scholarly journals Research biopsies in the context of early phase oncology studies: clinical and ethical considerations

2013 ◽  
pp. e5 ◽  
Author(s):  
Matilde Saggese ◽  
Divyanshu Dua ◽  
Emily Simmons ◽  
Charlotte Lemech ◽  
Hendrik-Tobias Arkenau
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Tumor Biology ◽  
Biological Response ◽  
Resistance Mechanisms ◽  
Dose Finding ◽  
Direct Result ◽  
Phase I Studies ◽  
Increasing Demand ◽  
Tumor Biopsies

The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

scholarly journals Research biopsies in the context of early phase oncology studies: clinical and ethical considerations

2013 ◽  
Vol 7 (1) ◽  
pp. 5 ◽  
Author(s):  
Matilde Saggese ◽  
Divyanshu Dua ◽  
Emily Simmons ◽  
Charlotte Lemech ◽  
Hendrik-Tobias Arkenau
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Tumor Biology ◽  
Biological Response ◽  
Resistance Mechanisms ◽  
Dose Finding ◽  
Direct Result ◽  
Phase I Studies ◽  
Increasing Demand ◽  
Tumor Biopsies

The Personalized Medicine approach in oncology is a direct result of an improved understanding of complex tumor biology and advances in diagnostic technologies. In recent years, there has been an increased demand for archival and fresh tumor analysis in early clinical trials to foster proof-of-concept biomarker development, to understand resistance mechanisms, and ultimately to assess biological response. Although phase I studies are aimed at defining drug safety, pharmacokinetics, and to recommend a phase II dose for further testing, there is now increasing evidence of mandatory tumor biopsies even at the earliest dose-finding stages of drug development. The increasing demand for fresh tumor biopsies adds to the complexity of novel phase I studies and results in different challenges, ranging from logistical support to ethical concerns. This paper investigates key issues, including patients’ perceptions of research biopsies, the need for accurate informed consent, and alternative strategies that may guide the drug development process.

Pharmacodynamic-guided, modified continuous reassessment method (mCRM)-based, dose finding study of rapamycin in adult patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3020-3020 ◽  
Author(s):  
A. Jimeno ◽  
P. Kulesza ◽  
G. Cusatis ◽  
A. Howard ◽  
Y. Khan ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Dose Finding ◽  
Phase I Trials ◽  
Dose Selection ◽  
Normal Tissues ◽  
Tumor Biopsies ◽  
Dose Levels

3020 Background: Pharmacodynamic (PD) studies, using either surrogate or tumor tissues, are frequently incorporated in Phase I trials. However, it has been less common to base dose selection, the primary endpoint in Phase I trials, in PD effects. We conducted a PD-based dose selection study with rapamycin (Rap). Methods: We used the modified continuous reassessment method (mCRM), a computer-based dose escalation algorithm, and adapted the logit function from its classic toxicity-based input data to a PD-based input. We coupled this design to a Phase I trial of Rap with 2 parts: a dose estimation phase where PD endpoints are measured in normal tissues and a confirmation phase where tumor tissue is assessed. Patients (pts) had solid tumors refractory to standard therapy. Rap was given starting at 2 mg/day continuously in 3-pt cohorts. The PD endpoint was pP70S6K in skin and tumor. Biopsies were done on days 0 and 28 of cycle 1, and a PD effect was defined as ≥ 80% inhibition from baseline. The first 2 dose levels (2 and 3 mgs) were evaluated before implementing the mCRM. The data was then fed to the computer that based on the PD effect calculated the next dose level. The mCRM was set so escalation continued until a dose level elicited a PD effect and the mCRM assigned the same dose to 8 consecutive pts, at which point the effect of that dose will be confirmed in tumor biopsies. Other correlates were PET-CT and pharmacokinetics. Results: Ten pts were enrolled at doses of 2 mg (n = 4), 3 mg (n = 3) and 6 mg (n = 3). Toxicity was anemia (4 G1, 1 G2), leucopenia (1 G1, 2 G2), low ANC (2 G2), hyperglycemia (2 G1, 1 G2), hyperlipidemia (4 G1), and mucositis (1 G1, 1 G2). PD responses were seen in 2 and 1 pt at 2 and 3 mg dose levels. Input of data to the mCRM selected a dose of 6 mg for the third cohort, where PD effect was seen in 1 pt, and thus a fourth dose around 9 mg will be tested. No responses by RECIST occurred, but 2 pts had a response by PET. The PK was consistent with prior data (t1/2 24.6 ± 10.2 h, CL 31.4 ± 12.0 L/h, vol of distribution 235 ± 65 L), and exposure increased with dose. Steady-state concentration were in the 5–20 nM range. Conclusions: mCRM-based dose escalation based on real-time PD assessment is feasible and permits the exploitation of PD effects for dose selection in a rational manner. No significant financial relationships to disclose.

