A Novel Cytoreductive Treatment for NETs

A Novel Cytoreductive Treatment for NETs
Phase 2 trial will test combination of cabozantinib and CB-839.

A phase 2 clinical trial funded by the Neuroendocrine Tumor Research Foundation will assess the efficacy of cabozantinib in combination with a glutaminase inhibitor, CB-839, as a cytoreductive treatment for small intestinal and pancreatic neuroendocrine tumors (NETs).

“Many of the therapies that have been developed over the last five to 10 years for the treatment of neuroendocrine tumors are cytostatic, meaning they slow tumor growth or freeze tumor growth, but they do not actually cause tumor regression. That’s a huge, huge problem,” said Satya Das, M.D., lead investigator on the grant and assistant professor of medicine at Vanderbilt University Medical Center.

Das notes there are two treatments currently being used to shrink NETs. One is a chemotherapy combination involving capecitabine and temozolomide. The other is a form of radiation treatment, peptide receptor radionuclide therapy (PRRT). “But again, even after these treatments, many patients have significant bulk of disease,” he explained.

Cabozantinib and CB-839

Cabozantinib is a tyrosine kinase inhibitor that blocks the vascular endothelial growth factor (VEGF) pathway, which many NETs rely on to promote tumorigenesis.

“The backbone of the new trial is the fact that cabozantinib, as a single agent, has already demonstrated impressive activity,” Das said. Results from a 2017 phase 2 study found cabozantinib caused tumor regression in about 15 percent of NETs. “This is a major improvement on the three to five percent regression we are used to seeing.”

CB-839 is a glutaminase inhibitor that prevents the conversion of glutamine to glutamate. “It turns out that a lot of these neuroendocrine tumors that rely on the VEGF pathway require huge amounts of glutamate to power themselves,” Das explained. “By stopping the conversion of glutamine to glutamate, we’re starving the tumors from a key energy-utilizing modality.”

“We’re starving the tumors from a key energy-utilizing modality.”

The combination treatment has shown early effectiveness for the treatment of renal cell cancer, which is a similar vascular tumor to NETs, prompting an ongoing phase 2 trial. In addition, preclinical data indicate that glutamate depletion in cell culture models is effective at inhibiting tumor cell growth.

Details of the Trial

The single-arm study will compare response rates and progression-free survival to data from the 2017 phase 2 study of cabozantinib. Patients will receive cabozantinib at a starting dose of 60 mg once a day and CB-839 at a starting dose of 800 mg twice a day in 28-day cycles.

Das expects that 37 patients will be enrolled. The study incorporates a two-stage design, requiring at least three responses to be seen in stage one before moving to stage two. Participants will include patients with grade 1, 2 or 3 well-differentiated pancreatic or small-intestinal NETs and progressive disease on one prior treatment regimen, excluding PRRT.

Das says the inclusion of patients with grade 3 tumors is a novelty of the study. “Patients with grade 3 NETs have been excluded from most clinical trials. No one knows how to categorize them. We are including them because we think this combination treatment may be better at shrinking fast-growing tumors than slower-growing tumors.”

To evaluate predictors of patient response, Das and colleagues will assess gene expression in tumor biopsies and imaging from PET scans. “Cancer cells are incredibly resourceful, and there’s not just one metabolic path to glutamate,” Das said. “What we anticipate is that tumor cells that have glutamine-independent glutamate production, and thereby high glutamate stores, will not respond as well to this combination compared to the tumors that are dependent on glutamine.”

The glutamine and glutamate PET tracers to be used in the study were developed in collaboration with Charles Manning, Ph.D., Vanderbilt-Ingram Cancer Center Director of Cancer Imaging Research.

Future Studies

The study aims to achieve a 30 percent response rate. “If this study is successful and meets its efficacy goal – which is a lofty goal, we’re trying to double response rate – that would automatically make this combination the most or second most cytoreductive option available for NET patients,” Das said.

If successful, Das is interested in comparing the cabozantinib plus CB-839 combination treatment to other active single agents in a subsequent randomized study. Das says the hunt for predictors of patient response may identify a subpopulation of patients for which the combination treatment is uniquely effective, informing a future trial.