Design and results of phase I cancer clinical trials: three-year experience at M.D. Anderson Cancer Center.

1996 ◽  
Vol 14 (1) ◽  
pp. 287-295 ◽  
Author(s):  
T L Smith ◽  
J J Lee ◽  
H M Kantarjian ◽  
S S Legha ◽  
M N Raber
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Alternative Methods ◽  
Recommended Dose ◽  
Cancer Center ◽  
Phase I Trials ◽  
Conducting Phase ◽  
Number Of Patients ◽  
Standard Design ◽  
Baseline Information

PURPOSE Alternatives to the standard design for conducting phase I trials are proposed with increasing frequency. This study was undertaken to determine how phase I trials are currently conducted and to provide a basis for evaluation of evolving methodology. SUBJECTS AND METHODS All published phase I trials from a single institution over a 3-year period were reviewed to determine the method of selection of the recommended dose for a phase II trial of a new agent, type and extent of toxicity, number of patients treated at the recommended dose, and clinical response. RESULTS All 23 published trials used the standard method of entering cohorts of patients at increasing dose levels and observing toxic effects to determine the dose recommended for phase II study. Among 610 patients, 26% were treated at or within 10% of the recommended dose and 35% were treated with less than 50% of the recommended dose or on a trial that yielded no recommended dose. Among 18 trials using agents previously tested in humans, fewer patients were treated at much less than the recommended dose. For trials in which myelosuppression was dose-limiting, the estimated probability of serious myelosuppression associated with the recommended dose ranged from 23% to 66%. Nineteen patients (3%) responded to therapy. CONCLUSION This summary of phase I trials recently conducted at M.D. Anderson Cancer Center confirms the need for alternative methods, provides baseline information against which alternatively conducted trials can be compared, and demonstrates some practical clinical trial issues not generally considered when alternative methods are proposed.

Hafnium oxide nanoparticles activated by SABR in combination with PD-1 inhibitors for the treatment of patients with advanced HNSCC or NSCLC: A phase I/II trial.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS23-TPS23 ◽  
Author(s):  
Tanguy Y. Seiwert ◽  
Corey Christian Foster ◽  
Christophe Le Tourneau ◽  
Valentin Calugaru ◽  
Sylvie Bonvalot
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase Ii ◽  
Hafnium Oxide ◽  
Response Rate ◽  
Locally Advanced ◽  
Recommended Dose ◽  
Oxide Nanoparticles ◽  
Intrinsic Resistance ◽  
Number Of Patients

TPS23 Background: Despite proven efficacy, a limited number of patients (pts) with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) or metastatic non-small cell lung cancer (NSCLC) benefit from anti-PD-1 treatment. Indeed, most pts do not respond to initial therapy due to intrinsic resistance to checkpoint inhibition. There is thus an important unmet medical need for a curative treatment in these pts and converting the local immune microenvironment to a “hot” phenotype may help to overcome therapeutic resistance. Hafnium oxide nanoparticles (NBTXR3) activated by radiotherapy (RT) increase radiation dose deposit within cancer cells compared to RT alone. Recently, a phase II/III randomized trial of NBTXR3 in locally advanced soft tissue sarcoma (STS) met primary and main secondary endpoints with significant superiority compared to RT alone. Furthermore NBTXR3+RT demonstrated an immunogenic cell death-mediated abscopal effect in a pre-clinical setting, and immune cell infiltration was observed in some tumors from STS pts treated with NBTXR3+RT but not in tumors from pts treated with RT alone. NBTXR3 is currently being evaluated in 7 clinical trials, including a phase I/II study in elderly frail patients with locally advanced HNSCC. To date, no early dose limiting toxicities (DLTs) have been observed. Methods: Overall, these results have led us to evaluate NBTXR3 activated by stereotactic ablative radiotherapy (SABR) in combination with an approved anti-PD-1 antibody in an open label phase I/II, non-randomized clinical trial in pts with more advanced diseases: locoregionally recurrent or metastatic HNSCC, metastatic NSCLC, and liver metastasis pts. The phase I primary objectives are to determine NBTXR3 maximum tolerated dose(s), incidence of early DLTs and recommended dose(s). The phase II primary objectives are Complete Response Rate of target lesions and Objective Response Rate for the locoregional recurrent and the metastatic group respectively by RECIST 1.1, and safety/tolerability of treatment at the recommended dose(s). [NCT02379845] [NCT01946867]. Clinical trial information: NCT03589339.