Informed consent in phase I clinical trials: Implications for trends in design.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14077-e14077
Author(s):  
Paul Henry Frankel ◽  
Susan G. Groshen
Keyword(s):  
Clinical Trials ◽  
Informed Consent ◽  
Phase I ◽  
Dose Finding ◽  
Institutional Review Boards ◽  
Severe Toxicity ◽  
Phase I Clinical Trials ◽  
Traditional Use ◽  
Phase I Studies ◽  
Definition Of

e14077 Background: Informed Consent (IC) is a critical aspect of human subjects protection. Institutional Review Boards are tasked with insuring proper IC as one aspect of protecting participants in clinical trials. Phase I trials in oncology present special issues with IC, as often neither the risks nor the benefits are well-known. This has resulted in carefully worded IC templates for Phase I studies based on the traditional use of dose-finding designs that are geared towards finding the “Maximum Tolerated Dose (MTD)”. As the definition of this term varies by study, the implication for patient risk and informed consent are rarely discussed. Methods: We reviewed Phase I designs to present options for improving the informed consent process for Phase I oncology trials. Results: Phase I studies have seen an increase in designs based on work from the early 1990s seeking a dose that results in a targeted percent of patients experiencing a “Dose Limiting Toxicity (DLT)” to define the MTD. The most common definition of a DLT is a treatment-related toxicity that results in a particularly concerning severe toxicity (grade 3 or higher) in the first cycle of therapy and the most common rate targeted (in designs that define toxicity as a goal) is 25%. In that setting, while lower doses may have a lower likelihood of DLT, higher doses or the expansion cohort are likely to have a 25% chance of DLT if the target is pursued. This information is rarely quantitatively communicated in the informed consent. Conclusions: IRBs and investigators should consider communicating through informed consent the quantitative summary of goals of the study and related risk. For example, transparency suggests conveying when the goal (target) of the study is to find the dose where there is a one in four chance of experiencing a severe adverse event in the first cycle.

Biomarker analysis (CTC and ctDNA/RNA) of GT0918 (Proxalutamide) new AR blocker in phase I mCRPC patients with dose escalation.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 186-186
Author(s):  
Karl Zhou ◽  
Phoebe Zhang ◽  
Youzhi Tong ◽  
Liandong Ma
Keyword(s):  
Phase I ◽  
Clinical Outcomes ◽  
Dose Escalation ◽  
Tumor Biology ◽  
Study Drug ◽  
Resistance Mechanisms ◽  
Development Programs ◽  
Dose Escalation Study ◽  
Biomarker Analysis ◽  
Monitoring Treatment

186 Background: AR blockade is an important treatment option for mCRPC in clinic and GT0918 is a new chemical entity of AR blocker in 2nd generation. A phase I dose escalation study was planned in pts with mCRPC progressed on multiple lines of SoC and experimental therapies. Daily oral administration of GT0918 has shown better clinical outcomes in 400mg and 500mg cohorts with no comprised toxicities. To study the tumor biology in response to study drug in clinical setting, CTC and cfDNA/RNA based biomarkers were explored. Methods: Pts with histologically confirmed mCRPC who progressed on enza, abi, docetaxel, etc were enrolled and treated with GT0918 continuously until PD, intolerable toxicity or withdraw. Blood samples were collected at baseline, on study drug every 8 wks during the trial and pts with ≥ 3 blood test samples were qualified for various assays for CTCs and cfDNA/RNA via EPIC and PredicinePlus platforms. Results: Total 40 pts were orally administrated GT0918 with dose increasing 50, 100, 200, 300, 400, 500 and 600 mg daily and shown well tolerated with mild to moderate toxicities. Pts received GT0918 over 16 weeks were run biomarkers in Predicine and/or Epic platforms. ctDNA/RNA based variants and CTCs are all detectable in selected pts samples. AR splicing variants (AR-V3 and AR-V7), AR hotspot mutations (W742C, T878A and S889G) and amplifications were detected and shown interesting trends with the clinical outcomes. Both exploratory biomarkers and CTCs suggested higher doses of GT0918 resulted in better clinical outcomes. Conclusions: This is a preliminary study to explore genomic alterations and the CTC enumeration in late stage of mCRPC pts in response to GT0918 treatment with dose increase. As non-invasive assays, both CTC and ctDNA/RNA assays provided valuable molecular insights for monitoring treatment effects besides PSA and imaging scan. Early detection of possible drug sensitivity/resistance mechanisms will facilitate clinical development programs. More patients will be tested in phase II study GT0918 in mCRPC progressed on either abiraterone or enzalutamide. Clinical trial information: NCT02826772. [Table: see text]

