A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma

Phillips, Tycel; Barr, Paul M.; Park, Sophie; Kolibaba, Kathryn S.; Caimi, Paolo; Chhabra, Saurabh; Kingsley, Edwin C.; Boyd, Thomas E.; Chen, Robert; Carret, Anne Sophie; Gartner, Elaina M.; Li, Hong; Yu, Cindy Chen; Smith, David C.

doi:10.1007/s10637-018-0655-0

Cited by 58 publications

(52 citation statements)

References 14 publications

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“…One of 18 patients with RCC achieved a PR and 13/18 (72%) patients had a SD, resulting in a clinical benefit rate of 78% 44. In patients with NHL, 1/20 patients achieved a CR and 3/20 a PR 49. However, further development of this compound was stopped due to the high occurrence rate (94%) of treatment-related adverse events (AEs).…”

Section: Cd27/cd70 Targeting Agents Under Developmentmentioning

confidence: 99%

“…Eighty-three per cent of patients in the early clinical development presented with at least one grade 3 treatment-related AE. The most frequently observed treatment-related AEs included thrombocytopenia (65%), neutropenia (30%) and anaemia (25%) 49. AMG 172 is another anti-CD70 ADC which was administered in n=37 patients with clear-cell RCC 45.…”

Section: Cd27/cd70 Targeting Agents Under Developmentmentioning

confidence: 99%

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New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)

2019

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Cluster of differentiation 27 (CD27) is a member of the tumour necrosis factor receptor superfamily and plays a key role in T-cell activation by providing a costimulatory signal. Bound to its natural ligand CD70, CD27 signalling enhances T-cell proliferation and differentiation to effector and memory T cells and therefore has potential as an immune modulatory target in cancer treatment. The CD27 agonistic antibody varlilumab showed promising efficacy in haematological as well as solid cancers. Current studies investigate the combination of the CD27 agonistic antibody varlilumab in combination with the PD1 axis targeting immune checkpoint inhibitors like nivolumab or atezolizumab. Further, CD70 expression is used as a therapeutic target for ADCs, antibodies inducing ADCC, as well as the immunological target for chimeric antigen receptor gene-modified T cells and specific dendritic cell vaccination. In line with this, targeting the CD27 axis was shown to be feasible and safe in early clinical trials with the most commonly occurring side effects being thrombocytopenia, fatigue and nausea. In this mini review, we aimed to elucidate the immunobiology of CD27 and its potential as a target in cancer immunotherapy.

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Section: Cd27/cd70 Targeting Agents Under Developmentmentioning

confidence: 99%

Section: Cd27/cd70 Targeting Agents Under Developmentmentioning

confidence: 99%

New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)

2019

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“…Frequently observed TEAEs such as febrile neutropenia, nausea, and fatigue are typical for patients being treated for R/R B-ALL, and elevated liver test results and rash have previously been observed in patients treated with either PBD dimer cytotoxin alone or with other ADCs containing the same PBD dimer. [16][17][18][19] Hematologic abnormalities by laboratory reporting were common because of the nature of the disease, with many patients having hematologic abnormalities at baseline. It is of note that the incidence of pleural and pericardial effusions and ascites was lower than that observed with loncastuximab tesirine in other indications, such as DLBCL.…”

Section: Discussionmentioning

confidence: 99%

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia

et al. 2020

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Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a therapeutic challenge. Loncastuximab tesirine is an antibody-drug conjugate against CD19, an antigen expressed in many B-cell malignancies. This open-label, single-arm, dose-escalation, dose-expansion study assessed the safety, tolerability, pharmacokinetics (PKs), immunogenicity, and preliminary clinical activity of loncastuximab tesirine in adults with R/R B-ALL. A total of 35 patients were enrolled, with a median age of 55 years (range, 20-80) and a median of 3 prior therapies (range, 1-15). All patients received at least 1 IV infusion of loncastuximab tesirine at 15 to 150 μg/kg once every 3 weeks (Q3W; n = 30) or 50 μg/kg IV weekly (n = 5). Common treatment-emergent adverse events (TEAEs) were nausea (42.9%), febrile neutropenia (37.1%), and reversible liver test abnormalities. Grade ≥3 TEAEs were reported in 85.7% patients, most commonly febrile neutropenia and other hematologic abnormalities and reversible liver test abnormalities. There were no treatment-related deaths. Four patients (11.4%) had grade 2 infusion-related reactions, and 1 patient (150 μg/kg Q3W) had a dose-limiting toxicity of hyperbilirubinemia that resolved within 6 days without further action. The maximum tolerated dose was not reached. Three patients achieved complete responses, 1 each at 30, 120, and 150 μg/kg Q3W. PK studies showed marked interpatient variability, with target-mediated drug disposition seeming to contribute to time- and dose-dependent disposition. No clinically relevant anti–drug-antibody formation occurred. The trial was terminated in the dose-escalation phase because of slow accrual. This trial was registered at www.clinicaltrials.gov as NCT02669264.

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“…This phase 1, dose‐escalation study (clinicaltrials.gov identifier NCT02216890) was designed to evaluate the safety and tolerability of SGN‐CD70A and to establish the maximum tolerated dose (MTD) in patients with mRCC and NHL. The current article reports only outcomes for patients with mRCC, and outcomes for those with NHL are presented in a separate report . Ten centers in the United States recruited patients between June 2015 and July 2016 under approval by an institutional review board in accordance with the Declaration of Helsinki.…”

Section: Methodsmentioning

confidence: 99%

A phase 1 trial of SGN‐CD70A in patients with CD70‐positive, metastatic renal cell carcinoma

Pal

Forero‐Torres

Thompson

et al. 2019

Cancer

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Background Cluster of differentiation 70 (CD70) is frequently expressed in renal cell carcinoma (RCC) and has immunomodulatory properties. An antibody‐drug conjugate targeting CD70, SGN‐CD70A, was developed to treat patients with CD70‐positive RCC. Methods The objective of this phase 1, open‐label, dose‐escalation, multicenter study was to evaluate the safety and tolerability of SGN‐CD70A and establish its maximum tolerated dose in patients with CD70‐positive, metastatic RCC (mRCC). All subtypes of RCC were permitted, and no limit was set on the number of prior therapies. Safety assessments consisted of monitoring and recording all adverse events (AEs) and dose‐limiting toxicities (DLTs). Treatment response was assessed by radiographic tumor evaluation according to the Response Evaluation Criteria for Solid Tumors, version 1.1. A model‐based, modified continual‐reassessment method was used to estimate the probabilities of DLT and response. Results The maximum tolerated dose was determined to be 30 μg/kg, with thrombocytopenia as the DLT. The most common AEs were fatigue (67%), anemia (61%), and thrombocytopenia (56%). Of 18 enrolled patients, 1 achieved a partial response and 13 achieved stable disease, for a clinical benefit rate of 78%. Limitations of the study included the heavily pretreated nature of patients, receipt of a median of 4 prior lines of therapy (range, 1‐8 prior lines of therapy), and diminishing response potential. Conclusions The modest antitumor activity of SGN‐CD70A does not support its development in mRCC. However, given the high disease control rate in a heavily pretreated population and the modest toxicity profile, CD70 remains of interest because of its immunomodulatory properties.

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A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma

Cited by 58 publications

References 14 publications

New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)

New emerging targets in cancer immunotherapy: CD27 (TNFRSF7)

Loncastuximab tesirine, an anti-CD19 antibody-drug conjugate, in relapsed/refractory B-cell acute lymphoblastic leukemia

A phase 1 trial of SGN‐CD70A in patients with CD70‐positive, metastatic renal cell carcinoma

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