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Selinexor is a first-in-class inhibitor of the nuclear exportin XPO1 that was recently approved by the US Food and Drug Administration for the treatment of multiple myeloma and diffuse large B-cell lymphoma. In relapsed/refractory acute myeloid leukemia (AML), selinexor has shown promising activity, suggesting that selinexor-based combination therapies may have clinical potential. Here, motivated by the hypothesis that selinexor's nuclear sequestration of diverse substrates imposes pleiotropic fitness effects on AML cells, we systematically catalog the pro- and anti-fitness consequences of selinexor treatment. We discover that selinexor activates PI3Kγ-dependent AKT signaling in AML by upregulating the purinergic receptor P2RY2. Inhibiting this axis potentiates the anti-leukemic effects of selinexor in AML cell lines, patient-derived primary cultures and multiple mouse models of AML. In a syngeneic, MLL-AF9-driven mouse model of AML, treatment with selinexor and ipatasertib outperforms both standard-of-care chemotherapy and chemotherapy with selinexor. Together, these findings establish drug-induced P2RY2-AKT signaling as an actionable consequence of XPO1 inhibition in AML.

Supplementary Figure 1. Pharmacokinetics of CPI-613 infused over 1 hour. Plasma CPI-613 levels following a 1 or 2 hour infusion shown on day 1 and day 6 on a linear scale. The number of patients in each analysis is indicated by n. **=p

Figure S1. Dose escalation schema. Figure S2. Acetyl-CoA synthetase is expressed in OCI-AML3 and MFL2 cells. Figure S3 Acetate and methyl-succinate rescue of CPI-613 cytotoxicity. Figure S4. Treatment schema. Figure S5. Efficacy of HiDAC, mitoxantrone and CPI-613. Figure S6. Baseline bone marrow mononuclear cell gene expression profiles of responders (n=10) versus nonresponders (n=7). Figure S7. SOD2 expression levels are higher in non-responders Figure S8. SOD2 confers resistance to CPI-613. Figure S9. Mutational analysis from RNA sequence data of baseline marrow samples. Supplemental Table 1. Dose and Response by Patient Supplementary Table 2. Gene ontology enrichment analysis of genes overexpressed in responding patients

Purpose: The lipoate derivative CPI-613 is a first-in-class agent that targets mitochondrial metabolism. This study determined the effects of CPI-613 on mitochondrial function and defined the MTD, pharmacokinetics, and safety in patients with relapsed or refractory hematologic malignancies.Experimental Design: Human leukemia cell lines were exposed to CPI-613 and mitochondrial function was assayed. A phase I trial was conducted in which CPI-613 was given as a 2-hour infusion on days 1 and 4 for 3 weeks every 28 days.Results: CPI-613 inhibited mitochondrial respiration of human leukemia cells consistent with the proposed mechanism of action. In the phase I trial, 26 patients were enrolled. CPI-613 was well tolerated with no marrow suppression observed. When the infusion time was shortened to 1 hour, renal failure occurred in 2 patients. At 3,780 mg/m2, there were two dose-limiting toxicities (DLT). At a dose of 2,940 mg/m2 over 2 hours, no DLTs were observed, establishing this as the MTD. Renal failure occurred in a total of 4 patients and resolved in all but 1, who chose hospice care. CPI-613 has a triphasic elimination with an alpha half-life of approximately 1.34 hours. Of the 21 evaluable, heavily pretreated patients, 4 achieved an objective response and 2 achieved prolonged stabilization of disease for a clinical benefit rate of 29%. Following drug exposure, gene expression profiles of peripheral blood mononuclear cells from responders demonstrated immune activation.Conclusion: CPI-613 inhibits mitochondrial function and demonstrates activity in a heavily pretreated cohort of patients. Clin Cancer Res; 20(20); 5255–64. ©2014 AACR.

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia.Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML.Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders.Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.

Supplementary Figure 2. Differential gene expression between responders and non-responders. The top 50 genes up regulated in responders (left side) or non-responders (right side) in PBMCs from 4 responders compared to 4 non-responders taken on day 1 of week 4. Red color indicates above-mean expression, green color indicates below-mean expression. Degree of color saturation reflects the magnitude of change. R= responders, N= non-responders. FC= the mean log base 2 fold change.

Background: Resistance to therapy and a poor outcome characterize relapsed or refractory acute myeloid leukemia (AML). There is a clear need for additional palliative approaches with acceptable toxicities. Vincristine sulfate liposome injection (VSLI) confers enhanced pharmacokinetics and activity when compared to the parent compound. It is effective and well tolerated in heavily pretreated acute lymphoblastic leukemia (ALL) patients. Preclinically VSLI has activity in vincristine-resistant cancers. As relapsed or refractory AML patients would have minimal exposure to vincristine it was hypothesized that VSLI would be well tolerated and may have activity. Methods: A pilot phase II clinical trial was conducted. Five patients with relapsed or refractory disease were treated using the Food and Drug Administration (FDA)-approved dose and schedule. Results: Of the five patients treated none completed more than one cycle; there were no responses and two patients did not complete one cycle of therapy. Surprisingly, three of the five patients had treatment-related constipation, and two had neuropathy consistent with the known toxicities of VSLI. Given the toxicity and lack of response, the trial was terminated early. Conclusions: VSLI had no activity against relapsed or refractory AML in this limited, single institution dataset. J Hematol. 2021;10(1):1-7 doi: https://doi.org/10.14740/jh771

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49–8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9–8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1–7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

OBJECTIVES: To investigate changes in inflammatory biomarkers during induction therapy for older adults with acute myeloid leukemia (AML) and their associations with geriatric assessment (GA) measures and outcomes. METHODS: This was a single institution ancillary study to a prospective observational study (N=20 consecutive adults aged ≥60 with newly diagnosed AML who received induction chemotherapy). Biomarkers (Interleukin-6 [IL-6], IL-6 soluble receptor [IL-6 sR], tumor necrosis factor alpha [TNFα], TNFα soluble receptor 1 [TNFα sR1], interleukin- 3 [IL-3], C-reactive protein [CRP]) were collected at start of induction, weekly for three weeks, and post-induction and were compared over time using paired t-tests. GA was administered at baseline and post-induction, and correlated with biomarker levels using Spearman correlations. Survival was estimated using Kaplan-Meier and compared by categorized biomarker level using Wilcoxon tests. RESULTS: Biomarker levels were stable during induction, except for CRP and IL-6 sR. Declines in objectively measured physical function [Short Physical Performance Battery (SPPB); r=0.71, p

Adenosine monophosphate activated protein kinase (AMPK) is a master regulator of cell metabolism and is involved in cancer as both a tumor suppressor and a source of resistance to metabolic stress. The role of AMPK in response to chemotherapy has been examined in solid tumor models but remains unclear in acute myeloid leukemia (AML). To determine the role of AMPK in chemotherapy response, AML cell lines were generated lacking AMPK activity. AMPK knock out cells demonstrated significant resistance to cytarabine and doxorubicin both in vitro and in vivo. Mitochondrial mass and function were unchanged in AMPK knockout cells. Mechanistically, AMPK knock out cells demonstrated a diminished DNA damage response with significantly lower γH2AX foci, p53 and p21 induction as well as decreased apoptosis following chemotherapy exposure. Most importantly, TCGA datasets revealed that patients expressing low levels of the PRKAA1 subunit of AMPK had significantly shorter survival. Finally, AML cells were sensitized to chemotherapy with the addition of the AMPK activator AICAR. These data demonstrate that AMPK sensitizes AML cells to chemotherapy and suggests a contribution of the cellular metabolic state to cell fate decisions ultimately affecting therapy response.

Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.

Introduction: AML is an aggressive disease with poor prognosis that predominantly affects older adults. Due to advanced age and associated comorbidities, many patients are not fit for intensive induction chemotherapy. Monotherapy with HMAs such as azacitidine (AZA) or decitabine (DEC) is often still considered as standard of care for these patients, despite mixed evidence from studies regarding the benefit of HMAs alone (Duchmann & Itzykson. Int J Hematol 2019). The aim of the current study is to evaluate patient characteristics, treatment patterns and outcomes of patients with AML treated with HMA monotherapy as first line (1L) in clinical practice in the US. Methods: This is a retrospective observational study of the Flatiron Health database; a nationwide, longitudinal, demographically and geographically diverse database representing more than 2.4 million patients with cancer in the US. The database contains de-identified data derived from electronic health records from over 280 cancer clinics, which are predominantly community oncology practices. Patients ≥18 years, diagnosed with AML between 1/1/2014 and 3/30/2020 (excluding acute promyelocytic leukemia and clinical trial enrollment), and who received HMAs as 1L treatment ≤30 days from AML diagnosis were evaluated. Descriptive analyses were conducted on patient characteristics and treatment patterns. Kaplan-Meier analyses were used to estimate time to last administration (TTLA; from initiation to last observed administration before death, end of follow-up or a gap of 60 days) and median overall survival (OS). Results: A total of 2589 patients with an AML diagnosis were included for analysis, where 574 (22%) were treated with 1L HMAs (AZA: n=341 [59%]; DEC: n=233 [41%]). The median age of 1L HMA patients was 79 years with 63% male. Most patients were treated in the community setting (n=511 [89%]; median age: 79 years); those treated in academic centers were slightly younger (n=63 [11%]; median age: 77 years). Characteristics for non-antecedent hematological disorder (AHD)-AML (n=327) and AHD-AML (n=247) patients are presented in Table 1. Median TTLA with 1L HMA was 77 days with a median of 3 cycles of both AZA and DEC. Of the 168 patients who received second-line (2L) therapy, 82% (n=138) received another low-intensity therapy or combination (of which only 14 received targeted therapies) (Figure 1). Overall, 44% of 1L HMA patients (n=254) had evidence of molecular testing before 1L treatment initiation (this was more common in later years). Of the 228 patients tested for FLT3, 30 (13%) were FLT3 positive; 7 (23%) FLT3-positive patients were treated with 2L or third-line (3L) FLT3-targeted therapies (gilteritinib, midostaurin or sorafenib). Of the 152 patients tested for IDH1/2, 35 (23%) were IDH1/2 positive; 5 (14%) IDH1/2-positive patients were treated with 2L or 3L targeted agents (enasidenib or ivosidenib). A median OS of 6.3 months (95% CI: 5.5-7.5) was observed in the overall 1L HMA cohort. Median OS in 1L HMA patients did not differ with respect to different types of AML (non-AHD-AML: 6.6 [95% CI: 5.5-7.9] months; AHD-AML: 6.0 [95% CI: 4.8-7.5] months, p=0.34) or practice setting (community: 6.0 [95% CI: 5.3-7.0] months; academic: 8.3 [95% CI: 6.9-13.3] months, p=0.14). One-year OS was 31.4% and 30.1% for non-AHD-AML and AHD-AML patients, respectively. Patients treated in the community setting had numerically lower 1-year OS (29.7% [95% CI: 25.8-34.3]) than those treated in the academic setting (39.5% [95% CI: 28.6-54.6]), which reflects the higher rates of 2L treatment in academic practice, though this analysis is unadjusted. Conclusions: This new database enabled a detailed analysis of 1L HMA-treated patients with newly diagnosed AML in routine clinical practice predominantly in the community setting. 1L HMA patients have poor survival outcomes (median OS 6.3 months) which are comparable to other real-world data from SEER-Medicare (Zeidan et al. Blood Adv 2020; median OS 7-8 months; median age: 77 years); but shorter than the median OS of 9-10 months observed in 1L HMA-treated AML patients in clinical trials (DiNardo et al. EHA 2020). Limitations of the study included limited conduct of bone marrow biopsies for response and lack of transfusion data. The observed survival outcomes highlight the importance of further treatment advances to address the unmet need in older patients with AML ineligible for intensive induction chemotherapy. Disclosures Pardee: Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau; Rafael Pharmaceuticals: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; AbbVie: Consultancy; Genentech, Inc.: Consultancy; Karyopharm: Research Funding. Oschwald:Roche Products Limited: Current Employment. Ma:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company. Xu:F. Hoffmann-La Roche Ltd: Current Employment, Other: All authors received support for third party writing assistance, furnished by Scott Battle, PhD, provided by F. Hoffmann-La Roche, Basel, Switzerland.. Montez:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Ramsingh:Genentech, Inc.: Current Employment; NEKTAR: Current equity holder in publicly-traded company; Exelixis: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Hong:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Choi:AbbVie: Current Employment, Current equity holder in publicly-traded company. Flahavan:Roche Products Ltd.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. OffLabel Disclosure: Discussion will include the use of decitabine for the treatment of AML.

