Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

• Published in: Clinical cancer research Vol. 23; no. 13; pp. 3277 - 3284
• Main Authors: Chung, Vincent, Mansfield, Aaron S, Braiteh, Fadi, Richards, Donald, Durivage, Henry, Ungerleider, Richard S, Johnson, Francis, Kovach, John S
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01-07-2017
• Subjects: Adenocarcinoma; Adult; Aged; Anemia; Anticancer properties; Antitumor activity; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - adverse effects; Cancer; Chondrosarcoma; Creatinine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions - classification; Drug-Related Side Effects and Adverse Reactions - pathology; Dyspnea; Experimental design; Female; Fibrosarcoma; Humans; Hyponatremia; Inhibitors; Lungs; Lymphopenia; Male; Middle Aged; Neoplasm Staging; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Pancreas; Patients; Phosphatase; Phosphoprotein phosphatase; Piperazines - administration & dosage; Piperazines - adverse effects; Prostate cancer; Protein phosphatase; Protein Phosphatase 2 - antagonists & inhibitors; Protein Phosphatase 2 - genetics; Respiration; Safety; Solid tumors; Thymoma; Toxicity; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-16-2299

To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors.
LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design.
There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m
level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (
= 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (
= 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m
daily for 3 days every 3 weeks.
The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies.
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