Phase II Trial Evaluates Safety of Pembrolizumab plus SurVaxM in Recurrent Glioblastoma

Cleveland Clinic researchers are testing a novel immunotherapy/cancer vaccine combination in patients with recurrent glioblastoma, in hopes of finding an effective treatment for a condition with poor survival outcomes and a shortage of viable therapeutic options.

The phase II clinical trial, which is currently enrolling, will evaluate the combination of pembrolizumab and SurVaxM in glioblastoma patients experiencing their first recurrence, either with or without prior immunotherapy. The researchers described the trial’s design and methodology in a presentation at the American Society of Clinical Oncology’s virtual 2020 scientific program.

“Glioblastoma is the most common type of malignant brain tumor in the United Sates — each year, 12,000 to 15,000 patients are diagnosed with the disease,” says principal investigator Manmeet Ahluwalia, MD, Associate Director of Cleveland Clinic’s Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center and Director of the Brain Metastasis Research Program. “Despite the advances in treatment with surgery, radiation and chemotherapy, the outcomes are fairly dismal, and most patients survive an average of 15 to 16 months.”

Glioblastoma’s infiltrative growth and the profoundly immunosuppressive tumor microenvironment complicate treatment and contribute to recurrence. Progression-free survival at six months after first recurrence is approximately 15%.

No Food and Drug Administration (FDA)-approved immunotherapy for GBM exists. “The role of immunotherapy in glioblastoma is still undergoing evaluation,” Dr. Ahluwalia says. “So far, single-modality immunotherapy approaches have not shown any benefit.”

Pembrolizumab is an immune checkpoint inhibitor (ICI) targeting the programmed cell death 1 (PD-1) receptor. It has shown clinical efficacy in several cancers and is under investigation for additional indications.

SurVaxM is a cancer vaccine consisting of a 15-amino acid antigenic peptide that targets survivin, a cell-survival protein present in many cancers that aids resistance to conventional treatments. SurVaxM stimulates the immune system to kill tumor cells containing survivin. The vaccine was developed at Roswell Park Comprehensive Cancer Center and awarded orphan drug status by the FDA in 2017 for glioblastoma treatment.

Overcoming the immunosuppressive tumor environment

Several previous trials have tested the efficacy of various immunotherapies in recurrent glioblastoma, namely nivolumab monotherapy vs. the anti-vascular endothelial growth factor antibody bevacizumab (CheckMate-143); pembrolizumab monotherapy (KEYNOTE-028); and a recombinant nonpathogenic polio–rhinovirus chimera.

Dr. Ahluwalia explains that the current Cleveland Clinic trial was prompted by previous phase I and II studies demonstrating the tolerability of SurVaxM in patients with glioblastoma.

In addition, a previous phase II multicenter trial of SurVaxM combined with chemotherapy (sargramostim) and radiation conducted in 63 patients with newly diagnosed glioblastoma demonstrated progression-free survival (PFS) and overall survival (OS) benefits.

“The OS [in the SurVaxM/sargramostim/radiation trial] was 26 months, which appears promising compared to the benchmark of 16 or so months,” says Dr. Ahluwalia, who served as the co-principal investigator.

By adding pembrolizumab to SurVaxM in the current glioblastoma study, Dr. Ahluwalia and his collaborators are hoping to achieve longer PFS in patients whose disease has returned after initial therapy.

“We are using the vaccine as a means to increase T cells to incite the immune response, and combining it with an ICI to see if a dual-immunotherapy approach will be more successful than a monotherapy approach,” he says.

Unlike lung cancer and melanoma, which are immunogenic and respond well to immunotherapy, glioblastoma and prostate cancer are considered “cold tumors” because they lack an inherent immunogenic component, explains Dr. Ahluwalia. Cold tumors are traditionally more difficult to target with immunotherapy.

“In glioblastoma in particular, there are not enough T cells in the tumor and the tumor is very immunosuppressive,” he says. “The vaccine acts by inducing the immune response in two ways: one is through T cell engagement and the other is through antibodies — we believe it induces antibody-driven tumor cytotoxicity.”

Focusing on patients with recurrent disease and limited treatment options

The trial is enrolling participants at Cleveland Clinic in two treatment arms:

• Arm A consists of 41 patients who have failed prior chemotherapy and radiation but were not treated with immunotherapy and are experiencing first recurrence.
• Arm B is an exploratory arm consisting of 10 patients who have failed prior treatment with an anti-PD1 agent.

“The 10-patient Arm B cohort is examining whether the combination of vaccine and anti-PD1 will be effective in patients who have progressed on anti-PD1,” says Dr. Ahluwalia. For the Arm A cohort, a safety/toxicity evaluation will be performed on the first 10 patients before enrolling the remaining 31 patients.

Enrollment criteria include:

• A diagnosis of glioblastoma.
• Age 18 years or older.
• Previous first-line treatment with at least radiotherapy with or without temozolomide.
• Documented first recurrence.
• Karnofsky performance status of 70.
• Normal organ function.

The trial’s primary endpoint is progression-free survival at 6 months, using Response Assessment in Neuro-oncology (RANO) criteria. Secondary endpoints include safety and tolerability, response rate, OS and PFS. Exploratory endpoints include measuring cellular and humoral immune responses during administration of pembrolizumab and SurVaxM. Patient enrollment is projected to conclude by late 2020 or early 2021.

Disclosure: Dr. Ahluwalia has stock options with MimiVax, the developer of SurVaxM.