Composite Complete Remission Rate Research Articles

Do Statins Enhance the Anti-Cancer Activity of Venetoclax?

▪Introduction: Venetoclax is an oral, small-molecule BCL-2 inhibitor capable of restoring apoptosis in susceptible cancers. It is approved in the US for treatment of relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion and in Europe for patients who are unsuitable for or who have failed B-cell receptor inhibitor (BCRi) therapy. It is also being evaluated in the broader CLL population and other hematologic malignancies. These diseases mostly afflict older patients, many of whom are treated with statins for high cholesterol. Aside from their cholesterol-lowering utility, statins have shown potential to induce apoptosis in various cancer cell lines, with evidence of synergism when combined with BCL-2 inhibition. On this background, post-hoc analyses of clinical trials in patients with CLL and multiple myeloma (MM) were undertaken to determine if statins have the potential to enhance the activity of venetoclax.Methods: Data from CLL subjects were pooled from 3 single-arm, open-label Phase 1 or 2 trials of venetoclax monotherapy in subjects with R/R disease: Study 1 (NCT01889186) enrolled subjects exclusively with 17p(del) CLL; Study 2 (NCT01328626) was a first-in-human, dose-escalation study in subjects with CLL/SLL and NHL; Study 3 (NCT02141282) enrolled CLL subjects previously treated with ibrutinib or idelalisib. MM data were from 2 single-arm, open-label Phase 1 studies in patients with R/R disease: Study 4 (NCT01794507) evaluated venetoclax in combination with bortezomib and dexamethasone (VenVd); Study 5 (NCT01794520) evaluated treatment with venetoclax monotherapy (Ven) or venetoclax plus dexamethasone (Vendex). Previously, it was reported that single-agent activity of venetoclax is almost entirely restricted to t(11;14) positive MM; therefore, analyses of response among subjects who received Ven or Vendex were limited to this subgroup. The following CLL endpoints were analyzed based on investigator assessment: overall remission rate (ORR), the composite complete remission (CR) rate (CR + CR with incomplete marrow recovery), progression free survival (PFS), and overall survival (OS). Odds ratios for ORR and CR were compared via Fisher exact test. PFS and OS were analyzed by Kaplan-Meier methodology. Multivariate analyses were conducted using Cox proportional hazard model (OS and PFS) and logistic regression model (ORR and CR) with implementation of a stepwise model selection procedure. For the MM studies, descriptive statistics were prepared based on investigator assessment for ORR, partial response (PR), and very good partial response (VGPR) or better. Exposure-response analyses have previously shown that higher exposures to venetoclax in CLL patients are associated with greater likelihood of CR and longer PFS; therefore, we also investigated the potential for statins to increase venetoclax exposures utilizing steady state pharmacokinetic sampling from Study 2.Results: In CLL studies, 22% of patients received a statin; statin users were more often male (79% vs. 67%), ≥65 years of age (73% vs. 54%), and enrolled at US sites (69% vs 46%). While the proportion of CLL subjects with any response (ORR) was similar for subjects with and without statin use (76% vs 75%), more statin users achieved CR, with cumulative CR rates of 26.7% vs. 15.2% in the pooled analysis. The unadjusted odds ratio (95% CI) for CR was 2.03 (1.099, 3.741; P=0.03) in favor of statin users, and the corresponding multivariable-adjusted odds ratio was 2.676 (1.338, 5.351; P<0.01). PFS and OS results were consistent with CR rates, with respective multivariable-adjusted hazard ratios of 0.61 (0.383, 0.956; P=0.03) and 0.50 (0.247, 1.007; P=0.05). The pharmacokinetic analysis showed no difference in venetoclax exposures between patients taking a statin versus those who did not. There were no unexpected safety observations in either group. The trend for improved response among statin-treated subjects was also present for the broad MM subject population treated with VenVd in Study 4 and t(11;14) positive MM subjects treated with Ven or Vendex in Study 5.Conclusions: Statins were associated with enhanced response to venetoclax in retrospective analyses of CLL and MM clinical trials. Given the post-hoc nature of these findings and lack of randomization, further evaluation in a prospective, randomized clinical trial is required to draw definitive conclusions. [Display omitted] DisclosuresRoberts:AbbVie: Employment, Equity Ownership. Xu:AbbVie: Employment, Equity Ownership. Jia:AbbVie: Employment, Equity Ownership. Agarwal:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Bellin:Abbvie: Employment, Equity Ownership. Lam:AbbVie: Employment, Equity Ownership.

Venetoclax and azacitidine combination in chemotherapy ineligible untreated patients with therapy-related myeloid neoplasms, antecedent myelodysplastic syndromes, or myelodysplastic/myeloproliferative neoplasms.

