key: cord-0952564-nr3ym20o
authors: Postel-Vinay, Sophie; Massard, Christophe; Soria, Jean-Charles
title: COVID-19 outbreak and Phase 1 trials: should we consider a specific patient management?
date: 2020-07-27
journal: Eur J Cancer
DOI: 10.1016/j.ejca.2020.07.009
sha: 5033e88c40d12defd819ce339c23071b7d2001c6
doc_id: 952564
cord_uid: nr3ym20o

The outbreak of the COVID-19 pandemic has deeply challenged health care systems and cancer patients care. Phase 1 studies are among the most complicated clinical trials, and require thorough patient selection as well as intensive patient monitoring. In this perspective, we discuss the key factors that should be considered for the conduct of Phase 1 trials and management of COVID-19-positive cancer patients enrolled in such trials. We notably present the risks and challenges raised by COVID-19 infected Phase 1 patients, in terms of safety, toxicity causality assessment, drug efficacy evaluation, and clinical research priorities. We finally propose some guidelines for the conduct of Phase 1 trials and management of COVID-19 infected patients in a pandemic time.

The outbreak of the COVID-19 pandemic has deeply challenged health care systems and cancer patients care. Phase 1 studies are among the most complicated clinical trials, and require thorough patient selection as well as intensive patient monitoring. In this perspective, we discuss the key factors that should be considered for the conduct of Phase 1 trials and management of COVID-19positive cancer patients enrolled in such trials. We notably present the risks and challenges raised by COVID-19 infected Phase 1 patients, in terms of safety, toxicity causality assessment, drug efficacy evaluation, and clinical research priorities. We finally propose some guidelines for the conduct of Phase 1 trials and management of COVID-19 infected patients in a pandemic time.

The outbreak of the COVID-19 pandemic has unexpected consequences on all aspects of life, society, economy and healthcare. In oncology, it is now well-established that cancer represents a comorbidity that is associated with a higher probability of severe forms of the SARS-Cov-2 infection 1, 2 . Phase 1 trials, which require an intensive monitoring of patients with multiple visits in in-patient and out-patient units, may represent by themselves an additional major risk of contamination in a pandemic context. Further, the saturation of intensive care units by COVID-19-infected patients adds a significant safety risk for cancer patients enrolled in phase 1 trials associated with frequent lifethreatening complications, such as cytokine release syndrome in protocols evaluating CAR-T cells or bispecific antibodies, or for patients undergoing challenging tumor biopsies.

Preliminary guidelines, which are being refined as experience on the SARS-Cov-2 infection management increases, have been established for the clinical practice of routine cancer treatments 1, 2 . These include postponing adjuvant chemotherapy, limiting dose-intensity of chemotherapy or intensifying surveillance in endemic areas and epidemic times. However, no recommendations currently exist on the management of COVID-19-positive patients included in Phase 1 trials. Phase 1 trials represent the first evaluation of a drug -or a drug combination -into humans and aim at establishing the optimal dose that can be administered safely and with a maximal efficacy. These trials have therefore some inherent specificities that require specific attention for the management of COVID-19-positive patients.

Here, we propose some elements of thought that may be considered for the conduct of Phase 1 trials and management of COVID-19-positive cancer patients who are candidates for such trials or already enrolled in them. Considering the current absence of clinical data in this field, these reflections are based on our Phase 1 experience only and are deemed to evolve and be enriched at a wider and international level in order to serve for the establishment of evidence-based guidelines.

Among retrospective studies that have reported series of patients with cancer and COVID-19 infection, the administration of an anticancer agent within 15 days prior to COVID-19 diagnosis has recurrently been identified as a risk factor for severe complications 1,2 . Several classes of investigational Phase 1 drugs could indeed influence the course of the COVID-19 infection. These include not only myelosuppressive agents, but also immune therapies -especially those interfering with the lymphoid cells function 3 , monocytes function 4 , or type I interferon response 5 -and epigenetic therapies (e.g. BET inhibitors that impact the hematopoietic cells differentiation and have anti-inflammatory properties 6, 7 ) . Drugs used to treat potential adverse events caused by immune therapies evaluated in Phase 1 trial could also interfere with the course of the COVID-19 infection, notably steroids, anti-IL-6 (tocilizumab, also used to treat the COVID-19-induced cytokine storm 8 ), anti-TNF therapies, or even potentially antibiotics -some of which are currently assessed in dedicated trials for potential therapeutic effects against the COVID-19 infection 9 . Therefore, the Phase 1 drug safety profile should be thoroughly considered in the decision of maintaining a COVID-19 positive patient on trial, and the investigational drug should be temporarily or permanently halted in case of any doubt of increased safety risk for the patient.

