The trial, so far being conducted at the Sarah Cannon Research Institute at Tennessee Oncology, is including patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin’s lymphomas (NHL), who received at least two prior lines of therapy.
BTK, short for Bruton’s tyrosine kinase, plays a key role in the survival and proliferation of healthy and malignant B-cells — the cells involved in some CLL/SLL and NHL lymphomas. Inhibiting this protein stops B-cell cancers from growing, which led to the approval of two BTK inhibitors in the U.S. — Imbruvica (ibrutinib) and Calquence (acalabrutinib).
While effective in the short-term, most patients either become resistant — most commonly by acquiring a mutation in BTK, usually the C481 mutation, that renders these inhibitors ineffective — or develop intolerance, due to the binding of BTK inhibitors to other, off-target molecules.
Therefore, Loxo developed LOXO-305 to bind BTK in the presence of the C481 mutation, thus reversing a patient’s acquired resistance, and also to be more selective and avoid binding to other proteins.
“FDA-approved BTK inhibitors, which all covalently (irreversibly) bind to their targets, have meaningfully improved the lives of patients with certain B-cell leukemias and lymphomas. However, we are now learning that many patients are discontinuing these therapies due to disease progression or intolerance,” Bilenker stated.
“When disease progression is caused by a resistance mechanism known as a C481 mutation, we believe that LOXO-305 has the potential to re-induce a response in affected patients. We also believe that the selectivity profile of LOXO-305 has the potential to avoid certain side effects. We look forward to working with our clinical investigators to determine whether LOXO-305 can deliver against these exciting possibilities,” he added.
In the first human trial of LOXO-305, the company is including patients with CLL/SLL and NHL who failed (did not respond to approved BTK inhibitors, or progressed after responding), or were intolerant of approved BTK inhibitors to determine LOXO-305’s safety and efficacy.
The trial runs in 2 phases. In Phase 1, patients will receive ascending doses of LOXO-305 to determine the maximum dose tolerated by patients, and a recommended dose for further testing. Researchers will also assess safety, preliminary indicators of anti-tumor activity, and determine how the medicine behaves from the moment it is administered, up to the point it is completely eliminated from the body.
In Phase 2, researchers will enroll patients in one of six groups. Group 1 will include CLL/SLL patients who failed a prior BTK inhibitor, and have the C481 mutation. Group 2 will include CLL/SLL patients who failed a prior BTK inhibitor, but do not have the mutation. Groups 3 and 4 will include NHL patients (particularly those with Waldenstrom’s macroglobulinemia, mantle cell lymphoma, or marginal zone lymphoma), who failed a prior BTK inhibitor, and have (group 3) or don’t have (group 4) the C481 mutation.
Group 5 will include CLL/SLL or NHL patients who were intolerant to an approved BTK inhibitor. Finally, group 6 will include CLL/SLL or NHL patients who failed a prior BTK inhibitor but whose C481 mutation status is unknown, or other patients — including patients with other kinds of NHL — who do not meet the criteria for any of the other groups.
In this part of the trial, the researchers seek to determine the proportion of patients who respond to the LOXO-305. Secondary objectives include finding the duration of patient response, time to disease progression or death, and overall survival.