7011 Background: Patients (pts) with therapy-related myeloid neoplasms (tMN), antecedent myelodysplastic syndrome, or antecedent myelodysplastic/myeloproliferative neoplasms (A-MDS/MPN) may have poor outcomes due to age and adverse genetic/karyotypic features. In the VIALE-A study, pts with tMN and A-MDS/MPN unfit for intensive chemotherapy treated with venetoclax (Ven) and azacitidine (Aza) demonstrated superior response rates and overall survival (OS) than Aza alone. Herein, the efficacy and safety of Ven+Aza among pts with tMN and A-MDS/MPN are described. Methods: Data were pooled from pts enrolled in VIALE-A (NCT02993523) comparing pts who received Ven+Aza or placebo (Pbo)+Aza and a prior phase 1b study (NCT02203773) where pts received Ven+Aza. Enrolled pts were ≥18 years, treatment-naïve with no prior exposure to hypomethylating agents, and ineligible for intensive chemotherapy. Pts on Ven+Aza received Ven 400 mg orally (days 1–28) and Aza (75 mg/m2; days 1-7/28-day cycle). Composite complete remission rate (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]), duration of response (DoR), and OS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: In this pooled analysis, tMN was observed in (Ven+Aza/Pbo+Aza) 31/9 and A-MDS/MPN in 59/26 pts. Poor-risk cytogenetics were observed in 18 (58%)/6 (67%) with tMN (5 or 5q deletion [del]: 4/1 ; 7 or 7q del: 6/1 ; complex [≥ 3 clonal abnormalities]: 10/4), and 19 (32%)/13 (50%) with A-MDS/MPN (5 or 5q del: 10/5; 7 or 7q del: 6/1; complex: 14/9). TP53 mutation was observed in 5/3 pts with tMN and 8/0 pts with A-MDS/MPN. Pts with tMN received a median (Ven+Aza/Pbo+Aza) of 5/4 cycles of treatment. CRc was achieved by 19 (61%)/1 (11%). The mDoR was not reached (NR) (95% CI: 17.8, NR)/8.5 (NR, NR) months. The mOS was 16.4 (95% CI: 4.1, NR)/11.3 (0.6, 17.5) months. Pts with A-MDS/MPN received a median (Ven+Aza/Pbo+Aza) of 9/5 cycles of treatment. CRc was achieved by 39 (66%)/7 (27%) pts with mDoR of 17.3 (95% CI: 9.6, NR)/5.8 (1.1, NR) mos. The mOS was 15.9 (95% CI: 11.5, NR)/10.1 (4.7, 14.5) mos. Common grade≥3 adverse events (Ven+Aza/Pbo+Aza) were febrile neutropenia (tMN: 39%/11% and A-MDS/MPN: 36%/12%) neutropenia (tMN: 29%/33%; A-MDS/MPN: 39%31%), and thrombocytopenia (tMN: 32%/33%; A-MDS/MPN: 39%/62%). Conclusions: Ven+Aza compared to Aza monotherapy resulted in higher CRc rates with longer DoR and median OS among treatment-naïve pts with tMN and A-MDS/MPN ineligible for intensive chemotherapy. The safety profile was similar to overall pts with the Ven+Aza combination. Outcomes by cytogenetic and molecular risk-groups will be presented. Clinical trial information: NCT02993523, NCT02203773.

Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆

The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin—a new, potent murine double minute 2 antagonist—alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN)

Real-World Data of Azacytidine Efficacy As Front-Line Treatment for AML Non-Eligible for Intensive Treatment and High-Risk MDS: A Peruvian Multicenter Study

Background:Acute Myeloid leukemia (AML) and High-risk Myelodysplastic Syndrome (MDS) are two aggressive myeloid neoplasms characterized by dismal outcomes in patients not suitable for intensive treatment. During the last decades, hypomethylating agents (HMA) represented a valuable treatment option for AML and MDS, particularly in older or unfit patients. However, the limited efficacy and high-costs concerns in developing countries limited its general use. Azacytidine is the most representative and available HMA in limited-sources facilities. We aimed to explore the efficacy of azacytidine as frontline treatment in terms of event-free (EFS) and overall survival (OS) for newly diagnosed patients with AML non-candidates to intensive chemotherapy and MDS in Peru. Methods: We reviewed medical records of patients diagnosed and managed for AML at three private cancer institutions in Lima-Peru (Oncosalud, Clinica Delgado and Clinica Angloamericana) between 2010 and 2019. Cytogenetics and molecular markers were not retrospectively available during data obtention. Clinical characteristics, laboratory data and outcomes were evaluated for patients with AML and MDS who received at least 1 cycle of AZA as frontline treatment. AZA was given at accumulated dose of 75mg/m2/daily for 7 days every 4 weeks, however further dose reductions were allowed by physician criteria. Best responses were assessed according to Leukemia.net consensus, but summarize as complete remission (CR), partial response (PR) and stable disease (SD). Survival curves (event-free and overall survival) were estimated using the Kaplan-Meier method and compared with the Log-rank test. Results:A total of 76 patients were included and had sufficient data for analysis. Fifty-two cases had AML and 24 MDS. Clinical characteristics, Laboratory data, Treatment and Outcomes were summarized in Table 1. Median ages for AML was 74 and 69 for MDS, 37% and 54% had less than 70 years in AML and MDS, respectively. Female/male ratio was 1:1 for AML and 1:3 for MDS. One-third of AML cases and 48% of MDS had an ECOG performance status ≤1. Twenty-five (48%) of AML patients had Secondary AML to MDS, and 25% had prior cancer treatment. Median number of cycles of AZA was 5 for both groups. A high composite CR rates were seen for AML (39%) and MDS (25%), PR were 10% and 8% for AML and MDS, respectively. The majority of MDS cases reached stable disease (62%), and 35% in AML. Three patients underwent to allo-transplant (2 AML and 1 MDS). Relapsed rates were more frequent in AML cases (AML 63% vs. 30%), however, deaths were similar in both groups. At a median follow-up of 4-years, the EFS was 3% for AML and 20% for MDS, and OS was 16% and 30% for AML and MDS patients, respectively. Conclusions: Azacytidine represents an effective and accessible therapy for AML non-candidates to intensive chemotherapy and MDS in limited-sources settings. Access to novel effective therapies must be warranted for these highly aggressive myeloid neoplasms in developing countries. Disclosures No relevant conflicts of interest to declare.

