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Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents. Bromodomain and extraterminal proteins (BET) are reported as targets for anticancer therapy. Here, the authors report the final results of a phase I clinical trial of the BET inhibitor trotabresib in patients with solid tumours and diffuse large B-cell lymphoma.

A randomized, multicenter, open-label, phase 3 study of patients with progressive, recurrent glioblastoma multiforme (GBM) for whom front-line therapy had failed was conducted. This study was designed to determine whether combination therapy with imatinib and hydroxyurea (HU) has superior antitumor activity compared with HU monotherapy in the treatment of recurrent GBM. The target population consisted of patients with confirmed recurrent GBM and an Eastern Cooperative Oncology Group performance status of 0–2 who had completed previous treatment comprising surgical resection, irradiation therapy, and first-line chemotherapy (preferably temozolomide (TMZ) containing regimen) and who have progressed despite treatment. If first-line chemotherapy did not contain TMZ, a second completed chemotherapy was acceptable. The primary efficacy parameter was progression-free survival (PFS). The primary comparison of combination therapy versus monotherapy for PFS was not significant (adjusted P  = 0.56). The hazard ratio (HR) (adjusted HR = 0.93) was not clinically relevant. The median PFS for the combination arm was low at 6 weeks and similar to the median PFS in the monotherapy arm (6 weeks). The 6-month PFS for the two treatment groups was very similar (5% in the combination arm vs. 7% in the monotherapy arm). No clinically meaningful differences were found between the two treatment arms, and the primary study end point was not met. Among the patients receiving imatinib, no adverse events were reported that were either previously unknown or unexpected as a consequence of the disease.

Imatinib mesylate blocks the activity of three protein tyrosine kinases: ABL, KIT, and platelet-derived growth factor receptor β (PDGFRB). These kinases have crucial roles in chronic myelogenous leukemia (ABL), gastrointestinal stromal tumors (KIT), and certain myeloproliferative diseases (PDGFRB). The first two types of neoplasms have been shown to respond to imatinib mesylate. This article reports that in four patients, a myeloproliferative disorder involving a rearranged PDGFRB gene also responded to the drug. The association of leukemia, eosinophilia, and abnormalities of chromosome 12p13 was originally reported by Keene et al. in 1987 1 ; two of the four patients included in that report also had translocations involving chromosome 5q3. Subsequently, Golub et al. 2 showed that the previously described t(5;12)(q31–q33;p13) chromosomal abnormality, characteristic of some cases of chronic myelomonocytic leukemia, was associated with a fusion gene linking TEL (now known as ETV6 ) with platelet-derived growth factor receptor beta ( PDGFRB ). At least 34 cases of chronic myeloproliferative disease associated with a t(5;12)(q31–q33;p13) translocation have now been reported, 3 and the PDGFRB gene is known . . .

Imatinib (Glivec) has been established as a highly effective therapy for chronic myeloid leukemia and gastrointestinal tumors. The recommended daily dosage of 400-600 mg requires simultaneous intake of up to six of the current 100-mg capsules. Due to the need to swallow multiple capsules per dose, there is a potential negative impact on treatment adherence; therefore, a new imatinib 400-mg film-coated tablet has been developed. To improve dosing flexibility, particularly with regard to the pediatric population and the management of adverse events, a scored 100-mg film-coated tablet has also been introduced. A group of 33 healthy subjects were randomly assigned to one of six treatment sequences, in which they received imatinib as 4 x 100-mg capsules (reference), 4 x 100-mg scored tablets (test), and 1 x 400-mg tablet (test). Blood sampling was performed for up to 96 h after dosing, followed by a 10-day washout period prior to the next sequence. After the third dosing, subjects were monitored to assess delayed drug-related adverse events. Pharmacokinetic parameters were assessed using concentration-time curves for plasma imatinib and its metabolite CGP74588. Median Tmax was 2.5 h for capsules and tablets. Mean AUC((0-inf)) values were 27,094, 26,081 and 25,464 ng.h/ml for 4 x 100-mg capsules, 4 x 100-mg tablets, and 1 x 400-mg tablets, respectively. Cmax values were 1748, 1638 and 1606 ng/ml, and t(1/2) values were 15.8, 15.9 and 15.7 h. The test/reference ratios for AUC((0-inf)), AUC((0-96) (h)), and C(max) were 0.98, 0.98 and 0.95 for 4 x 100-mg tablets versus 4 x 100-mg capsules, and 0.95, 0.95 and 0.92 for 1 x 400-mg tablet versus 4 x 100-mg capsules. The 95% confidence intervals were fully contained within the interval (0.80, 1.25). Eight mild and one moderate adverse event considered to be drug related were reported. These events showed no clustering by type of dosage form and were of little to no clinical significance. Film-coated 100-mg (scored) and 400-mg tablet dose forms of imatinib are bioequivalent to the commercial 100-mg hard-gelatin capsule, and are as safe and well tolerated.