Phase 1 multicenter trial of brentuximab vedotin for steroid-refractory acute graft-versus-host disease

Chen, Yi Bin; Perales, Miguel Angel; Li, Shuli; Kempner, Maria E.; Reynolds, Carol; Brown, Jami; Efebera, Yvonne A.; Devine, Steven M.; El‐Jawahri, Areej; McAfee, Steven L.; Spitzer, Thomas R.; Soiffer, Robert J.; Ritz, Jérôme; Cutler, Corey

doi:10.1182/blood-2017-03-772210

Cited by 41 publications

(24 citation statements)

References 21 publications

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“…Shortly after the initiation of this study, the dose of PSMA ADC was reduced from 2.5 to 2.3 mg/kg due to dose‐limiting toxicities (eg, neutropenia and sepsis), which were occurring during the first 3 weeks of treatment (cycle 1). These toxicities have also been reported with other ADCs utilizing MMAE, such as brentuximab vedotin and glembatumumab vedotin . The most common AE that resulted in study discontinuation was peripheral neuropathy.…”

Section: Discussionsupporting

confidence: 52%

“…This AE and the toxicity profile more generally are possibly related to systemic concentrations of free MMAE that result following its release from the PSMA antibody. 19,30 The incidences of most common AEs and SAEs were similar in chemotherapy-naïve and chemotherapy-experienced groups. The most commonly reported treatment-related AEs were neutropenia, fatigue, decreased electrolytes, anemia, and neuropathy.…”

Section: Discussionmentioning

confidence: 92%

“…The most common AE that resulted in study discontinuation was peripheral neuropathy. This AE and the toxicity profile more generally are possibly related to systemic concentrations of free MMAE that result following its release from the PSMA antibody …”

Section: Discussionmentioning

confidence: 99%

“…These toxicities have also been reported with other ADCs utilizing MMAE, such as brentuximab vedotin and glembatumumab vedotin. [30][31][32][33] The most common AE that resulted in study discontinuation was peripheral neuropathy. This AE and the toxicity profile more generally are possibly related to systemic concentrations of free MMAE that result following its release from the PSMA antibody.…”

Section: Discussionmentioning

confidence: 99%

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PSMA ADC monotherapy in patients with progressive metastatic castration‐resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open‐label single‐arm phase 2 study

et al. 2019

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Background Prostate‐specific membrane antigen (PSMA) is a well‐established therapeutic and diagnostic target overexpressed in both primary and metastatic prostate cancers. PSMA antibody‐drug conjugate (PSMA ADC) is a fully human immunoglobulin G1 anti‐PSMA monoclonal antibody conjugated to monomethylauristatin E, which binds to PSMA‐positive cells and induces cytotoxicity. In a phase 1 study, PSMA ADC was well tolerated and demonstrated activity as measured by reductions in serum prostate‐specific antigen (PSA) and circulating tumor cells (CTCs). To further assess PSMA ADC, we conducted a phase 2 trial in metastatic castration‐resistant prostate cancer (mCRPC) subjects who progressed following abiraterone/enzalutamide (abi/enz) therapy. Methods A total of 119 (84 chemotherapy‐experienced and 35 chemotherapy‐naïve) subjects were administered PSMA ADC 2.5 or 2.3 mg/kg IV q3w for up to eight cycles. Antitumor activity (best percentage declines in PSA and CTCs from baseline and tumor responses through radiological imaging), exploratory biomarkers, and safety (monitoring of adverse events [AEs], clinical laboratory tests, and Eastern Cooperative Oncology Group performance status) were assessed. Results PSA declines ≥50% occurred in 14% of all treated (n = 113) and 21% of chemotherapy‐naïve subjects (n = 34). CTC declines ≥50% were seen in 78% of all treated (n = 77; number of subjects with ≥5 CTCs at baseline and a posttreatment result) and 89% of chemotherapy‐naïve subjects (n = 19); 47% of all treated and 53% of chemotherapy‐naïve subjects had a transition from ≥5 to less than 5 CTCs/7.5 mL blood at some point during the study. PSA and CTC reductions were associated with high PSMA expression (CTCs or tumor tissue) and low neuroendocrine serum markers. In the chemotherapy‐experienced group, the best overall radiologic response to PSMA ADC treatment was stable disease in 51 (60.7%) subjects; 5.7% of subjects in the chemotherapy‐naïve group had partial responses. The most common treatment‐related AEs ≥Common Terminology Criteria for AE (CTCAE) grade 3 were neutropenia, fatigue, electrolyte imbalance, anemia, and neuropathy. The most common serious AEs were dehydration, hyponatremia, febrile neutropenia, and constipation. Two subjects who received 2.5 mg/kg died of sepsis. Conclusions PSMA ADC demonstrated some activity with respect to PSA declines, CTC conversions/reductions, and radiologic assessments in abi/enz treated mCRPC subjects. Clinically significant treatment‐related AEs included neutropenia and neuropathy.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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PSMA ADC monotherapy in patients with progressive metastatic castration‐resistant prostate cancer following abiraterone and/or enzalutamide: Efficacy and safety in open‐label single‐arm phase 2 study

et al. 2019

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“…Steroid-refractory acute GVHD was defined as (1) progressive GVHD after 3 days of systemic corticosteroids ( 1 mg/kg/day of prednisone equivalent) or (2) no improvement in GVHD after at least 7 days on 1 mg/kg/day of prednisone equivalent. 5 Acute GVHD grading was according to the Consensus criteria. 6 Response to AAT was defined by the following standard criteria 5 : CR was resolution of all signs and symptoms of GVHD in all organs.…”

mentioning

confidence: 99%