BACKGROUND Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (FLT3) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3-mutated AML. METHODS In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission. RESULTS Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P

Devimistat (CPI-613®) is a novel lipoate analog that inhibits the tricarboxcylic acid cycle at two key carbon entry points. Through its inhibition of pyruvate dehydrogenase and a-ketoglutarate dehydrogenase complexes, devimistat inhibits the entry of glucose and glutamine derived carbons, respectively. Pancreatic cancer is dependent on mitochondrial function for enhanced survival and aggressiveness. In a Phase I study of modified FOLFIRINOX, in combination with devimistat for metastatic pancreatic cancer patients, there was a 61% objective response rate including a 17% complete response rate. This report outlines the rationale and design of the AVENGER 500 study, a Phase III clinical trial of devimistat in combination with modified FOLFIRINOX compared with FOLFIRINOX alone for patients with previously untreated metastatic adenocarcinoma of the pancreas. Clinical trial registration: NCT03504423

Devimistat (CPI-613®) is an intravenously administered, novel lipoate analog that inhibits two key tricarboxcylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). These complexes control TCA cycle entry of glucose and glutamine-derived carbons, respectively. Acute myeloid leukemia (AML) cells upregulate the TCA cycle in response to DNA damaging agents and treatment with devimistat increases sensitivity to them. A Phase I study of devimistat in combination with cytarabine and mitoxantrone produced a complete remission rate of 50% in patients with relapsed or refractory AML. In the combined Phase I/II experience, older patients with R/R AML treated with 2000 mg/m2 of devimistat had a 52% complete remission/complete remission with incomplete hematologic recovery rate and a median survival of 12.4 months. This report outlines the rationale and design of the ARMADA 2000 study, a Phase III clinical trial of devimistat in combination with high dose cytarabine and mitoxantrone compared with high dose cytarabine and mitoxantrone alone for older patients (≥60 years of age) with relapsed or refractory AML. Clinical trial registration: NCT#03504410

TPS11595 Background: CCS of the soft tissues is a rare and aggressive subtype of sarcoma that often starts in the tendons of the arms or legs. It is molecularly characterized by t(12;22)(q13;q12) translocation, resulting in EWSR1-ATF1 or EWSR1-CREB1 gene fusion. Despite reports of occasional responses to systemic therapies, currently available therapies have shown limited efficacy in advanced CCS. Therefore, there is a significant unmet medical need for more active agents in CCS. Devimistat is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzymes of the tricarboxylic acid (TCA) cycle preferentially within the mitochondria of cancer cells. Devimistat induces autophagy in cancer cells. In a metastatic mouse model of CCS, treatment with devimistat in combination with chloroquine significantly suppressed tumor growth (Egawa et al, 2018). Based on this data, we hypothesized that inhibition of autophagy with HCQ may sensitize cancer cells to devimistat with increased efficacy and acceptable toxicity. Given its expected synergy, we have initiated a single-arm phase I/II prospective, multicenter, open-label, non-randomized study to evaluate maximally tolerated dose (MTD), safety, and efficacy of devimistat in combination with HCQ in patients with R/R CCS. Methods: In the phase 1 portion of the study, patients with R/R CCS and other fusion-positive R/R sarcomas will be enrolled and a standard 3+3 design will be followed to evaluate toxicity, MTD, and recommended phase 2 dose. There will be two patient groups based on weight, and dose escalation will be conducted separately for each group. Starting dose of HCQ will be 5mg/kg PO BID for patients < 45 kg and 200 mg PO BID for patients ≥45 kg on days 1 through 5 of every 28 days. The first dose of HCQ each day will be followed 2 hours later by 1,000 mg/m2 devimistat (for patients < 45 kg) and 2,000 mg/m2 of devimistat (for patients ≥ 45 kg) administered over 2 hours. A maximum of 36 patients will be enrolled for the phase I portion, 18 for each patient group. In the phase 2 portion of the study, only relapsed or refractory CCS patients will be enrolled, and the response rate will be determined using RECIST 1.1. In phase 2, pharmacokinetics, duration of response, clinical benefit rate, progression-free survival, overall survival, safety, and patient-reported outcomes will also be assessed. This portion of the study will utilize Simon’s admissible two-stage design with 29 patients. This study started enrolling participants in November 2021 and has dosed six patients to date. The first two dose-escalation cohorts for patients ≥45 kg have been completed without DLT and the third dose level will be opening shortly. Clinical trial information: NCT04593758.

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.

Acute myeloid leukemia (AML) is an aggressive malignancy with poor outcomes. Nucleoside analogs are subject to resistance mechanisms including downregulation of equilibrative nucleoside transporter (ENT1) and deoxycytidine kinase (dCK). KPC34 is a novel phospholipid mimetic that when cleaved by phospholipase C (PLC) liberates gemcitabine monophosphate and a diacylglycerol mimetic that inhibits the classical isoforms of protein kinase C (PKC). KPC34 acts independently of ENT1 and dCK. KPC34 was active against all AML cell lines tested with IC50s in the nanomolar range. Enforced expression of PLC increased response to KPC34 in vivo. In an orthotopic, xenograft model, KPC34 treatment resulted in a significant increase in survival compared to control animals and those treated with high-dose cytarabine. In a PDX model with activated PKC, there was a significant survival benefit with KPC34, and at progression, there was attenuation of PKC activation in the resistant cells. In contrast, KPC34 was ineffective against a syngeneic, orthotopic AML model without activated PKC. However, when cells from that model were forced to express PKC, there were significantly increased sensitivity in vitro and survival benefit in vivo. These data suggest that KPC34 is active against AML and that the presence of activated PKC can be a predictive biomarker.

PURPOSE: To investigate the impact of hyperglycemia and glycemic variability during intensive acute myeloid leukemia therapy (AML) on outcomes by age. METHODS: Retrospective study of 262 consecutive patients with newly diagnosed AML hospitalized for intensive induction. Hyperglycemia was assessed by mean blood glucose (BG) (mg/dL) during hospitalization and glycemic variability was determined by the standard deviation (SD) of mean BG. Outcomes were complete remission ± incomplete count recovery (CR + CRi), and overall survival (OS). We used logistic regression to evaluate CR + CRi, and Cox proportional hazard models for OS, stratified by age (< 60 vs ≥ 60 years). RESULTS: Older patients (N = 138, median age 70) had higher baseline comorbidity (CCI > 1 60.1% vs 25.8%) and prevalence of diabetes (20.3% vs 7.3%) compared to younger (N = 124, median age 47). The mean ± SD number of BG values obtained per patient during hospitalization was 61 ± 71. The mean (± SD) glucose (mg/dL) during hospitalization was 121.7 (25.9) in older patients (≥ 60 years) versus 111.6 (16.4) in younger. In older patients, higher mean glucose and greater glycemic variability were associated with lower odds of remission (OR 0.80, 95% CI 0.69–0.93 and OR 0.73, 95% CI 0.61–0.88 respectively, per 10-unit increase) and higher mortality rates (HR 1.13, 95% CI 1.05–1.21 and HR 1.17, 95% CI 1.09–1.26, respectively, per 10-unit increase) in multivariate analyses. CONCLUSIONS: Our observations that hyperglycemia and increased glycemic variability were associated with lower remission rates and increased mortality in older patients suggest glycemic control may be a potentially modifiable factor to improve AML outcomes.

