Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive hairy cell leukemia

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation–positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation–positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation–positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation–positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.</p

Dabrafenib plus trametinib in BRAFV600E-mutated rare cancers:the phase 2 ROAR trial

BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43), gastrointestinal stromal tumor (n = 1), adenocarcinoma of the small intestine (n = 3), low-grade glioma (n = 13), high-grade glioma (n = 45), hairy cell leukemia (n = 55) and multiple myeloma (n = 19). The primary endpoint of investigator-assessed overall response rate in these cohorts was 56%, 53%, 0%, 67%, 54%, 33%, 89% and 50%, respectively. Secondary endpoints were median duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Median DoR was 14.4 months, 8.9 months, not reached, 7.7 months, not reached, 31.2 months, not reached and 11.1 months, respectively. Median PFS was 6.7 months, 9.0 months, not reached, not evaluable, 9.5 months, 5.5 months, not evaluable and 6.3 months, respectively. Median OS was 14.5 months, 13.5 months, not reached, 21.8 months, not evaluable, 17.6 months, not evaluable and 33.9 months, respectively. The most frequent (=20% of patients) treatment-related adverse events were pyrexia (40.8%), fatigue (25.7%), chills (25.7%), nausea (23.8%) and rash (20.4%). The encouraging tumor-agnostic activity of dabrafenib plus trametinib suggests that this could be a promising treatment approach for some patients with BRAFV600E-mutated advanced rare cancers. ClinicalTrials.gov registration: .Y

Chemoselective Deoxygenation of Nitrones and N-Oxides with Tetrathiomolybdate

Reaction of nitrones and N-oxides with benzyltriethylammonium tetrathiomolybdate in acetonitrile $(25^oC)$ yielded the corresponding imines and amines in good yields. Sulfoxides and azoxy benzenes are unaffected

Prop-2-ynyl as a protective group for carboxylic acids: A mild method for the highly selective deprotection of prop-2-ynyl esters using tetrathiomolybdate

It is shown that prop-2-ynyl esters are useful protecting groups for carboxylic acids and that they are selectively deprotected in the presence of other esters on treatment with tetrathiomolybdate under mild conditions

Selective deprotection of propargyl ethers using tetrathiomolybdate

Benzyltriethylammonium tetrathiomolybdate, [PhCH2NEt3](2)MoS4, 1 deprotects propargyl ethers of alcohols and phenols in a selective manner in high yields. Easily reducible groups like nitro, aldehyde, keto and allyl are not affected

A Facile Conversion of Amides and Lactams to Thioamides and Thiolactams using Tetrathiomolybdate

Chloro iminium salts generated in situ from amides and lactams using $(COCl)_2$ or $POCl_3$ reacted very readily with the new sulfur transfer reagent, benzyltriethylammonium tetrathiomolybdate to afford the corresponding thioamides and thiolactams in exellent yields under mild reaction conditions

A facile conversion of amides and lactams to thioamides and thiolactams using tetrathiomolybdate

Chloro iminium salts generated in situ from amides and lactams using (COCl)2 or POCl3 reacted very readily with the new sulfur transfer reagent, benzyltriethylammonium tetrathiomolybdate to afford the corresponding thioamides and thiolactams in exellent yields under mild reaction conditions

Sulfur transfer reactions of tetrathiomolybdate in water: Synthesis of alkyl disulfides from alkyl halides

Reaction of a number of alkyl halides with tetrathiomolybdate in water as the solvent affords the corresponding disulfides in good yields