable with the CRM. No significant financial relationships to disclose.

scholarly journals Unconventional Anticancer Agents: A Systematic Review of Clinical Trials

2006 ◽  
Vol 24 (1) ◽  
pp. 136-140 ◽  
Author(s):  
Andrew J. Vickers ◽  
Joyce Kuo ◽  
Barrie R. Cassileth
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Phase Ii ◽  
Dose Finding ◽  
Phase Iii ◽  
High Dose ◽  
Free Text ◽  
Phase Ii Trials ◽  
Off Label

Purpose A substantial number of cancer patients turn to treatments other than those recommended by mainstream oncologists in an effort to sustain tumor remission or halt the spread of cancer. These unconventional approaches include botanicals, high-dose nutritional supplementation, off-label pharmaceuticals, and animal products. The objective of this study was to review systematically the methodologies applied in clinical trials of unconventional treatments specifically for cancer. Methods MEDLINE 1966 to 2005 was searched using approximately 200 different medical subject heading terms (eg, alternative medicine) and free text words (eg, laetrile). We sought prospective clinical trials of unconventional treatments in cancer patients, excluding studies with only symptom control or nonclinical (eg, immune) end points. Trial data were extracted by two reviewers using a standardized protocol. Results We identified 14,735 articles, of which 214, describing 198 different clinical trials, were included. Twenty trials were phase I, three were phase I and II, 70 were phase II, and 105 were phase III. Approximately half of the trials investigated fungal products, 20% investigated other botanicals, 10% investigated vitamins and supplements, and 10% investigated off-label pharmaceuticals. Only eight of the phase I trials were dose-finding trials, and a mere 20% of phase II trials reported a statistical design. Of the 27 different agents tested in phase III, only one agent had a prior dose-finding trial, and only for three agents was the definitive study initiated after the publication of phase II data. Conclusion Unconventional cancer treatments have not been subject to appropriate early-phase trial development. Future research on unconventional therapies should involve dose-finding and phase II studies to determine the suitability of definitive trials.

Phase I study of topotecan and cisplatin in patients with advanced solid tumors: a cancer and leukemia group B study.

1994 ◽  
Vol 12 (12) ◽  
pp. 2743-2750 ◽  
Author(s):  
A A Miller ◽  
J B Hargis ◽  
R C Lilenbaum ◽  
S Z Fields ◽  
G L Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Topoisomerase I ◽  
Advanced Solid Tumors ◽  
Phase Ii Trials ◽  
Grade 3 ◽  
Dose Levels

PURPOSE The objectives of this phase I trial were to determine the dose-limiting toxicities (DLTs) of the novel topoisomerase I inhibitor topotecan combined with cisplatin, to define the maximum-tolerated doses (MTDs) of the combination without and with the use of filgrastim, and to define recommended doses for phase II trials. PATIENTS AND METHODS Patients with advanced solid tumors were eligible if they had normal bone marrow, renal, and hepatic function and had not previously been treated with platinum compounds. Topotecan was administered intravenously on days 1 through 5 and cisplatin was administered intravenously on day 1 of a 21-day cycle. The topotecan dose was fixed at 1.0 mg/m2/d on the first four dose levels, and cisplatin was escalated in 25-mg/m2 increments from 25 to 100 mg/m2 without filgrastim. After encountering DLT, the dose of cisplatin was decreased by one level and topotecan dose escalation was attempted. After defining the MTD without growth factor, the study proceeded with escalating cisplatin doses to define the MTD with filgrastim 5 micrograms/kg subcutaneously (SC) daily starting on day 6 of treatment. Priming with filgrastim 5 micrograms/kg SC on days -6 to -2 before the first course was explored last. RESULTS Of 38 patients entered, 37 were eligible, 35 assessable for toxicity in the first course, and 28 assessable for response. The principal toxicity was grade 4 neutropenia, which had to last more than 7 days to be considered dose-limiting. No DLT was observed at the starting cisplatin dose of 25 mg/m2 (dose level 1). On level 2 (cisplatin 50 mg/m2, one patient had dose-limiting neutropenia and one patient had grade 3 renal toxicity. On level 3 (cisplatin 75 mg/m2), two patients had dose-limiting neutropenia. Therefore, cisplatin dose escalation was stopped. On dose level 5 (cisplatin 50 mg/m2 and topotecan 1.25 mg/m2/d), one patient had grade 4 neutropenia that lasted more than 7 days and one patient died of neutropenic sepsis. The remaining dose levels used topotecan 1.0 mg/m2/d plus cisplatin 75 mg/m2 (level 6) and 100 mg/m2 (levels 7 and 8) with filgrastim. No DLT was observed on level 6. On level 7, two patients had dose-limiting neutropenia and one patient had grade 3 hyperbilirubinemia. Priming with filgrastim on level 8 demonstrated no obvious advantage over level 7, and one patient had grade 4 thrombocytopenia that lasted more than 7 days. Three patients with non-small-cell lung cancer achieved a partial response and one patient with breast cancer had a complete response. CONCLUSION Topotecan and cisplatin in combination cause more neutropenia than expected from either drug given alone at the same dosage. The recommended phase II doses are topotecan 1.0 mg/m2/d for 5 days in combination with cisplatin 50 mg/m2 on day 1 without filgrastim or cisplatin 75 mg/m2 on day 1 with filgrastim support.