Two main phases can be distinguished within phase 1 trials. The first one is the dose-escalation phase, where the optimal dose is not yet established; in this phase, toxicities (and their causality) have to be thoroughly monitored and reported at each dose level; also, the Dose-Limiting Toxicity (DLT) period, which usually corresponds to the first cycle of treatment, is of crucial importance, as toxicities observed during this phase will guide the dose-escalation (or dose de-escalation) process. The second phase is the dose expansion phase, which aims at confirming that the dose determined during the dose-escalation phase is adequate. Although the monitoring of adverse events is still very important during this phase, the toxicity profile of the drug is usually, at least in part, already known, which makes the causality assessment of adverse events (AEs) and severe AEs (SAEs) potentially easier.

The screening and management of COVID-19-infection should therefore probably differ between these phases. Traditionally, patients with active severe infections or chronic viral infections (e.g. Hepatitis C or HIV) have been excluded from Phase 1 trials. We would suggest that any phase 1 candidate is screened for SARS-COV-2 using PCR prior to starting the experimental treatment, and that patients with a positive PCR are subsequently excluded from the trial, even if asymptomatic at the time of diagnosis. Indeed, considering the variety of clinical forms that can take the SARS-Cov-2 infection (including gastro-intestinal, cardiac, cutaneous, neurological, olfactive, psychiatric, thromboembolic, etc.), we can anticipate that it would be very difficult to precisely establish the etiology of (S)AEs in patients with an active infection. Even if the presence of a fever -observed in the majority of COVID-19 infected patients -could orientate towards an active infection, this causality establishment would remain extremely challenging for isolated biological findings such as elevated liver, pancreatic, muscle or cardiac enzymes; indeed, such asymptomatic enzyme elevations are regularly observed in phase 1 trials, are drug-related, but are most often deemed to be nonclinically significant; by contrast, such biological abnormalities could be important in the context of COVID-19 infection, as they have been reported to be associated with a worse outcome 3 . An inadequate causality assessment during the dose-escalation phase could lead to wrongly halting the drug's dose-escalation, which may have deleterious and irreversible consequences for subsequent drug development.

For these reasons, we would recommend screening weekly for SARS-Cov-2 PCR during the DLT period, and replacing patients who develop a clinical or biological (i.e. asymptomatic but PCRpositive) SARS-Cov-2 infection during the DLT period. Beyond the screening phase and the DLT period, we would suggest to perform a regular SARS-Cov-2 PCR, e.g. at the end of the DLT period and subsequently every four cycles and/or upon clinical symptoms. Patients who develop a COVID-19 infection after the DLT period or during the dose-expansion phase may stay on trial, as long as the treatments received for the management of the COVID-19 infection do not interfere with the Phase 1 drug metabolism (pharmacodynamics and pharmacokinetics) or efficacy, and criteria suggested below are met.

The COVID-19 infection may also have consequences affecting the Phase 1 treatment efficacy. For example, a significant proportion of phase 1 trials currently evaluate novel immune therapies (as monotherapy or as combinations with an anti-PD-(L)1 backbone), whose efficacy relies on the (re-)activation of a cytotoxic T-cell antitumor response. However, a key feature of the COVID-19 infection is lymphocytopenia, which is observed in more than 80% of the patients and whose severity correlates with worse prognosis 1-3 . Although intratumor lymphocytes may be a distinct population from peripheral circulating lymphocytes, we might hypothesize that such profound COVID-19induced lymphocytopenia may negatively impact on the efficacy of immune therapies aiming at triggering a T-cell based antitumor response. Similarly, the administration of steroids, such as dexamethasone, to treat severe forms of COVID-19 infections may negatively impact the efficacy of some anticancer immunotherapies 10 . Although theoretical at this stage, such elements should be considered for maintaining a patient on trial and for evaluating Phase 1 drugs' efficacy.

From a regulatory point of view and by law, a patient cannot be included in two different therapeutic interventional trials. Therefore, a patient with cancer that develops a COVID-19 infection could either be included in a Phase 1 cancer study or in a COVID-19-related investigational trial. Unless there is a strong rationale for including the patient in a Phase 1 trial (e.g. molecular alteration with a matched drug, positivity for a specific efficacy biomarker for a drug administered at the recommended phase 2 dose, etc.), the inclusion in a study evaluating treatments against COVID-19 should probably be favored, especially considering the current pandemic and emergency for identifying efficient therapeutic strategies. Once the COVID-19 infection has resolved, the Phase 1 trial could be proposed to the patient. Provisions may be envisioned in future Phase 1 cancer protocols to allow the inclusion of such patients earlier than the commonly requested 21-days symptoms-free window, as long as blood counts have recovered to levels that are compatible with the trial's inclusion criteria. Indeed, unnecessarily delaying a potentially efficacious anticancer treatment could also impact the long-term prognosis of the patient 11,12 .

