Dosing Begins in Study of TP-0903, With or Without Imbruvica, for Advanced CLL and SLL

Dosing with the investigational therapy TP-0903 has begun in patients with previously treated chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in an ongoing Phase 1/2 trial, its developer, Tolero Pharmaceuticals, announced.

The open-label study (NCT03572634) aims to recruit 108 patients who have failed to respond to prior therapies. Enrollment is underway at the six sites in the U.S.; information is available here.

Participants will be assigned to oral TP-0903 either alone (group 1) or combined with Imbruvica (ibrutinib) (group 2).

Those intolerant of, or unresponsive to, treatment with inhibitors of the B cell receptor (BCR) pathway (like Imbruvica) or B-cell lymphoma-2 (BCL-2) inhibitors will be included in group 1. Group 2 will include patients whose disease progressed despite treatment with Imbruvica, and who may respond better when Imbruvica is given in combination with TP-0903.

In a first part of the trial, each group will receive escalating doses of oral TP-0903. In the monotherapy group 1, patients will start with a 25 mg dose administered orally once daily for cycles of 28 days, until a maximum-tolerable dose is reached; in the combo therapy group 2, they will start with 20 mg of TP-0903 in a similar administration regimen, with Imbruvica given at the dose used before the trial.

The primary goal is to determine the safety of escalating doses of TP-0903, and the optimal dose that will then be further tested in the trial’s second part. Researchers in Phase 1 will also determine the therapy’s processing and stability inside the body (pharmacokinetics).

In Phase 2, participants will continue to take oral TP-0903 either alone and n combination with Imbruvica as before. The primary goal here is to determine patients’ response rate to the treatments. Secondary goals include duration of response and overall survival.

“Although there have been significant advances in the treatment of CLL and SLL in recent years, there remains an area of clinical unmet need for patients who have had disease progression or relapse with available therapies,” David J. Bearss, PhD, CEO of Tolero Pharmaceuticals, said in a press release.

TP-0903 is an investigational oral inhibitor of AXL, a receptor tyrosine kinase (RTK) that is found at high levels in several cancers. Its signaling promotes cancer cell survival, proliferation, migration, and invasion. AXL is also known to promote tumor resistance to chemotherapy.

In vitro (in the lab) studies showed that TP-0903 can halt the transition of cancer cells into an invasive state, and sensitize these cells to other anti-cancer therapies.

“The initiation of this study will allow us to learn more about the clinical profile of TP-0903 and the role of AXL receptor tyrosine kinase (RTK) inhibition in patients with previously treated CLL and SLL,” Bearss added.

Tolero is also conducting a Phase 1b study to assess the safety and efficacy of TP-0903 in patients with advanced solid tumors (NCT02729298), including non-small cell lung cancer, colorectal cancer, recurrent ovarian cancer, and BRAF-mutated melanoma. The trial is also enrolling at sites across the U.S.; more information is available here.