Background: MK-8628 is a first-in-class BRD inhibitor blocking BRD2/3/4 motifs binding to acetylated histones on oncogenes, with clinical activity in advanced hematologic malignancies including acute ...myeloid leukemia and non-Hodgkin lymphoma and therapeutic potential in several solid tumor models. MK-8628 was evaluated for the first time in patients (pts) with selected advanced solid tumors to determine the recommended dose and administration schedule for phase II studies (P2RD). Patients and Methods: 47 pts with NUT midline carcinoma (NMC), castrate-resistant prostate cancer (CRPC), KRASmut or ALK+ non-small cell lung cancer (NSCLC) were enrolled in 6 centers/4 countries from Nov 2014 to Jan 2016. Two dosing regimens were evaluated in parallel with a 3+3 escalation scheme: oral MK-8628 once daily (QD) continuously (21/21) or QD for 7 consecutive days every 3 weeks (7/21) at starting doses of 80 and 100 mg respectively. Efficacy was determined in indication-specific expansion cohorts. Safety and PK were evaluated. Results: 46 pts were treated (26 CRPC, 10 NMC, 9 KRASmut and 1 ALK+ NSCLC). In the absence of dose-limiting toxicity (DLT) in the first 10 pts at dose level (DL) 1 (6 at 21/21, 4 at 7/21) and early signs of activity including pain relief with opioid cessation and PSA stabilization/decrease in CRPC pts irrespective of schedule, the Safety Monitoring Committee added more pts to further explore DLL For 21/21, 3 of 13 evaluable pts (23%) had DLT at 80 mg (grade G 3-4 thrombocytopenia), and 2 of 3 evaluable pts at 100 mg (treatment interruption >7 days for G2 gastrointestinal toxicity, G4 thrombocytopenia) and escalation was halted. 6 NMC pts were treated in an expansion cohort at 80 mg (21/21), 1 having G3 ALT/bilirubin increase. Maximal tolerated dose (MTD) was not reached in the 7/21 regimen with no DLT {13 pts at 100 mg, 3 pts at 120 mg, 6 pts at 160 mg). Overall, common toxicities were G3-4 thrombocytopenia in 9 pts (20%), G3 anemia in 4 pts (9%) and G3 fatigue in 3 pts (7%). 4 pts (3 NMC 80 mg 21/21; CRPC 120mg 7/21) had partial response (RECIST; 1.4-4+ months). Sustained SD occurred in 2 KRASmut NSCLC pts at 100 and 160 mg 7/21 (5.5-8 months), and 5 CRPC pts (4-8 months). PK describes a 1-compartment model with dose-proportional increase in MK-8628 exposure and rapid absorption (Ka = 0.616 h1) with Tmax 2-3 h, clearance 9.02 L/h, and a large volume of distribution (51.9 L). Conclusions: Oral MK-8628 has dose-proportional exposure witn a favorable tolerance profile in solid tumor pts, compelling evidence of clinical activity in NMC pts, and clinical improvement in heavily pretreated CRPC pts. 80 mg QD is the P2RD for the 21/21 regimen while the MTD for the 7/21 regimen was not reached. Given MK-8628 preclinical synergy/additivity with current CRPC treatments, further combination studies are warranted.
Posttransplant lymphoproliferative disorders (PTLD) represent a rare and potentially life-threatening complication after liver transplantation. Classical Hodgkin lymphoma (cHL), with an incidence of ...approximately 1.8–3.4% of all PTLD cases, represents a minority of PTLD, mainly presenting as a late transplant complication. The main risk factors for the development of PTLD are Epstein-Barr virus (EBV) infection and intensive immunosuppression. However, other risk factors like hepatitis C virus may, together with EBV infection, contribute to the development of PTLD. Here we present a case of late-onset EBV-positive cHL that occurred 10 years after an unrelated donor liver transplantation. To our knowledge, this is the first report of cHL occurring with such a long interval after liver transplantation. Given the low incidence of cHL PTLD, there is little information regarding pathology, clinical characteristics, and management of this disease. The development of individual, risk-adapted treatments may improve the long-term outcome of cHL PTLD.
Background: TAS-114 is a first-in-class oral deoxyuridine triphosphatase (dUTPase) inhibitor, which acts as a modulator of the pyrimidine nucleotide metabolic pathway, by enhancing incorporation of ...uracil and fluorouracil into DNA. A phase 1 study of combination treatment with TAS-1 14 and S-i is underway to investigate the safety, and to determine the maximum-tolerated dose (MTD) and recommended dose (SD) in patients (pts) with advanced solid tumors refractory to standard therapy. The secondary endpoints include efficacy, pharmacokinetics (P1<) and pharmacodynamics (PD). Material and Methods: TAS-114 and S-i were administrated orally BID for 14 days followed by 7 days rest at the starting dosage of 5mg/rn2 with the fixed dosage of 25mg/rn2, respectively. The study consists of 2 stages (Dose escalation and MTD expansion). Dose-limiting toxicity (DLT) was evaluated during the first cycle in the dose escalation, using the combination of accelerated titration (up to DL3) and 3 + 3 design (DL4 thereafter). In the MTD expansion, PK interaction and PD analysis using a biopsy post S-i single administration followed by a biopsy post S-1/TAS-114 administration were also conducted. Results: A total of 96 pts were enrolled with 37 pts in the dose escalation and 59 pts in the MID expansion. In the dose escalation, the dosages of TAS-114 and S-i were escalated up to 240 mg/rn2 and 36 mg/rn2, respectively. There were 2 DLTs (1 patient with Grade 3 rash and 1 patient with Grade 2 rash and Grade 2 hand-foot syndrome) observed at lAS-i 14, 240 mg/m2 in combination with S-i at 36 rng/m2 therefore, the combination of TAS-i 14 at 240 mg/rn2 and S-i at 30mg/rn2 was considered as the MTD and RD. The most common treatment related adverse events were anemia and rash. In the expansion, 59 patients with various cancer types were enrolled (22 colorectal, 10 non-small cell lung, 8 breast, 8 pancreas, 6 biliary tract, 2 pancreas neuroendocrine, 1 hepatocellular, 1 endometrial and 1 stomach). Four confirmed partial responses were observed in 2 non-small cell lung pts, 1 pancreas pt and 1 colorectal cancer pt to date (median It prior therapies: 3). In addition, there were noticeable number of pts who were responsive to continue the combination treatment for more than 6 months (long SD). PK of TAS-1 14 and S-i components was found dose proportional and there was no clear drug-drug interaction observed. PD analysis clearly showed the target engagement of TAS-114 by reducing amount of dUMP, a product of dUTPase inhibition following TAS-114/S-1 combination as compared to S-i singe agent administration. Conclusions: TAS-114 in combination with S-i was well tolerated in pts with heavily treated advanced solid tumors. resulting in promising antitumor efficacy. The activity of the combination regimen is being further evaluated in an ongoing international randomized Phase 2 trial.
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