scholarly journals 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

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Alexander Grunenberg ◽  
Lisa M. Kaiser ◽  
Stephanie Woelfle ◽  
Birgit Schmelzle ◽  
Andreas Viardot ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Marginal Zone ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Pi3k Inhibitor ◽  
Clinical Activity ◽  
Induction Phase ◽  
Link Type

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.

Treatment of Extranodal Marginal Zone Lymphoma and Primary Cutaneous B Cell Lymphoma with Rituximab: A Single Institution Experience.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4502-4502
Author(s):  
Robert Chen ◽  
Glen Peterson ◽  
Diana Vucurevich ◽  
Choon-kee Lee ◽  
William Robinson ◽  
...  
Keyword(s):  
B Cell ◽  
Induction Therapy ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
Single Agent ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Extranodal Marginal Zone Lymphoma ◽  
Large B Cell ◽  
Cutaneous B Cell Lymphoma

Abstract Extranodal marginal zone lymphoma is a low grade B cell lymphoma. It comprises about 5% of all non-hodgkin’s lymphoma. They typically present in the lung, thyroid, breast, lacrimal and salivary gland, orbit, and skin. Primary cutaneous B cell lymphoma is an extremely rare form of lymphoma with 3 histological variants: marginal zone, follicular, and diffuse large B cell. In general, they have a high remission rate with overall survival up to 80% at 10 years. At the University of Colorado Health Sciences Center, we have seen ten such cases from July 2005 to July 2007. There is no standard treatement for either extranodal marginal zone lymphoma or primary cutaneous B cell lymphoma, but prior reports have shown long term survival with surgery, radiation, and chemotherapy. Most institutions use radiation therapy as the main modality after excisional biopsy. There is one report by Gitelson et al (leuk lymphoma 2006) using single agent rituximab as the only modality. Out of the ten cases at our institution, six cases were primary cutaneous B cell lymphoma (4 marginal zone, 1 follicular, one diffuse large B cell), and four cases were extranodal marginal zone lymphoma. Four out of six cases of primary cutaneous B cell lymphoma and three out of four of extranodal marginal zone lymphoma was treated with single agent rituximab. Two out of the six cases of primary cutaneous B cell lymphoma and one out of four of extranodal marginal zone lymphoma was treated with radiation. Patients were given induction therapy rituximab at the dose of 375mg/m2 IV weekly x 4 weeks and maintenance therapy at 375 mg/m2 IV every two to three month interval for 8 cycles. 7 patients were given rituximab single agent. All achieved CR (100%) immediately after induction therapy at 1 month. They were also given maintenance treatment. No relapses has occured at the medium follow up of 7 month (3–24 month). Our preliminary result supports the recent report of single agent rituximab. Even though extranodal marginal zone lymphoma is a rare disorder and primary cutaneous B cell lymphoma even more rarer, we feel that a well designed prospective randomized trial would determine the role of rituximab for this disease.

Treatment of Relapsed or Refractory Lymphoma with the Oral Isotype-Selective Histone Deacetylase Inhibitor MGCD0103: Interim Results from a Phase II Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2571-2571 ◽  
Author(s):  
Anas Younes ◽  
Amanda Wedgwood ◽  
Peter McLaughlin ◽  
Charalambos Andreadis ◽  
Sarit E. Assouline ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
B Cell Lymphoma ◽  
Clinical Activity ◽  
Large B Cell Lymphoma ◽  
Refractory Lymphoma ◽  
Large B Cell

Abstract Purpose: MGCD0103 is an oral inhibitor of histone deacetylases (HDACs) with isotype-selective activity against HDAC-1, -2, -3, and -11. MGCD0103 exhibits significant biological activity in preclinical models of hematopoietic cancers. Although several HDAC inhibitors have shown promising clinical activity in patients (pts) with T-cell lymphoid malignancies, the clinical activity of HDAC inhibitors have not been previously examined in B-cell lymphoma. The purpose of this study was to examine the efficacy and tolerability of MGCD0103 as monotherapy for the treatment of relapsed or refractory follicular and diffuse large B-cell lymphoma. Methods : This was an open-label, multi-center, phase II trial in adults (≥18 years) with relapsed or refractory lymphoma. The trial contained 2 cohorts of pts with diagnoses of either diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Eligibility required the presence of ≥1 site of measurable disease (≥2.0 cm) and an ECOG performance status of 0 or 1. Oral MGCD0103 was initially dosed at 110 mg 3× per week in 4-week cycles, with escalation to 135 mg or reductions to 85 and 60 mg permitted based on patient tolerance. Pts enrolled later in the trial had starting doses of 85 mg, with escalation to 110 mg and reductions to 60 and 40 mg permitted. On day 1 of cycle 1, blood samples were collected for PK analysis before dosing and at 0.5, 1, 2, 4, 6, and 24 hours. Results: To date, 38 pts (mean age, 60.3 ± 13.0 yrs; male, n=18) have been dosed: 19 with DLCBL and 19 with FL, all of whom have received prior Rituxan. Nineteen of 24 pts (79%) who had tumor size reassessed by CT scan after treatment initiation exhibited some tumor reduction; 12 (50%) exhibited >30% reduction and 7 (29%) exhibited >40% reduction. Twenty-five pts (1 pt has not yet had disease reassessed) were formally evaluable for clinical response; 16 (64%) have completed ≥3 cycles (12 weeks) of treatment. A CR was observed in 1 pt with FL after 2 cycles. PRs were observed in 2 pts with DLBCL after 2 and 4 cycles respectively and 1 pt with FL after 6 cycles. Twenty pts required dose reductions for management of toxicities. In 35 pts evaluable for safety, the most common non-hematologic toxicities were fatigue (24 pts), nausea (22), diarrhea (17), anorexia and decreased appetite (12), vomiting (10), and weight loss (9). Grade 3 toxicities occurred in 10 pts; fatigue and weight decrease being the most common. There were no grade 4 non-hematological toxicities. Hematological toxicities were minimal, with 1 pt requiring dose modification for thrombocytopenia and 2 for neutropenia. Significant inhibition of HDAC activity in PBMCs was seen in the majority of pts evaluated. Population PK (N=16) revealed: Cmax 119 ± 73 ng/ml, AUC (0–24) 715 ± 495 ng*hr/ml. Conclusions: Interim results from this ongoing trial suggest that single-agent MGCD0103 demonstrates significant anti-cancer activity in relapsed or refractory non-Hodgkin’s lymphoma (DLCBL and FL subtypes) and has a manageable side effect profile.

