Objective responses in a phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma

Younes, Anas; Forero-Torres, A.; Bartlett, Nancy L.; Leonard, John P.; Rege, B.; Kennedy, Dallas C.; Lorenz, Jennie M.; Sievers, Eric L.

doi:10.1200/jco.2008.26.15_suppl.8526

Cited by 49 publications

(45 citation statements)

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“…Although not approved in this setting, rituximab (chimeric anti-CD20) is the only commercially available unmodified mAb routinely demonstrating antitumor activity in HL (6,30). Arming of mAbs by linking them to cellular toxins, drug conjugates such as brentuximab vedotin (11), or radionuclides to target these agents specifically to tumors may provide valuable augmentation of antitumor activity. Indeed the US Food and Drug Administration has approved brentuximab vedotin for the treatment of relapsed HL after failure of autologous stem cell transplantation or after the failure of at least two prior multiagent chemotherapeutic regimens (7).…”

Section: Immunohistochemistry Tomentioning

confidence: 99%

“…These include mAbs linked to drugs or toxins targeting CD25 or CD30 expressed on Reed-Sternberg cells (6)(7)(8)(9)(10)(11). Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has induced a significant number of responses in refractory HL (7,11). Although other antibody immunotoxins have demonstrated some clinical efficacy, they have yielded few complete responses (CRs) (6,9,10).…”

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confidence: 99%

“…To date more than 30 different mAb preparations directed toward antigens expressed by malignant Reed-Sternberg cells have been studied (6). These include mAbs linked to drugs or toxins targeting CD25 or CD30 expressed on Reed-Sternberg cells (6)(7)(8)(9)(10)(11). Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has induced a significant number of responses in refractory HL (7,11).…”

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confidence: 99%

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⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Janik

Morris

O’Mahony

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Despite significant advances in the treatment of Hodgkin's lymphoma (HL), a significant proportion of patients will not respond or will subsequently relapse. We identified CD25, the IL-2 receptor alpha subunit, as a favorable target for systemic radioimmunotherapy of HL. The scientific basis for the clinical trial was that, although most normal cells with exception of Treg cells do not express CD25, it is expressed by a minority of Reed-Sternberg cells and by most polyclonal T cells rosetting around Reed-Sternberg cells. Forty-six patients with refractory and relapsed HL were evaluated with up to seven i.v. infusions of the radiolabeled anti-CD25 antibody 90 Y-daclizumab. 90 Y provides strong β emissions that kill tumor cells at a distance by a crossfire effect. In 46 evaluable HL patients treated with 90 Y-daclizumab there were 14 complete responses and nine partial responses; 14 patients had stable disease, and nine progressed. Responses were observed both in patients whose Reed-Sternberg cells expressed CD25 and in those whose neoplastic cells were CD25 − provided that associated rosetting T cells expressed CD25. As assessed using phosphorylated H2AX (γ-H2AX) as a bioindicator of the effects of radiation exposure, predominantly nonmalignant cells in the tumor microenvironment manifested DNA damage, as reflected by increased expression of γ-H2AX. Toxicities were transient bone-marrow suppression and myelodysplastic syndrome in six patients who had not been evaluated with bone-marrow karyotype analyses before therapy. In conclusion, repeated 90 Y-daclizumab infusions directed predominantly toward nonmalignant T cells rosetting around Reed-Sternberg cells provided meaningful therapy for select HL patients.T reatment with combination chemotherapy, radiation, and hematopoietic stem cell transplantation has increased the disease-free survival in Hodgkin's lymphoma (HL) from less than 5% in 1963 to more than 80% at present (1-6). Recently the US Food and Drug Administration approved brentuximab vedotin for the treatment of relapsed HL (7). Furthermore the anti-PD1 agent pembrolizumab has shown promising results in classic HL (8). Nevertheless, a significant fraction of patients do not respond to treatment or subsequently relapse. To date more than 30 different mAb preparations directed toward antigens expressed by malignant Reed-Sternberg cells have been studied (6). These include mAbs linked to drugs or toxins targeting CD25 or CD30 expressed on Reed-Sternberg cells (6-11). Brentuximab vedotin, an anti-CD30 antibody drug conjugate, has induced a significant number of responses in refractory HL (7, 11). Although other antibody immunotoxins have demonstrated some clinical efficacy, they have yielded few complete responses (CRs) (6, 9, 10). An alternative strategy has been to arm mAbs with radionuclides. Radioimmunotherapy using 90 Y-anti-ferritin and 131 I-anti-CD30 antibodies has resulted in partial (PRs) and CRs in HL (12-15). Deficiencies with these approaches reflect the lack of tumor specificity of ferritin-targ...