Reassessing the role of high dose cytarabine and mitoxantrone in relapsed/refractory acute myeloid leukemia.

A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18–77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17–0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16–0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.

A Phase 1/2 Study of Quizartinib (Q) in Combination with Re-Induction Chemotherapy and As Single-Agent Continuation Therapy in Pediatric and Young Adult Patients with Relapsed/Refractory (R/R) FLT3-ITD Acute Myeloid Leukemia (AML)

Background Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations occur in 10%-15% of pediatric/adolescent patients with AML and are associated with treatment resistance, risk of relapse, and poor survival. Nearly 50% of children with newly diagnosed FLT3-ITD AML fail treatment or relapse as their first event (Levis, et al, Intl J Hematol 2005; Gilliland, Blood 2002). Therefore, targeting FLT3-ITD may improve clinical responses or prevent relapse in younger patients with FLT3-ITD mutations. No FLT3 inhibitors are approved for use in children. Q is an oral, highly potent and selective, type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, Q monotherapy prolonged overall survival vs salvage chemotherapy in adult patients with R/R FLT3-ITD AML (Cortes, et al, Lancet Oncol 2019). In another study, Q combined with chemotherapy in pediatric patients (age ≤ 21 years) with R/R AML or acute lymphoblastic leukemia, regardless of FLT3-ITD status, resulted in a marked reduction in bone marrow blasts for patients with FLT3-ITD vs other patients (Cooper, et al, Clin Cancer Res 2016). Thus, there is a strong rationale to investigate Q for treatment of R/R FLT3-ITD AML in pediatric/adolescent patients. Study Design and Methods This open-label, multicenter, single-arm, phase 1/2 study (NCT03793478) consists of dose-escalation and -expansion phases. Patients will be stratified into 2 age groups: 1 to &lt; 12 months (younger age group) and 1 to ≤ 21 years (older age group). Key inclusion criteria are diagnosis of FLT3-ITD AML, first relapse or refractory to first-line high-dose chemotherapy with adequate organ function. Patients who received prior therapy with other FLT3 inhibitors or prior stem cell transplant (SCT) are eligible. Key exclusion criteria include acute promyelocytic leukemia or juvenile myelomonocytic leukemia, significant cardiovascular disease (including QTc &gt; 450 ms), active systemic infections, liver disease, or HIV infection. Phases 1 and 2 include ≤ 2 reinduction cycles, optional consolidation therapy, and continuation therapy for those having a partial response (PR) or remission. Reinduction therapy will consist of fludarabine and cytarabine (FLA; 30 mg/m2/day and 2000 mg/m2/day, respectively) followed by Q in 28-day cycles. Patients will be treated with intrathecal (IT) triple chemotherapy prophylaxis before reinduction cycles 1 and 2 and after cycle 2. Additional IT triple chemotherapy prophylaxis may be given at investigator discretion for patients with CNS2 disease. Patients achieving at least a PR after reinduction may receive optional consolidation chemotherapy as a bridge to allogeneic hematopoietic SCT (HSCT). Optional consolidation regimens are high-intensity chemotherapy (cytarabine 500 mg/m2/day + etoposide 100 mg/m2/day) followed by Q, or low-intensity consolidation with either Q monotherapy or cytarabine (75 mg/m2/day). Patients who achieve at least a PR after reinduction or continue to be in remission after HSCT may receive continuation therapy with Q monotherapy (for up to twelve 28-day cycles). In phase 1, the starting dose of Q for the reinduction cycle for patients 1 to ≤ 21 years will be 40 mg/m2 once daily with body surface area (BSA) &lt; 1.5 m2 or 60 mg once daily for patients with BSA ≥ 1.5 m2. The starting dose of Q for younger patients in phase 1 will be determined from the recommended phase 2 dose (RP2D) from the older age group and pharmacokinetic (PK) modeling. Up to 9 patients per dose level will be enrolled in the older age group, and younger patients will be enrolled using a rolling 6 design. Patients in phase 2 will receive the RP2D for their respective age group. The planned sample size is 41-65 patients to meet the target of 41 response-evaluable patients at the RP2D. QTc based dose modifications will be instituted for Q. The primary endpoints are safety, composite complete remission rate (CRc; defined as complete remission + complete remission with incomplete recovery), and PK parameters. Secondary endpoints include duration of responses, relapse rates, overall survival, and event-free survival at 1, 2, and 3 years, number of patients proceeding to HSCT, pharmacodynamics, gene mutations in bone marrow blasts, minimal residual disease, and FLT3 allelic ratio. This study is recruiting and being conducted in collaboration with the Children's Oncology Group in North America and the Innovative Therapies for Children with Cancer Consortium in Europe. Disclosures Zwaan: Servier: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Janssen: Consultancy; Roche: Consultancy; Celgene: Consultancy, Research Funding; Sanofi: Consultancy; Jazz Pharmaceuticals: Other: Travel support; Incyte: Consultancy; Novartis: Consultancy. Mires:Daiichi Sankyo: Employment. Vigliotti:Daiichi Sankyo, Inc.: Employment. Xie:Daiichi Sankyo, Inc.: Employment. Downs:Daiichi Sankyo, Inc.: Employment. DeCillis:Pyramid: Consultancy; Codiak: Consultancy; Eleven: Consultancy; Arvinas: Consultancy; Exelixis: Consultancy; Novartis: Consultancy; Genocea: Consultancy; Daiichi Sankyo, Inc.: Consultancy; CytomX: Consultancy.

