Conducting phase 1 cancer clinical trials during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related disease pandemic

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

Download Full-text

Phase 1 cancer clinical trials, evolving by complexity.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.15_suppl.e17545 ◽

2015 ◽

Vol 33 (15_suppl) ◽

pp. e17545-e17545

Author(s):

Alex V Mejia ◽

Laeeq Malik ◽

Jonathan Gelfond ◽

Devalingam Mahalingam ◽

John Sarantopoulos ◽

...

Keyword(s):

Clinical Trials ◽

Phase 1 ◽

Cancer Clinical Trials

Download Full-text

The impact of severe acute respiratory syndrome coronavirus 2 on patients in cancer clinical trials

Polish Archives of Internal Medicine ◽

10.20452/pamw.15733 ◽

2020 ◽

Author(s):

Mikołaj Bartoszkiewicz ◽

Joanna Kufel-Grabowska ◽

Maria Litwiniuk

Keyword(s):

Clinical Trials ◽

Severe Acute Respiratory Syndrome ◽

Cancer Clinical Trials ◽

The Impact

Download Full-text

A Focus on the Nowadays Potential Antiviral Strategies in Early Phase of Coronavirus Disease 2019 (Covid-19): A Narrative Review

Life ◽

10.3390/life10080146 ◽

2020 ◽

Vol 10 (8) ◽

pp. 146

Author(s):

Caterina Monari ◽

Valeria Gentile ◽

Clarissa Camaioni ◽

Giulia Marino ◽

Nicola Coppola ◽

...

Keyword(s):

Clinical Trials ◽

Severe Acute Respiratory Syndrome ◽

Randomized Clinical Trials ◽

Scientific Evidence ◽

Antiviral Agents ◽

Narrative Review ◽

Definitive Evidence ◽

Treatment Regimens ◽

Related Disease ◽

Critical Issues

Background: The outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the related disease (COVID-19) has rapidly spread to a pandemic proportion, increasing the demands on health systems for the containment and management of COVID-19. Nowadays, one of the critical issues still to be pointed out regards COVID-19 treatment regimens and timing: which drug, in which phase, for how long? Methods: Our narrative review, developed using MEDLINE and EMBASE, summarizes the main evidences in favor or against the current proposed treatment regimens for COVID-19, with a particular focus on antiviral agents. Results: Although many agents have been proposed as possible treatment, to date, any of the potential drugs against SARS-CoV-2 has shown to be safe and effective for treating COVID-19. Despite the lack of definitive evidence, remdesivir remains the only antiviral with encouraging effects in hospitalized patients with COVID-19. Conclusions: In such a complex moment of global health emergency, it is hard to demand scientific evidence. Nevertheless, randomized clinical trials aiming to identify effective and safe drugs against SARS-CoV-2 infection are urgently needed in order to confirm or reject the currently available evidence.

Download Full-text

An Investigation of the Traditional Algorithm-Based Designs for Phase 1 Cancer Clinical Trials

Drug Information Journal ◽

10.1177/009286150203600415 ◽

2002 ◽

Vol 36 (4) ◽

pp. 865-873 ◽

Cited By ~ 26

Author(s):

Seung-Ho Kang ◽

Chul W. Ahn

Keyword(s):

Clinical Trials ◽

Phase 1 ◽

Cancer Clinical Trials ◽

Traditional Algorithm

Download Full-text

Ovarian cancer clinical trials: Study the studies to terminate the terminations.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.6069 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 6069-6069

Author(s):

Daniel Spinosa ◽

Elizabeth Howell ◽

D'Erryl Williams ◽

Catherine Watson ◽

Tomi F. Akinyemiju ◽

...

Keyword(s):

Ovarian Cancer ◽

Clinical Trials ◽

Cancer Patients ◽

Phase 1 ◽

Early Termination ◽

Single Type ◽

Cancer Clinical Trials ◽

Academic Center ◽

Early Phase Trials ◽

Missed Opportunity

6069 Background: Clinical trials safely expand the arsenal of treatments available to future patients while providing hope to current patients, particularly ovarian cancer patients who often have poor prognoses. Trial termination for lack of efficacy or unacceptable toxicity are consistent with the aim of protecting patients in the pursuit of knowledge, but those are not the only reasons trials terminate early. Understanding why some clinical trials do not achieve their stated goals may aid in the design of future trials. Methods: Data were gathered from clinical trials registered to ClinicalTrials.gov. Included trials were interventional (as opposed to observational), were closed between 2004 and 2019, enrolled ovarian cancer patients, had submitted results, and were open at one or more domestic sites. For each trial, data were captured regarding study completion, reason for non-completion (if applicable), sites, phase, sponsor (defined as the study initiator, not necessarily the funder), and intervention type. Results: A total of 313 trials were examined, of which 262 met inclusion criteria. Of the 262 evaluable trials, 189 (72%) were completed and 72 (27%) terminated early. The most common reasons for early termination were low accrual (27 trials, 38%), lack of efficacy (15 trials, 21%), or insufficient funding (9 trials, 13%). Five trials (7%) were terminated early due to toxicity. Early phase trials are less likely to complete enrollment, with 11 out of 16 (65%) phase 1 trials, 135 out of 180 (75%) phase 2 trials, and 15 out of 16 (94%) phase 3 trials completed. Trials initiated by an academic center were twice as likely to be terminated early (41/103, 40%) as those initiated by industry (16/80, 20%), with remaining trials initiated by consortia, NCI, or non-academic oncology practices. Terminated trials were open at an average of 11 sites (range 1-317), while completed trials were open at an average of 27 sites (range 1-632). Trials that had multiple types of interventions, for instance a drug and a procedure, had a 34% early termination rate which was higher than the rate for trials with any single type of intervention. Conclusions: More than one in four ovarian cancer clinical trials are terminated early, rarely due to treatment efficacy or tolerability. Trials terminated for reasons other than patient outcomes represent a misallocation of resources or a missed opportunity for innovation. Further research is needed to understand the circumstances that allow for clinical trial completion such that available resources maximize patient benefit.