Clinical outcomes of adolescents and young adults (AYA) with advanced solid tumors participating in phase I trials.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10536-10536 ◽  
Author(s):  
Raghav Sundar ◽  
Terri Patricia McVeigh ◽  
Ann Petruckevitch ◽  
Nikolaos Diamantis ◽  
Joo Ern Ang ◽  
...  
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Outcomes ◽  
Published Data ◽  
Hereditary Cancer Syndrome ◽  
Phase I Trials ◽  
Advanced Solid Tumors ◽  
Phase I Studies ◽  
Development Unit

10536 Background: AYA cancer patients are relatively under-represented in clinical trials, with no published data regarding their outcomes in phase I studies. Trials utilizing novel therapeutic agents are often considered in these patients, due to their tendency to have good organ reserve, and ability to tolerate additional lines of therapy. This study describes the experience of AYA patients with advanced solid tumors treated in a specialized drug development unit. Methods: Patient characteristics and clinical outcomes of AYA patients (defined as age 15 to 39 years at time of initial cancer diagnosis) treated at the Drug Development Unit, Royal Marsden Hospital, United Kingdom, between 2002 and 2016, were captured and analyzed from case and trial records. Results: From a database of 2631 patients treated on phase I trials, 219 AYA patients (8%) were identified. Major tumor types included gynaecological cancer (24%), sarcoma (18%), gastrointestinal (16%) and breast cancer (11%). Patients had a median of 3 previous lines of systemic chemotherapy (range 0 – 6), and 19% participated in 2 or more phase I studies. Twenty (9%) had a known hereditary cancer syndrome (most commonly BRCA), 27% had a family history (FH) of cancer, 15% no FH and 49% no FH documented. Molecular characterization of tumors (n = 45) identified mutations most commonly in p53 (33%) , PI3KCA (18%) and KRAS (9%) . Major trial categories included DNA damage repair (16%), PI3K (16%) and anti-angiogenesis (15%) agents. Grade 3/4 toxicities were experienced in 25% of patients (10% hematological). Of the 214 evaluable patients, objective response rate was 12%, with clinical benefit rate at 6 months of 22%. Median progression free survival was 2.3 months (95% CI: 1.9 to 2.8), median OS was 7.6 months (95% CI: 6.3 to 9.5), and 2-year OS was 11%. Of patients with responses, 35% were matched to phase I trials based on germline or somatic genetic aberrations. Conclusions: A sub-group of AYA patients with advanced solid tumors derive considerable benefit from participating in trials involving novel therapeutics. Future research must focus on predictive biomarkers and molecular profiling to identify those that would benefit from novel therapies.

Early targeted drug development: Pilot FDA review of PI3K inhibitor phase I studies using a knowledge management database.

2011 ◽  
Vol 29 (15_suppl) ◽  
pp. 3060-3060
Author(s):  
G. M. Blumenthal ◽  
R. Charlab Orbach ◽  
I. Zineh ◽  
P. Cortazar ◽  
R. L. Justice ◽  
...  
Keyword(s):  
Knowledge Management ◽  
Drug Development ◽  
Phase I ◽  
Pi3k Inhibitor ◽  
Phase I Studies ◽  
Targeted Drug ◽  
Management Database

