New requirements for phase I trials: a challenge for Italian clinical research

2018 ◽  
Vol 104 (1) ◽  
pp. 15-21 ◽  
Author(s):  
Emanuela Marchesi ◽  
Manuela Monti ◽  
Oriana Nanni ◽  
Lisette Bassi ◽  
Martina Piccinni-Leopardi ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Practice ◽  
Phase I ◽  
Good Clinical Practice ◽  
Phase I Trials ◽  
Highly Qualified ◽  
Phase I Clinical Trials ◽  
Oncology Research ◽  
Standard Operating ◽  
Near Future

Background: In 2015, the Italian Medicines Agency (Agenzia Italiana del Farmaco; AIFA) issued the Determination 809/2015 with new requirements for phase I clinical trials. Before it came into force, we explored the extent to which several Italian oncology centers were working to implement it. Methods: A survey was conducted among 80 Italian centers involved in clinical trials. Investigators and research coordinators were surveyed. Results: Answers from 42 institutions were collected: among them 88.1% were involved in oncology research. In the last 5 years, 55% had conducted from 1 to 5 phase I trials, and only 16.7% more than 5. A third were involved in not-first-in-human research and none with healthy volunteers. The majority (57.1%) of the centers did not run any projects and trials are non-commercial, and about 35%, no more than 2. While 9.5% already met the standards for self-certification, 71.4% were working to achieve them. Standard operating procedures dedicated to research and the required good clinical practice training had been established by 57.1% and 76.2%, respectively. Fifty percent of laboratories were almost compliant with the Determination. After 10 months from its coming into force, 98 sites had applied for certification, of which 34 were oncology units. Conclusions: The new AIFA Determination imposes a certified organizational model on units and laboratories involved in phase I trials. Our results showed that great efforts were made to qualify for phase I research suggesting that other oncology units will apply for certification in the near future. Predictably, Italy will set the pace as a highly qualified country in which to conduct early-phase research.

scholarly journals Healthy Volunteers’ Perceptions of the Benefits of Their Participation in Phase I Clinical Trials

2018 ◽  
Vol 13 (5) ◽  
pp. 494-510 ◽  
Author(s):  
Jill A. Fisher ◽  
Lisa McManus ◽  
Megan M. Wood ◽  
Marci D. Cottingham ◽  
Julianne M. Kalbaugh ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Healthy Volunteers ◽  
Employment Status ◽  
Qualitative Interviews ◽  
Trial Participation ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Financial Compensation ◽  
Trial History

Other than the financial motivations for enrolling in Phase I trials, research on how healthy volunteers perceive the benefits of their trial participation is scant. Using qualitative interviews conducted with 178 U.S. healthy volunteers enrolled in Phase I trials, we investigated how participants described the benefits of their study involvement, including, but not limited to, the financial compensation, and we analyzed how these perceptions varied based on participants’ sociodemographic characteristics and clinical trial history. We found that participants detailed economic, societal, and noneconomic personal benefits. We also found differences in participants’ perceived benefits based on gender, age, ethnicity, educational attainment, employment status, and number of clinical trials completed. Our study indicates that many healthy volunteers believe they gain more than just the financial compensation when they accept the risks of Phase I participation.

scholarly journals Race and ethnicity representation in clinical trials: findings from a literature review of Phase I oncology trials

2021 ◽  
Author(s):  
D Ross Camidge ◽  
Haeseong Park ◽  
Karen E Smoyer ◽  
Ira Jacobs ◽  
Lauren J Lee ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Predominantly White ◽  
Race And Ethnicity ◽  
Phase I Trials ◽  
Minimal Representation ◽  
Phase I Clinical Trials ◽  
Demographic Representation ◽  
The Usa ◽  
Race Ethnicity

Aim: To provide an assessment of published literature on the demographic representation in Phase I trials of biopharmaceutical oncology agents. Materials & methods: We conducted a rapid evidence assessment to identify demographic representation reported in Phase I clinical trials for biopharmaceutical oncology agents published in 2019. Results: Globally, the population was predominantly White/Caucasian (62.2%). In the USA, the distribution was heavily skewed toward White/Caucasian (84.2%), with minimal representation of Blacks/African–Americans (7.3%), Asians (3.4%), Hispanics/Latinos (2.8%) or other race/ethnicity groups. Conclusion: Our data highlight that Phase I oncology trials do not reflect the population at large, which may perpetuate health disparities. Further research is needed to understand and address barriers to participation, particularly among under-represented groups

scholarly journals Investigator Disclosure and Advanced Cancer Patient Understanding of Informed Consent and Prognosis in Phase I Clinical Trials