PS1065 OPEN‐LABEL STUDY OF GILTERITINIB, GILTERITINIB PLUS AZACITIDINE, OR AZACITIDINE ALONE IN NEWLY DIAGNOSED FLT3‐MUTATED AML PATIENTS INELIGIBLE FOR INTENSIVE CHEMOTHERAPY: RESULTS FROM THE SAFETY COHORT

Background:The FLT3 inhibitor, gilteritinib, showed antileukemic activity and favorable tolerability in patients (pts) with FLT3‐mutated (FLT3 mut+) relapsed/refractory AML. Gilteritinib plus azacitidine (AZA) induced apoptosis and inhibited MV4–11 cell and tumor growth. A clinical trial investigating gilteritinib plus AZA vs either agent alone in pts with newly diagnosed (ND) FLT3 mut+ AML ineligible for intensive induction chemotherapy was initiated; we present data from the Safety Cohort, which evaluated combination therapy.Aims:A clinical trial investigating gilteritinib plus AZA vs either agent alone in pts with newly diagnosed (ND) FLT3 mut+ AML ineligible for intensive induction chemotherapy was initiated; we present data from the Safety Cohort, which evaluated combination therapy.Methods:Adults with ND FLT3 mut+ AML are being enrolled in this clinical trial (NCT02752035). To determine the appropriate gilteritinib dose for combination therapy prior to the randomized portion of the study, a Safety Cohort was initiated, in which pts received 80 or 120 mg/day gilteritinib (Days 1–28) plus subcutaneous/intravenous AZA (75 mg/m2/day; Days 1–7) and were observed for dose‐limiting toxicities (DLTs) through Cycle 1. Treatment continued until lack of clinical benefit or unacceptable toxicity. Safety/tolerability and antileukemic response were assessed.Results:Fifteen pts (median age, 76 years [range: 65–86]) were enrolled into the Safety Cohort (n = 9, 80 mg gilteritinib; n = 6, 120 mg gilteritinib); 14 were FLT3 mut+ (ITD alone, n = 10; TKD alone, n = 3; ITD and TKD, n = 1). As of 25 June 2018, 56% (n = 8/15; Figure) of pts had been treated for &gt;6 mo, 9 discontinued, and 6 remained on treatment. A DLT (tumor lysis syndrome) occurred in a pt who received 80 mg gilteritinib plus AZA; no DLTs occurred in the 120 mg gilteritinib plus AZA cohort. All 15 pts had ≥1 AE; 12 (80%) experienced treatment‐related AEs. Common AEs were anemia (n = 7), febrile neutropenia and nausea (n = 6 each), increased ALT/AST, constipation, diarrhea, neutropenia, thrombocytopenia, and pyrexia (n = 5 each), and decreased appetite, fatigue, increased blood creatinine, and hypocalcemia (n = 4 each). Common grade ≥3 AEs were febrile neutropenia (n = 6), anemia and neutropenia (n = 5 each), and thrombocytopenia (n = 4). Serious AEs in &gt;2 pts were febrile neutropenia (n = 5), and anemia and pyrexia (n = 3 each). Eight pts had fatal AEs; none were treatment‐related and 3 occurred early in treatment: septic shock (Day 2), respiratory failure (Day 6), and cerebral hemorrhage in the setting of acute kidney injury and uremia (Day 17). Of 13 pts with post‐baseline laboratory data, none had clinically significant AST/ALT or total bilirubin values or maximum post‐baseline QTcF interval &gt;500 msec.The composite complete remission rate was 67% (n = 10/15); complete remission and complete remission with incomplete hematologic recovery was achieved in 4 and 6 pts, respectively (Figure); 2 pts (13%) achieved a partial response, giving an overall response rate of 80%. One DLT from the 11 DLT‐evaluable pts (ie, pts who experienced a DLT, or in the absence of DLT, received ≥23 of 28 gilteritinib doses and ≥5 of 7 AZA doses during DLT observation) informed the decision to proceed to randomization at 120 mg/day gilteritinib for combination treatment.Summary/Conclusion:In ND FLT3 mut+ AML pts unfit to receive standard induction chemotherapy, gilteritinib and AZA were well tolerated, and induced antileukemic responses. Based on these results, enrollment into the randomized portion of the study has begun and pts in the combination arm will receive 120 mg gilteritinib.image

A randomized phase II trial of CX-01 with standard therapy in elderly patients with acute myeloid leukemia (AML).

