Phase 1 Study of Molibresib (GSK525762), a Bromodomain and Extra-Terminal Domain Protein Inhibitor, in NUT Carcinoma and Other Solid Tumors

Abstract

Background: Bromodomain and extra-terminal domain proteins are promising epigenetic anticancer drug targets. This first-in-human study evaluated the safety, recommended phase II dose, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the bromodomain and extra-terminal domain inhibitor molibresib (GSK525762) in patients with nuclear protein in testis (NUT) carcinoma (NC) and other solid tumors.

Methods: This was a phase I and II, open-label, dose-escalation study. Molibresib was administered orally once daily. Single-patient dose escalation (from 2 mg/d) was conducted until the first instance of grade 2 or higher drug-related toxicity, followed by a 3 + 3 design. Pharmacokinetic parameters were obtained during weeks 1 and 3. Circulating monocyte chemoattractant protein-1 levels were measured as a pharmacodynamic biomarker.

Results: Sixty-five patients received molibresib. During dose escalation, 11% experienced dose-limiting toxicities, including six instances of grade 4 thrombocytopenia, all with molibresib 60-100 mg. The most frequent treatment-related adverse events of any grade were thrombocytopenia (51%) and gastrointestinal events, including nausea, vomiting, diarrhea, decreased appetite, and dysgeusia (22%-42%), anemia (22%), and fatigue (20%). Molibresib demonstrated an acceptable safety profile up to 100 mg; 80 mg once daily was selected as the recommended phase II dose. Following single and repeat dosing, molibresib showed rapid absorption and elimination (maximum plasma concentration: 2 hours; t1/2: 3-7 hours). Dose-dependent reductions in circulating monocyte chemoattractant protein-1 levels were observed. Among 19 patients with NC, four achieved either confirmed or unconfirmed partial response, eight had stable disease as best response, and four were progression-free for more than 6 months.

Conclusions: Once-daily molibresib was tolerated at doses demonstrating target engagement. Preliminary data indicate proof-of-concept in NC.

© The Author(s) 2019. Published by Oxford University Press.

Figures

Figure 1.

Pharmacokinetic parameters and pharmacodynamic profiles of molibresib. A) Pharmacokinetic profiles of molibresib (80-mg dose) and its major active human metabolites M5 and M13 measured together at week 1 day 1 (left) and week 3 day 4 (right). B) Maximum change in platelet count from baseline (%) by molibresib dose (left) by exposure measured on week 1 day 1 (right). Platelet data are for the initial dose level during the first 60 days on treatment and limited to patients who received the planned first 2 weeks of treatment. C) Percent maximum change in Factor VII from baseline by molibresib dose at week 1 (left) and week 3 (right). D) Percent maximum change in MCP-1 from baseline by molibresib dose at week 1. AUC(0–24) = area under the concentration–time curve from 0 to 24 hours; MCP-1 = monocyte chemoattractant protein 1. In B–D, predicted values represent the line of best fit (ie, a simple maximum effect [Emax] model) through observed values.

Figure 2.

Antitumor activity of molibresib. A) Maximum tumor reduction (% from baseline) and best clinical responses for all treated patients who had measurable disease and at least one complete postbaseline assessment (n = 46 of 65 enrolled). B) Maximum tumor reduction (% from baseline) and best clinical responses for NC patients who had measurable disease and at least one complete postbaseline assessment (n = 14 of 19 enrolled). In A and B, NE indicates patients with clinical progression, with the postbaseline scan performed before 28 days from baseline. Patients not depicted in A and B were removed from the trial for early clinical progression or progression based on evidence of new lesion(s) without reassessment of baseline target lesions or had nonmeasurable disease at outset. C) Progression-free survival (PFS) in the NC cohort for patients who received at least 60 mg daily (n = 11). Tick marks represent censored patients: If a patient received subsequent anticancer therapy before the date of documented events, PFS was censored at the last adequate assessment before the initiation of therapy. Otherwise, if a patient did not have a documented date of events, PFS was censored at the date of the last adequate assessment. aMaximum reduction from baseline is 0%. bRemained on treatment for greater than 4 months. cConfirmed response. CRC = colorectal cancer; NC = NUT carcinoma; NSCLC = non-small cell lung cancer; NUT = nuclear protein in testis; SCLC = small cell lung cancer; PD = progressive disease; PR = partial response; QD = once daily; SD = stable disease.