2018 ◽  
Vol 14 (6) ◽  
pp. e357-e367 ◽  
Author(s):  
Fay J. Hlubocky ◽  
Nancy E. Kass ◽  
Debra Roter ◽  
Susan Larson ◽  
Kristen E. Wroblewski ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Phase I ◽  
Advanced Cancer ◽  
Interaction Analysis ◽  
Trial Participation ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Advanced Cancer Patients ◽  
Medical Benefits

Purpose: Advanced cancer patients (ACPs) who participate in phase I clinical trials often report a less-than-ideal understanding of the required elements of informed consent (IC) and unrealistic expectations for anticancer benefit and prognosis. We examined phase I clinical trial enrollment discussions and their associations with subsequent ACP understanding. Methods: Clinical encounters about enrollment in phase I trials between 101 ACPs and 29 oncologists (principal investigators [PIs] and fellows) at three US academic medical institutions were recorded. The Roter Interaction Analysis System was used for analysis. ACPs completed follow-up questionnaires to assess IC recall. Results: PIs disclosed the following phase I IC elements to ACPs in encounters: trial purpose in 40%; specific physical risks in 60%; potential specific medical benefits gained by trial participation (eg, disease stabilization) in 48.2%; and alternatives to phase I trial participation in 47.1%, with 1.1% of encounters containing palliative and 2.3% hospice information. PIs provided ACP-specific prognoses in 29.0% of encounters but used precise terms of death in only 4.7% and terminal in 1.2%. A significant association existed between PI disclosure of the trial purpose as dosage/toxicity, and ACPs subsequently correctly recalled trial purpose versus PIs who did not disclose it (85% v 13%; P < .05). Conclusion: Many oncologists provide incomplete disclosures about phase I trials to ACPs. When disclosure of certain elements of IC occurs, it seems to be associated with better recall, especially with regard to the research purpose of phase I trials.

scholarly journals Do Patients With Advanced Cancer Have the Ability to Make Informed Decisions for Participation in Phase I Clinical Trials?

2018 ◽  
Vol 36 (24) ◽  
pp. 2483-2491 ◽  
Author(s):  
Fay J. Hlubocky ◽  
Greg A. Sachs ◽  
Eric R. Larson ◽  
Halla S. Nimeiri ◽  
David Cella ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Clinical Trials ◽  
Executive Function ◽  
Phase I ◽  
Advanced Cancer ◽  
Phase I Trials ◽  
Trail Making Test ◽  
Phase I Clinical Trials ◽  
Trail Making

Purpose Patients with advanced cancer (ACPs) participating in phase I clinical trials inadequately understand many elements of informed consent (IC); however, the prevalence and impact of cognitive impairment has not been described. Patients and Methods ACPs enrolled onto phase I trials underwent neuropsychological assessment to evaluate cognitive functioning (CF) covering the following domains: memory (Hopkins Verbal Learning Test), executive functioning (Trail Making Test B), language (Boston Naming Test-Short Version and Controlled Oral Word Association Test), attention (Trail Making Test A and Wechsler Adult Intelligenence Scale-IV Digit Span), comprehension (Wechsler Adult Intelligence Scale-IV), and quality of life (Functional Assessment of Cancer Therapy–Cognitive Function). Structured interviews evaluated IC and decisional capacity. Psychological measures included distress (Hospital Anxiety Depression Scale) and depression (Beck Depression Inventory-II). Results One hundred eighteen ACPs on phase I trials were evaluated, with CF ranging from mild impairment to superior performance. Only 45% of ACPs recalled physician disclosure of the phase I trial purpose. The 50% of ACPs who correctly identified the phase I research purpose had greater CF compared with ACPs who did not, as revealed by the mean T scores for memory (37.2 ± 5.6 v 32.5 ± 5.1, respectively; P = .001), attention (29 ± 2.7 v 26.9 ± 2.4, respectively; P < .001), visual attention (35.2 ± 6.6 v 31.5 ± 6.2, respectively; P = .001), and executive function (38.9 ± 7.5 v 34 ± 7.1, respectively; P < .001). Older ACPs (≥ 60 years) were less likely to recall physician disclosure of phase I purpose than younger ACPs (30% v 70%, respectively; P = .02) and had measurable deficits in total memory (34.2 ± 5.0 v 37.3 ± 5.6, respectively; P = .002), attention (24.5 ± 2.6 v 28 ± 2.8, respectively; P < .001), and executive function (32.8 ± 7.3 v 36.4 ± 7.6, respectively; P = .01). Older ACPs, compared with younger ACPs, also had greater depression scores (10.6 ± 9.2 v 8.1 ± 5.2, respectively; P = .03) and lower quality-of-life scores (152 ± 29.6 v 167 ± 20, respectively; P = .03). After adjustment by age, no psychological or neuropsychological variable was further significantly associated with likelihood of purpose identification. Conclusion CF seems to play a role in ACP recall and comprehension of IC for early-phase clinical trials, especially among older ACPs.

