Deciphera starts new study of rebastinib in solid tumors

Deciphera Pharmaceuticals has initiated an open-label, multicenter, phase 1b/2 study of rebastinib, the company’s investigational small molecule switch control inhibitor of TIE2 kinase, in combination with carboplatin in patients with advanced or metastatic solid tumors.

Deciphera president and CEO Dr Michael Taylor said: “We are extremely pleased with the recent progress made on our rebastinib program, including today’s announcement that we have initiated a second Phase 1b/2 clinical study of rebastinib in combination with chemotherapy.

“This second clinical study will evaluate rebastinib in combination with carboplatin, a treatment regimen that, based on preclinical observations, we believe has the potential to be an important new approach to treating patients with advanced solid tumors.”

Part 1 (3+3 dose escalation) of this two part study is designed to evaluate the safety, tolerability and pharmacokinetics of 50 mg and 100 mg rebastinib twice daily (BID) when administered in combination with carboplatin, and to determine the recommended phase 2 dose (RP2D) of rebastinib in combination with carboplatin, in patients with advanced or metastatic solid tumors that are refractory to standard therapies.

In part 2, the safety, tolerability and efficacy of the RP2D of rebastinib in combination with carboplatin administered once every 3 weeks will be assessed across multiple disease cohorts, including: breast cancer, ovarian cancer, and mesothelioma.

This trial is expected to enroll up to 117 patients in total, with approximately 18 patients in part 1 and up to 99 patients in part 2.

Deciphera chief scientific officer Dr Daniel Flynn said: “The biological mechanisms by which tumors co-opt the surrounding microenvironment to grow, survive and become more invasive, are becoming better understood.

“Recent research indicates that TIE2 kinase is involved in multiple mechanisms favoring a pro-tumoral microenvironment, including the regulation of a population of immunosuppressive macrophages, promotion of tumor angiogenesis, and function of perivascular pumps that lead to tumor cell recruitment and metastasis.”

In addition, use of chemotherapeutic agents are believed to enhance the recruitment of these macrophages, leading to increased tumor vascularization and dissemination. In preclinical studies rebastinib has been shown to block these unintended effects of chemotherapy, providing rationale for the potential combination of rebastinib with chemotherapy.”

Rebastinib is an investigational, orally administered, potent and selective inhibitor of the TIE2 kinase, the receptor for angiopoietins, an important family of vascular growth factors in the tumor microenvironment that also activate pro-tumoral TIE2 expressing macrophages. In a Phase 1 clinical study, biomarker data have demonstrated rebastinib-induced increases in the TIE2 ligand angiopoietin 2, secondary to TIE2 inhibition.

Rebastinib is currently being evaluated in a Phase 1b/2 clinical study in combination with paclitaxel (NCT03601897), in a Phase 1b/2 clinical study in combination with carboplatin (NCT03717415), and in an investigator sponsored Phase 1b trial in patients with metastatic breast cancer in combination with paclitaxel or eribulin (NCT02824575).

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