7001 Background: Elderly AML patients have poor outcomes irrespective of therapy. CX-01 is a low anticoagulant heparin derivative that retains heparin’s ability to alter the activity of the CXCL12/CXCR4 axis, P-selectin, extracellular histones, and Platelet Factor 4. A pilot study of CX-01 combined with standard therapy for AML led to a complete remission (CR) rate of 92% ( Blood Adv 2:381, 2018). We conducted a randomized, dose-finding study of the same combination in newly diagnosed elderly AML patients. Methods: 76 fit patients older than 59 were randomized to induction with idarubicin and cytarabine on a 7+3 schedule only (Group 1); 7+3 with a lower dose of CX-01 (0.125 mg/kg/hour) (Group 2); or 7+3 with a higher dose of CX-01 (0.25 mg/kg/hour) (Group 3). Patients in CR received consolidation therapy consisting of up to 3 cycles of intermediate dose cytarabine (1000 mg/m2 every 12 hours on Days 1, 3, 5) without or with the same dose of CX-01 for Groups 1, 2, and 3, respectively. CX-01 was given as a continuous infusion after a 4 mg/kg bolus until completion of chemotherapy. Results: 66 of 75 treated patients were evaluable for response. Ten patients were not evaluable due to withdrawal of consent (6 patients), introduction of midostaurin after its approval (3 patients), or death due to hepatic sinusoidal obstructive disease at Day 21 (1 patient in Group 2). We present results for evaluable patients and not on an intent to treat basis. Baseline characteristics were similar across groups. The composite CR rate (CR + CRi) was highest for patients in Group 3 with 89% patients achieving a composite CR as compared to 58% and 50% in Groups 1 and 2, respectively. Kaplan-Meier curves indicated a statistically significant improvement in event free survival (EFS) (P = 0.019) and a non-significant trend (P = 0.10) to improvement in OS in Group 3 as compared to Group 1. Groups 1 and 2 were comparable for EFS and OS. CX-01 was well tolerated without increased incidence of bleeding in Groups 2 and 3. Conclusions: The encouraging CR rate and EFS in elderly fit patients with newly diagnosed AML suggests that CX-01 may potentiate the efficacy of standard AML induction therapy. A randomized study to confirm these findings with the higher dose of CX-01 is warranted. Clinical trial information: NCT02873338.

Multicenter, Open-Label, 3-Arm Study of Gilteritinib, Gilteritinib Plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy: Findings from the Safety Cohort

Multicenter, Open-Label, 3-Arm Study of Gilteritinib, Gilteritinib Plus Azacitidine, or Azacitidine Alone in Newly Diagnosed FLT3 Mutated (FLT3mut+) Acute Myeloid Leukemia (AML) Patients Ineligible for Intensive Induction Chemotherapy: Findings from the Safety Cohort

Intensive chemotherapy vs. hypomethylating agents in older adults with newly diagnosed high-risk acute myeloid leukemia: A single center experience

Acute myeloid leukemia (AML) in older patients is often associated with biologic and clinical characteristics that predict poor outcomes to cytarabine and anthracycline based induction chemotherapy (IC). The impact of hypomethylating agents (HMA) in the treatment of these high-risk patients is unknown. Here we retrospectively examined the remission rates and survival outcomes of 201 newly diagnosed patients ≥60 years old with therapy-related (t-AML), secondary (s-AML), or AML with myelodysplasia-related changes (AML-MRC). Ninety-eight patients received IC, and 103 received HMA. Patients in the IC cohort were younger than those who received HMA (68 vs. 74 years; p < 0.01) with lower comorbidity burden. Composite complete remission rates (CR) were 39% in IC and 27% in the HMA cohorts (p = 0.10). Overall survival (OS) was not significantly different between the two cohorts (7.59 mos vs. 5.49 mos; HR 0.75 95% CI 0.55–1.02) despite the fact that more patients in the IC cohort (33% versus 5%, p < 0.01) underwent allogeneic stem cell transplant. Patients with t-AML (HR 0.56; 95% CI 0.33–0.97) and complex karyotype without monosomal karyotype (CK + MK-; HR 0.37; 95% CI 0.19–0.75) had better OS following IC. Patients with CK + MK+ (HR 2.00; 95% CI 1.08–3.70) had improved OS following HMA. Our results support the use of HMA as an alternative upfront regimen in older individuals with newly diagnosed high-risk AML based on similar clinical outcomes to IC.

Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia.

TPS7069 Background: Elderly acute myeloid leukemia (AML) is a biologically and clinically distinct disease with a diminished response to chemotherapy, low remission rates, and short disease-free and overall survival. Venetoclax (VEN) is a potent, selective small-molecular inhibitor of BCL-2. In preclinical models, venetoclax has been shown to kill AML cells as a single agent with demonstrated synergistic activity in combination with the DNA methyltransferase inhibitor azacitidine (AZA). Early clinical data from a phase 1b study (NCT02203773) showed that VEN plus AZA had an acceptable safety profile and promising efficacy in treatment-naïve elderly patients with AML. The current phase 3 study continues to evaluate the combination for this AML population. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT02993523) is designed to assess VEN plus AZA compared with placebo plus AZA in treatment-naïve elderly and adult patients with AML who are not eligible for standard induction therapy due to age or comorbidities. Primary objectives of the study are to evaluate if VEN with AZA will improve overall survival (OS) and composite complete remission rate (CR+CRi) versus placebo with AZA. Secondary objectives include event-free survival, CR+CRi rate at the end of Cycle 1, and if combining VEN plus AZA reduces fatigue and improves global health status/quality of life based on patient reported outcomes versus placebo with AZA. Exploratory objectives are to evaluate biomarkers predictive of VEN activity including minimal residual disease negativity rate, and BCL-2 expression and outcome measures of overall survival and complete remission rate, as well as the impact of VEN on additional quality of life measures. Patients will be randomized 2:1 to VEN plus AZA (arm A) or placebo plus AZA (arm B). Patients on arm A will receive once daily 400 mg VEN orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days in a 28-day cycle. Patients on arm B will receive once daily placebo orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days on a 28-day cycle. Study recruitment began in February 2017, with target enrollment of 400 patients. Clinical trial information: NCT02993523.