scholarly journals A phase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma)

Haematologica ◽  
2012 ◽  
Vol 98 (3) ◽  
pp. 353-356 ◽  
Author(s):  
B. Kiesewetter ◽  
M. Troch ◽  
W. Dolak ◽  
L. Mullauer ◽  
J. Lukas ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Malt Lymphoma ◽  
Lymphoid Tissue ◽  
Marginal Zone ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma

Transformation of a primary cutaneous marginal zone lymphoma into a cutaneous diffuse large B-cell lymphoma

Piel ◽  
2017 ◽  
Vol 32 (5) ◽  
pp. 314-316
Author(s):  
Carolina Areán ◽  
Alicia Córdoba ◽  
Juan García ◽  
Amaia Larumbe
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Marginal Zone Lymphoma ◽  
Large B Cell Lymphoma ◽  
Large B Cell

scholarly journals Dramatic Response with Single-Agent Ibrutinib in Multiply Relapsed Marginal Zone Lymphoma with MYD88L265P Mutation

2017 ◽  
Vol 10 (3) ◽  
pp. 813-818 ◽  
Author(s):  
Ryan C. Lynch ◽  
Ranjana H. Advani
Keyword(s):  
B Cell ◽  
Signaling Pathway ◽  
Marginal Zone ◽  
Single Agent ◽  
Cell Receptor ◽  
Marginal Zone Lymphoma ◽  
B Cell Receptor ◽  
Receptor Signaling Pathway ◽  
B Cell Receptor Signaling ◽  
Cell Receptor Signaling

The B-cell receptor signaling pathway is important in the lymphomagenesis of many lymphomas, including marginal zone lymphoma (MZL). Herein we describe a case of extranodal MZL refractory to multiple lines of therapy. The presence of an IgM paraprotein prompted further evaluation, and the patient was found to have an MYD88L265P mutation. Treatment with ibrutinib led to a dramatic response with prompt resolution of symptoms and significant improvement in measurable sites of disease. The excellent response to ibrutinib in our patient with MYD88L265P-mutated refractory MZL supports a biological rationale for its use.

scholarly journals Durable ibrutinib responses in relapsed/refractory marginal zone lymphoma: long-term follow-up and biomarker analysis

2020 ◽  
Vol 4 (22) ◽  
pp. 5773-5784
Author(s):  
Ariela Noy ◽  
Sven de Vos ◽  
Morton Coleman ◽  
Peter Martin ◽  
Christopher R. Flowers ◽  
...  
Keyword(s):  
B Cell ◽  
Marginal Zone ◽  
Single Agent ◽  
Final Analysis ◽  
Marginal Zone Lymphoma ◽  
Safety And Efficacy ◽  
Pathway Gene ◽  
Biomarker Analysis

Abstract Advanced marginal zone lymphoma (MZL) is an incurable B-cell malignancy dependent on B-cell receptor signaling. The phase 2 PCYC-1121 study demonstrated the safety and efficacy of single-agent ibrutinib 560 mg/d in 63 patients with relapsed/refractory MZL treated with prior rituximab (RTX) or rituximab-based chemoimmunotherapy (RTX-CIT). We report the final analysis of PCYC-1121 with median follow-up of 33.1 months (range: 1.4-44.6). Overall response rate (ORR) was 58%; median duration of response (DOR) was 27.6 months (95% confidence interval [CI]: 12.1 to not estimable [NE]); median progression-free survival (PFS) was 15.7 months (95% CI: 12.2-30.4); and median overall survival (OS) was not reached (95% CI: NE to NE). Patients with prior RTX treatment had better outcomes (ORR: 81%; median DOR: not reached [95% CI: 12.2 to NE]; median PFS: 30.4 months [95% CI: 22.1 to NE]; median OS: not reached [95% CI: 30.3 to NE]) vs those with prior RTX-CIT treatment (ORR: 51%; DOR: 12.4 months [95% CI: 2.8 to NE]; PFS: 13.8 months [95% CI: 8.3-22.5]; OS: not reached [95% CI: NE to NE]). ORRs were 63%, 47%, and 62% for extranodal, nodal, and splenic subtypes, respectively. With up to 45 months of ibrutinib treatment, the safety profile remained consistent with prior reports. The most common grade ≥3 event was anemia (16%). Exploratory biomarker analysis showed NF-κB pathway gene mutations correlated with outcomes. Final analysis of PCYC-1121 demonstrated long-term safety and efficacy of ibrutinib in patients with relapsed/refractory MZL, regardless of prior treatment or MZL subtype. This trial was registered at www.clinicaltrials.gov as #NCT01980628.

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