ALBERT

Description: Background:MDM2, a negative regulator of the tumor suppressor p53, is overexpressed in a number of cancers including hematological malignancies. Disrupting the MDM2-p53 interaction represents an attractive approach to treat cancers expressing wild-type functional p53, and the inhibition of MDM2 and antitumor activity with the small molecule DS3032b has been demonstrated in preclinical studies and in patients with solid tumors. Here, we report the initial results of the Phase I trial aimed at characterizing the safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) profiles and preliminary efficacy of DS3032b in in patients with hematological malignancies. Methods:This study (NCT02319369) is a dose escalation study of DS-3032b as an oral single agent with a starting dose of 60 mg and escalating through 90 mg, 120 mg, 160 mg and 210 mg dose levels guided by a modified continuous reassessment method using a Bayesian logistic regression model following escalation with overdose control principle. The drug was administered orally once daily (QD) in 21 of 28 days per cycle (QD 21/28). The patient population included relapsed/refractory AML and high-risk MDS. Results:Thirty eight subjects with relapsed/refractory AML or high-risk MDS were enrolled in the study in 5 dose levels; 60 mg (7 pts), 90 mg (6 pts), 120 mg (12 pts), 160 mg (8 pts) and 210 mg (5 pts). Twenty four (63%) subjects were males. The median age was 68.5 (range 30-88) years, with approximately two-thirds over 65 years. Thirty-seven of 38 patients were p53 wild type, and one subject had known pathogenic insertion mutation with an allele frequency of about 20%. DS-3032b was tolerated up to 160 mg QD in the 21/28 days schedule that was determined to be the maximum tolerated dose. All subjects experienced at least one treatment emergent adverse event (TEAE) of any grade, and 93% subjects experienced a grade ≥3 TEAE at a data cut off on May 2, 2016. The most common (≥20%) TEAEs of any grade regardless of attribution were nausea (73%), diarrhea (57%) vomiting (33%), fatigue (37%), anemia (33%), thrombocytopenia (33%), neutropenia (20%) hypotension (30%), hypokalemia (23%) and hypomagnesemia (20%). A total of 5 subjects experienced dose limiting toxicities; two subjects in the 160 mg cohort due to grade 3 hypokalemia and grade 3 diarrhea, and three subjects in the 210 mg cohort due to grade 3 nausea and vomiting, grade 2 creatinine elevation/ renal insufficiency, and grade 3 anorexia and fatigue.. Preliminary PK results showed plasma exposure (Cmax and AUClast) increased with dose; and approximately 2-fold drug accumulation was observed on Day 15 following the daily oral dosing. Increase in the serum levels of macrophage inhibitory cytokine (MIC-1) as a p53 target gene was used as a circulating pharmacodynamic biomarker, where magnitude of MIC-1 serum level increase corresponded with DS3032 plasma exposure. Clinical activity of single agent DS-3032b was observed from the reduction in bone marrow blasts by the end of cycle 1 (4 weeks) in 15 of 38 patients. Complete remission was observed in 2 subjects with AML; 1 subject each at 120 mg and at 160 mg, with a remission duration of 〉4 and 〉10 months, respectively. One subject with MDS achieved marrow CR with platelet improvement, of 4 months duration, at the 120 mg dose level. Of note, each of these three subjects developed a TP53 mutation while on treatment, two at the time of disease progression and one subject who remains in an ongoing response. Further evaluation of DS-3032b in rational combinations such as with hypomethylating agents is being planned. Conclusions: Disruption of MDM2-p53 interaction by DS-3032b appears to be a promising approach to treat haematological malignancies. MDM2 expression/amplification in leukemic blasts is being investigated as a potential predictor of response. Rational combinations with agents targeting different mechanistic pathways may offer the most promise for further development. Disclosures DiNardo: Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Zernovak:Daiichi Sankyo: Employment. Kumar:Daiichi Sankyo: Employment. Gajee:Daiichi Sankyo: Employment. Chen:Daiichi Sankyo: Employment. Rosen:Daiichi Sankyo: Employment. Song:Daiichi Sankyo: Employment. Kochan:Daiichi Sankyo: Employment. Limsakun:Daiichi Sankyo: Employment.

Description: Cell surface transmembrane receptors often form nanometer- to micrometer-scale clusters to initiate signal transduction in response to environmental cues. Extracellular ligand oligomerization, domain-domain interactions, and binding to multivalent proteins all contribute to cluster formation. Here we review the current understanding of mechanisms driving cluster formation in a series of representative receptor systems: glycosylated receptors, immune receptors, cell adhesion receptors, Wnt receptors, and receptor tyrosine kinases. We suggest that these clusters share properties of systems that undergo liquid–liquid phase separation and could be investigated in this light.