Mitochondria have long been controversial organelles in cancer. Early discoveries in cancer metabolism placed much emphasis on cytosolic contributions. Initial debate focused on if mitochondria had a role in cancer formation and progression at all. More recently the contributions of mitochondria to cancer development and progression have become firmly established. This has led to the identification of novel targets and inhibitors being studied as new therapeutic approaches. This review will summarize the role of mitochondria in cancer and highlight several agents under development.

Purpose: CPI-613, a lipoate analogue that inhibits pyruvate dehydrogenase (PDH) and α-ketogluterate dehydrogenase (KGDH), has activity in patients with myeloid malignancies. This study explored the role of mitochondrial metabolism in chemotherapy response and determined the MTD, efficacy, and safety of CPI-613 combined with high-dose cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia. Experimental Design: The role of mitochondrial response to chemotherapy was assessed in cell lines and animal models. A phase I study of CPI-613 plus cytarabine and mitoxantrone was conducted in patients with relapsed or refractory AML. Results: Exposure to chemotherapy induced mitochondrial oxygen consumption that depended on PDH. CPI-613 sensitized AML cells to chemotherapy indicating that mitochondrial metabolism is a source of resistance. Loss of p53 did not alter response to CPI-613. The phase I study enrolled 67 patients and 62 were evaluable for response. The overall response rate was 50% (26CR+5CRi/62). Median survival was 6.7 months. In patients over 60 years old, the CR/CRi rate was 47% (15/32) with a median survival of 6.9 months. The response rate for patients with poor-risk cytogenetics also was encouraging with 46% (11/24 patients) achieving a CR or CRi. RNA sequencing analysis of a subset of baseline bone marrow samples revealed a gene expression signature consistent with the presence of B cells in the pretreatment marrow of responders. Conclusions: The addition of CPI-613 to chemotherapy is a promising approach in older patients and those with poor-risk cytogenetics. Clin Cancer Res; 24(9); 2060–73. ©2018 AACR.

Introduction: New treatment strategies with low intensity therapy have emerged for acute myeloid leukemia (AML) patients who are not candidates for intensive therapy. To date, there is limited data on the frequency of invasive fungal infections (IFIs) in patients treated with low intensity regimens, and there is no consensus on the most appropriate prophylactic antifungal agent to use in either the newly diagnosed or relapsed/refractory setting. At our institution, fluconazole is the prophylactic antifungal agent of choice for neutropenic patients receiving low intensity therapy, however the appropriateness of fluconazole is being questioned due to the depth and duration of neutropenia observed in these patients. Rates of breakthrough IFIs need to be better characterized to optimize antifungal prophylaxis in this patient population. Methods: This is a retrospective review of AML patients treated with low intensity therapy from January 2017 through May 2020 for both newly diagnosed and relapsed/refractory disease. Patients were included if they received fluconazole as prophylaxis during periods of neutropenia and received at least two cycles of low intensity treatment. Low intensity regimens included hypomethylating agent (HMA) monotherapy or a combination of venetoclax with either a HMA or low dose cytarabine (LDAC). Any patient with a contraindication to fluconazole or those who received prophylaxis with an alternative antifungal agent (i.e. posaconazole, voriconazole, isavuconazole, and micafungin), history of previous IFI, or history of a stem cell transplant were excluded. The primary objective was to determine the incidence of breakthrough IFIs. The secondary objective was to further characterize IFI occurrences as possible, probable or proven using criteria defined by the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium (EORTC/MSGERC). An occurrence of IFI was defined as receipt of any systemic antifungal agent, aside from fluconazole, for four or more days for suspected IFI. Patients were evaluated for antifungal escalation from the time of low intensity treatment initiation through 30 days after treatment discontinuation. Results: Eighty encounters were included for analysis. The median age of the cohort was 73 years (interquartile range [IQR] 67 - 80) and 70% of patients were newly diagnosed (n = 56). HMA/venetoclax was the most commonly utilized regimen (66%, n = 53) followed by HMA monotherapy (29%, n = 23) and LDAC/venetoclax (5%, n = 4). The median number of treatment cycles was 5 (IQR 3 - 9). Nineteen IFI occurrences (24%) were documented, with ten in the newly diagnosed population (18%, n = 10/56) and nine in relapsed/refractory patients (38%, n = 9/24). There were no proven, four probable and fourteen possible IFIs. Of the four probable infections, three were in relapsed/refractory patients. Median times to IFI onset from low intensity treatment initiation were 82 and 80 days for the newly diagnosed and relapsed/refractory populations, respectively. Of the patients with an IFI, 15/19 (79%) were neutropenic at IFI onset. Conclusions: IFIs are a serious complication of AML as these infections are associated with significant morbidity and mortality. With 24% of patients requiring antifungal escalation, our study demonstrates that breakthrough IFIs remain a concern for patients receiving low intensity therapy and fluconazole prophylaxis. Incidence of IFI was higher in the relapsed/refractory setting, which is an expected finding as these patients are typically subjected to multiple lines of therapy, leading to poor hematopoietic reserves and more prolonged periods of profound neutropenia. Additional analysis is needed for determination of risk factors, beyond relapsed/refractory disease, to potentially identify subsets of patients at highest risk of developing IFIs as these patients may benefit from closer monitoring and longer durations of prophylaxis. Given these findings, it is reasonable to consider prophylaxis with an extended spectrum antifungal agent against molds for patients receiving low intensity therapy. Figure 1 Figure 1. Disclosures Ellis: Rafael Pharmaceuticals: Consultancy. Pardee: Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rafael Pharmaceuticals: Consultancy, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

