Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody–drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer

Liu, J. F.; Moore, Kathleen N.; Birrer, Michael J.; Berlin, Suzanne; Matulonis, Ursula A.; Infante, J. R.; Wolpin, Brian M.; Poon, Kirsten Achilles; Firestein, Ron; Xu, Jianping; Kahn, Richard L.; Wang, Yulei; Wood, Katie; Darbonne, Walter C.; Lackner, Mark R.; Kelley, Sean K.; Lu, Xln; Choi, Youn Jeong; Maslyar, Daniel; Humke, Eric W.; Burris, Howard A.

doi:10.1093/annonc/mdw401

Cited by 74 publications

(63 citation statements)

References 14 publications

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“…The most commonly reported treatment‐related AEs were neutropenia, fatigue, decreased electrolytes, anemia, and neuropathy. These findings were similar to those observed with other ADC‐based therapies as well as with first‐line cytotoxic therapies for mCRPC, such as docetaxel in combination with prednisone . The overall most common SAEs reported in this study were dehydration, hyponatremia, and febrile neutropenia.…”

Section: Discussionsupporting

confidence: 88%

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: 88%

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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“…All clinical trials were conducted in accordance with the Declaration of Helsinki and in compliance with good clinical practice guidelines and quality assurance procedures. More details on the studies included in the data set can be found in the previous clinical publications …”

Section: Methodsmentioning

confidence: 99%

A New Method to Model and Predict Progression Free Survival Based on Tumor Growth Dynamics

Yu¹,

Wang²,

Kågedal³

2020

CPT Pharmacom & Syst Pharma

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Progression‐free survival (PFS) has been increasingly used as a primary endpoint for early clinical development. The aim of the present work was to develop a model where target lesion dynamics and risk for nontarget progression are jointly modeled for predicting PFS. The model was developed based on a pooled platinum‐resistant ovarian cancer dataset comprising four different treatments and a wide range of dose levels. The target lesion progression was derived from tumor growth dynamics based on the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The nontarget progression hazard was correlated to the first derivative of target lesion tumor size with respect to time. The PFS time was determined by the first occurring event, target lesion progression, or nontarget progression. The final joint model not only captured target lesion tumor growth dynamics but also predicted PFS well. A similar approach can potentially be used to predict PFS in future oncology studies.

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“…It was in a Phase I trial where positive responses were seen in patients with high MUC16 levels [42], but no developments seem to have occurred since the middle of 2015.

NCT01335958: Safety and Pharmacokinetics of DMUC5754A Administered Intravenously to Patients with Platinum-Resistant Ovarian Cancer or Unresectable Pancreatic Cancer.

…”

Section: Auristatinsmentioning

confidence: 99%

“…

NCT01335958: Safety and Pharmacokinetics of DMUC5754A Administered Intravenously to Patients with Platinum-Resistant Ovarian Cancer or Unresectable Pancreatic Cancer. Phase I: Completed and details published [42].

…”

Section: Auristatinsmentioning

confidence: 99%

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

Newman¹,

Cragg²

2017

Marine Drugs

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In this review, we have attempted to describe all of the antibody–drug conjugates using a marine-derived compound as the “warhead”, that are currently in clinical trials as listed in the current version of the NIH clinical trials database (clinicaltrials.gov). In searching this database, we used the beta-test version currently available, as it permitted more specific search parameters, since the regular version did not always find trials that had been completed in the past with some agents. We also added small discussion sections on candidates that are still at the preclinical stage, including a derivative of diazonamide that has an unusual interaction with tubulin (DZ-23840), which may also be a potential warhead in the future.

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Phase I study of safety and pharmacokinetics of the anti-MUC16 antibody–drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer or unresectable pancreatic cancer

Cited by 74 publications

References 14 publications

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

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

A New Method to Model and Predict Progression Free Survival Based on Tumor Growth Dynamics

Current Status of Marine-Derived Compounds as Warheads in Anti-Tumor Drug Candidates

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