Download Full-text

Optimal biological dose: a systematic review in cancer phase I clinical trials

BMC Cancer ◽

10.1186/s12885-021-07782-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

J. Fraisse ◽

D. Dinart ◽

D. Tosi ◽

C. Bellera ◽

C. Mollevi

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Phase I ◽

Dose Escalation ◽

Phase 1 ◽

Dose Finding ◽

Cancer Clinical Trials ◽

Phase I Clinical Trials ◽

Cancer Trial ◽

Biological Dose

Abstract Background Classical phase 1 dose-finding designs based on a single toxicity endpoint to assess the maximum tolerated dose were initially developed in the context of cytotoxic drugs. With the emergence of molecular targeted agents and immunotherapies, the concept of optimal biological dose (OBD) was subsequently introduced to account for efficacy in addition to toxicity. The objective was therefore to provide an overview of published phase 1 cancer clinical trials relying on the concept of OBD. Methods We performed a systematic review through a computerized search of the MEDLINE database to identify early phase cancer clinical trials that relied on OBD. Relevant publications were selected based on a two-step process by two independent readers. Relevant information (phase, type of therapeutic agents, objectives, endpoints and dose-finding design) were collected. Results We retrieved 37 articles. OBD was clearly mentioned as a trial objective (primary or secondary) for 22 articles and was traditionally defined as the smallest dose maximizing an efficacy criterion such as biological target: biological response, immune cells count for immunotherapies, or biological cell count for targeted therapies. Most trials considered a binary toxicity endpoint defined in terms of the proportion of patients who experienced a dose-limiting toxicity. Only two articles relied on an adaptive dose escalation design. Conclusions In practice, OBD should be a primary objective for the assessment of the recommended phase 2 dose (RP2D) for a targeted therapy or immunotherapy phase I cancer trial. Dose escalation designs have to be adapted accordingly to account for both efficacy and toxicity.

Download Full-text

Feasibility of conducting Phase 1 clinical trials in low-middle income countries (LMIC) - The case of Argentina

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.wcp2018.0_po1-13-8 ◽

2018 ◽

Vol WCP2018 (0) ◽

pp. PO1-13-8

Author(s):

Ventura A Simonovich ◽

Mariana G Fernandez ◽

Paula Scibona ◽

Cintia V Cruz ◽

Valeria Beruto ◽

...

Keyword(s):

Clinical Trials ◽

Phase 1 ◽

Middle Income ◽

Conducting Phase ◽

Middle Income Countries ◽

Low Middle Income Countries

Download Full-text

Prostate cancer clinical trials consortium: A multicenter mechanism for the rapid design, development, and implementation of early phase clinical trials

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e16065 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e16065-e16065

Author(s):

J. Vinson ◽

P. Mathew ◽

T. M. Beer ◽

M. A. Carducci ◽

W. Oh ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

Data Storage ◽

Early Phase ◽

Phase 1 ◽

Cancer Center ◽

Cancer Clinical Trials ◽

Research Centers ◽

Design Development ◽

Multicenter Studies

e16065 Background: Leading investigators in prostate cancer have hypothesized that clinical trials (CT) are optimally conducted as multicenter studies. To test this, the Prostate Cancer Clinical Trials Consortium (PCCTC) was formed with support from the Prostate Cancer Foundation (PCF) and the Department of Defense Clinical Consortium Award (DOD). Since the PCCTC's inception in 2006, members have cooperatively designed, carried out, and evaluated phase 1 and 2 multicenter studies in prostate cancer. Methods: PCF and DOD awards support a consortium of 13 cancer research centers. Memorial Sloan-Kettering Cancer Center serves as the coordinating center and is charged with creating an infrastructure to conduct early phase, multicenter trials. Annually, each participating center is required to introduce at least one CT for consideration by the PCCTC and accrue at least 35 patients to PCCTC studies. Investigators meet face-to-face twice per year to discuss the PCCTC's progress, and hold monthly conference calls to discuss scientific objectives, trial design, and ongoing studies. Results: Since inception, the PCCTC has expanded from 8 to 13 leading research centers. Through September 2008, it has opened 47 trials and accrued 1,282 patients at member sites. Members utilize a CT management system for protocol tracking, electronic data capture, and data storage. A legal framework has been instituted, and standard operating procedures, administrative structure, editorial support, centralized budgeting, and mechanisms for scientific review have been established. Each year, the number of trials presented and patients accrued increases, and three concepts have progressed to the next phase of clinical testing. Conclusions: The PCCTC fulfills a congressional directive to create a CT instrument dedicated to rapid accrual to early-phase, multicenter studies in prostate cancer. The member institutions have built a shared administrative, informatics, legal, financial, statistical, and scientific infrastructure to support this endeavor. As the PCCTC has expanded and taken an increasingly active role in designing and evaluating protocols, clinical trials continue to open and accrue in excess of federally mandated goals. No significant financial relationships to disclose.

Download Full-text