Introduction Assessment of frailty is central to medical decision-making for older adults with newly diagnosed acute myeloid leukemia (AML), but validated frailty tools used at the point of care are lacking in this setting. An electronic frailty index (eFI), based on the theory of deficit accumulation, has been developed from routinely collected outpatient primary care data and embedded in the electronic health record (EHR) at Wake Forest Baptist Health (WFBH). The embedded eFI predicts hospitalization and mortality for older adults in a primary care cohort but has yet to be assessed for older adults with AML. The objectives of this analysis were to evaluate this tool among a cohort of newly diagnosed older adults with AML by determining the percent with available data to calculate a score, assessing the distribution of eFI categories (fit, pre-frail, and frail) at the time of treatment by therapy type, and exploring an association of eFI categories with survival. Methods Participants in this retrospective cohort study were adults aged ≥ 60 years with newly diagnosed AML from January 2018 - October 2020 who received treatment at WFBH. Patients with acute promyelocytic leukemia (APL) were excluded. Calculation of the EHR embedded eFI requires at least two ambulatory visits over a 2-year period. The eFI comprises demographic information, vital signs, smoking status, ICD-10 diagnosis codes, select outpatient laboratory measurements, and functional information (if available from past Medicare Annual Wellness Visits) during the 2 years prior to diagnosis. For this analysis, eFI was derived using date of treatment initiation as the reference date. Frailty status is categorized as fit (eFI ≤0.10), pre-frail (0.100.21) based on the proportion of deficits present over the total number evaluated. Intensive therapy is defined as receipt of anthracycline-based chemotherapy. Less-intensive therapy includes hypomethylating agents, low dose cytarabine, and/or venetoclax. The association of eFI category to therapy type was evaluated using a chi square test. Median survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Results Among N=163 older adults treated for non-APL AML, 78 (43.3%) had a calculable eFI score. Among those with a calculable score, average age was 74.7 years (range 60 to 90), 68% were male, 90% were white, and average hematopoietic cell transplantation-comorbidity index (HCT-CI) score was 3.5 ± 2.7. Approximately 17% had favorable, 23% had intermediate, and 59% had unfavorable cytogenetics; 54% had secondary AML. Among those with a calculable eFI, 38.5% were classified as fit, 48.7% as pre-frail, and 12.8% as frail. For those who received intensive therapy (N=35), the majority were classified as fit (60%) and the remaining were pre-frail (40%); none were frail. The distribution of eFI categories differed for patients who received less-intensive therapies (N=43), with the majority classified as pre-frail (56%), a smaller proportion classified as fit (21%), and almost one-quarter as frail (23 %) (p Conclusions The embedded eFI derived from a longitudinal primary care population was not calculable using available data for most older adults with AML. This may reflect a skewed population referred to a Comprehensive Cancer Center that has higher-risk cytogenetics and/or does not receive primary care through the academic medical center. Among those with a calculable eFI, frailty categories significantly differed by treatment type. There was no association between survival and eFI category within treatment type in exploratory analyses. Our observations highlight the opportunity to adapt the EHR embedded eFI data capture process, including incorporation of inpatient labs, to the AML setting to effectively test the utility of a cancer-adapted passive digital marker for frailty. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

Introduction: Patients (pts) with primary refractory or relapsed high-grade lymphoma (HGL) including Burkitt lymphoma (BL) and high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6 (double-hit lymphoma, DHL) have a dismal prognosis with patients almost never achieving a meaningful remission to second line therapy. No standard second line therapeutic approach exists, particularly for BL. The characteristic hallmark of these diseases is a dysregulated MYC oncogene with both downstream effects on proliferation and a high metabolic fluxes which use tricarboxylic acid (TCA) cycle intermediates as biosynthetic precursors. CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis. In the initial phase I trial (n=26) one patient with multiply refractory BL had a partial remission sustained for over one year and then consolidated by surgical resection. She remains alive 7 years later. As of July 2021, 20 clinical studies for various cancers have been conducted (ongoing/completed) with devimistat with over 700 patients having received study drug. We initiated a phase II trial to further explore efficacy in HGL. Devimistat has FDA orphan status for BL and 4 other cancers. Methods: NCT03793140 is a multicenter study aiming to enroll 17 patients on each of two cohorts, BL and DHL, with a Simon's 2-stage design for each cohort, requiring one response among the first 9 treated patients to expand to 17. Patients must have had at least one prior line of therapy or are refusing standard of care and must be more than 3 months after a prior stem cell transplant. Active central nervous system (CNS) parenchymal disease is excluded, but prior leptomeningeal disease is allowed if the CSF is negative for more than 4 weeks at enrollment and maintenance intrathecal therapy is ongoing. Devimistat is given by central line over 2 hours daily x 5 days for two 14-day cycles and then as maintenance x5 days every 21 days. Pts were evaluable for response if they received at least 4 infusions over 5 days of the first cycle. Results: 9 pts were enrolled in the DHL/THL arm. Mediannumber of prior therapies were 3 (range, 1-6). No responses were seen, with only 1 patient achieving stable disease as best response, resulting in cohort closure. Thus far, 8 BL pts were enrolled. Median number of prior therapies was 3 (range, 2-4). Two patients were inevaluable for response. 1/6 patients had stable disease through cycle 7 and one had a complete response (CR). This CR patient (HIV+) with 4 prior therapies entered the study with only a biopsy proven thigh mass. He was not a transplant candidate for social reasons. He had a near complete metabolic remission after 4 cycles of devimistat and a CR after cycle 7. (Table and Figure) As of July 2021, he is in cycle 11, having had a 4-week treatment delay of cycle 5 due to CoVID 19 infection. ECOG improved from 3 to 0. Adverse events (AE): As of July30, 2021, no patient experienced a serious adverse event related to study drug. Four patients had grade 3 events at least possibly related: 2 neutropenia, 1 thrombocytopenia and 1 elevated bilirubin. 1 patient had a dose reduction for grade 2 alanine aminotransferase increase. Conclusions: Although our results are preliminary, the complete remission in this patient is promising in a disease where no viable treatment options exist in the relapsed, refractory BL. Enrollment to the BL cohort is ongoing. Figure 1 Figure 1. Disclosures Nikolaenko: Pfizer: Research Funding; Rafael Pharmaceuticals: Research Funding. Pardee: Celgene/BMS: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; CBM Biopharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Rafael Pharmaceuticals: Research Funding. Abramson: Genentech: Consultancy; Kymera: Consultancy; Karyopharm: Consultancy; AbbVie: Consultancy; Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy. Horwitz: Vividion Therapeutics: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Tubulis: Consultancy; Verastem: Research Funding; ONO Pharmaceuticals: Consultancy; Myeloid Therapeutics: Consultancy; SecuraBio: Consultancy, Research Funding; Trillium Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millennium /Takeda: Consultancy, Research Funding; Kura Oncology: Consultancy; Janssen: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Forty Seven, Inc.: Research Funding; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Celgene: Research Funding; Aileron: Research Funding; Affimed: Research Funding; Acrotech Biopharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Matasar: GlaxoSmithKline: Honoraria, Research Funding; Teva: Consultancy; Janssen: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Genentech, Inc.: Consultancy, Honoraria, Research Funding; Merck Sharp & Dohme: Current holder of individual stocks in a privately-held company; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; TG Therapeutics: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Memorial Sloan Kettering Cancer Center: Current Employment; Pharmacyclics: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Rocket Medical: Consultancy, Research Funding. Noy: Rafael Parhma: Research Funding; Morphosys: Consultancy; Targeted Oncology: Consultancy; Medscape: Consultancy; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Epizyme: Consultancy. OffLabel Disclosure: CPI-613 (devimistat) is a non-redox active analogue of lipoic acid, a required cofactor for two key mitochondrial enzymes of the TCA cycle, pyruvate dehydrogenase and alpha ketoglutarate dehydrogenase. Disruption of mitochondrial function by CPI-613 results in a shutdown of ATP and biosynthetic-intermediate production, leading to cancer cell death by apoptosis or necrosis

