Trial of Pembrolizumab for HIV-Positive Patients with Recurrent or Refractory Cancer
Name of the Trial
Pembrolizumab in Treating Patients with HIV and Relapsed, Refractory, or Disseminated Malignant Neoplasms (NCI-16-C-0066; CITN-12). See the protocol summary.
Dr. Thomas Uldrick, NCI Center for Cancer Research
Why This Trial Is Important
Antiretroviral therapy has increased the lifespans of people infected with human immunodeficiency virus (HIV). In fact, many HIV-positive individuals are now living as long as those who have not been infected with the virus. Although longer lifespans represent a triumph of medical research, living longer also means that more and more HIV-positive people are developing cancers, including those not associated with HIV infection. Cancer is now the leading cause of morbidity and mortality among people with HIV.
Clinical trials of new cancer treatments often exclude people with HIV, citing concerns about drug interactions or immunodeficiency. Therefore, how to extend the latest advances in cancer care to HIV-positive patients remains an important area of cancer research. NCI recommends that HIV-positive patients be included in clinical trials, unless there is a specific reason they need to be excluded. Additionally, cancer studies specific to people with HIV remain important and offer opportunities to evaluate the effect of some cancer agents on HIV infection itself.
NCI’s HIV and AIDS Malignancy Branch is collaborating with the Cancer Immunotherapy Trials Network to conduct a phase I clinical trial of pembrolizumab (Keytruda®) in HIV-positive patients with a variety of recurrent or refractory cancers. Pembrolizumab is an immune checkpoint inhibitor that targets a protein on cytotoxic T lymphocytes called PD-1. Cancer cells often express another protein called PD-L1 that binds to PD-1. The interaction of these two molecules causes T-cell inactivation in the tumor microenvironment, thereby allowing the cancer cells to escape immune attack. Blocking the interaction of PD-1 and PD-L1 with pembrolizumab leads to increased T-cell activity against cancer cells in the tumor microenvironment.
“Checkpoint inhibition may be a useful way to treat a variety of cancers in people with HIV because increased expression of PD-1 is associated with HIV infection itself,” said Dr. Thomas Uldrick, the trial’s principal investigator. Furthermore, many of the cancers commonly seen in people with HIV, such as lung cancer and Hodgkin lymphoma, can be effectively treated with drugs like pembrolizumab in people without HIV.
“However, evaluation of checkpoint inhibitors has never been studied in people with both HIV and cancer.” The use of checkpoint inhibitors in people with HIV requires specific safety evaluation because they may have a range of immune dysfunction, commonly assessed by CD4-positive T-lymphocyte counts, depending on when they started their antiretroviral therapy.
“Consequently, there could be immune-related side effects that might be specific to this patient population. So it’s important that we evaluate the safety of these drugs in people with HIV across a range of CD4-positive T-cell counts,” Dr. Uldrick explained.
“Our hypothesis is that treatment with pembrolizumab will be safe and well-tolerated in people with HIV using treatment strategies that are used in the general population,” he said.
In this trial, HIV-positive patients receiving combination antiretroviral therapy who have cancer that has recurred after or has not responded to previous treatment will receive intravenous pembrolizumab every 3 weeks until either their disease progresses or they experience unacceptable side effects. Treatment may continue for up to 2 years.
Participating patients will be grouped into three cohorts based on their degree of immune dysfunction. Immune dysfunction will be determined by CD4-positive T-cell counts, with patients being classified as having moderate (100-199 CD4+ T cells/microliter [mcL] blood) or mild (200-350 CD4+ T cells/mcL blood) immune dysfunction or relatively normal (greater than 350 CD4+ T cells/mcL blood) immune function. Doctors will monitor the safety and try to determine the efficacy of pembrolizumab treatment in patients taking part in the study.
In addition to cancer endpoints, the researchers will also look at HIV-specific endpoints. “We are working with other HIV researchers to conduct correlative studies looking at questions related to the reservoir of latent HIV in the body and improving immune system function against HIV with the use of pembrolizumab,” Dr. Uldrick said