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

Ariela Katz
Published: Friday, Jun 16, 2017
John F. Gerecitano,

John F. Gerecitano, MD, PhD

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.1

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 (Figure 1). The CHRONOS-4 trial is evaluating copanlisib with either rituximab plus bendamustine (Treanda) or with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; Figure 2) 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 co-principal investigator for both CHRONOS trials.

Although advances in immuno-chemotherapy have led to improvement in the prognosis for patients with NHL, relapsed and refractory disease is still a challenge to treat successfully. “These patients require lifelong intermittent therapies for their disease, since these are incurable diagnoses, and we’re trying to develop more targeted agents that will be less toxic than traditional cytotoxic chemotherapies,” said Gerecitano, clinical director of Outpatient Lymphoma Services at Memorial Sloan Kettering Cancer Center and assistant professor of medicine at Cornell Weill Medical College, both in New York City.

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.2 Copanlisib is a highly selective and potent pan-class I PI3K inhibitor, preferentially active against the alpha and delta isoforms.2 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.2,3

CHRONOS Trial Details

The CHRONOS-3 and CHRONOS-4 trials are both open to patients with the indolent NHL subtypes of FL grades 1 to 3a, small lymphocytic leukemia (SLL), lymphoplasmacytoid lymphoma (LHL)/ Waldenström macroglobulinemia (WM), and marginal zone lymphoma (MZL). Patients with a histologically confirmed diagnosis of FL grade 3b, disease transformation, or chronic lymphocytic leukemia are excluded.

In 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. 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.

Prior to treatment, blood samples will be collected for safety and pharmacokinetic analyses. Archival tumor tissue and blood samples will also be collected for biomarker analysis and central pathology review. The primary endpoint is progression- free survival (PFS); secondary endpoints are objective tumor response, duration of response (DOR), overall survival (OS), complete response, and time to disease progression. The investigators will also be assessing the safety and tolerability of the combination.

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