Introduction: Chimeric antigen receptor-based T cell therapy (CAR-T) has shown great promise in B cell malignancies. CD30-targeted therapies like brentuximab vedotin have activity in T cell malignancies expressing CD30. There is interest in developing CD30-targeted CAR-T therapies for the treatment of relapsed T cell malignancies. As the process of generating autologous T cells takes several weeks, there is a need for active bridging therapeutic regimens that can reduce tumor burden to facilitate subsequent treatment with CAR-T cell therapy. We propose the use of devimistat, a TCA cycle inhibitor, in combination with bendamustine as bridging therapy for the treatment of CD30+ T cell lymphoma (TCL) prior to the use of CAR-T cells. We hypothesize that TCA cycle inhibition will increase the sensitivity of TCL cells to bendamustine, negatively impact the function of immunosuppressive cell populations that depend on mitochondrial metabolism, and create a conducive environment for enhanced CAR-T cell efficacy. To test our hypothesis, we developed a model of CD30+ TCL, evaluated the efficacy of the combination, and characterized its effects by transcriptome profiling of immune cell populations in tumors. Methods: Mouse TCL cell line EL4-LUC2 was engineered to express human CD30 by retroviral transduction. Single and combination in vitro efficacy was evaluated by viability assays. Combination indices (CI) were calculated using Compusyn. CD30+ EL4-LUC2 cells (EL4.CD30) were inoculated subcutaneously into the flanks of C57Bl6 mice, tumor volumes were calculated, and CD30 expression in tumors was evaluated by immunohistochemical staining and flow cytometry. Transcriptome profiling was performed on a representative subset of tumors by single cell RNA sequencing (scRNA-seq). Results: EL4.CD30 cells displayed comparable CD30 expression to the human TCL cell line Karpas 299. EC 50 values for Devimistat and bendamustine in EL4.CD30 cells were 64.9 mM (95% CI: 62.4-67.4) and 101.2 mM (96.2-106.4), respectively; in Karpas 299, EC 50 values for Devimistat and bendamustine were substantially higher: 117.2 mM (114.7-119.6) and 188.2 mM (180.0 - 196.8), respectively. When dosed in combination, devimistat and bendamustine (D/B) showed synergy (CI = 0.5-0.8) at effect levels > 0.9 in 8 of the 16 dose combinations tested. D/B synergy at an effect level > 0.9 was less overt in Karpas 299 with only 2 of 16 tested combination levels displaying CI values of 0.5-0.9. Efficacy studies with EL4.CD30 tumor-bearing mice revealed potent D/B anti-tumor activity relative to vehicle and single-agent treatment groups. Six complete regressions and 4 partial regressions were observed in the D/B group (Fig. 1A). Moreover, tumor growth rates and median survival values were significantly different (p Conclusions: Our data demonstrate that D/B has potent pharmacological activity in vitro and in vivo and promotes CTL influx into tumors. This suggests that D/B creates an immunopermissive environment fit for CAR-T cell activity. Subsequent studies will investigate the efficacy of CD30.CAR-T cells following D/B treatment. A Phase II pilot study evaluating the feasibility, safety, and tolerability of D/B in patients with relapsed/refractory T-cell Non-Hodgkin Lymphoma is currently ongoing (NCT04217317). Figure 1 Figure 1. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy, Research Funding; Karyopharm Pharmaceuticals: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genetech: Membership on an entity's Board of Directors or advisory committees; BMS: Speakers Bureau; Pharmacyclics: Speakers Bureau.

Context/Objective: Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+ BCP-ALL.1 Blinatumomab is infused continuously (cIV) 28 days/cycle. Severe adverse events (AEs), e.g., cytokine release syndrome (CRS) and neurologic toxicity (NT), may occur; thus, hospitalization is recommended for cycle 1: days 1–3 (C1:D1–3) and C2:D1–2. However, the incidence of severe AEs is low (CRS: 2%, NT: 13%).1 We believe that with digital monitoring, blinatumomab can be safely administered as an outpatient. Design: Adult patients (n=45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at ≤25 sites, with endpoint: grade ≥3 AE (Amgen NCT04506086). Patient suitability and outpatient monitoring are established. Patients receive 2–4 blinatumomab cycles. Cycles are initiated in the outpatient setting, and digital monitoring devices are activated/attached. Once home, patients set up the home hub and real-time data transfer to the healthcare provider (HCP) begins. The devices are worn continuously, 24 hours/day, for C1:D1–3 and C2:D1–2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless wearable health monitoring at home. The CHWMS provides continuous oxygen saturation, respiratory rates, and heart rates; an axillary sensor provides continuous temperature. Patients manually measure blood pressure every 3–6 hours around the clock. Patients have an integrated tablet to contact the HCP if needed. HCP/designee has a smartphone and receives vital signs constantly. The CHWMS platform generates a loud alert based on pre-specified vital sign thresholds or for data transfer interruption. Regardless of whether there is an alert, HCP may initiate direct audio/video contact with the patient, assess the patient’s condition, and make appropriate interventions. Patients are required to have a caregiver present during monitoring. Patients have a full set of replacement devices and a 24/7 support hotline. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gokbuget, Blood, 2018. © 2021 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2021 ASCO Annual Meeting. All rights reserved.

Summary Background Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. Methods In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0–1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m 2 , leucovorin at 400 mg/m 2 , irinotecan at 140 mg/m 2 , and fluorouracil 400 mg/m 2 bolus followed by 2400 mg/m 2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m 2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. Findings Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m 2 . The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4–19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250–602). Two patients enrolled at a higher dose of 1000 mg/m 2 , and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3–4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3–4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1–3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. Interpretation A maximum tolerated dose of CPI-613 was established at 500 mg/m 2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. Funding Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