Phase I trial of subcutaneous interleukin-6 in patients with advanced malignancies.

1993 ◽  
Vol 11 (3) ◽  
pp. 499-506 ◽  
Author(s):  
J Weber ◽  
J C Yang ◽  
S L Topalian ◽  
D R Parkinson ◽  
D S Schwartzentruber ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Interleukin 6 ◽  
Phase Ii Trials ◽  
Organ Toxicity ◽  
Advanced Malignancies ◽  
Major Organ ◽  
Dose Levels ◽  
Grade Iii

PURPOSE Based on preclinical evidence in murine models that interleukin-6 (IL-6) mediates regression of metastatic tumors, we performed a phase I study of recombinant human IL-6 in patients with refractory advanced malignancies to determine its pharmacokinetics, toxicities, and possible immunologic and antitumor effects. PATIENTS AND METHODS Recombinant IL-6 was administered as a single subcutaneous dose daily for 7 days, with 7 days off therapy followed by another 7 days of IL-6. Doses were escalated in cohorts of three patients starting at 3 micrograms/kg/d, provided that toxicity at the preceding dose level was not dose-limiting. Dose-limiting toxicity was defined as grade III or IV major organ toxicity that did not resolve to grade II or less in 24 hours after stopping IL-6, using the National Cancer Institute Common Toxicity Criteria. Patients were treated with 3, 10, and 30 micrograms/kg/d IL-6 subcutaneously. RESULTS Three patients each were treated at the 3- and 10-micrograms dose levels. Two of five patients treated with 30 micrograms/kg/d IL-6 subcutaneously had grade III major organ toxicity that required IL-6 therapy to be discontinued. All patients experienced fever, chills, and minor fatigue. Significant increases in C-reactive protein (CRP), fibrinogen, platelet counts, and lymphocyte IL-2 receptor levels were seen in patients at the 10- and 30-micrograms/kg dose levels. Decreases in albumin and hemoglobin were observed, particularly at the 30-micrograms/kg dose level. The half-life (T1/2 beta) was 4.2 hours, with a peak IL-6 level at 5 hours. No antitumor responses were seen. CONCLUSION A safely tolerated dose of daily subcutaneous IL-6 is 10 micrograms/kg, with hepatotoxicity and cardiac arrhythmia being the dose-limiting toxicities at 30 micrograms/kg. Phase II trials of IL-6 administered subcutaneously daily for at least 7 days for two cycles with an intervening week of rest are recommended for phase II trials. However, patients with extensive replacement of liver by tumor and abnormal liver functions should receive IL-6 therapy with caution.

