Is the maximal tolerated dose still the best primary endpoint? Analysis of 288 dose-seeking phase I trials

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2513-2513
Author(s):  
J. Bonneterre ◽  
A. Adenis ◽  
E. Dansin ◽  
C. Ferté ◽  
S. Clisant ◽  
...  
Keyword(s):  
Risk Factors ◽  
Phase I ◽  
Targeted Therapies ◽  
Phase 1 ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Phase I Trials ◽  
Molecular Targeted Therapies ◽  
Anti Cancer ◽  
Definition Of

2513 Background: For decades, the phase-2-recommended dose (P2RD) depends on toxicity (especially ‘the maximal tolerated dose', MTD) experienced by patients enrolled in dose-escalating phase 1 trials. Recent studies suggest that this policy is not suitable for modern anti-cancer agents. Methods: We retrospectively studied288 recently (1997–2008) published phase-I-trials using the maximal tolerated dose (MTD) to define the P2RD. We analysed how the P2RD was actually defined and then identified the risk factors for failure to establish the P2RD. Results: Seventeen percent (37/288) of the trials failed to identify the P2RD: 13% of studies investigating cytotoxic agents, 23% of studies investigating molecular targeted therapies and 33% of studies investigating immunostimulant agents. The risk factors for this failure were: trials investigating immunostimulant agents (Relative risk (RR)=2.9 [1.1–8.0]) or molecular targeted therapy (RR=3.1 [1.6–6.0]), single-agent regimen (RR=2.5 [1.3–4.9]), dose increments using of Fibonacci-modified series (RR=3.0 [1.5–5.8]), other method of escalation than ‘classical 3+3’ (RR=4.9 [1.6–14.2]) and almost the absence of clear definition of the MTD (RR=10.7 [3.6–32.2]). Indeed, in 9% of these studies (26/288), the definition of the MTD was not clearly established. Moreover, in 17% of all studies (38/288), the authors had proposed alternative but not standardised definitions of the P2RD (13 different definitions). These alternative definitions of P2DR were used in 18% of studies investigating cytotoxic agents, in 19% of studies investigating immunostimulant agents and in 24% of studies investigating molecular targeted therapies. Conclusions: In studies investigating cytotoxic agents, the definition of the MTD needs to be clarified in its 3 dimensions: severity of toxicity, duration of toxicity and proportion of patients experiencing this toxicity. Nevertheless, this appears less relevant for studies investigating immunostimulant agents and molecular targeted therapies. We have to explore and standardise alternative definitions of the P2DR in the era of modern agents. [Table: see text]

Survival of patients considered for participation to contemporary dose-seeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2549-2549
Author(s):  
Juliette Bouchet ◽  
Nicolas Isambert ◽  
Philippe Alexandre Cassier ◽  
Carlos Alberto Gomez-Roca ◽  
Stephanie Clisant ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factor ◽  
Phase I ◽  
Dose Level ◽  
Cox Model ◽  
Phase 1 ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Phase 1 Trial ◽  
Dose Levels

2549 Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p=0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.34-0.66; p=0.0001) in pts enrolled in phase 1 compared and 3.54 (1.92-6.52; p=0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p=0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p=0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0+1 vs 2+3: HR=3.80 [1.76-8.20], p=0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.

Dose-seeking phase I trials (DSP1T) for currently approved molecular-targeted therapies (MTT): We are still far from using appropriate designs.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 3034-3034
Author(s):  
Nuria Kotecki ◽  
Ahmad Awada ◽  
Jacques Bonneterre ◽  
Mohamed Hebbar ◽  
Antoine Adenis ◽  
...  
Keyword(s):  
Phase I ◽  
Targeted Therapies ◽  
Phase I Trials ◽  
Molecular Targeted Therapies

Frequency and management of troponin I elevation in patients treated with molecular targeted therapies in phase I trials

2010 ◽  
Vol 30 (2) ◽  
pp. 611-615 ◽  
Author(s):  
Stephane Ederhy ◽  
Christophe Massard ◽  
Ghislaine Dufaitre ◽  
Ratio Balheda ◽  
Catherine Meuleman ◽  
...  
Keyword(s):  
Phase I ◽  
Targeted Therapies ◽  
Troponin I ◽  
Phase I Trials ◽  
Molecular Targeted Therapies

scholarly journals Revisiting Risk and Benefit in Early Oncology Trials in the Era of Precision Medicine: A Systematic Review and Meta-Analysis of Phase I Trials of Targeted Single-Agent Anticancer Therapies

2021 ◽  
pp. 17-26
Author(s):  
Michael P. Mackley ◽  
Nicholas R. Fernandez ◽  
Benjamin Fletcher ◽  
Christy G. Woolcott ◽  
Conrad V. Fernandez
Keyword(s):  
Phase I ◽  
Targeted Therapies ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
P Value ◽  
Phase I Trials ◽  
Eligibility Criteria ◽  
Tumor Types ◽  
Single Tumor

PURPOSE Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.

