No abstract

Introduction AC220 (Quizartinib) is a novel FLT3 inhibitor that has shown a high level of activity as monotherapy in patients with advanced FLT3 +ve disease, and more modest activity in FLT3 -ve patients across Phase 1 and 2 studies. This is the first presentation of quizartinib use in combination with chemotherapy in newly diagnosed (FLT3 +ve and FLT3 -ve) older AML patients. Study Aim In preparation for a prospective Phase 3 trial (NCRI AML 18) in older patients with newly diagnosed AML, we tested the feasibility and dose of AC220 which could be sequentially given two days after each of two courses of ADE (Ara-C/ Daunorubicin/ Etoposide) followed by one course of DA (2+5) in patients over age 60 with FLT3 +ve or FLT3 –ve newly diagnosed AML. Six cohorts with escalating doses (60mg, 90mg or 135mg based on doses used in the Phase 2 ACE study with quizartinib) for 7 or 14 days were planned. If 60mg was not tolerated there was provision to de-escalate to 40mg for 7 or 14 days. The study was based on a 3+3 design whereby if 1 of 3 developed a DLT a cohort expansion was required but if >2 of 6 had a DLT, the cohort failed. A DLT was defined as any grade 4 non-haematological toxicity or failure of count recovery by day 42 in the absence of marrow blasts, or a grade 3 toxicity that did not recover to at least grade 2 within 7 days. Because of the increased sensitivity in females to QTc prolongation, each cohort required a minimum of 3 females. The day of safety evaluation was on completion of the chemotherapy in course 2. Results 55 patients with a median age of 69 years (62-87) entered of whom 48 were evaluable. 4 patients were FLT3 ITD +ve. 13 patients (4 males, 9 females) entered cohort 1 (AC220 60mg for 7days). No DLTs were seen in males but 3 DLTs occurred in females (all grade 4:1 cardiac (MI), 1 hypokalaemia; 1 mucositis) so this cohort exceeded tolerability for females. 8 patients (all males) entered cohort 2 (AC220 60mg for 14 days) where 4 DLTs (all grade 3; 3 QTC, 1 appetite loss) were seen, so this cohort exceeded tolerability for males. The de-escalation cohort (cohort 3) was activated (AC220 40mg for 7 days). 2 DLTs (1 grade 4 lung; 1 lung infection grade 3 >7days) in 7 evaluable females and 0 DLTs in 9 evaluable males were seen, so both males and females progressed to Cohort 4 (AC220 40mg for 14 days). There was 1 DLT (haematological) of 5 evaluable males and 0 of 8 evaluable females had a DLT. The DLTs were similarly distributed between males (5/25) and females (5/23). Induction death (death with 30 days) occurred in 3/46 (6.5%) evaluable patients. CR was achieved in 33/42 (79%; including all 4 FLT3 ITD +ve) of patients evaluable for CR or 60% of all 55 patients. Overall median time to neutrophil and platelet count recovery (neutrophils to 1.0x109/l; platelets to 100x109/l) was prompt (28 and 22 days post course 1; 22 and 19 days post course 2 respectively). No patients received SCT. The median OS is currently 15 months. Conclusion AC220 at 40mg for 14 days can safely be given sequentially after chemotherapy in older patients with newly diagnosed AML. The Phase 3 AML 18 study is planned to start in early 2014 and will incorporate AC220 into multiple courses of DA therapy as well as maintenance therapy. On behalf of the UK NCRI AML Working Group. We acknowledge the support from Ambit Biosciences for this study. Disclosures: Burnett: Ambit: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: AC220 for newly diagnosed AML. Hills:Ambit: Consultancy.

Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3 + AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering CR, but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at day 26 (Mann-Whitney p < 0.0001). Day 26 Flt3L was also associated with survival: Flt3L ≤ 291pg/ml was associated with inferior event-free survival; and, Flt3L >1185pg/ml was associated with higher overall survival (p = 0.0119). Serial measurement of Flt3L in patients who had received a hematopoietic stem cell transplant for AML further illustrated the potential value of declining Flt3L to identify relapse. Together these observations suggest that measurement of Flt3L provides a non-invasive estimate of progenitor cell mass in most patients with AML, with the potential to inform clinical decisions.