Sequential or combined designs for Phase I/II clinical trials? A simulation study

2019 ◽  
Vol 16 (6) ◽  
pp. 635-644 ◽  
Author(s):  
Caroline Rossoni ◽  
Aurélie Bardet ◽  
Birgit Geoerger ◽  
Xavier Paoletti
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Therapeutic Index ◽  
Maximum Tolerated Dose ◽  
Correct Decision ◽  
Operating Characteristics ◽  
In Series ◽  
Expansion Cohort

Background: Phase I and Phase II clinical trials aim at identifying a dose that is safe and active. Both phases are increasingly combined. For Phase I/II trials, two main types of designs are debated: a dose-escalation stage to select the maximum tolerated dose, followed by an expansion cohort to investigate its activity (dose-escalation followed by an expansion cohort), or a joint modelling to identify the best trade-off between toxicity and activity (efficacy–toxicity). We explore this question in the context of a paediatric Phase I/II platform trial. Methods: In series of simulations, we assessed the operating characteristics of dose-escalation followed by an expansion cohort (DE-EC) designs without and with reassessment of the maximum tolerated dose during the expansion cohort (DE-ECext) and of the efficacy–toxicity (EffTox) design. We investigated the probability to identify an active and tolerable agent, that is, the percentage of correct decision, for various dose-toxicity activity scenarios. Results: For a large therapeutic index, the percentage of correct decision reached 96.0% for efficacy–toxicity versus 76.1% for dose-escalation followed by an expansion cohort versus 79.6% for DE-ECext. Conversely, when all doses were deemed not active, the percentage of correct decision was 47% versus 55.9% versus 69.2%, respectively, for efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Finally, in the case of a narrow therapeutic index, the percentage of correct decision was 48.0% versus 64.3% versus 67.2%, respectively, efficacy–toxicity, dose-escalation followed by an expansion cohort and DE-ECext. Conclusion: As narrow indexes are common in oncology, according to the present results, the sequential dose-escalation followed by an expansion cohort is recommended. The importance to re-estimate the maximum tolerated dose during the expansion cohort is confirmed. However, despite their theoretical advantages, Phase I/II designs are challenged by the variations in populations between the Phase I and the Phase II parts and by the lagtime in the evaluation of toxicity and activity.

Lazertinib, a 3rd generation EGFR-TKI, in patients with EGFR-TKI resistant NSCLC: Updated results of phase I/II Study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9037-9037 ◽  
Author(s):  
Myung-Ju Ahn ◽  
Ji-Youn Han ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Dong-Wan Kim ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Egfr Mutations ◽  
Duration Of Treatment ◽  
Open Label ◽  
T790m Mutation ◽  
Dose Levels ◽  
Egfr Tki

9037 Background: Lazertinib (YH25448) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. We report the updated results from a Phase I/II study of lazertinib (NCT03046992). Methods: Patients with advanced and metastatic NSCLC who had progressed after treatment with standard EGFR-TKIs with/without asymptomatic brain metastases (BM) were enrolled in an open-label, multicenter, phase I/II study with dose-escalation and expansion cohorts. Lazertinib was administered once daily at doses between 20 to 320 mg in a 21-day cycle. Patients were assessed for safety, tolerability and efficacy. T790M mutation was required in the dose-expansion cohorts. Results: As of 26 Nov 2018, a total of 127 patients were enrolled. The dose-escalation cohort included 38 patients administered with 20 to 320 mg across 7 dose levels, and 89 patients in the dose-expansion cohort were administered with 40 to 240 mg across 5 dose levels. No dose-limiting toxicities were observed. The median duration of treatment was 9.7 months and 58 patients are still ongoing. The objective response rate (ORR) was 60% in all patients, 64% in T790M+ patients, and 37% in T790M- patients by investigators assessment. In BM patients with measurable lesion (n = 14), the intracranial ORR was 50%. The median progression-free survival (PFS) was 8.1 months in all patients, 9.5 months in T790M+ patients, and 5.4 months in T790M- patients. Subgroup analysis showed that ORR was 65% and PFS was 12.2 months in T790M+ patients with ≥ 120 mg (n = 62). The most common treatment-emergent adverse events (TEAEs) were pruritus (27%), rash (24%), constipation (20%), decreased appetite (19%) and diarrhea (14%). TEAEs leading to dose discontinuation were observed in 3% of patients. Drug related TEAEs of grade ≥ 3 was observed in 3% of the patients. Conclusions: Lazertinib was safe, well-tolerated and exhibits promising systemic and intracranial antitumor activity in EGFR T790M+ NSCLC patients. Dose extension cohorts in the 1st and 2nd line settings are underway at 240 mg dose. Clinical trial information: NCT03046992.

