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Clinical Trial
. 2021 Nov;21(11):e886-e894.
doi: 10.1016/j.clml.2021.06.021. Epub 2021 Jul 2.

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma

Matthew J Matasar  1 , Martin Dreyling  2 , Sirpa Leppä  3 , Armando Santoro  4 , Michael Pedersen  5 , Viktoriya Buvaylo  6 , Monique Fletcher  7 , Barrett H Childs  6 , Pier Luigi Zinzani  8
Affiliations
Clinical Trial

Feasibility of Combining the Phosphatidylinositol 3-Kinase Inhibitor Copanlisib With Rituximab-Based Immunochemotherapy in Patients With Relapsed Indolent B-cell Lymphoma

Matthew J Matasar et al. Clin Lymphoma Myeloma Leuk. 2021 Nov.

Abstract

Background: When treating indolent B-cell lymphoma, combining continuously administered oral phosphatidylinositol 3-kinase (PI3K) inhibitors with immunochemotherapy has been associated with toxicity. CHRONOS-4 (Phase III; NCT02626455) investigates the intravenous, intermittently administered pan-class I PI3K inhibitor copanlisib in combination with rituximab plus bendamustine (R-B) or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with relapsed indolent B-cell lymphoma. We report safety run-in results.

Patients and methods: Patients aged ≥18 years with relapsed CD20-positive indolent B-cell lymphoma received copanlisib (45 mg, increasing to 60 mg if no dose-limiting toxicities) weekly on an intermittent schedule with R-B or R-CHOP. Primary objective was to identify a recommended Phase III dose (RP3D). We also assessed objective response, safety, and tolerability.

Results: Ten patients received copanlisib plus R-B and 11 received copanlisib plus R-CHOP. No dose-limiting toxicities were reported; RP3D was 60 mg. All patients had ≥1 treatment-emergent adverse event (TEAE), most commonly (all grade/grade 3/4) for copanlisib plus R-B: decreased neutrophil count (80%/50%), nausea (70%/0%), decreased platelet count (60%/10%), hyperglycemia (60%/50%); for copanlisib plus R-CHOP: hyperglycemia (82%/64%), hypertension (73%/64%), decreased neutrophil count (64%/64%). Two and 8 patients had serious TEAEs with copanlisib plus R-B and R-CHOP, respectively. Among evaluable patients, objective response rates were 90% (5 complete, 4 partial) and 100% (3 complete, 7 partial) with copanlisib plus R-B and R-CHOP, respectively.

Conclusion: Copanlisib is the first PI3K inhibitor to demonstrate safe, tolerable, and effective combinability with immunochemotherapy in patients with relapsed indolent B-cell lymphoma at full dose (60 mg). Further evaluation is ongoing.

Keywords: Bendamustine; CHRONOS-4; Phase III; R-CHOP; Safety run-in.

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Conflict of interest statement

Disclosure MJM: consultancy: Bayer, Daiichi Sankyo, Roche, Genentech, Juno Therapeutics, Merck, Rocket Medical, Seattle Genetics, Takeda, Teva; honoraria: Bayer, Roche, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Seattle Genetics, Takeda; research funding: Bayer, Roche, Genentech, GlaxoSmithKline, ImmunoVaccine Technologies, Janssen, Pharmacyclics, Rocket Medical, Seattle Genetics. MD: scientific advisory boards: Amgen, AstraZeneca, Bayer, Beigene, BMS/Celgene, Genmab, Gilead/Kite, Janssen, Novartis, Roche; speaker honoraria: Amgen, AstraZeneca, Bayer, BMS/Celgene, Gilead/Kite, Janssen, Roche; institutional research support: AbbVie, Bayer, Celgene, Janssen, Roche. SL: consultancy: Celgene, CHO Pharma USA, Incyte, Gilead, Janssen, Merck, Novartis, Roche, Takeda; honoraria: Merck, Roche, Takeda; research funding: Bayer, Celgene, Genmab, Janssen, Nanovector, Novartis, Roche, Takeda. AS: speaker bureau: AbbVie, Amgen, ArQule, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eisai, Gilead, Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Servier, Takeda; advisory boards: Bayer, Bristol Myers Squibb, Eisai, Gilead, MSD, Pfizer, Servier; consultancy: ArQule. VB, BHC: employees of Bayer HealthCare Pharmaceuticals, Inc. MF: employee of Bayer AG. PLZ: honoraria: AbbVie, ADC Therapeutics, Bristol Myers Squibb, EUSA Pharma, Gilead, Incyte, Janssen, Kyowa Kirin, Merck, MSD, Roche, Servier, Takeda, TG Therapeutics, Verastem; board of directors or advisory committee memberships: AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Sandoz, Servier, Takeda, Verastem; speaker bureau: AbbVie, ADC Therapeutics, Bristol Myers Squibb, Celgene, Celltrion, EUSA Pharma, Gilead, Immune Design, Incyte, Janssen, Janssen-Cilag, Kyowa Kirin, Merck, MSD, Portola, Roche, Servier, Takeda, TG Therapeutics, Verastem; consultancy: EUSA Pharma, Janssen, MSD, Sanofi, Verastem; research funding: Portola. MP: none.

Figures

Figure 1
Figure 1. Study design of the CHRONOS-4 Phase III study—safety run-in.
CHOP treatment includes cyclophosphamide 750 mg/m2 i.v., doxorubicin 50 mg/m2 i.v., and vincristine 1.4 mg/m2 i.v. (maximum dose 2.0 mg) on day 2 of a 21-day cycle, and prednisone 100 mg tablets on days 2 to 6 of a 21-day cycle. Abbreviations: B = bendamustine; CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; i.v. = intravenous; R = rituximab; R-B = rituximab plus bendamustine; R-CHOP = rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; RP3D = recommended Phase III dose.
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