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Apatinib in Patients with Relapsed Or Refractory Diffuse Large B Cell Lymphoma: a Phase II, Open-Label, Single-Arm, Prospective Study

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Apatinib in Patients with Relapsed Or Refractory Diffuse Large B Cell Lymphoma: a Phase II, Open-Label, Single-Arm, Prospective Study Drug Design, Development and Therapy Dovepress open access to scientific and medical research Open Access Full Text Article CLINICAL TRIAL REPORT Apatinib in Patients with Relapsed or Refractory Diffuse Large B Cell Lymphoma: A Phase II, Open-Label, Single-Arm, Prospective Study This article was published in the following Dove Press journal: Drug Design, Development and Therapy Xinran Ma * Purpose: Treatment options for relapsed or refractory diffuse large B-cell lymphoma (RR Ling Li* DLBCL) represent an unmet medical need. Apatinib is a new oral tyrosine kinase inhibitor Lei Zhang mainly targeting vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit tumour fi Xiaorui Fu angiogenesis. In the present study, we evaluated the ef cacy and safety of apatinib for Xin Li patients with RR DLBCL. Patients and Methods: In this phase II, open-label, single-arm, prospective study, we Xinhua Wang enrolled patients aged 14–70 years with treatment failure of at least two chemotherapeutic Jingjing Wu regimens using Simon’s two-stage design. All patients were administered apatinib at an Zhenchang Sun initial dose of 500 mg on a 4-week cycle at home and visited the outpatient clinic every two Xudong Zhang cycles to evaluate efficacy and to record adverse events. We considered objective response Xiaoyan Feng rate (ORR) as the primary end point, and progression-free survival (PFS), and overall Yu Chang survival (OS) plus duration of response (DoR) as the secondary end point. (This trial was Zhiyuan Zhou registered at ClinicalTrials.gov, identifier: NCT03376958.). Feifei Nan Results: From January 2017 to February 2019, we screened 35 patients and enrolled 32 Jieming Zhang eligible patients. At the cutoff point (April 2019), we noted 2 (6.3%) complete responses, 12 Zhaoming Li (37.5%) partial responses, and 9 (28.1%) stable diseases, attributing to an ORR of 43.8% and Mingzhi Zhang a disease control rate of 71.9%. The median PFS and OS were 6.9 (95% confidence interval [CI], 5.8–7.9) and 7.9 months (95% CI, 7.0–8.7), respectively. The median DoR was 5.0 Department of Oncology, The First – – Affiliated Hospital of Zhengzhou months (95% CI, 3.5 6.5) for patients who achieved PR. The most common grade 3 4 University, Lymphoma Diagnosis and adverse events (AE) were hypertension (12.6%), hand–foot syndrome (9.4%), and leucope- Treatment Center of Henan Province, nia (6.3%). No apatinib-related deaths were noted. ’ Zhengzhou, Henan, People s Republic of fi China Conclusion: Home administration of apatinib shows promising ef cacy and manageable AEs in patients with RR DLBCL. *These authors contributed equally to Keywords: apatinib, relapsed or refractory diffuse large B-cell lymphoma, VEGFR-2, this work efficacy, safety Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoid system Correspondence: Mingzhi Zhang malignancy in adults, accounting for 30–40% of all non-Hodgkin lymphomas Department of Oncology, The First 1 Affiliated Hospital of Zhengzhou (NHLs). For patients with newly diagnosed DLBCL, rituximab combined with University, Lymphoma Diagnosis and cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)-like regi- Treatment Centre of Henan Province, Zhengzhou 450002, Henan, People’s men is the current standard, and local radiotherapy is recommended for those who Republic of China meet the conditions. After initial treatment, approximately one-third of all patients Tel +86-13838565629 2 Email [email protected] manifest relapse or refractory disease. For this group of patients, second-line submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 275–284 275 DovePress © 2020 Ma et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php – http://doi.org/10.2147/DDDT.S227477 and incorporate the Creative Commons Attribution Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Ma et al Dovepress regimens, such as ifosfamide, carboplatin, and etoposide (ICE); dexamethasone, cytarabine, and cisplatin (DHAP); and gemcitabine, dexamethasone, and cisplatin (GDP) with or without rituximab are often chosen as salvage treatment; however, the long-term survival rate is <10%, and most patients die within 2 years.3 For eligible patients, we aim for autologous stem cell transplantation (ASCT), but many patients are ineligible. However, ASCT has limitations, such as a recurrence rate of 41.2% reported by a retrospective study.4 Clinical trials are recommended for patients with relapsed or refractory DLBCL (RR DLBCL).5 Angiogenesis plays a crucial part in the development and progression of a series of malignancies, including lymphoma.6,7 Apatinib is a new oral kinase inhibitor mainly targeting vascular endothelial