A randomized controlled trial to evaluate the impact of an educational DVD on cancer patients considering participation in a phase I clinical trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6011-6011
Author(s):  
E. L. Strevel ◽  
C. Newman ◽  
G. R. Pond ◽  
M. Maclean ◽  
L. L. Siu
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Controlled Trial ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Randomized Controlled ◽  
Clinic Appointment ◽  
The Mean ◽  
The Impact ◽  
Self Administered Questionnaire

6011 Background: Informed consent for phase I trials is controversial; gaps in patient (pt) knowledge regarding the purpose of these studies are central to this debate. This study assessed the impact of viewing an educational DVD on pt knowledge and satisfaction in cancer pts newly referred to a phase I trials clinic. Methods: Prior to physician (MD) appointment, 49 pts were randomly assigned to view either an educational DVD (n = 22) which provided information about phase I trials, or a placebo DVD (n = 27) which described research achievements by local scientists. Upon completion of DVD viewing, pts completed a self-administered questionnaire addressing their understanding of phase I trials (knowledge) and their satisfaction with the DVD (perception). The interviewing MD (n = 8), who was blinded to the intervention, also rated the pt’s understanding of phase I trials upon completion of the clinic appointment. Results: The mean pt age was 56 and 61% were male. Prior to attending the phase I clinic, most pts (86%) had previously heard of clinical trials, but only 49% were aware of phase I trials. Pts who viewed the educational DVD were less likely to believe that the goal of phase I trials is to determine the efficacy of a new drug (p = 0.019), more likely to correctly assess that drugs undergoing phase I evaluations have not been thoroughly studied in humans (p = 0.003), and less likely to believe that phase I drugs have proven activity against human cancers (p = 0.008). More pts who viewed the educational DVD than the placebo DVD agreed/strongly agreed that the DVD provided useful information (p < 0.001), believed that they had a good knowledge of phase I trials (p = 0.031), felt that the DVD helped them decide whether to enter a phase I trial (p = 0.011), and perceived that they would have more questions for their physicians as a result of watching the DVD (p = 0.017). No statistically significant differences in MD satisfaction was observed. Conclusions: Exposure to an educational DVD increased both objective measures of pt knowledge as well as pt satisfaction regarding participation in phase I clinical trials. The educational DVD did not significantly impact MD perception of pt understanding. No significant financial relationships to disclose.

Analysis of renal function in patients entered onto CTEP-sponsored phase I studies since 1979

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2519-2519 ◽  
Author(s):  
W. M. McHayleh ◽  
R. Sehgal ◽  
D. M. Potter ◽  
R. B. Royds ◽  
T. G. Nekrassova ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Renal Function ◽  
Phase I ◽  
Creatinine Clearance ◽  
Renal Dysfunction ◽  
Antineoplastic Agents ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Phase I Studies ◽  
Administration Methods