Phase I study of pemetrexed plus cisplatin in unresectable, advanced gastric carcinoma in Taiwan

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14009-14009
Author(s):  
J. Chen ◽  
Y. Chao ◽  
L. Chen ◽  
C. Li ◽  
W. Reece ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Phase I ◽  
Phase Ii ◽  
Performance Status ◽  
Recommended Dose ◽  
Ecog Performance Status ◽  
Advanced Gastric Carcinoma ◽  
Post Surgery ◽  
Number Of Patients ◽  
Grade 3

14009 Background: Phase I of this Phase I/II study (H3E-AA-S038) was conducted to determine the recommended dose of pemetrexed (PT) when given with cisplatin (Cis) to patients with unresectable, advanced gastric carcinoma. Methods: Patients 18 to 70 years of age, with stage IV disease or post-surgery recurrence, no prior palliative chemotherapy, and an ECOG performance status of 0 or 1 were included. Patients received PT and Cis on Day 1 every 21 days. Cis was dosed at 75 mg/m2. PT dosage was planned at 600, 700, 800, and 900 mg/m2. Vitamin B12 and folic acid supplementation, and dexamethasone (or equivalent corticosteroid) prophylaxis were required. The initial number of patients to be enrolled per dose level (DL) was 3. If 0/3 patients had dose-limiting toxicity (DLT), PT dose was escalated. If 1/3 patients had DLT, 3 more patients were enrolled at that DL. If ≥2 patients had DLT, the dose was not escalated further. The recommended dose of PT for Phase II was the highest dose at which <2/6 patients experienced DLT. The following toxicities were defined as DLT: death due to toxicity; neutropenia [<0/5 × 109/L for ≥5 days, or <1.0 × 109/L with fever (≥38.5 ºC)]; thrombocytopenia (<10.0 × 109/L, or <50.0 × 109/L with bleeding); AST or ALT >20 × ULN; and non-hematological toxicities of CTC grade 3 or 4 (except nausea and vomiting). Intra-patient dose escalation was not permitted. Results: Sixteen patients were enrolled. The mean (±SD) age of enrolled patients was 52.8 (±10.0) years, and the majority were male (62.5%). At DL1, 0/3 patients experienced DLT. At DL2, 1/6 patients had DLT. At DL3, 3/7 patients had DLT, and so PT dose was not escalated. All DLTs occurred in cycle 1; 2 involved neutropenia, 1 tumor hemorrhage, and 1 hypokalemia. Grade 3/4 toxicities were experienced by 12/16 (75%) patients, including 9 (56%) hematological and 10 (63%) non-hematological events. Five out of thirteen (38%) patients with measurable disease had a RECIST response (2 had a complete response, 1 each at DL1 and DL2; 3 had a partial response, 2 at DL2 and 1 at DL3). At this interim analysis, 2 patients were still on therapy. Conclusions: The recommended dose of PT is 700 mg/m2. Phase II will examine response and safety of PT plus Cis in advanced gastric carcinoma. [Table: see text]

scholarly journals Lessons From the Development of the Immune Checkpoint Inhibitors in Oncology

2018 ◽  
Vol 17 (4) ◽  
pp. 1012-1015 ◽  
Author(s):  
Denis L. Jardim ◽  
Débora de Melo Gagliato ◽  
Razelle Kurzrock
Keyword(s):  
Phase I ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Dose Finding ◽  
Priority Review ◽  
Marketing Approval ◽  
Phase I Trials ◽  
Clinical Cancer Research ◽  
Number Of Patients

Immunotherapies are becoming increasingly important in the treatment armamentarium of a variety of malignancies. Immune checkpoint inhibitors are the most representative drugs receiving regulatory approval over the past few years. In a recent study published in Clinical Cancer Research, we demonstrated that these agents are being developed faster than other prior anticancer therapies. All checkpoint inhibitors received priority review, being granted with at least one Food and Drug Administration expedited program. Hence, some of them are getting marketing approval after preliminary trials. The model continues to rely on phase I trials, designed with traditional models for dose definition, although a substantial number of patients are treated during the dose expansion cohorts. We demonstrated that efficacy and safety are reasonably predicted from the dose-finding portion of phase I trials with these agents, assuring a low treatment-related mortality for patients throughout the development process. In this article, we further discuss and summarize these findings and update some recent approval information for immune checkpoint inhibitors.

Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2

2019 ◽  
Vol 37 (3) ◽  
pp. 230-238 ◽  
Author(s):  
Teresa Macarulla ◽  
Roberto Pazo-Cid ◽  
Carmen Guillén-Ponce ◽  
Rafael López ◽  
Ruth Vera ◽  
...  
Keyword(s):  
Phase I ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Phase Ii ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Ductal Adenocarcinoma ◽  
Tolerability Profile ◽  
Ecog Performance Status ◽  
Actuarial Survival ◽  
Number Of Patients

Purpose Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS. Patients and Methods In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m2 [arm A] or 125 mg/m2 [arm C]) plus gemcitabine 1,000 mg/m2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m2 [arm B] or 125 mg/m2 [arm D]) plus gemcitabine 1,000 mg/m2. The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival. Results Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively). Conclusion NAB-paclitaxel administered at either 100 and 125 mg/m2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

scholarly journals Use of Expansion Cohorts in Phase I Trials and Probability of Success in Phase II for 381 Anticancer Drugs

2017 ◽  
Vol 23 (15) ◽  
pp. 4020-4026 ◽  
Author(s):  
Diogo D.G. Bugano ◽  
Kenneth Hess ◽  
Denis L.F. Jardim ◽  
Alona Zer ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Drugs ◽  
Phase Ii ◽  
Phase I Trials ◽  
Probability Of Success

Ethical issues in phase I oncology research: a comparison of investigators and institutional review board chairpersons.

1992 ◽  
Vol 10 (11) ◽  
pp. 1810-1816 ◽  
Author(s):  
E Kodish ◽  
C Stocking ◽  
M J Ratain ◽  
A Kohrman ◽  
M Siegler
Keyword(s):  
Phase I ◽  
Ethical Issues ◽  
Institutional Review Board ◽  
Phase I Trials ◽  
Conducting Phase ◽  
Institutional Practice ◽  
Oncology Research ◽  
Institutional Review ◽  
Differences Of Opinion ◽  
Board Chairpersons

PURPOSE Phase I research trials assess the safety of agents never before administered to humans. In the field of oncology, this practice raises several important ethical questions. We examined the ethics of these trials by surveying phase I oncology investigators and institutional review board (IRB) chairpersons at major cancer research centers around the country. METHODS Questionnaires were mailed to 78 investigators and 47 chairpersons to obtain their views on the ethical propriety of conducting phase I oncology research, and on institutional practice regarding these trials. The response rate was 68% in each group. RESULTS The majority of each group reported that phase I oncology trials face no more scrutiny or resistance in their institution's IRB process than other research protocols. Nevertheless, IRB chairpersons were more likely than investigators to favor special procedural safeguards to protect subjects in phase I oncology trials. Nearly all respondents agreed that although actual medical benefit was very uncommon, most patients entered for a chance at a therapeutic effect. Investigators were more likely than chairpersons to report that patients obtained psychologic benefit from participation in phase I trials. CONCLUSION Although individual IRB chairpersons and oncology investigators may have important differences of opinion concerning the ethics of phase I trials, these disagreements do not represent a widespread area of ethical conflict in clinical research.

Multi-Institutional Phase I Trials of Anticancer Agents

2008 ◽  
Vol 26 (12) ◽  
pp. 1926-1931 ◽  
Author(s):  
Afshin Dowlati ◽  
Sudhir Manda ◽  
Joseph Gibbons ◽  
Scot C. Remick ◽  
Lauren Patrick ◽  
...  
Keyword(s):  
Phase I ◽  
Anticancer Agents ◽  
Maximum Tolerated Dose ◽  
National Institutes Of Health ◽  
Cytotoxic Agents ◽  
Phase I Trials ◽  
Tumor Type ◽  
Targeted Agents ◽  
Phase I Studies ◽  
Number Of Patients

