Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist beta-naphthoyl-brevetoxin.

Brevetoxins are neurotoxic compounds produced by the dinoflagellate Karenia brevis. Extensive blooms induce neurotoxic shellfish poisoning (NSP) and asthma-like symptoms in humans. beta-naphthoyl-brevetoxin, the first semisynthetic brevetoxin antagonist, has been defined as the lead compound in the investigation of the mechanisms of bronchoconstriction induced by inhaled brevetoxins and relaxation or reversal of those effects by selected derivatives. In pursuit of more potent and effective brevetoxin antagonists, a series of beta-naphthoyl-brevetoxin analogues have been synthesized. Activities were determined by competitive displacement of tritiated brevetoxin-3 from rat brain synaptosomes and by lung resistance measurements in sheep. Additionally, preliminary computational structural studies have been performed. All analogues bound to rat brain synaptosomes with affinities similar to beta-naphthoyl-brevetoxin but exhibited very different responses in sheep. The biological evaluations along with computational studies suggest that the brevetoxin binding site in rat brain synaptosome might be different from the ones in lung tissue and both steric and electrostatic factors contribute to the efficacy of brevetoxin antagonism.

Natural and derivative brevetoxins: historical background, multiplicity, and effects.

Symptoms consistent with inhalation toxicity have long been associated with Florida red tides, and various causal agents have been proposed. Research since 1981 has centered on a group of naturally occurring trans-fused cyclic polyether compounds called brevetoxins that are produced by a marine dinoflagellate known as Karenia brevis. Numerous individual brevetoxins have been identified from cultures as well as from natural bloom events. A spectrum of brevetoxin derivatives produced by chemical modification of the natural toxins has been prepared to examine the effects of functional group modification on physiologic activity. Certain structural features of natural and synthetic derivatives of brevetoxin appear to ascribe specific physiologic consequences to each toxin. Differential physiologic effects have been documented with many of the natural toxins and derivatives, reinforcing the hypothesis that metabolism or modification of toxin structures modulates both the specific toxicity (lethality on a per milligram basis) and potentially the molecular mechanism(s) of action. A series of naturally occurring fused-ring polyether compounds with fewer rings than brevetoxin, known as brevenals, exhibit antagonistic properties and counteract the effects of the brevetoxins in neuronal and pulmonary model systems. Taken together, the inhalation toxicity of Florida red tides would appear to depend on the amount of each toxin present, as well as on the spectrum of molecular activities elicited by each toxin. Toxicity in a bloom is diminished by the amount brevenal present.

Synthesis of the cytotoxic sponge metabolite haliclamine A.

A new convergent and unified synthesis of the marine natural alkaloid haliclamine A is described. The synthesis of 3-alkylpyridine monomers 8 and 9 was first achieved from a common thiophene intermediate 5. These syntheses make use of thiophene chemistry and the ability of cyclopropylcarbinols 20 and 21 to rearrange to the homoallylic bromides 22 and 23, respectively. The Zincke procedure for the synthesis of pyridinium salts was then applied to the corresponding amino derivatives 8 and 9 to give efficiently unsymmetrical bis-pyridinium macrocycle 1, whose reduction afforded haliclamine A.