In case an asymptomatic or non-severe COVID-19 infection is confirmed in a Phase 1 patient outside the DLT period, this patient could stay on trial in most cases. However, adjustments should be done whenever feasible until the patient has recovered clinically and biologically (i.e. presents a negative PCR), after discussion and approval of the trial sponsor, including: (i) minor deviations in order to limit hospital visits (e.g. pooling of laboratory testing, disease evaluations, biopsies, treatment administration and delivery, etc.); (ii) teleconsulting at increased frequency with the Phase 1 investigator, combined with regular home visits from the patient's local general practitioner and blood tests at a local facility, in order to thoroughly collect AEs and regularly check for signs of severe COVID-19 infection; (iii) treatment shipping to the patient's domicile; (iv) 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 AE; (v) stronger personal protection for the patient; (vi) active and regular reminder to strictly avoid any self-medication and over the counter drugs (notably non-steroidal anti-inflammatory drugs). In order to limit the risk of COVID-19 infection in Phase 1 patients, the patient and its household should also be regularly reminded of strictly respecting the self-protection measures, and be provided personal protection equipment whenever needed. During that period, the Drug Development Department (DITEP) continued its activity with the following measures: (i) all lung biopsies were canceled, in order to limit the risk of severe complications such as pneumothorax that would require access to the intensive care unit for pleural drainage or artificial ventilation; (ii) all patients were tested at least at C1D1 using rapid PCR; (iii) visits to the hospital were cancelled whenever feasible and teleconsultation was favored as well as treatment shipment at home, whenever feasible. Recommendations were given to patients, who were managed according to the guidelines presented in Table 1 .

Three patients who received bispecific agents and developed a cytokine release syndrome were successfully managed in our ward, in strong interaction with the Gustave Roussy intensive care unit. Rapid PCR tests identified four 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 on trial as he remained completely asymptomatic and did not develop ay AE; and two patients at later stages of the phase 1 trial (cycles 10 and 12) who required a treatment delay because of self-isolation. No COVID-19-related death occurred.

General hospitals and clinical trial units have shown a remarkable ability to rapidly adapt their routine practice to the COVID-19 outbreak, in order to be able to treat COVID-19-infected patients while maintaining some other essential activities for patients with life-threatening or severe chronic diseases. Maintaining such activity is indeed absolutely crucial for cancer patients, for which any treatment delay most often results in a loss-of-chance and worse outcome 12 .

Phase 1 trials are the most resource-consuming and complicated form of clinical trials, from a safety and organizational point of view, as they involve multiple hospital teams (clinical trial unit, pharmacy, interventional radiology, etc.), clinical research organizations and drug companies, and require intensive patient monitoring. During the peak of the pandemic in France, we successfully managed to maintain our drug development unit open and to treat patient without any additional delay, while not causing any nosocomial COVID-19 infection. However, treating COVID-19-infected patients in Phase 1 trials is not straightforward and specific precautions, described above, should be taken regarding their inclusion and management. The COVID-19 infection could indeed not only influence the patient safety, but also have consequences on the drug efficacy and the whole drug development process outcome.

As further waves of pandemic may re-occur, we need to be prepared and have specific management guidelines ready so that Phase 1 trials are minimally disrupted and patients remain optimally treated. We would therefore suggest to create an international registry and taskforce for Phase 1 patients infected with COVID-19 infections, so that various practices can be compared 14 

Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China

Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China

Clinical Characteristics of Coronavirus Disease 2019 in China

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

Type 1 interferons as a potential treatment against COVID-19

BET protein inhibition regulates cytokine production and promotes neuroprotection after spinal cord injury

Bromodomain inhibitor JQ1 reversibly blocks IFN-gamma production

Tocilizumab, an anti-IL6 receptor antibody, to treat Covid-19-related respiratory failure: a case report

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Encouraging Trends in Modern Phase 1 Oncology Trials

Colletaral damage: the impact on cancer outcomes of the COVID-19 pandemic

Outcome of cancer patients infected with COVID19, including toxicity of cancer treatments

Increased vulnerability of clinical research units during the COVID-19 crisis and their protection

Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co

Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Chugai Pharmaceutical Co

JCS was a full-time employee of Medimmune/Astra Zeneca from