NCI Combats COVID-19 Issues

Norman E. “Ned” Sharpless, MD

Investigation into the use of anticancer agents to treat patients with coronavirus disease 2019 (COVID-19), emphasis on clinical trial flexibility, and research in critical serology for increased understanding of the virus are just some of the initiatives taken by the National Cancer Institute (NCI) to help battle the pandemic, according to Norman E. “Ned” Sharpless, MD, the agency’s director.¹

As of early December 2020, nearly 70 million cases of COVID-19 and more than 1.4 million deaths from the disease have been reported worldwide, according to the World Health Organization.² In the United States, the CDC has recorded over 10 million cases, including over 250,000 deaths, since January 21, 2020.³

Investigators are working to understand the impact of a COVID-19 diagnosis on patients with cancer. NCI-designated cancer centers are among more than 120 institutions that are part of the COVID-19 and Cancer Consortium (CCC19), which collects and analyzes data on adult patients who have received a diagnosis of COVID-19 and have a history of cancer or who currently have an invasive solid tumor or hematologic malignancy.

The data have revealed factors associated with increased 30-day, all-cause mortality in patients with cancer and COVID-19: increased age, male sex, smoking status, treatment with hydroxychloroquine plus azithromycin versus treatment with neither, and 2 or more comorbidities requiring treatment. Results showed factors that are not associated with mortality such as race and ethnicity, obesity, type of malignancy, type and recency of anticancer treatment, and recent surgery (TABLE).⁴

The NCI has significant expertise…and a lot of external capabilities to do cutting-edge research in an emergency setting,” Sharpless said during a virtual meeting presentation. “As such, I think it was natural when the pandemic really got going that the NCI was asked to step in and help provide some scientific response.”

Model Projects the Impact of Care Disruptions

A modeling effort was performed earlier this year, and results were published in the June edition of Science. It utilized the NCI’s Cancer Intervention and Surveillance Monitoring Network (CISNET) to better understand cancer control interventions in terms of prevention, screening, and treatment, in addition to their impact on population trends in both incidence and mortality.⁵

“We asked the CISNET investigators to consider what we thought at that time were quite significant disruptions to cancer care, [in terms of] screening, diagnosis, and delayed therapy,” Sharpless said. “We asked [them to make] what we thought were significant assumptions about disruption of care [so we can gain some insight into] what would happen to cancer mortality over the next decade.”

Investigators looked specifically at breast and colorectal cancers because their CISNET models were advanced, Sharpless said. When analyzing the modeled cumulative excess deaths from these diseases from 2020 to 2030, investigators projected that there would be an excess of 10,000 deaths, or a 1% increase in mortality over the next decade, Sharpless said. The same disruptions are believed to be at play in other malignancies, as well.

“We feel that the assumptions we made about the disruptions to care, were, if anything, conservative estimates, and the disruptions that we’re actually seeing in hospitals across the country are greater than what we had predicted back then in June,” Sharpless said. “This is something that we all have to bear in mind. We need to share some collective responsibility [to determine] how to preserve the cancer care enterprise during a pandemic and ensure that we’re not exchanging one public health crisis for another.”

During the pandemic, data have indicated that there has been a decline in cancer screenings, diagnoses, and decreased or deferred care.6 These disruptions likely will have long-term implications for cancer mortality, Sharpless stressed. To combat this, the oncology community needed to come together to find safe, innovative ways to prioritize care for patients with cancer, he added.

“We don’t want our patients to be at risk for COVID-19, nor their caregivers; however, we need to get back to business,” Sharpless said.

NCI Takes Action

The NCI’s response to the pandemic includes repurposing anticancer drugs to treat COVID19, launching the NCI COVID-19 in Cancer Patients Study (NCCAPS), providing guidance and special procedures for clinical trials in the field of oncology, conducting serology research on SARS-CoV-2 (the virus that causes COVID19), and offering flexibility and opportunities to study participants.

Repurposing Cancer Drugs

Certain medications with activity in solid tumor and hematologic malignancies have also shown activity against symptoms of COVID-19.

The therapeutic benefit of leronlimab, which has gained traction with the FDA for the treatment of breast malignancies,7 had been demonstrated in patients with COVID-19 in the recent phase 2 CD10 trial (NCT04343651) for mild-to-moderate symptoms of COVID-19.⁸

“We have become very knowledgeable of leronlimab’s potential [in patients with COVID-19] due to our completed phase 2 trial for mild-to-moderate symptoms,” Nader Pourhassan, PhD, president and chief executive officer of CytoDyn, the company responsible for manufacturing the agent, said in a statement.

In November, a protocol had been filed with the FDA for a phase 2 clinical trial aimed to evaluate leronlimab as treatment of patients with COVID19 who are suffering from long-hauler symptoms. If successful, the treatment would be the first for patients experiencing lingering symptoms of the virus, who account for up to 10% of all patients with COVID-19.

Adapting Clinical Trial Efforts

During the pandemic, many laboratories had to close down, timelines for clinical trials were delayed, and adjustments were required to continue the investigation of potentially lifesaving drugs in patients who needed them most.

Recognizing the challenges posed by the pandemic with regard to clinical trials, the NCI collaborated with the FDA to provide flexibility for their supported efforts. For example, patient care now can be transferred to different participating study sites. Local health care providers are able to provide study activities to encourage the continuity of care. Oral drugs now may be shipped from the NCI and trial sites directly to the study participant to decrease unnecessary risk. Remote informed consent via telephone has become acceptable in conjunction with a patient signature on a written document.