growth factor receptor-2 (VEGFR-2) to inhibit tumour angiogenesis and has shown encouraging anti-tumour effects in multiple solid tumours, including gastric cancer, ovarian cancer, non-small-cell lung Figure 1 Trial protocol. cancer, breast cancer, osteosarcoma, etc.8–12 To date, clin- ical evidence of apatinib as a potential treatment choice for RR DLBCL remains scarce. Laboratory work shows that at least one measurable lesion based on the Cheson 15 apatinib inhibits the proliferation of various NHL cell lines criteria, an Eastern Cooperative Oncology Group in a dose-dependent manner and significantly postpone (ECOG) performance status of 0–2, adequate haematolo- 9 tumour growth and prolong the survival of xenograft mice gic function (absolute neutrophil count ≥1.5 × 10 /L, hae- model derived from human DLBCL cells.13 Additionally, moglobin concentration of ≥80 g/L, platelet count ≥75 × 9 ≤ we had conducted a clinical trial on apatinib for relapse or 10 /L), hepatic function (total bilirubin 1.5 × upper limit ≤ refractory NHL (RR NHL) in our centre. We enrolled 27 of normal [ULN], alanine aminotransferase 2.0 × ULN, ≤ patients with RR NHL, including 11 patients with RR aspartate aminotransferase 2.0 × ULN) and renal function ≤ DLBCL, accounting for an ORR of 47.6%, suggesting an (serum creatinine 1.5 × ULN, creatinine clearance rate ≥ – anti-tumour effect of apatinib to improve the response rate 50 mL/mins [Cockcroft Gault formula]), negative preg- and survival of patients with RR NHL.14 Based on precli- nancy test for female patients of reproductive age. Patients nical and clinical data, we conducted this open-label, single- with unmanageable hypertension (systolic blood pressure ≥ ≥ arm, prospective trial to further investigate the efficacy and 140 mmHg/diastolic blood pressure 90 mmHg and can- safety of oral administration of apatinib as salvage treatment not be controlled successfully with drugs), unstable angina for patients with RR DLBCL. or heart failure with cardiac function higher than grade II as defined by the New York Heart Association were excluded. Another key exclusion criterion was gastroin- Materials and Methods testinal bleeding risk, including active ulcerative lesions Inclusion and Exclusion Criteria with positive occult blood (OB) test result, melena, or Patients aged 14–70 years with histological or pathological hematemesis history within 3 months before this study. confirmation of DLBCL were enrolled in this trial An endoscope examination was required for patients with (Figure 1). All patients had experienced treatment failure primary gastrointestinal DLBCL with positive OB test with at least two chemotherapeutic regimens. The patients result. Patients with any one or more of the following enrolled were not eligible for ASCT or chimeric antigen conditions were also excluded: abnormal coagulation func- receptor T cells (CART) treatment or had rejected both tion (INR>1.5 × ULN, APTT>1.5 × ULN), 24-hrs urinary treatments through their conscious freewill choice without total protein (24-hrs UTP) ≥1.0 g, central nervous system any intentional induction. Other inclusion criteria included metastasis, concomitant malignancies, or any severe 276 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2020:14 DovePress Dovepress Ma et al medical problems that may impede the compliance of the Adverse Events (version 4.03) and were noted during their trial. (Full inclusion and exclusion criteria are shown in monthly outpatient clinic visit or by telephone follow-up. Appendix 1.) Assessments Ethical Clearance We considered objective response rate (ORR) as the primary This trial was performed in accordance with the Good end point, and progression-free survival (PFS), overall sur- Clinical Practice Guidelines and the Helsinki Declaration vival (OS) plus duration of response (DoR) as the secondary and was approved by the ethical committee of the First end point. ORR was defined as the ratio of patients who Affiliated Hospital of Zhengzhou University. All patients achieved complete response (CR) or partial response (PR) were fully informed of the nature and possible AEs caused based on the Cheson criteria.15 PFS was counted from by apatinib and submitted written informed consent before assignment to documented disease progression or death of their participation. For patients younger than 18 years, any reason, and OS was counted from assignment to death written informed consent was provided by their parents of any reason. For patients without disease progression, PFS or legal guardians. and OS were both counted as the time from assignment to the last documented survival assessment. DoR was defined Study Design as the interval from the first documented onset of response to Each enrolled patient was administered apatinib 500 mg disease progression or death. PFS, OS, and DoR were esti- once daily as an initial dose. One treatment cycle consists mated using the Kaplan–Meier method with 95% CIs.
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