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Conducting Phase I Clinical Trials During the COVID-19 Pandemic

An experience of the Drug Development Department of the Gustave Roussy
05 Aug 2020

In a perspective article published on 27 July 2020 in the European Journal of Cancer, Dr Sophie Postel-Vinay and colleagues of the Drug Development Department (DITEP), Gustave Roussy in Villejuif, France discuss the key factors to be considered in conducting the phase I clinical trials during the COVID-19 pandemic, as well as in the management of COVID-19-positive cancer patients who are enrolled in those trials. In particular, the authors present the risks and challenges in COVID-19-positive cancer patients enrolled in the phase I clinical trials from the aspects of safety, toxicity causality assessment, drug efficacy evaluation and clinical research priorities. They proposed the guidelines for conducting phase I clinical trials and management of COVID-19 positive cancer patients during the pandemic.

The authors wrote in the background that cancer is associated with a higher probability of severe forms of COVID-19. Phase I clinical trials trials require an intensive monitoring of patients with multiple in-patient and out-patient unit visits which may represent an additional risk factor for SARS-CoV-2 infection. The occupancy of intensive care units (ICUs) by COVID-19 patients is a significant additional factor to consider when enrolling cancer patients in phase I clinical trials due to frequent life-threatening complications, such as cytokine release syndrome (CRS) in trials evaluating CAR-T cells or bispecific antibodies or in those undergoing complicating tumour biopsies.

Currently, there are no recommendations for the management of COVID-19-positive cancer patients included in phase I clinical trials. The authors wrote that their reflections are based on their experience only. The phase I drug safety profile should be considered in the decision of maintaining a COVID-19 positive patient in the trial. The investigational drug should be temporarily or permanently halted in case of any doubt of increased safety risk.

The authors suggested that any candidate for phase I clinical trial should be screened for SARS-CoV-2 by using PCR prior starting the experimental treatment. The patients with a positive PCR should be excluded from the clinical trial, even if asymptomatic at the time of diagnosis. Furthermore, they recommended screening weekly for SARS-CoV-2 by PCR during the dose limiting toxicity (DLT) period and replacing patients who develop a clinical or biological (e.g. asymptomatic but PCR positive) SARS-CoV-2 infection during the DLT period. Beyond the screening phase and the DLT period, they suggested to perform a regular SARS-CoV-2 PCR at the end of the DLT period and subsequently every four cycles and/or upon clinical symptoms. Patients who develop COVID-19 after the DLT period or during the dose-expansion phase may stay in the trial, as long as the treatments received for the management of the COVID-19 do not interfere with the phase I drug metabolism or efficacy.

In terms of clinical research priorities, the authors wrote that from a regulatory point of view and by law, a patient cannot be included in two different therapeutic interventional trials. However, inclusion in a study evaluating treatments against COVID-19 should probably be favoured at current time.

The authors wrote that in case of an asymptomatic or non-severe COVID-19 confirmed in a patient included in the phase I trial outside the DLT period, the patient could stay in the trial in most cases. However, adjustments should be done whenever feasible until the patient has recovered clinically and biologically, after discussion and approval of the trial sponsor, including minor deviations in order to limit hospital visits, teleconsulting at increased frequency with the phase I investigator, combined with regular home visits from the patient’s local general practitioner and blood tests at a local facility, treatment shipping to the patient’s domicile, skipping of some surveillance clinics at the hospital when the patient has been stable and on trial for more than 6 months and does not present any evolving drug-related adverse event, stronger personal protection for the patient, active and regular reminder to strictly avoid any self-medication and over the counter drugs. In order to limit the risk of COVID-19 in cancer patients included in phase I clinical trial, the patient and its household should also be regularly reminded of strictly respect the self-protection measures.

The Gustave Roussy experience

The authors wrote that COVID-19 was intense in the Paris region from mid March to end of April 2020. From 14th March to 28th April 2020, 178 cancer patients were managed for COVID-19 at the Gustave Roussy. In total, 125 patients (70.2%) were hospitalised for COVID-19, 47 patients (26.4%) developed clinical worsening and 31 patients (17.4%) died.

During that period, the DITEP continued its activity but all lung biopsies were cancelled to limit the risk of severe complications such as pneumothorax that would require access to the ICU, all patients were tested at least at Cycle 1 Day 1 using rapid PCR, visits to the hospital were cancelled whenever feasible and teleconsultation was favoured as well as treatment shipment at home.

The patients were managed according to next principles:

  • In case of asymptomatic patients with both COVID-19 PCR and serology negative statuses, or PCR negative but serology positive status, social distancing and mask was recommended;
  • In case of asymptomatic patients with COVID-19 PCR positive, but serology negative status, delay in unnecessary visit and treatment was recommended;
  • In case of symptomatic patients with COVID-19 PCR positive and serology negative status, delay or stop of participation in phase I clinical trial was recommended.

The authors reported that 3 patients who received bispecific agents and developed a cytokine release syndrome were successfully managed in their ward with strong interaction with the Gustave Roussy intensive care unit.

Rapid PCR tests identified 4 patients with a COVID 19-positive PCR: one patient in screening, for which Cycle 1 Day 1 was delayed; one patient in the DLT period, who was maintained in the trial as he remained completely asymptomatic and did not develop any adverse event; and two patients at later stages of the phase I clinical trial (cycles 10 and 12) who required a treatment delay because of self-isolation. No COVID-19-related death occurred.

Phase I clinical trials are the most resource-consuming and complicated form of clinical trials, from a safety and organisational point of view, as they involve multiple hospital teams (clinical trial unit, pharmacy, interventional radiology, etc.), clinical research organisations and drug companies, and require intensive patient monitoring. The authors concluded that during the peak of the pandemic in France, they successfully managed to maintain their drug development unit open and to treat patients without any, while not causing any nosocomial COVID-19 infection.

The authors also suggested creation of an international registry and Task Force for phase I cancer patients with COVID-19, so that various practices can be compared and eventually the consensus guidelines to be established.

Reference

Postel-Vinay S, Massard C, Soria J-CS. COVID-19 outbreak and Phase 1 trials: should we consider a specific patient management? European Journal of Cancer; Published online on 27 July 2020. DOI: https://doi.org/10.1016/j.ejca.2020.07.009

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