2519 Background: The NCI and FDA utilize different criteria for classifying renal dysfunction. We analyzed renal function in all patients entered onto CTEP-sponsored phase I clinical trials since 1979 to evaluate the percentage of patients with acceptable renal function according to criteria utilized by the National Cancer Institute, as compared with those advocated by the Food and Drug Administration. Methods: Data from 12575 patients entered onto CTEP-sponsored phase I studies since 1979 were evaluated. Renal function was characterized by calculating creatinine clearance (CrCl) by three different formulae (Cockroft-Gault, Jelliffe, and Levey), as well as GFR according to MDRD. Results: Of the 12,575 patients, data were available to calculate renal function with all the 4 formulae in 5,177. Distributions of CrCl and GFR were defined, and patients were classified as having normal renal function or severe, moderate, or mild renal dysfunction according to FDA or NCI criteria. The resulting distributions are indicated in the table below. Conclusions: Approximately 40% of patients entered into CTEP-sponsored phase I trials have mild renal dysfunction according to FDA criteria and approximately 95% have CrCls > 50 ml/min. These data imply that moderate and severe are the only renal dysfunction categories that need to be evaluated in renal dysfunction studies of novel antineoplastic agents and that FDA guidelines should be applicable. Whether patients in the NCI database with CrCls of 50–80 ml/min experience more toxicities than those with creatinine clearances > 80 ml/min is undergoing evaluation. [Table: see text] [Table: see text]

Characteristics and outcomes of patients with advanced hepatocellular carcinoma treated on phase I trials.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 281-281 ◽  
Author(s):  
Ishwaria Mohan Subbiah ◽  
Filip Janku ◽  
Apostolia Maria Tsimberidou ◽  
Aung Naing ◽  
Ahmed Omar Kaseb ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Clinical Trials ◽  
Phase I ◽  
Serum Sodium ◽  
Prognostic Score ◽  
Univariate Analysis ◽  
Single Agent ◽  
Advanced Hepatocellular Carcinoma ◽  
Phase I Trials ◽  
Phase I Clinical Trials

281 Background: Patients with advanced hepatocellular carcinoma (HCC) have limited effective therapies. With that purpose, we analyzed the outcomes and prognostic factors of such pts treated on phase I trials w an emphasis on locoregional and targeted agents. Methods: We reviewed the records of 100 consecutive pts referred to the Phase I Clinical Trials Program from March 2004 and assessed characteristics, types of clinical trials, progression-free survival (PFS), overall survival (OS) and oncogenic mutations. Results: Of 100 referred pts, 39 were not treated mainly due to poor performance status (n=22). Of 61 treated pts (49 male, 12 female, median age 60yrs), median # of prior therapies was 3 (range, 0-8). There were no treatment-related mortalities. One pt on a sorafenib regimen had g3 hand foot syndrome unresponsive to dose reduction. A 2nd pt developed a L-sided visual blurriness after 5 days on a sunitinib regimen; CT showed a small R parieto-occipital hemorrhage, possibly related to therapy. Of 61 treated pts, 7 (11%) had stable disease (SD) > 6 months, 4 (7%) partial response (PR), on protocols combining bevacizumab+sorafenib, pazopanib+everolimus, or single-agent novel oral multikinase inhibitor of VEGFR2-TIE2, or hepatic arterial infusion (HAI) of paclitaxel or oxaliplatin w IV bevacizumab. Median PFS on Phase I trials was 2.2 months vs. 4.4 months and 4.1 months for their 1st- and 2nd-line FDA-approved therapy (p 0.019). In univariate analysis, the presence of ascites, portal hypertension, cirrhosis, serum sodium, albumin, and poor Royal Marsden Hospital (RMH) prognostic score were associated with shorter PFS and OS (p < 0.05). On multivariate analysis, independent factors of shorter OS were Caucasian race (p = 0.031), cirrhosis (p = 0.016), serum sodium (p = 0.0013), and poor RMH prognostic score (p = 0.0015). Molecular analysis in progress will be updated. Conclusions: Phase I therapy offer a reasonable therapeutic option for patients with advanced HCC. The RMH prognostic score was validated in this population. The SD > 6 months/PR rate of 18% was observed with regimen of multikinase inhibitors with mTOR inhibitors and HAI therapy.

