Intratumoral Injection of Cisplatin and Vinblastine, with or without Pembrolizumab, Improves Intracellular Transport in Patients with Advanced Solid Tumors

August 2020 Vol 13, Special Issue - Emerging Therapies
Chase Doyle
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A novel intratumoral chemotherapy agent delivered by direct injection permits the dispersion of cytotoxic drugs into cancer cells to eradicate tumors. Data from a phase 1/2 trial of intratumoral INT230-6, alone and in combination with pembrolizumab (Keytruda), in patients with advanced solid tumors was presented at the ASCO 2020 virtual annual meeting by Jacob Stephen Thomas, MD, Assistant Professor of Clinical Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles.

“INT230-6 is composed of cisplatin, vinblastine, and an amphiphilic cell-penetration excipient small molecule that improves intracellular transport and tissue dispersion by passive diffusion,” said Dr Thomas. “When cytotoxic agents alone are administered, the majority of the drug leaks out of the tumor. In contrast, the novel INT230-6 formulation enables cytotoxic drugs to disperse and stay within the tumor, which has resulted in prolonged disease control in several patients with different tumor types,” said Dr Thomas.

“When INT230-6 is injected, little to no drug leaks out of the tumor, and on bisection, the drug disperses equally throughout the tumor,” said Dr Thomas. “Histologically, we see significant cytotoxic effects with this agent, and preclinical experiments have shown strong synergy with a PD-1 antibody.”

Furthermore, “The treatment has been well tolerated both as monotherapy and in combination with pembrolizumab,” he added.

Dr Thomas and colleagues enrolled patients with solid tumors that had progressed with standard treatment. A significant proportion of patients had received previous treatment with platinum, as well as with a PD-1 inhibitor. The median number of previous therapies was 3, with a maximum of 10 therapies.

The dose of INT230-6 was set by tumor volume, and dose escalation was done by increasing the number of tumors injected, loading per tumor, and total dose. Pembrolizumab was also combined with INT230-6 in a separate arm of the study. Patients were monitored for safety weekly while receiving INT230-6, and blood and tumors were assessed for pharmacokinetics and pharmacodynamics.

At the time of the data cutoff, 59 patients with highly refractory disease had been recruited, including 52 in the monotherapy cohort and 7 in the combination arm with pembrolizumab. A total of 13 patients with highly refractory tumors have had disease stabilization for >6 months, and 10 patients had some size reduction of ≥1 noninjected lesions in the lymph nodes, liver, lung, perineum, and retroperitoneal areas.

“There’s evidence of preliminary efficacy with INT230-6. We see prolonged disease control in several patients with different tumor types,” Dr Thomas said.

Pharmacokinetics have been favorable. Intratumoral dosing of INT230-6 with an equivalent of 10 mg of vinblastine led to approximately 5% systemic absorption when compared with a historic control.

Adverse Events

When INT230-6 was given as monotherapy, patients had relatively few grade 3 adverse events and no grade 4 adverse events.

“The most common treatment-related adverse event was localized pain at the injection site, which is typically transient and managed well with supportive care and pain medications,” said Dr Thomas.

INT230-6 in combination with pembrolizumab was similarly well-tolerated. The most common adverse event was localized pain, and no dose-limiting toxicities have been observed to date.

In patients responding to injection of INT230-6, investigators observed systemic increases of CD4-positive and CD8-positive T-cells compared with nonresponding patients, suggesting systemic immune-cell activation.

The study continues to enroll patients in the INT230-6 monotherapy cohort, as well as in the cohort of INT230-6 in combination with pembrolizumab. In addition, a cohort receiving INT230-6 in combination with ipilimumab (Yervoy) is planned to open soon, said Dr Thomas.

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