Multi-institutional phase I trials involve more patients and longer accrual time compared to single institution trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2500-2500
Author(s):  
A. Dowlati ◽  
S. Manda ◽  
L. Patrick ◽  
S. Remick ◽  
J. Gibbons ◽  
...  
Keyword(s):  
Phase I ◽  
Targeted Therapies ◽  
Statistical Significance ◽  
Drug Action ◽  
Cytotoxic Agents ◽  
Study Endpoint ◽  
Phase I Trials ◽  
Clinical Cancer Research ◽  
Phase I Studies ◽  
Number Of Patients

2500 Background: There has been a suggested increase in the number of multi-institutional phase I trials over the past decade. Methods: We reviewed all published phase I studies between 1/98 and 12/05 from the Journal of Clinical Oncology and Clinical Cancer Research. 452 phase I studies were identified. The following data were obtained from each study: sponsor (NIH/foreign equivalent vs. pharma), year published, number of participating institutions, mechanism of drug action (8 categories; most common are cytotoxic and targeted therapies), country, number of patients accrued, accrual time and study endpoint (maximum tolerated dose-MTD vs. optimal biological dose- OBD). Results: 55% of phase I trials were single institutional and 21% accrued patients from = 3 institutions. There was no increase over time in the number of multi-institutional studies and no significant association was seen between sponsor and number of institutions. No association was seen between mechanism of drug action and number of participating institutions. There was a highly significant association between number of institutions and number of patients enrolled with multi-institutional studies having higher number of patients per trial (p=0.0003). Pharmaceutical sponsored studies are associated with a greater number of patients per trial (mean 32.8±0.9) as compared to government sponsored (28.4±1) (p<0.05). Only 34% of trials report accrual time. Accrual time is increased in multi-institutional studies (= 3 centers) as compared to single institutional studies (mean 25 vs 22.5 mos) but does not reach statistical significance (p=0.613). No correlation was seen between endpoint of the phase I trial (MTD vs OBD) and number of institutions. OBD studies were strongly associated with agents defined as “targeted”. Studies of cytotoxic agents defined the MTD in 99% of trials versus only 64% of agents categorized as targeted therapies (p<0.0001). Conclusions: Although there has been no increase in the number of published multi-institutional phase I studies, these multi- institutional trials accrue more patients only to reach the same study endpoint but at a cost of greater accrual time. The clinical value of multi- institutional phase I studies is not apparent. Supported by K23 CA109348–01 No significant financial relationships to disclose.

Investigating the disparate enrollment of older adults on phase I clinical trials: Evolving participation patterns of patients 65 years and older w advanced cancer on phase I trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 12044-12044
Author(s):  
Ishwaria Mohan Subbiah ◽  
Aman Buzdar ◽  
Ecaterina Elena Ileana Dumbrava ◽  
Siqing Fu ◽  
Filip Janku ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trials ◽  
Phase I ◽  
Oldest Old ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Dose Finding ◽  
Phase I Trials ◽  
Phase I Clinical Trials

12044 Background: While safety and dose-finding remain the primary objective of Phase 1 trials, the potential for clinical benefit has taken a greater meaning in the last decade with the novel therapies. With data from phase I trials being submitted for regulatory approval, the finer details of these studies are under even more scrutiny: in particular, do the trial participants reflect the general patient population for whom the drug may be indicated? To that end, we investigated age-based enrollment on phase I clinical trials over time. Methods: We queried a prospectively maintained database at a major phase I trials center to identify eligible patients and demographic + clinical variables including phase I trial characteristics, age at date of enrollment into 3 age-based cohorts: AYA ages 15-39y, mid-age 40-64y, older adults aged 65y+. We calculated descriptive statistics, and explored correlations (Pearson/Spearman) and associations (linear regression) between age and independent variables. Results: Over a 3-year period (1/1/17 to 12/31/19), we identified 6267 pts enrolled on 338 phase I trials. Median overall age 58.4y (range 15.5-95.1y). 729 (12%, median age 34.8y) were AYA, 3652 (58%, median age 55.4y) mid-age and 1886 (30%, median 70y) older adults, of whom 870 pts were aged 70-79y and 76 pts aged 80y+ (18 being >85y). There was no association b/w senior participation and year of enrollment (2017 31%, 2018 29%, 2019 30%, b/w age and type of therapy (i.e. targeted vs immunotherapy, etc.) or b/w age and # of drugs given on trial (single agent vs combo) (all p > 0.05). Conclusions: Older adults remain underrepresented on phase I trials esp. when compared to incidence of cancer in that age group (30% enrollment vs 60% incidence), a discordance more staggering in the oldest old pts (85y+; only 18 pts enrolled over 3 yrs when compared to 140,690 pts 85y+ w a new cancer dx in just 2019). Once enrolled, older adults received similar types of phase I therapies with comparable number of drugs as compared to middle age patients, i.e. older adults were just as likely to get immunotherapy or targeted therapy as well mono- vs combo therapy as mid-age pts. [Table: see text]

Dose-Seeking Phase I Trials for Currently Approved Molecular-Targeted Therapies in the USA: The Dose-Limiting Toxicity Definition Issue