Survival and clinical outcomes of ovarian cancer patients enrolled in phase I clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5559-5559
Author(s):  
Bradley Corr ◽  
Marisa Moroney ◽  
Jeanelle Sheeder ◽  
Brandon Sawyer ◽  
S. Gail Eckhardt ◽  
...  
Keyword(s):  
Risk Factors ◽  
Ovarian Cancer ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Phase I ◽  
Cancer Patients ◽  
Ca 125 ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Heavily Pretreated

5559 Background: Ovarian cancer patients who enroll in Phase I clinical trials are typically platinum resistant, heavily pretreated patients with a poor prognosis. Historically, clinical benefit of Phase I trials in this patient population has been uncertain. We assessed prognostic factors and survival in women with recurrent, previously treated ovarian cancer who enrolled in Phase I clinical trials. Methods: We performed a retrospective analysis of all ovarian cancer patients who were treated on Phase I clinical trials from 2008 through 2018 at the University of Colorado Cancer Center. Patient characteristics, treatment-related toxicities and survival data were assessed. Descriptive statistics and Cox proportional hazards models were utilized to identify risk factors associated with survival time. Results: A total of 132 individual patients were treated on Phase I clinical trials. Patients had a median age of 59 years (range 33-88) with a median of 5.5 (range 1-13) previous chemotherapy lines. 53/132 (40%) of patients were treated on multiple Phase I trials with a median of 1 (range 0-5) prior Phase 1 clinical trial enrollments. All patients had an ECOG performance status of 0 or 1. Overall response rate (defined as complete or partial response) was 9% and disease control rate (defined as complete or partial response or stable disease as best response) was 33%. Median overall survival (OS) was 11.5 months (95% CI: 9.3-13.7). Two patients died on trial due to progression of disease while no patients died due to treatment-related toxicity. In multivariate analysis, independent risk factors predicting shorter survival were elevated CA-125 (HR 2.8; 95% CI: 1.6-5.2) and albumin < 3.5 g/dL (HR 2.5; 95% CI: 1.65-3.79). BMI > 25 predicted longer survival (HR 0.65; 95% CI: 0.44-0.96). Conclusions: Phase I clinical trials for heavily pretreated ovarian cancer patients are safe by a standard of no patients experiencing toxicity-related deaths in our study. They are clinically efficacious with patients experiencing OS of 11.5 months, which is comparable to existing approved therapies. Elevated CA-125 and low albumin levels predict shorter survival, while BMI > 25 predicts longer survival. Phase I clinical trial options should be considered for all heavily pretreated ovarian cancer patients if available to them.

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.

scholarly journals Adaptive Dose-Finding Studies: A Review of Model-Guided Phase I Clinical Trials

2014 ◽  
Vol 32 (23) ◽  
pp. 2505-2511 ◽  
Author(s):  
Alexia Iasonos ◽  
John O'Quigley
Keyword(s):  
Clinical Trials ◽  
Phase I ◽  
Dose Escalation ◽  
Late Onset ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Design Parameters ◽  
Phase I Trials ◽  
Phase I Clinical Trials ◽  
Trial Duration

Purpose We provide a comprehensive review of adaptive phase I clinical trials in oncology that used a statistical model to guide dose escalation to identify the maximum-tolerated dose (MTD). We describe the clinical setting, practical implications, and safety of such applications, with the aim of understanding how these designs work in practice. Methods We identified 53 phase I trials published between January 2003 and September 2013 that used the continual reassessment method (CRM), CRM using escalation with overdose control, or time-to-event CRM for late-onset toxicities. Study characteristics, design parameters, dose-limiting toxicity (DLT) definition, DLT rate, patient-dose allocation, overdose, underdose, sample size, and trial duration were abstracted from each study. In addition, we examined all studies in terms of safety, and we outlined the reasons why escalations occur and under what circumstances. Results On average, trials accrued 25 to 35 patients over a 2-year period and tested five dose levels. The average DLT rate was 18%, which is lower than in previous reports, whereas all levels above the MTD had an average DLT rate of 36%. On average, 39% of patients were treated at the MTD, and 74% were treated at either the MTD or an adjacent level (one level above or below). Conclusion This review of completed phase I studies confirms the safety and generalizability of model-guided, adaptive dose-escalation designs, and it provides an approach for using, interpreting, and understanding such designs to guide dose escalation in phase I trials.

Sign in / Sign up

Export Citation Format

Share Document