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Section: Immunohistochemistry Tomentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

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⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Janik

Morris

O’Mahony

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…A study performed by the Cancer and Leukemia Group B combining this antibody with a gemcitabine-based chemotherapy regimen was closed early because of unexpected severe pulmonary toxicity [51]. More recently, anti-CD30 antibodies conjugated to monomethyl auristatin E, a potent antitubulin agent, were tested in heavily pretreated HL patients [52]. They were generally well tolerated, with 86% of patients achieving some degree of tumor reduction and 20% achieving a CR.…”

Section: Monoclonal Antibody Therapymentioning

confidence: 99%

Salvage Therapy in Hodgkin’s Lymphoma

Mendler

Friedberg

2009

The Oncologist

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1. Appraise the most important properties of a salvage chemotherapy regimen and name at least three effective regimens.2. Evaluate poor-risk clinical features pre-HDCT/ASCT that reduce the chance for cure and design a more effective alternative transplant approach.3. Hypothesize the reasons for the effectiveness of monoclonal antibodies that have shown activity against relapsed HL.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTHodgkin's lymphoma (HL) is a commonly cured malignancy. Unfortunately, patients who are refractory to or relapse after first-line treatment pose a significant therapeutic challenge. There is evidence that these patients are best treated with an approach involving salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT/ASCT). This approach may result in cure, with better results in patients with low-risk relapse. In patients with high-risk relapse and refractory disease, HDCT/ASCT is rarely curative. More aggressive transplant approaches have shown promising results in this group and are currently under active investigation. For those relapsing after HDCT/ASCT, there exists a range of therapeutic options, including further salvage chemotherapy, reduced-intensity allogeneic transplantation, monoclonal antibody therapy, and novel agents. All patients in this category should be considered for enrollment in clinical trials. This review discusses the evidence behind the current practice in patients with relapsed or refractory HL. Specifically, the efficacy of various salvage chemotherapy regimens, the risk factors influencing outcome with HDCT/ASCT, and the results with alternative transplant approaches, monoclonal antibody therapies, and novel agents are addressed. We conclude by providing our approach to these patients, with the hope that this will serve as a framework for the practicing oncologist.

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“…To do so, the chimeric anti-CD30 antibody cAC10 was humanized by optimizing human string content administered by intravenous infusions every 3 weeks. 21 A total of 45 patients were treated with escalating doses ranging between 0.1 and 3.6 mg/kg. Forty-two had relapsed HL, of whom 76% were previously treated with high-dose therapy and autologous stem cell transplant (ASCT).…”

Section: Cd30mentioning

confidence: 99%

Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma

Younes¹

2009

Hematology

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Although classical Hodgkin lymphoma (HL) is considered one of the most curable human cancers, the treatment of patients with relapsed and refractory disease, especially those who relapse after autologous stem cell transplantation, remains challenging. Furthermore, because the median age of the patients is in the mid-30s, the impact of early mortality on the number of years lost from productive life is remarkable. Patients with HL whose disease relapses after stem cell transplantation are rarely cured with current treatment modalities. New drugs and novel treatment strategies that are based on our understanding of the disease biology and signaling pathways are needed to improve treatment outcome for these patients. This review will focus on emerging new treatment modalities that are currently under investigation for patients with relapsed classical HL. 1 In spite of its high cure rate, patients who are not cured with front-line or second-line therapy, including stem cell transplantation, have an estimated median survival of less than 3 years.2 As the median age of this patient population is the mid-30s, the impact of early mortality on the number of years lost from productive life is remarkable. Because of the relatively rare incidence and high cure rate, the development of new drugs for the treatment of relapsed HL has been very challenging. In fact, no new drugs have been approved for HL by the US Food and Drug Administration (FDA) in more than 30 years. Thus, drug development in this area will address a significant unmet medical need. 3With recent advances in our understanding of HL pathology, biology, and immunology, several therapeutic targets have been identified and are currently under preclinical and clinical investigation.

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Objective responses in a phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma

Cited by 49 publications

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⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Salvage Therapy in Hodgkin’s Lymphoma

Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma

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Objective responses in a phase I dose-escalation study of SGN-35, a novel antibody-drug conjugate (ADC) targeting CD30, in patients with relapsed or refractory Hodgkin lymphoma

Cited by 49 publications

References 0 publications

90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

90Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

Salvage Therapy in Hodgkin’s Lymphoma

Novel treatment strategies for patients with relapsed classical Hodgkin lymphoma

Contact Info

Product

Resources

About

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma

⁹⁰Y-daclizumab, an anti-CD25 monoclonal antibody, provided responses in 50% of patients with relapsed Hodgkin’s lymphoma