Two Late-Stage Trials Test Novel PI3K Inhibitor in Non-Hodgkin Lymphoma

Copanlisib (BAY 80-6946), a novel PI3K inhibitor, is being combined with standard rituximab (Rituxan)-based regimens in patients with relapsed, indolent non-Hodgkin lymphoma (NHL) in 2 phase III clinical trials that investigators hope will expand treatment options in refractory disease settings, particularly with less toxic alternatives.

The clinical trials are continuing while the FDA reviews a new drug application for copanlisib as a treatment for patients with relapsed/refractory follicular lymphoma (FL), which is among several subtypes of CD20-positive NHL included in the late-stage trials. FL is the most common subtype of indolent NHL, accounting for about 22% of newly diagnosed cases.

RATIONALE

The FDA agreed on May 17 to review the application based on earlier clinical trial data under its priority review program, in which the agency is scheduled to decide within 6 months versus the standard 10-month review, according to Bayer, which is developing the drug.

The CHRONOS-3 trial is comparing the combination of copanlisib plus rituximab with rituximab plus placebo in patients with relapsed indolent B-cell NHL. The CHRONOS-4 trial is evaluating copanlisib with either rituximab plus bendamustine (Treanda) or with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) in a similar patient population.

“The trials are designed to give clear data about what will improve upon standards for treatment in these patient populations,” said John F. Gerecitano, MD, PhD, who is the global coprincipal investigator for both CHRONOS trials. The PI3K pathway, which regulates proliferation and survival in various cell types, has emerged as a promising target for anticancer therapy, particularly in hematologic malignancies. Copanlisib is a highly selective and potent pan-class I PI3K inhibitor, preferentially active against the alpha and delta isoforms. PI3K delta is expressed only in hematopoietic cells and has been shown to play a critical role in B-cell function, while expression of the alpha isoform is increased upon relapse and may be a factor in tumor escape mechanisms.

TRIAL DESIGN

In the CHRONOS-3 trial (NCT02367040), investigators are seeking to determine whether copanlisib in combination with rituximab is superior to rituximab with placebo in patients who have relapsed after 1 or more prior lines of rituximab-containing therapy.

The CHRONOS-4 trial (NCT02626455) is investigating whether copanlisib in combination with standard immunochemotherapy is effective and safe compared with placebo in combination with standard immunochemotherapy.

WHO IS ELIGIBLE?

In the CHRONOS-3 trial, an estimated 567 patients will be randomized in a 2:1 ratio to either the combination copanlisib and rituximab arm or the rituximab and placebo arm.

The trial is enrolling patients with a histologically confirmed diagnosis of relapsed, CD20-positive indolent B-cell NHL and an Eastern Cooperative Oncology Group performance status less than or equal to 2. There can be no known lymphomatous involvement of the central nervous system. Patients cannot have documented evidence of resistance to prior treatment with idelalisib or other PI3K inhibitors.

In CHRONOS-4, an estimated 676 patients will be stratified into 2 groups based on prior treatment, with the first group consisting of patients who have previously received R-CHOP or R-CVP (rituximab plus cyclophosphamide, vincristine, and prednisone) and the second group made up of participants who have received rituximab plus bendamustine (RB). Patients will also be stratified based on NHL histology (FL vs other indolent NHL) and duration of treatment-free interval (6-12 months vs >12 months). Participants in the first group will then be randomized 1:1 to receive either copanlisib plus RB or placebo plus RB. Those in the second group will be randomized to either copanlisib plus R-CHOP or placebo plus R-CHOP. The trial is open to patients who have relapsed after 1 or more prior lines of therapy, including those who have received rituximab and alkylating agents. Notably, patients who may have had previous exposure to PI3K inhibitors also are eligible, provided there is no documented resistance. There must also be no evidence of resistance to rituximab at any line of therapy.