CASCADE: A phase 3, randomized, double-blind study of vadastuximab talirine (33A) versus placebo in combination with azacitidine or decitabine in the treatment of older patients with newly diagnosed acute myeloid leukemia (AML).

TPS7066 Background: AML is associated with poor survival rates in patients (pts) who are not eligible for intensive chemotherapy or allogeneic stem cell transplant (allo-SCT) due to advanced age, comorbidities, and/or disease risk factors. Non-intensive therapies, such as the hypomethylating agents (HMAs) azacitidine and decitabine, are frequently employed in this setting; however, response rates and survival remain suboptimal in this pt population. Vadastuximab talirine (33A) is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Upon binding, 33A is internalized and transported to the lysosomes where PBD is released via proteolytic cleavage of the linker, leading to DNA crosslinking and cell death. In preclinical studies, HMA priming followed by 33A exposure upregulated CD33 expression, increased DNA incorporation of the PBD dimer, and enhanced cytotoxicity. In a phase 1 study, 33A plus HMA was generally well tolerated without a significant pattern of off-target toxicity. Activity of the combination was markedly improved compared to historical data of HMA monotherapy, with a high MRD-negative remission rate and activity maintained in the highest risk subgroups (Fathi et al, ASH 2016). Methods: This phase 3, randomized, double-blind, placebo-controlled global study was designed to compare overall survival between pts treated with 33A plus HMA vs. pts treated with placebo plus HMA (NCT02785900). Secondary endpoints include composite complete remission rate (CR/CRi), event-free survival, and safety. Approximately 500 pts will be randomized in a 1:1 manner to one of the study arms. Investigators may select either HMA (azacitidine or decitabine). Eligible pts are adults with newly diagnosed, previously untreated, de novo or secondary AML, and have intermediate or adverse cytogenetic risk. Pts must not have AML associated with favorable risk karyotype or be a candidate for allo-SCT. Combination treatment may be repeated every 4 weeks until disease progression, leukemic recurrence, or unacceptable toxicity. Study enrollment began in June 2016.

Recurrent Mutations in CCND3 Confer Clinical Resistance to FLT3 Inhibitors

Background. Activating mutations in FLT3 occur in ~30% of adult acute myeloid leukemia (AML) cases, including internal tandem duplication (ITD) mutations (~25%) and point mutations in the tyrosine kinase domain (KD). In recent years, multiple selective and potent FLT3 inhibitors such as quizartinib, PLX3397, crenolanib and ASP2215 have demonstrated encouraging preliminary clinical activity in FLT3 mutant AML. Both quizartinib (Schiller et al, ASCO 2014) and ASP2215 (Levis et al, ASCO 2015) have reported composite complete remission rates (CRc) as high as ~50% in phase II trials. Despite these high response rates, the majority of patients relapse after initial response (acquired resistance) and a significant proportion of patients also fail to respond at all (primary resistance). On-target resistance due to secondary KD mutations in FLT3 is a common cause of acquired resistance to the clinically active FLT3 inhibitors quizartinib (Smith et al. Nature 2012) and PLX3397 (Smith et al, Cancer Discovery 2015). However, the causes of primary clinical resistance to FLT3 inhibitors have not been characterized. We performed targeted capture based sequencing of sorted pre-treatment blasts from 8 responding (R) and 21 non-responding (NR) patients treated on the phase I/II trial of PLX3397 in FLT3-ITD+ AML. We deeply sequenced the coding regions of 585 genes known to be mutated in hematologic malignancies/solid tumors and identified genes mutated only in NR patients (compared to genes mutated in both R and NR patients).Results. The number of mutations detected in genes other than FLT3 ranged from 2-18 per sample. There was no increase in the number of mutations found in patients with pre-existing hematologic conditions or in NR patients. Surprisingly, one of the most frequently mutated genes observed exclusively in NR patients was CCND3, the gene encoding cyclin D3, which has rarely been reported to be mutated in AML, though it is mutated in 38% of sporadic Burkitt's lymphoma (BL). A total of 4 individual mutations in CCND3 (Q276*, Q280fs, R271fs, and T283A) were identified in 3/21 NR patients (one patient had both Q276* and Q280fs). No CCND3 mutations were found in R patients. The identified mutations were the same mutations commonly found in BL, known to result in a more stable isoform of cyclin D3 and retain sensitivity to CDK4/6 inhibitors (Schmitz et al., Nature 2012). Expression of the Q276* and T283A mutations in FLT3-ITD+ MV4;11 cells conferred resistance to apoptosis induced by several FLT3 inhibitors (PLX3397, AC220 and crenolanib). However, inhibition of CDK4/6 activity in CCND3 mutant MV4;11 cells by either the CDK4/6 inhibitor palbociclib or the combined FLT3-CDK4/6 inhibitor AMG925 (FLX925) was unable to restore sensitivity to FLT3 inhibition. Moreover, CCND3 mutant MV4;11 cells demonstrated no increase in Rb phosphorylation, suggesting resistance to FLT3 inhibitors facilitated by CCND3 mutations is not predicated on CDK4/6 activation of Rb-dependent E2F-mediated transcription.Conclusions. We have identified recurrent mutations in CCND3, a gene not previously known to be commonly mutated in AML, as a novel cause of clinical primary resistance to FLT3 inhibitors in AML. This represents the first report of a specific non-FLT3 dependent mechanism of clinical resistance to FLT3 inhibitors. Unlike in BL, the functional effects of CCND3 mutations in FLT3-ITD+ AML do not appear to be mediated via CDK4/6 activity and is therefore unresponsive to CDK4/6 inhibition. The molecular mechanism(s) of CCND3-mediated resistance to FLT3 inhibitors are currently being investigated. DisclosuresSmith:Plexxikon: Research Funding; Astellas: Research Funding. Off Label Use: Investigational use of PLX3397 in AML. Hsu:Plexxikon Inc.: Employment. West:Plexxikon Inc.: Employment. Bollag:Plexxikon Inc.: Employment. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees. Shah:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Plexxikon Inc.: Research Funding.