scholarly journals Focusing on the Treatment of COVID-19: A Comprehensive Analysis of 226 Trials Registered on Clinicaltrials.gov and ChiCTR

2021 ◽  
Author(s):  
Jincai Guo ◽  
Hui Xie ◽  
Hao Wu
Keyword(s):  
Clinical Trials ◽  
Chinese Medicine ◽  
Phase I ◽  
Phase Ii ◽  
Western Medicine ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Double Blind ◽  
Intervention Measures ◽  
Chinese Medicine Treatment

Abstract Background: The purpose of this study is to analyze the registered clinical trials of COVID-19, and to provide a reference for the clinical treatment of COVID-19. Methods: Chinese ClinicalTrial Registry (ChiCTR) and Clinicaltrials.gov databases were searched for clinical trials of COVID-19, which were registered from inception to February 29, 2020, to screen out the clinical trials on the treatment of COVID-19, and the research units and regions, sample size, study types, study stages, and intervention measures were analyzed. Results: There were 226 clinical trials on COVID-19 in the 2 databases, and all of them were registered by research units in China. The top five registered areas were Hubei, Beijing, Shanghai, Guangdong, and Zhejiang. The study type was as follows: interventional study (207, 91.6%) and observational study (18, 8.0%). Clinical trial staging was as follows: exploratory studies/preliminary trials (91, 40.3%), phase I trials (4, 1.8%), phase II trials (12, 5.3%), phase III trials (12, 5.3%), phase IV trials (47, 20.8%), phase I/II trials (2, 0.9%), phase II/III trials (5, 2.2%), and other trials (57, 25.2%). Intervention measures were as follows: there were 143 (63.3%) trials of western medicine treatment, 50 (22.1%) trials of Chinese medicine treatment, and 21 (9.3%) trials of integrated Chinese medicine treatment and western medicine treatment. Conclusion: Researchers have registered a large number of clinical trials in a short time. The number of existing patients of COVID-19 is not enough to support hundreds of clinical trials. There is a lack of multicenter, randomized, double-blind, placebo-controlled trials.

Identification of a predictive biomarker and two pharmacodynamic biomarkers to ADG106 treatment, a novel anti-CD137 agonist antibody, in phase I clinical trials.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14505-e14505
Author(s):  
Li Zhang
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Predictive Biomarker ◽  
Phase I Trials ◽  
Tumor Shrinkage ◽  
Target Engagement ◽  
Phase I Clinical Trials ◽  
Phase Ii Trials ◽  
Pharmacodynamic Biomarkers