Purpose Physicians involved in the conduct of phase I studies of novel anticancer agents have raised concerns about the emergence of multi-institutional phase I trials and about using the optimal biologic dose (OBD) as an alternative to the maximum-tolerated dose (MTD) as the primary end point in early drug development. We sought to determine the factors associated with multi-institutional phase I studies and OBD determination. Patients and Methods We reviewed all published phase I trials between January 1998 and June 2006 from two major clinical cancer journals. The following components from each trial were determined: number of participating sites, sponsor, nation where study was conducted, MTD or OBD established, number of patients accrued, mechanism of action of the studied agent, accrual time, and tumor type. Results We identified 463 trials. Fifty-six percent were performed in single institutions. Only 30% reported accrual time. The number of patients enrolled on single institution studies was significantly lower than on multi-institutional studies (P < .05), but there was no difference in accrual time. There was no association between the number of institutions and the sponsor or the mechanism of drug action. National Institutes of Health–sponsored trials enrolled fewer patients per trial than pharmaceutical-sponsored trials (P < .05). Although 99% of trials with cytotoxic agents determined an MTD, only 64% of trials with targeted agents did. Conclusion Multi-institutional phase I studies do not decrease the time to study completion and result in an increase in number of patients per trial. One third of trials with targeted agents failed to determine an MTD.

Final Results of a Phase I/II Study of the Combination of the Hypomethylating Agent 5-aza-2′-Deoxycytidine (DAC) and the Histone Deacetylase Inhibitor Valproic Acid (VPA) in Patients with Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 408-408 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Hagop Kantarjian ◽  
Blanca Sanchez-Gonzalez ◽  
Hui Yang ◽  
Gary Rosner ◽  
...  
Keyword(s):  
Phase I ◽  
Histone Acetylation ◽  
Phase Ii ◽  
Response Rate ◽  
Stopping Rules ◽  
Clinical Activity ◽  
Dna Hypomethylation ◽  
Global Methylation ◽  
Platelet Recovery ◽  
Number Of Patients

Abstract The combination of DAC and VPA has synergistic antileukemia activity in vitro. Based on this, we developed a phase I/II study of this combination for patients with leukemia. The dose of DAC was fixed: 15 mg/m2 IV daily x 10. Three dose levels of VPA were studied: 20, 35 and 50 mg/kg orally daily x 10 concomitantly with DAC. The phase I portion of the study followed a classic 3+3 schema. The phase II targeted a response rate of 30%. Patients with relapsed/refractory chronic and acute leukemia with adequate renal, hepatic functions and performance status were eligible. Patients older than 60 years of age with untreated disease were eligible if they were not candidates for higher priority therapies. Fifty four patients have been registered and treated on this study that is now closed to new patient accrual. Median age was 60 years (range 5 to 80). All, but 2 patients with MDS, had AML. Median number of prior therapies was 2 (range 0–5). Thirty patients (56%) had abnormal cytogenetics. No non-hematological VPA dose limiting toxicities were observed during the phase I portion of the study. Therefore the phase II combination consisted of VPA at a dose of 50 mg/kg daily with DAC. Ten patients achieved a CR and 2 a CRP (same criteria as of CR but without complete platelet recovery), for an overall response rate of 22%. The study did not meet any of its planned stopping rules and the maximal number of patients (n=40) was accrued in the phase II portion of the study. Ten out 40 patients (25%) achieved a response in that phase. Two out 12 patients (16%) achieved a response at lower doses of VPA. Five out of 11(45%) previously untreated older patients achieved a CR. The median overall survival (OS) for the whole group was 5.3 months, and it has not been reached for those patients achieving a response. The median duration of response is 8.3 months. Complete cytogenetic responses were observed in 4 out 4 patients with informative karyotypes. A trend toward higher VPA levels was observed in responders (p=0.02). Twelve out 35 (34%) patients receiving VPA at a dose of 50 mg/kg had evidence of histone acetylation compared to 1 out 12 (8%) at lower doses. Histone acetylation was transient. The effects on global methylation were assessed using the LINE assay. Median LINE methylation pretreatment was 44% (range 35.7–57.6%) and it decline to 37.08% (p=0.000) by day 10 to return to baseline by day 28. Methylation of p15, p57, p73, MDR1 and THSB1 was measured pretreatment and serially during therapy. Pretreatment p15 methylation was observed in 36 out 46 patients (78%) with a median value of 18.4% (range 0–80) to decline to 11.7% (range 1.3–67.8), p=0.005, by day 10. Methylation of THSB2 was observed in 19 out 48 patients (39.5%) but it was not affected by the therapy. Methylation of p57KIP2, p73 and MDR1 were rare events in this population. p15 hypomethylation was associated with the the induction of p15 mRNA expression. In summary, the combination of DAC with VPA has significant clinical activity in patients with AML and MDS and effect potentially mediated by the induction of DNA hypomethylation and histone acetylation.

Sign in / Sign up

Export Citation Format

Share Document