Book distributed under the Attribution-NonCommercial-NoDerivs (CC BY-NC-ND) which allows third parties to download the articles and share them with others as long as they credit the author and the Abstract Book, but they cannot change the content in any way or use them commercially.

Background CCS1477 is a first in class potent, selective and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in haematological malignancies. In pre-clinical studies, CCS1477 was found to be a potent inhibitor of cell proliferation in acute myeloid leukaemia (AML) multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines. In primary patient AML blast cells CCS1477 inhibited proliferation through a combination of cell cycle arrest at the G1/S transition and an induction of differentiation (up-regulation of CD11b and CD86). CCS1477 has significant anti-tumour activity, inducing tumour regressions in xenograft models of AML and MM. These effects were accompanied by significant reductions in tumour MYC and IRF4 expression. Additionally, there are molecular features of certain haematological malignancies that are likely to increase the sensitivity to p300/CBP inhibition with CCS1477. For example, in B-cell lymphomas there are frequent loss of function mutations in CBP that are associated with heightened sensitivity to pre-clinical inhibition of corresponding non-mutated p300. CCS1477 represents a novel and differentiated approach to inhibiting cell proliferation and survival and offers a potential new therapeutic option for patients who have relapsed or are refractory to current standard of care therapies in AML, MM or NHL. Study Design and Methods This study is the first time that CCS1477 is being dosed in patients with haematological malignancies. The Phase I/IIa study aims to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy in patients with haematological malignancies. This study will also characterise the pharmacokinetics (PK) of CCS1477 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers. The trial aims to enrol approximately 90 patients and is currently recruiting in the UK with plans to open additional sites in the USA. Key inclusion criteria include patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (AML, MM and NHL). Patients must have received standard therapy which for the majority of therapeutic indications is at least 2 prior lines of therapy. Single dose and steady state pharmacokinetics will be determined in all patients. AML response will be measured in bone marrow samples. Myeloma response will be evaluated according to the 'International Myeloma Working Group Response Criteria' based on changes in M protein in blood and/or urine, changes in serum free light chains if measurable, and changes on imaging and/or bone marrow if applicable and according to the guidelines. In NHL patients, tumour assessments will be done for measurable disease, non-measurable disease, and new lesions on CT (or magnetic resonance imaging [MRI]) and/or combined with visual assessment of [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) for response assessment per recent International Working Group consensus criteria (RECIL 2017), until progression The study will begin with two parallel monotherapy dose-escalation arms; Arm 1: Relapsed or refractory NHL and MM; Arm2: Relapsed or refractory AML/high-risk MDS. Once a recommended phase 2 dose/schedule is reached, three monotherapy expansion arms will be opened in AML/high-risk MDS (15 patients), MM (15 patients) and NHL (30 patients). Blood samples along with bone marrow biopsies and aspirates will be collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. This will include the analysis of tumour-specific and circulating biomarkers, such as tumour DNA, mRNA, proteins or metabolites. In NHL patients, analysis of CBP (and p300) mutations will be undertaken to allow retrospective correlation with tumour response and to determine if loss of function mutations in the genes for either proteins can be utilised as response predictive biomarkers in future studies. Disclosures Clegg: CellCentric Ltd: Employment, Equity Ownership. Brooks:CellCentric Ltd: Employment, Equity Ownership. Ashby:CellCentric Ltd: Employment, Equity Ownership. Pegg:CellCentric Ltd: Employment, Equity Ownership. West:CellCentric Ltd: Employment, Equity Ownership. Somervaille:Novartis: Consultancy. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Davies:ADCT Therapeutics: Honoraria, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioInvent: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; GSK: Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.