e14505 Background: ADG106 is a fully human agonistic anti-CD137 monoclonal IgG4 antibody that mediates anti-tumor activities via unique mechanisms of action. Here we provide safety and efficacy updates from our phase I trials and report the findings of a predictive biomarker and two pharmacodynamic biomarkers which correlate with patients’ clinical responses to ADG106 treatment and demonstrate target engagement, respectively. Methods: Formalin fixed and paraffin embedded (FFPE), blood and plasma specimens were collected from 92 patients enrolled in our phase I trials. We measured expression across a panel of protein biomarkers in FFPE specimens using three highly sensitive detection technologies: multiple immunohistochemical (IHC) staining of protein expression, the BD Multitest 6-color TBNK reagent for profiling immune cell subpopulations, and the MSD-ECL electrochemiluminescence assay for detection of soluble CD137. Objective tumor responses were determined using RECIST v1.1 for solid tumor patients and Lugano classification for lymphoma patients. Results: As of November 30, 2020, ADG106 has demonstrated a favorable safety profile and efficacy in the phase I clinical trials with a disease control rate of 56%. From a retrospective analysis of 28 pretreatment FFPE specimens, we identified a predictive biomarker that correlated with tumor shrinkage upon ADG106 treatment. We identified four biomarker positive specimens from two patients with lymphoma and two with solid tumors. Three out of four biomarker positive patients achieved greater than 30% tumor shrinkage after 3mg/kg or 5mg/kg ADG106 treatment. One biomarker positive patient with stable disease received a low dose ADG106 treatment at 0.5mg/kg during dose escalation. None of the 24 biomarker negative patients showed significant clinical response. A tissue microarray study confirmed expression of this predictive biomarker in a variety of tumor types suggesting a broad indication for ADG106 therapy. Our biomarker studies also demonstrated target engagement with increased NK cell proliferation and soluble CD137 upon ADG106 treatment. Analysis of safety, efficacy, PK and PD data allowed us to select a recommended dose for the upcoming phase II study. Conclusions: We identified a biomarker predictive of response to antitumor CD137 blockade by ADG106, as well as demonstrated the involvement of NK cells in ADG106 mediated anti-tumor activities. In upcoming phase II trials, we plan to enrich for populations expressing this predictive biomarker to demonstrate a clinical benefit to ADG106 therapy further validating early biomarker-based patient stratification. We will also explore the potential of selecting patients for combination treatment with anti-PD-1 therapies. Clinical trial information: NCT03802955.

Outcome of phase II oncology clinical trial abstracts presented at annual meeting of the American Society of Clinical Oncology (ASCO)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6010-6010 ◽  
Author(s):  
R. T. Hoeg ◽  
J. A. Lee ◽  
M. A. Mathiason ◽  
K. Rokkones ◽  
S. L. Serck ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Phase I ◽  
Sample Size ◽  
Annual Meeting ◽  
Phase Ii ◽  
Country Of Origin ◽  
Phase Ii Trials ◽  
Oncology Clinical Trials ◽  
American Society

6010 Background: Translation of evidence-based medicine into clinical practice depends on timely and full publication of clinical trials. Previous studies have shown that a substantial number of phase I and III trials presented at the annual meetings of ASCO remain unpublished more than 5 years after presentation. We investigated the outcome of phase II trials presented at ASCO. Methods: We searched for phase II trials using the 1997 ASCO Annual Meeting Proceedings. We excluded trials reporting only preliminary data or interim analyses. The following information were extracted from each study: type of presentation, country of origin, sample size, sponsor, treatment modality, novelty of treatment, and efficacy. A literature search was performed using the Medline and EMBASE databases up until January 2006 for full publications in peer-reviewed journals. If a trial was not found, the authors were contacted by E-mail. Results: We identified 124 phase II trials with 13.7%, 30.6%, and 55.6% presented orally, in poster, and in print, respectively. Most trials were either submitted from countries in North America (50.8%) or Europe (34.7%). Funding came from the pharmaceutical companies (24.2%), governments (20.2%), study institutions (15.3%), private foundations (9.7%), or was not specified (30.6%). The top 5 cancers studied were lung, breast, ovarian, gastric, and sarcoma. Treatment included mostly chemotherapy, either alone (87.1%) or in combination with other modalities (3.2%). To date only 70.2% of the trials have been published. The median time to publication for all abstracts was 23 months. The cumulative rates of publication were 12.9%, 34.7%, 51.6%, 64.5%, and 68.5% at 1, 2, 3, 5, and 7 years, respectively. None of the factors we analyzed, including type of presentation, country of origin, sample size, sponsor, novelty of treatment, and efficacy, influenced the likelihood of or time to publication. Conclusions: About a third of phase II oncology clinical trials initially presented as abstracts at the 1997 ASCO annual meeting have not been published almost a decade later. Similar to phase I and III trials, underreporting of phase II trials is an important problem with serious implications for clinical practice that needs to be addressed. No significant financial relationships to disclose.

