A phase II study of the PI3K inhibitor copanlisib in combination with the anti-CD20 monoclonal antibody rituximab for patients with marginal zone lymphoma: treatment rationale and protocol design of the COUP-1 trial

Alexander Grunenberg, Lisa M Kaiser, Stephanie Woelfle, Birgit Schmelzle, Andreas Viardot, Peter Möller, Thomas F E Barth, Rainer Muche, Jens Dreyhaupt, Markus Raderer, Barbara Kiesewetter, Christian Buske, Alexander Grunenberg, Lisa M Kaiser, Stephanie Woelfle, Birgit Schmelzle, Andreas Viardot, Peter Möller, Thomas F E Barth, Rainer Muche, Jens Dreyhaupt, Markus Raderer, Barbara Kiesewetter, Christian Buske

Abstract

Background: Advanced stage marginal zone lymphoma (MZL) is an incurable indolent B-cell lymphoma, for which a wide variety of treatments ranging from single agent rituximab to more dose intense immunochemotherapy exists. One of the major goals in this palliative setting is to develop chemotherapy-free treatments, which approach the efficacy of immunochemotherapies, but avoid chemotherapy associated toxicity in this often elderly patient population. The PI3K inhibitor copanlisib has recently shown remarkable clinical activity in refractory or relapsed indolent B-cell lymphomas, among them MZL. Based on these data, copanlisib monotherapy was granted breakthrough designation by the FDA for the treatment of adult patients with relapsed marginal zone lymphoma who have received at least two prior therapies. However, data are still limited in particular for MZL. Based on this, the COUP-1 trial aims at testing the toxicity and efficacy of copanlisib in combination with rituximab in treatment naive and relapsed MZL.

Methods: COUP-1 is a prospective, multicenter, single-arm, open-label, non-randomized phase II trial of 6 cycles (28 days cycle) of copanlisib (60 mg intravenous day 1, 8, 15) and rituximab (375 mg/m2 intravenous day 1) in the induction phase followed by a maintenance phase of copanlisib (d1, d15 every 4 weeks for a maximum of 12 cycles) and rituximab (d1 every 8 weeks for a maximum of 12 cycles) in patients aged ≥18 years with previously untreated or relapsed MZL in need of treatment. A total of 56 patients are to be enrolled. Primary endpoint is the complete response (CR) rate determined 12 months after start of induction therapy. Secondary endpoints include the overall response (OR) rate, progression free survival (PFS), overall survival (OS), safety and patient related outcome with quality of life. The study includes a translational bio-sampling program with the prospect to measure minimal residual disease. The study was initiated in November 2019.

Discussion: The COUP-1 trial evaluates the efficacy and toxicity of the treatment of copanlisib in combination with rituximab in patients with MZL and additionally offers the chance for translational research in this heterogenous type of lymphoma.

Trial registration: ClinicalTrials.gov : NCT03474744 . Registration date: 03/23/2018.

Keywords: Copanlisib; Marginal zone lymphoma; PI3K inhibitor; Rituximab.

Conflict of interest statement

Copanlisib and Rituximab are provided by Bayer AG and Celltrion Healthcare. The authors declare no conflicts of interest. The study was not externally reviewed. The authors have no financial relationship with Bayer AG or Celltrion Healthcare.

Figures

Fig. 1
Fig. 1
PI3K signaling pathway in physiological and malignant B-cells. PI3K activity is regulated in both a B-cell receptor (BCR) and receptor tyrosine kinase (RTK) mode. Upon RTK stimulation PI3K catalyses phosphatidylinositol 4,5-bisphosphonate (PIP2) to generate phosphatidylinositol 3,4,5-triphosphate (PIP3), resulting in recruitment of AKT (Protein kinase B) and activation of the mTOR (mechanistic target of rapamycin) pathway. On the other hand, BCR stimulation leads to the recruitment of BTK (bruton tyrosine kinase) via PIP3 with downstream activation of the MAPK (mitogen-activated protein kinase) and NFĸB (nuclear factor ‘kappa-light-chain-enhancer’ of activated B-cells) signaling pathway. Pathological triggering of both signaling pathways eventually results in increased proliferation and survival advantage of the B-cell. MZL = marginal zone lymphoma, Syk = spleen tyrosine kinase, Lyn = kinase
Fig. 2
Fig. 2
Trial design. i.v. = intravenous
Fig. 3
Fig. 3
Timeline of biomarker analyses of the COUP-1 trial

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