Constitutively Activating Mutations At the FLT3 Activation Loop Residue D835 Are Associated with Clinical Resistance to AC220

Abstract 674 Background.Activating mutations in FLT3 occur in ∼30% of adult acute myeloid leukemia (AML) cases, including internal tandem duplication (ITD) mutations (∼25%) and point mutations in the tyrosine kinase domain (KD), primarily at the activation loop (AL) residue D835 (∼5%). FLT3-ITD and FLT3-AL mutations can co-occur in individual patients. AC220 (quizartinib) is a potent selective investigational FLT3/KIT inhibitor with encouraging preliminary clinical activity in FLT3-ITD+ AML, as evidenced by a composite complete remission rate of 45% in 53 chemotherapy refractory/relapsed patients in an interim analysis of a phase II study (Cortes et al, ASH 2011 abstract #614). While some patients without FLT3 mutations in the AC220 phase I dose escalation study responded, no objective response was observed in a small number of FLT3-AL mutant patients (Cortes et al, ASH 2008 abstract #767). We recently reported that secondary mutations at F691, D835 and Y842 in FLT3-ITD confer in vitro resistance to AC220, and that relapse in 8/8 AML patients who initially responded to AC220 was associated with evolution of secondary KD mutations in the FLT3-ITD+ allele (Smith et al., Nature, 2012). In 6 of 8 patients, relapse was associated with D835 substitutions, making this amino acid position the most commonly substituted residue in FLT3-ITD+ patients at the time of disease relapse. Given that D835 mutations in FLT3-ITD appear to confer a high degree of pre-clinical and clinical resistance to AC220, we hypothesized that D835 mutations in the absence of the ITD might also confer resistance to AC220 and could be associated with clinical relapse, especially in patients harboring a mixture of FLT3-WT, FLT3-ITD+, and FLT3-AL mutant blasts. Results.In vitro binding studies revealed that FLT3-D835V and FLT3-D835Y have decreased affinity for AC220 (Kd=4.8 and 7nM, respectively) compared to native FLT3 (Kd=1.8nM). In proliferation assays of BaF/3 cells, FLT3-D835V/Y mutants demonstrated increased relative AC220 resistance (IC50 24 and 6.8nM) compared to FLT3-ITD (IC50 0.13nM). To sensitively and precisely determine the frequency and phase (ITD+ vs ITD-) of mutations in clinical isolates, we utilized single molecule real-time (SMRT; Pacific Biosciences, Menlo Park, CA) sequencing, which can generate reads of sufficient length to enable focused interrogation of the KD of FLT3 ITD+ and ITD- alleles. We analyzed ITD- sequences from pretreatment and relapse samples obtained from the 8 FLT3-ITD-positive AML patients with acquired AC220 resistance reported in our previous analysis. Interestingly, all 6 patients with secondary mutations at D835 in ITD+ alleles at relapse also harbored D835 mutant ITD- alleles. All D835 mutations detected in ITD- alleles were also observed in ITD+ alleles from the same patient sample. In ITD+ alleles, we detected D835Y (n=6), D835V (n=3), and D835F (n=2) (range 2.7–50.6% of ITD+ alleles). In ITD- alleles, we found D835Y (n=6), D835V (n=2), and D835F (n=1) (range 3.8–50% of ITD- alleles). One patient had 2 D835 mutations (D835Y/F) in ITD- alleles at relapse. Although 2 of 8 patients evolved the F691L mutation in ITD+ alleles at relapse, this substitution was not detectable in ITD- sequences in any patient. In 7/8 patients, samples obtained immediately prior to AC220 administration were available for analysis. We were unable to document the presence of AC220-resistant mutations in either ITD+ or ITD- sequences in these pretreatment samples, suggesting that these mutants evolved under the selective pressure of AC220 treatment. We are currently performing single cell RT-PCR to determine if D835 mutations in ITD+ and ITD- alleles occur in distinct leukemic cells, which would suggest a polyclonal blast population at relapse. Conclusions.FLT3-AL mutations at D835 confer resistance to AC220 in vitro. The evolution of D835 substitutions in ITD- alleles in the majority of patients who respond and relapse on AC220 suggests that constitutively activating FLT3-AL mutations at residue D835 can confer acquired clinical resistance to AC220. AML patients with FLT3-D835 mutations may exhibit de novo resistance to AC220 and other FLT3 inhibitors. Our findings predict that the clinical activity of potent FLT3 inhibitors that are tolerant of D835 substitutions will mechanistically involve inhibition of D835 mutants in both the presence and absence of an ITD mutation. Disclosures:Chin:Pacific Biosciences: Employment. Levis:Astellas Pharma: Consultancy; Plexxikon: Consultancy; Symphogen: Consultancy; Ambit: Joined performance of clinical trial, Joined performance of clinical trial Other. Perl:Astellas Pharmaceuticals: Consultancy. Travers:Pacific Biosciences: Employment. Kasarskis:Pacific Biosciences: Equity Ownership. Radich:Ariad: Consultancy; Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding. Shah:Ariad: Consultancy, Research Funding.

