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: X-linked neutropenia (XLN, OMIM #300299) is a rare cause of severe congenital neutropenia and was first described in a three-generation Belgian family with 5 affected members. Reported features of XLN include severe congenital neutropenia and monocytopenia with recurrent bacterial infections, a decreased CD4/CD8 ratio and bone marrow maturation arrest at the promyelocyte/metamyelocyte stage. In the Belgian family, a L270P WAS mutation was identified, causing constitutive activity of the Wiskott-Aldrich-syndrome protein (WASP) toward actin polymerisation (Devriendt et al. Nat.Genet. 2001). Here, we report the clinical phenotype of a second large family with XLN and with a I294T WAS mutation. In this three-generation family, 10 affected males (7–45 y) and 8 female carriers were identified. Variable non-cyclic neutropenia is present in affected males (0.2–3.3*109/L in those not on G-CSF; 0.1–1.0*109/L on G-CSF). Five of 10 affected males in the I294T family have monocytopenia. A consistent feature in all cases is a reduced NK cell number. In fact, 3 of 3 tested L270P cases also had reduced NK cell counts. The severity of the clinical phenotype is variable without apparent correlation with the degree of neutropenia. Five of 10 affected males are receiving treatment with G-CSF because of recurrent infections. Four of 10 are reported healthy in the absence of G-CSF. One case with a borderline neutrophil count (2.4*109/L) is not on G-CSF, despite recurrent infections. In addition, two males with a history of recurrent infections, at least one of whom had neutropenia, died of infectious causes at age 5 and 18 years. Platelet counts are variably reduced in affected males, but with normal platelet volume. No consistent abnormalities in CD4/CD8 ratio are found. Available bone marrows have revealed no myelodysplastic features or cytogenetic abnormalities. Of note, female carriers show intermediate findings in neutrophil, platelet and NK cell counts. Only 1 female carrier is known with recurrent upper respiratory and ear infections and is treated with G-CSF. The T916C mutation we found in exon 9 of WAS, has recently been described (Ancliff et al. Blood online 2006) and results in a I294T mutation of the WASP GTPase-binding domain (GBD). The I294T GBD-VCA construct has a lower melting temperature (36°C) as measured by circular dichroism spectroscopy (78°C for wild-type). In the absence of Cdc42, I294T GBD-VCA is nearly completely active toward the Arp2/3 complex, contrary to wild-type GBD-VCA, but similar to the L270P construct. Thus, these data provide new and independent genetic evidence that mutations that disrupt the auto-inhibitory domain of WASP are the cause of XLN. In addition, based on this largest XLN kindred to date, reduced NK cell counts appear a consistent feature. None of the affected males presented with myelodysplasia. Finally, female carriers have moderately reduced neutrophil counts, mostly without clinical consequences. Thus, the presence of mild neutropenia in potential female carriers does not rule out the possibility of XLN in related males with neutropenia. Further investigation is needed to reveal how the L270P and the I294T WAS mutations lead to XLN.