Background: Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and chemotherapy resistance. Devimistat (CPI-613®) is a novel agent that inhibits two key tricarboxylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). Our lab has shown that genetic and pharmacologic inhibition of PDH sensitizes cells to chemotherapy and recent clinical trials of chemotherapy plus devimistat have been promising. However, the means by which AML cells adapt to PDH inhibition during devimistat treatment is unknown. Methods: Murine AML cells were used to knockout PDH through the CRISPR-CAS9 system. Viability assays were done using EZQuant or Cell-Titer Glo assays. Glycolytic flux was assessed by measurement of the extracellular acidification rate (ECAR) using the XF24 Extracellular Flux Analyzer. Glucose uptake was measured by Glucose Uptake-Glo assay. Protein levels were assessed by Western blot. Gene expression was measured by qPCR. Amino acid dependencies were assessed by incubating cells in Hank's Balanced Salt Solution with devimistat and either asparagine or glutamate for 4 hours followed by return to complete media and viability assayed after 72-hours. Results: Previous studies have shown that glycolysis can compensate for mitochondrial inhibition so we determined glycolytic rates during PDH inhibition. We have shown previously that genetic PDH loss decreases ECAR levels consistent with decreased glycolytic flux. Devimisat treatment also decreased ECAR levels in K562 and OCI cells in a dose dependent manner. We next examined glucose uptake. PDH knockout cells showed decreased glucose uptake compared to control. This could be due to reduced glucose import or reduced glucose retention. The expression of glucose importer GLUT1 was significantly decreased in cells with genetic or pharmacologic inhibition of PDH. LDHA expression was also reduced in PDH KO cells and devimistat treated cells, contributing to the ECAR decrease. Hexokinase II (HKII) traps glucose in AML cells and docks at the mitochondrial membrane. It can be dislodged with mitochondrial stress and subsequently degraded via the proteasome. PDH knockout cells and devimistat treated cells demonstrated reduced levels of HKII that could be rescued with the proteasomal inhibitor bortezomib. Taken together this data shows that genetic and pharmacologic inhibition of PDH decreases glycolysis by decreasing glucose import and retention. To assess the necessity of the diminished glycolytic activity we treated PDH knockout and devimistat treated cells with the glycolytic inhibitor 2-deoxy-D-glucose. Both devimistat treated and PDH KO cells were exquisitely sensitive to glycolysis inhibition. We next assessed the importance of gluconeogenic amino acids. We specifically looked at glutamate and asparagine as they have been shown to be highly utilized in cancers. Asparagine but not glutamate rescued AML cells from devimistat treatment. Asparaginase which catalysis the conversion of asparagine to aspartic acid, thus limiting the amount of asparagine in the cells sensitizes cells to both genetic and pharmacologic PDH inhibition. Asparagine can be converted into oxaloacetate which can be converted into phosphoenolpyruvate (PEP) for gluconeogenesis. Phosphoenolpyruvate carboxykinase (PCK2) catalyzes the rate limiting step in gluconeogenesis converting oxaloacetate to PEP which can travel backwards through glycolysis. We found that PCK2 was highly upregulated in both the PDH knock cells and devimisat treated cells. Indicating that with the reduced glucose import and retention the cells rely on gluconeogenesis from amino acids to maintain needed glycolytic intermediates. Conclusions: This data shows that PDH inhibition leads to diminished glycolytic rate, increased reliance on amino acid metabolism and increased gluconeogenesis. This in turn suggests that glycolysis inhibition and amino acid deprivation in combination with devminisat mediated PDH inhibition should be explored in clinical trials. Disclosures Pardee: Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Rafael: Research Funding; Karyopharm: Research Funding; BMS: Consultancy, Honoraria, Speakers Bureau; Genentech, Inc.: Consultancy; AbbVie: Consultancy; Rafael Pharmaceuticals: Consultancy. OffLabel Disclosure: Devimistat for the treatment of AML

Background: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow characterized by resistance to treatment and dismal outcomes, especially in the elderly. Novel approaches are desperately needed. Exportin 1 (XPO1) is involved in the selective nuclear export of certain proteins and RNA species. It is overexpressed in a subset of AML, conferring an adverse prognosis. Selinexor is a small-molecule inhibitor of XPO1 with activity in AML. Selinexor sensitizes AML cells to anthracyclines by retaining topoisomerase II in the nucleus resulting in increased DNA strand breaks. Furthermore, selinexor has shown encouraging results when combined with chemotherapy in AML. This abstract reports the ongoing results of a randomized phase II study of induction and consolidation with or without selinexor in newly diagnosed patients with AML, 60 years of age or older and preclinical studies to assess the mechanisms of chemo-sensitization. Methods: Patients 60 years of age or older with newly diagnosed de novo AML were randomized 3:1 between 7+3+selinexor or 7+3. Responding patients could go on to high dose cytarabine consolidation with or without selinexor as per initial randomization. Patients in the selinexor arm who completed all consolidation could then move to maintenance therapy with selinexor alone. Induction consisted of cytarabine 100 mg/m2/d by continuous infusion for 7 days and daunorubicin 60 mg/m2 on days 1-3. Consolidation consisted of cytarabine at 1.5 gm/m2 given Q12 hours days 1-3 with G-CSF given 24 hours following the last dose of cytarabine. Selinexor was dosed at 60 mg PO on days 1, 3, 8, 10, 15 and 17 during induction and consolidation and on days 1 and 8 every 21 days during maintenance. Preclinical studies were conducted with murine AML cell lines. Results: Twenty-seven of a planned twenty-eight patients were enrolled to date. Of the 27 evaluable patients, 20 were randomized to the selinexor arm and 7 to the control arm. Baseline demographics are listed in Table 1. In the standard arm, both 30- and 60-day mortality were 14% (1/7). In the selinexor arm, both 30- and 60-day mortality were 10% (2/20). In the standard arm, 43% (3/7) of patients achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi). Of the 3 responders 1 has gone on to transplant. In the selinexor arm, 85% (17/20) of patients achieved a CR or CRi. Of the 17 responders, 4 have gone on to transplant. Progression free and overall survival both favor the selinexor arm with trends towards significance despite the small size of the trial (Figure 1 and Table 2). No difference in the AE profile was noted between arms and no unexpected side effects were observed. Selinexor induces retention of topoisomerase II in the nucleus increasing sensitivity to anthracyclines. To determine if selinexor sensitized to cytarabine viability assays using murine AML cell lines were done (Figure 2A). Selinexor significantly sensitized both cell lines to cytarabine. AML cells increase mitochondrial oxygen consumption in response to cytarabine leading to resistance. The ability of selinexor to interfere with this response was assessed using Seahorse flux analysis. AML cells treated with cytarabine for 16 hours showed a diminished mitochondrial oxygen response when co-treated with selinexor (Figure 2B). Conclusions: Selinexor in combination with standard induction and consolidation therapy appears highly active in older patients with de novo AML. Selinexor may increase response to cytarabine by interfering with nuclear-mitochondrial communication. Enrollment is ongoing. Disclosures Pardee: Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Ellis:Rafael Pharmaceuticals: Consultancy. Howard:Jazz Pharmaceuticals: Consultancy. Powell:Jazz Pharmaceuticals: Consultancy, Other: Advisor, Research Funding; Genentech: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Rafael Pharmaceuticals: Consultancy, Other: Advisor, Research Funding. OffLabel Disclosure: Selinexor for the treatment of AML