2016 ◽  
Vol 30 (3) ◽  
pp. 143-147
Author(s):  
Nuria Kotecki ◽  
Ahmad Awada ◽  
Jacques Bonneterre ◽  
Mohamed Hebbar ◽  
Antoine Adenis ◽  
...  
Keyword(s):  
Phase I ◽  
Targeted Therapies ◽  
Phase I Trials ◽  
Molecular Targeted Therapies ◽  
The Usa ◽  
Dose Limiting Toxicity

Revisiting the ethics of phase 1 oncology trials in the era of precision medicine: A systematic review.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14060-e14060
Author(s):  
Michael Patrick Mackley ◽  
Nicholas R Fernandez ◽  
Benjamin Fletcher ◽  
Christy Woolcott ◽  
Conrad Vincent Fernandez
Keyword(s):  
Systematic Review ◽  
Phase I ◽  
Stable Disease ◽  
Targeted Therapies ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
Objective Response ◽  
Phase I Trials ◽  
Cancer Therapies

e14060 Background: Phase 1 clinical trials are a crucial step in the evaluation of new cancer therapies. However, critics cite a low rate of response to therapy (5%), together with a not insignificant risk of death from associated toxicities (0.5%), suggesting a risk-benefit ratio that may limit the ethics of inviting patients to participate in Phase 1 trials. With the introduction of novel targeted therapies, a contemporary estimate of the risks and benefits is needed. Methods: A systematic review was conducted. Eligible for inclusion were phase 1 trials in both adult and pediatric populations published between Jan 2015 to July 2018 of targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents for solid and hematological malignancies. We systematically searched PubMed and Embase. Rates of objective response (complete and partial), stable disease, and Grades 3, 4 and 5 treatment-related adverse events were extracted and pooled. The protocol was prospectively registered in PROSPERO (CRD42018100386). Results: 116 trials (109 adult, 6 pediatric, 1 mixed) met inclusion criteria. The studies reported on nearly 4300 patients (52% male, 48% female), ages ranging from 1 to 90. Most trials reported on molecularly targeted therapies (58%), followed by immunomodulators (33%). The combined overall objective response rate was 6% (95% CI 4% to 8%), with a complete response rate of 0.3% (0.1% to 0.7%) and a partial response rate of 5% (3% to 7%). The rate of stable disease was 34% (30% to 38%). Of the three types of therapies, the objective response rate appeared highest in the molecularly targeted therapies, at 8% (5% to 11%). Overall, the rate of treatment-related deaths was 0.02% (0% to 0.2%). Conclusions: Our results suggest that response rates for single agent, targeted phase I anti-cancer therapies are not materially different from estimates derived in the conventional chemotherapy setting. In an era where providers tout the benefits of precision medicine, this is an important consideration when counselling patients considering participation in phase I trials. Treatment-related death rates were very low, weakening criticism that participation puts patients at great risk. Reporting was highly inconsistent across included studies, highlighting a need to improve the quality of reporting in phase I trials.

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.

Multi-Agent Phase I Trials in Childhood Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4528-4528
Author(s):  
Richard Sposto ◽  
Elizabeth A. Raetz ◽  
Charles P. Reynolds ◽  
Paul S. Gaynon
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Cell Transplant ◽  
Phase I Trials ◽  
Hematopoietic Stem ◽  
The Impact

Abstract Background: Single agent phase I trials with conventional methodology may not be suitable for children with relapsed leukemia. Accrual of children with ALL in relapse to single-agent phase I trials is poor due to clinical urgency and a &gt; 30% likelihood of complete response (CR) with a variety conventional agents combinations (Br J Haematol.2005; 131(5): 579) with the option of hematopoietic stem cell transplant in remission. As most drugs are ultimately used in combination, a Phase I trial testing a new agent in combination with conventional agents would seem most useful and might increase accrual. However, with conventional phase I methodologies determination of a maximum tolerated dose is complicated by the toxicities of the accompanying conventional agents and by the background morbidity of relapsed leukemia. Methods: The Children’s Oncology Group (COG) study, AALL01P2, employed vincristine, prednisone, doxorubicin, and pegylated asparaginase for children with ALL in first marrow relapse. We determined the incidence of conventional non-hematologic dose limiting toxicities (DLT’s) and modeled the impact on a hypothetical phase I trial of a candidate agent with no additional toxicity. Results: Among 111 patients on AALL01P2, 19% had conventional non-hematologic DLT’s. Induction therapy was judged clinically acceptable. With a traditional Phase I escalation scheme that accepts 0/3 and 1/6 DLT’s at a dose-level and rejects 2/3 and 2/6 DLT’s, an agent that adds no morbidity would be rejected as too toxic at any dose 30% of the time. Conclusion: Background morbidity confounds identification of an acceptable dose of a non-toxic new agent tested in combination with conventional drugs for recurrent ALL. We propose a modification to the traditional Phase I design that increases the DLT thresholds to 1/3 and 2/6, which effectively compensates for background toxicity and reduces the chance of falsely rejecting an acceptable agent.

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