Validation of FLT3-ITD As a Therapeutic Target in Human Acute Myeloid Leukemia

Abstract 937 Background. Activating in-tandem duplication (ITD) mutations within the FLT3 juxtamembrane region are detected in ∼25% of adult acute myeloid leukemia (AML) cases and portend a poor prognosis. AC220 (quizartinib) is a potent selective investigational FLT3/KIT inhibitor with encouraging preliminary clinical activity, as evidenced by a composite complete remission rate of 43% in 53 chemotherapy refractory/relapsed AML patients evaluable for an interim analysis of the ongoing phase II study in FLT3-ITD+ relapsed/refractory AML (Cortes et al, EHA 2011 abstract 1019). Many patients who initially respond ultimately suffer disease progression. We sought to utilize the clinical efficacy of AC220 to determine if FLT3-ITD is a valid therapeutic target in human AML. A saturation mutagenesis strategy identified amino acid substitutions at three amino acid residues (F691, D835, Y842) in FLT3-ITD that confer a high degree of resistance to AC220 in vitro. Of these, substitutions at F691 and D835 conferred the greatest degree of relative resistance. Results. To assess the validity of FLT3-ITD as a therapeutic target in AML, we analyzed paired pretreatment and relapse samples obtained from a cohort of 9 FLT3-ITD-positive AML patients enrolled in the exploratory part of the ongoing phase II study of AC220 in relapsed/refractory AML (clinicaltrials.gov NCT00989261) who relapsed after initially achieving morphologic clearance of bone marrow blasts to <5% on treatment. Through RT-PCR subcloning and sequencing of the FLT3 kinase domain, we observed evolution of one or more acquired kinase domain mutations on the FLT3-ITD containing allele in all 9 cases at relapse. Clinically detected mutations were restricted to the “gatekeeper” residue F691 and/or the activation loop residue D835 (F691L, n=3, D835Y, n=4; D835V, n=2, D835F, n=1). Each of these mutations successfully transformed Ba/F3 cells to IL-3 independence and conferred substantial resistance to AC220 in cell growth and cell-based biochemical assays. All of the AC220-resistant mutations conferred substantial in vitro cross-resistance to sorafenib, which has been reported to harbor clinical activity in a small number of FLT3-ITD-associated AML cases.In an expanded analysis of genomic DNA samples from 30 patients enrolled in the exploratory part of the Phase II study who discontinued study drug for any reason, we observed the occurrence of acquired mutations in the kinase domain (D835 and F691) in a total of 10 of 30 (33%) patients at the off study timepoint. One patient had a D835Y mutation prior to going on AC220.Molecular docking studies were undertaken to provide mechanistic insights into the structural basis of resistance conferred by AC220-resistant mutations. These studies revealed that AC220 likely binds strongly to the DFG-out inactive FLT3 kinase domain. AC220 directly interacts with the gatekeeper residue F691, explaining the drug-resistance associated with the F691L mutation. Mutations at D835 and Y842 may potentially de-stabilize the inactive conformation, and result in a more active, AC220 binding-deficient FLT3 kinase. Indeed, substitutions at these residues are known to activate FLT3 in the absence of an ITD mutation.To more precisely assess the frequency and identity of resistance-conferring mutations at relapse, we analyzed a subset of samples using single molecule real-time (SMRT™; Pacific Biosciences, Menlo Park, CA) sequencing, which can generate reads of sufficient length to enable focused interrogation of the kinase domain of FLT3-ITD alleles. With this assay, more than 350 reads of >1000 nucleotides were reliably obtained. Analyses of pretreatment and relapse samples from four patients confirmed the presence of resistance-conferring FLT3-ITD kinase domain mutations at F691 or D835 at relapse in 36–60% of FLT3-ITD sequence reads. Additionally, this method detected polyclonal resistance in two of the four samples assessed. Conclusions. Our studies validate FLT3-ITD as a therapeutic target in a proportion of AML cases, and demonstrate that the clinical activity of AC220 is mediated by FLT3-ITD inhibition. AC220-resistant FLT3-ITD gatekeeper and activation loop mutations identified in clinical samples from relapsing patients represent high-value therapeutic targets for next-generation FLT3 inhibitors. Disclosures:Off Label Use: AC220 is an investigational agent and has no approved drug indication in AML. Chin:Pacific Biosciences: Employment. Hunt:Ambit Biosciences: Employment. Levis:Ambit Biosciences, Inc: Consultancy. Travers:Pacific Biosciences: Employment. Wang:Pacific Biosciences: Employment. Kasarskis:Pacific Biosciences: Employment, Equity Ownership. Schadt:Pacific Biosciences: Employment, Equity Ownership.