A phase I study of 17-AAG in relapsed/refractory pediatric patients with solid tumors: A Children’s Oncology Groups study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9018-9018 ◽  
Author(s):  
B. Weigel ◽  
S. Blaney ◽  
J. Kersey ◽  
R. Bagatell ◽  
S. P. Ivy ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Dose Escalation ◽  
Phase I Study ◽  
Drug Exposure ◽  
Mononuclear Cells ◽  
Surrogate Marker ◽  
Hsp90 Inhibition ◽  
Recommended Phase Ii Dose ◽  
Dose Levels

9018 Background: A pediatric phase I study of 17-allylaminogeldanamycin (17-AAG), an Hsp90 inhibitor, was conducted to determine the dose limiting toxicities (DLTs), the recommended phase II dose, the pharmacokinetics (PK), and to evaluate a surrogate marker for Hsp90 inhibition in peripheral blood mononuclear cells (PBMCs). Methods: Cohorts of 3–6 pts were enrolled at dose levels of 150, 200, 270 and 360 mg/m2/dose, administered as a 60 min infusion, on days 1, 4, 8 and 11 of a 21-day cycle. PK and PBMC evaluations were done during the first course of therapy. Results: 17 pts (7 male), median 7 yrs of age (range 1–19), were enrolled. 5 pts who developed PD prior to completing a full cycle of therapy were not considered evaluable for toxicity. No DLTs occurred. Non-DLTs included elevated transaminases (n=6), anemia (n=3), and vomiting (n=3). Based on the adult recommended dose and challenges posed by infusing the large volumes of DMSO, dose escalation was stopped at dose level 4. No CRs or PRs were observed; 3 patients remain on therapy at 6, 7 and 9 months with SD. One patient with hepatoblastoma had a reduction in AFP and SD over 3 cycles. PK data is available from the initial 3 dose levels. Drug exposure increases in proportion to dose for both17-AAG and its metabolite 17-AG. At 270 mg/m2/dose the Cmax and AUC of 17-AAG were 5,303 ± 1,591 ng/ml and 13,150 ± 5,086 ng/ml*hr, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.0 ± 0.5 hrs. Induction of Hsp72, a surrogate marker for inhibition of Hsp90 was detected at all dose levels. Conclusions: The recommended phase II dose of 17AAG is 360mg/m2/day. Non-DMSO formulations may allow for further dose escalation in children and should be studied. No significant financial relationships to disclose.

The changing face of phase I protocols: A closer look at study requirements

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3061-3061
Author(s):  
B. S. Craft ◽  
R. Kurzrock ◽  
R. Herbst ◽  
K. Culotta ◽  
C. Stewart ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Phase Ii ◽  
Medical Oncology ◽  
Current Phase ◽  
Recent Experience ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Phase Ii Trials ◽  
Versus Phase

3061 Background: We have studied our recent experience in the MDACC Clinical Translational Research Center (CTRC), the Phase I Program, and the Dept. of Thoracic/Head & Neck Medical Oncology to compare the extent of regulatory and other requirements for current phase I and II cancer clinical trials. Methods: We developed a comprehensive database, together with a Microsoft Excel spreadsheet matrix to analyze the number and extent of diagnostic and therapeutic requirements for each protocol. We then examined the demands for pharmacokinetic (PK) sampling as well as electrocardiography (ECG) in the first cycle of a protocol as a surrogate for study complexity. Results: Since October, 2002, 250 protocols have been conducted in the CTRC; 54.6% were Phase I clinical trials. We reviewed 65 trials, approximately one quarter of the total. Of these, 48 were phase I trials carried out by the Phase I Program. For comparison, we identified 17 phase II trials managed by the Dept. of Thoracic/Head & Neck Medical Oncology during the same time period. In the phase I trials there were significantly more PKs (mean ± SE = 16.69 ± 1.93) than in the phase II trials (mean ± SE = 1.82 ± 1.17) (p<0.0001). Similarly, there were more ECGs in the phase I versus phase II trials (4.46 ± 1.18 vs. 1.41 ± 0.35; p=0.017). Conclusions: Pharmacokinetic collection and ECG monitoring in Phase I trials are complex and labor-intensive. In addition, they represent only a small portion of time-intensive requirements, with increasingly complicated correlates and monitoring (physical exams, imaging, etc.). Successful and accurate Phase I clinical trials require resources and commitment for research infrastructure considerably greater than later phase studies. No significant financial relationships to disclose.

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