A mismatch between methods and objectives in phase I drug development: Statistical limitations and personalized medicine—A California Cancer Consortium (CCC) study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2538-2538
Author(s):  
Paul Henry Frankel ◽  
Stephen Shibata ◽  
Susan G. Groshen ◽  
Jeff Longmate ◽  
Sumanta Kumar Pal ◽  
...  
Keyword(s):  
Drug Development ◽  
Phase I ◽  
Statistical Methods ◽  
Dose Level ◽  
Patient Selection ◽  
Survey Methods ◽  
Small Sample ◽  
Reliable Estimate ◽  
Phase I Studies ◽  
Grade 3

2538 Background: Patient variation in drug response and toxicity impacts all phases of drug development. While detailed sample-size calculations and analysis based on statistical methodology are critical for addressing variation in late stage trials, phase I studies pose unique and largely unsolved challenges related to variability. Changes in patient selection during the study, small sample-sizes and large patient variation in toxicity are exactly the kind of problems that statistical methods cannot address in small, isolated phase I studies, regardless of apparent mathematical rigor. We have documented these problems via a physician survey. Methods: A 10-question anonymous survey was sent to 670 oncologists at National Comprehensive Cancer Network (NCCN) and CCC institutions via an online survey. 19 % (126/670) of the oncologists polled responded. 78/126 (62%) specialized in Medical Oncology. The number of years in practice varied from 2-45 yrs with a median of 17 yrs. Results: a) 66% of all respondents stated that non-DLT toxicities on one dose level would impact their patient selection on the following dose level, conflicting with the assumption of random patient selection implicit in simulations used in evaluating statistical designs. b) Only 13% stated a desire to target a non-heme toxicity as high as 20% grade 3, while 87% desired a 10% or less grade 3 rate; c) More than half the respondents would prefer not to escalate if 3/3 patients experienced grade 2 LFTs; d) 82% of the respondents thought the appropriate target toxicity differed for patients depending on their potential for becoming a surgical candidate, furthering the need for personalized dosing. Conclusions: Statistical methods in phase I trials are unable to address many of the salient features of phase I study conduct and investigator goals. We will present several approaches we have initiated to address these limitations, and present future plans to help produce a more reliable estimate of a recommended dose. Supported in part by NCI grants U01CA062505, N01-CM-62209, and NCCN data collection assistance.

scholarly journals Analysis of Impact of Post-Treatment Biopsies in Phase I Clinical Trials

2016 ◽  
Vol 34 (4) ◽  
pp. 369-374 ◽  
Author(s):  
Randy F. Sweis ◽  
Michael W. Drazer ◽  
Mark J. Ratain
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Phase I ◽  
Maximum Tolerated Dose ◽  
Phase I Clinical Trials ◽  
Early Phase Clinical Trials ◽  
Pharmacodynamic Biomarkers ◽  
Tumor Biopsies ◽  
Phase Ii And Iii ◽  
The Impact

Purpose The use of biopsy-derived pharmacodynamic biomarkers is increasing in early-phase clinical trials. It remains unknown whether drug development is accelerated or enhanced by their use. We examined the impact of biopsy-derived pharmacodynamic biomarkers on subsequent drug development through a comprehensive analysis of phase I oncology studies from 2003 to 2010 and subsequent publications citing the original trials. Methods We conducted a search to identify and examine publications of phase I oncology studies including the use of biopsy-derived pharmacodynamic biomarkers between 2003 and 2010. Characteristics of those studies were extracted and analyzed, along with outcomes from the biomarker data. We then compiled and reviewed publications of subsequent phase II and III trials citing the original phase I biomarker studies to determine the impact on drug development. Results We identified 4,840 phase I oncology publications between 2003 and 2010. Seventy-two studies included a biopsy-derived pharmacodynamic biomarker. The proportion of biomarker studies including nondiagnostic biopsies increased over time (P = .002). A minimum of 1,873 tumor biopsies were documented in the 72 studies, 12 of which reported a statistically significant biomarker result. Thirty-three percent of studies (n = 24) were referenced by subsequent publications specifically with regard to the biomarkers. Only five positive biomarker studies were cited subsequently, and maximum tolerated dose was used for subsequent drug development in all cases. Conclusion Despite their increased use, the impact of biopsy-derived pharmacodynamic biomarkers in phase I oncology studies on subsequent drug development remains uncertain. No impact on subsequent dose or schedule was demonstrated. This issue requires further evaluation, given the risk and cost of such studies.

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