“We know that this has been a successful [effort].

Accrual on NCI therapeutic trials has largely returned to normal…We have polled investigators and they really like some of these flexibilities,” Sharpless said. “This is, perhaps, the silver lining of the pandemic. We’ve learned how to do trials in the modern era of Zoom chat and telehealth. We won’t forget those lessons. Many of these flexibilities will be good for clinical trials going forward and will affect how the NCI does business even after the pandemic is [over].”

Collecting Data

NCCAPS (NCT04387656) is a longitudinal natural history study of COVID-19 in patients with cancer. Investigators are following patients and collecting relevant data to better understand how the virus and its symptoms develop and evolve.⁸ The trial’s goal is to help inform the future treatment decisions for patients with cancer who also receive a diagnosis of COVID19. The comprehensive data set will collect information on cancers, treatments, symptoms, course, recovery, and comorbidities with longitudinal follow-up.

In the study, investigators gather blood samples to estimate antibody response and genetic susceptibility. These samples also will be used for biomarker development. The trial has a projected enrollment of 2000 patients.

We launched this trial in about 6 weeks last spring, and it is now open at nearly 1000 sites in the United States. It has begun fairly robust accrual for patients with a history of cancer and COVID-19 infection,” Sharpless said. “We believe it will be very valuable to understand the biomarkers that predict bad outcomes in patients with cancer, as well as to understand the longitudinal history of this disease or the so-called long-haul COVID-19 conditions that we are now seeing in some patients.”

Joining Serology Research

In October 2020, the NCI launched the Serological Sciences Network (SeroNet) for COVID-19 with the goal of increasing the nation’s capacity for antibody testing and assisting the country’s research community to glean a better understanding of immune response to the virus.⁹

“The NCI has a long history in serology research, and it has a fantastic [laboratory] that does serology research for human papillomavirus vaccine response; it was one of the standard study labs for the World Health Organization and other international agencies,” Sharpless said. “When the pandemic began, we repurposed that lab to become a SARS-CoV-2 coronavirus lab….[We wanted to] create a network to increase capacity for coronavirus testing and serology testing in the United States.”

The agency expects SeroNet to engage more than 25 academic, government, and private sector biomedical research institutions in evaluating immune response to the virus as a means for producing rapid testing and developing novel therapeutics and vaccines. To assist this initiative, the United States Congress authorized $306 million for the NCI to develop, validate, improve, and apply serological testing and associated technologies, according to the NCI.

Staying Flexible on Research Grants

The NCI also has worked to provide certain flexibilities for grantees who experienced disruptions to their research efforts.

“This has been [a] hard [time] for trainees who need to move to the next stage of their training or [who need to] get a job,” Sharpless noted. “This has also been difficult for scientists whose [laboratories] have been closed or whose clinical research efforts have been put on pause. The NCI, along with the broader National Institutes of Health [NIH], has been trying to send the message to grantees that we are going to allow every possible flexibility during the pandemic so that research can get back to normal as quickly as possible.”

Some of the flexibilities offered by the NIH include extending deadlines for applications, permitting institutions to use NCI grant funds to maintain salaries and stipends, extending project timelines and reporting requirements, extending eligibility periods for early-stage investigators and trainees, and carrying over institutional training grants with previous approval.

_References:

_{1. Sharpless N. COVID-19: View from NCI. Presented at: 38th Annual CFS® virtual conference; November 4-6, 2020.}

_{2. Weekly epidemiological update – 1 December 2020. World Health Organization. Updated December 7, 2020. Accessed December 7, 2020. https://bit.ly/37LtWZy}

_{3. CDC COVID data tracker. Centers for Disease Control and Prevention. Updated November 5, 2020. Accessed November 5, 2020. https://bit.ly/2JwiYyD}

_{4. Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. 2020;395(10241):1907-1918. doi:10.1016/S0140-6736(20)31187-9}

_{5. Sharpless NE. COVID-19 and cancer. Science. 2020;368(6497):1290. doi:10.1126/science.abd3377}

_{6. Ducharme J, Barone E. How the COVID-19 pandemic has changed cancer care, in 4 charts. Time. August 28, 2020. Accessed November 5, 2020. https://bit.ly/350rmic}

_{7. CytoDyn’s first mTNBC patient in phase 1b/2 is in remission and oncologist ordered termination of treatment with carboplatin (chemotherapy drug) and remains on leronlimab only as monotherapy; patient’s testimony about her condition after nearly 6 months of leronlimab treatment is very strong. News release. CytoDyn, Inc. March 12, 2020. Accessed December 7, 2020. https://bit.ly/2VOiuqE}

_{8. Cytodyn Files Protocol with U.S. FDA for Phase 2 Clinical Trial for COVID-19 Patients with Long-Hauler Symptoms. News Release. CytoDyn Inc. November 17, 2020. Accessed December 7, 2020. https://bit.ly/2HuucTP}

_{9. NCI COVID-19 in Cancer Patients Study (NCCAPS). National Cancer Institute. May 21, 2020. Accessed November 5, 2020. https://bit.ly/3mX95sb}

_{10. NIH to launch the Serological Sciences Network for COVID-19, announce grant and contract awardees. News release. National Institutes of Health. October 8, 2020. Accessed November 5, 2020. https://bit.ly/3esNLrG}

_{11. Carolan A. Ned Sharpless: “Nothing will stop us”—NCI commemorates 50th anniversary of the National Cancer Act. The Cancer Letter. October 16, 2020. Accessed November 5, 2020. https://bit.ly/3l6ZUVQ}