Background: Gilteritinib monotherapy provides a CR/CRh rate of 34% and a median event-free survival of 2.3 months in relapsed FLT3 mutant AML. Many AML patients (pts) who relapse after gilteritinib still express mutant FLT3 receptor and could potentially respond to FLT3 inhibition. Crenolanib is a type I, pan-FLT3 inhibitor which can be given as monotherapy or combined at full doses with standard salvage chemotherapy. Methods: We here report our experience with 7 consecutive pts who received crenolanib on compassionate basis after progressing on gilteritinib. IRB/local ethics approval was obtained prior to treatment for each pt and all pts signed informed consent forms. Results: Prior Treatment history: From Sep 2019 to July 2020, 7 consecutive pts with multiply relapsed FLT3-mutant AML who received compassionate use crenolanib after progressing on gilteritinib were identified. Four pts had relapsed after allogeneic HSCT (one pt had undergone two HSCT) and the other 3 were primary refractory despite multiple prior lines of therapy (range 2-5, median 4). Clinical presentation: At the time of treatment all pts had bone-marrow infiltration or greater than 20% circulating blasts. 1 pt did not undergo BM assessment prior to salvage chemotherapy and crenolanib but had 87% circulating blasts in the peripheral blood. One pt had cranial nerve palsy due to leukemic meningitis, another pt had extramedullary relapse in spleen and lymph nodes. Five pts had FLT3-ITD (1 of whom also had the gate-keeper FLT3-F691L mutations); 1 had FLT3-D835 and 1 had both FLT3-ITD and TKD. Crenolanib treatment: Crenolanib at 100mg TID was administered with intensive salvage therapy in 3 pts (FLAG-IDA in 2, HiDAC in 1). In the other 4 pts crenolanib was given with a palliative intent (with decitabine in 2, with azacytidine in 1 and as monotherapy in 1). Tolerability of crenolanib: Crenolanib has been clinically well tolerated, with mild nausea and vomiting reported in 3 pts which was controlled by antiemetics without causing any drug interruptions. Two pts had elevated transaminases (which resolved as concomitant medications were discontinued). There were no cardiac toxicities, pericardial effusion, fluid retention or weight gain. Response to crenolanib: At the time of this abstract, 5 of the 7 pts remain on crenolanib from a period of 18-160 days. Six of 7 pts reported clinical benefit with crenolanib. Of the 3 pts being treated with curative intent, the pt with extramedullary disease in the spleen and lymph nodes had complete resolution of her AML by PET scan. She also had exhibited clearance of bone-marrow blasts with full count recovery and became FLT3 negative. The pt with FLT3-F691 mutation and cranial nerve palsy due to CNS leukemia had clearance of CNS blasts and improvement in cranial nerve function after HIDAC, crenolanib, and intrathecal cytarabine; this patient achieved morphologic leukemia free state and FLT3 negativity in the BM. A 22-year-old pt treated with FLAG-IDA has only received 18 days of crenolanib at time of data cutoff. All pts treated with curative intent continue on crenolanib. Of the 4 pts treated with palliative intent, the pt with mutant TP53 had no benefit following crenolanib and azacytidine and died within two months. One patient, who had had two prior HSCTs, had 90% reduction in circulating blasts with azacytidine + crenolanib, but chose to discontinue treatment after 9 days. The other 2 pts continue on crenolanib 2 and 5 months after starting treatment. Conclusion: With the widespread availability of gilteritinib, more pts are now in need of treatment options after gilteritinib refractoriness or treatment failure. These pts often have resistant clones due to either acquisition of the gate-keeper FLT3-F691 mutation or RAS mutant clones. In this consecutive case series of 7 post-gilteritinib pts, treated in US and Europe, crenolanib can be given at full doses in combination with intensive salvage chemotherapy or decitabine/azacitidine. The individual-patient-level experience suggests crenolanib could effectively clear FLT3-ITD and variant FLT3-TKD mutations in pts progressing from multiple lines of treatment including gilteritinib. Clinical trials combining crenolanib with salvage chemotherapy in relapsed and refractory AML with FLT3 mutations are ongoing. More information about crenolanib compassionate use program is available by emailing compassionate@arogpharma.com. Disclosures Goldberg: Celgene: Consultancy; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aptose: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Aprea: Research Funding; AROG: Research Funding; Celularity: Research Funding; Dava Oncology: Honoraria; Pfizer: Research Funding. Geyer:Amgen: Research Funding. Pardee:Rafael Pharmaceuticals: Consultancy; AbbVie: Consultancy; Genentech, Inc.: Consultancy; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Research Funding; Rafael: Research Funding; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Pharmacyclics: Speakers Bureau. Grunwald:Cardinal Health: Consultancy; Amgen: Consultancy; Amgen: Consultancy; Agios: Consultancy; Merck: Consultancy; Merck: Consultancy; Abbvie: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Abbvie: Consultancy; Abbvie: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Incyte: Consultancy, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Astellas: Consultancy; Genentech/Roche: Research Funding; Premier: Consultancy; Premier: Consultancy; Janssen: Research Funding; Genentech/Roche: Research Funding; Genentech/Roche: Research Funding; Forma Therapeutics: Research Funding; Merck: Research Funding; Janssen: Research Funding; Forma Therapeutics: Research Funding; Forma Therapeutics: Research Funding; Trovagene: Consultancy; Premier: Consultancy; Merck: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Cardinal Health: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Cardinal Health: Consultancy. Wang:Arog Pharmaceuticals: Current Employment. Pathan:Arog Pharmaceuticals: Current Employment. Messahel:AROG Pharmaceuticals: Current Employment.

Devimistat is a novel TCA cycle inhibitor being studied in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML. A combined analysis of the phase I and II datasets was conducted to determine the optimal phase III dose. A dose response in older but not younger patients was observed. Gene set enrichment analysis of RNA sequence data from patient samples revealed an age-related decline in mitochondrial function and biogenesis. In cell line models there was a strong direct correlation between the baseline mitochondrial membrane potential and the sensitizing effects of devimistat and metformin could render resistant cells sensitive. Additional mechanistic studies revealed that TCA cycle inhibition with devimistat or by genetic manipulation induced mitochondrial turnover. Pharmacological or genetic inhibition of mitophagy sensitized AML cells to devimistat. These data support a model whereby devimistat preferentially benefits older patients with reduced mitochondrial quality and biosynthetic capacity.

Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11–positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged

TPS4158 Background: Patients (pts) with advanced biliary tract cancers (BTC) have poor prognosis despite systemic chemotherapy. Gemcitabine and cisplatin is a standard first-line systemic therapy with an overall response rate (ORR) of 26% and a median overall survival of 11.7 months. This investigator-initiated, multi-institutional phase 1b/2 trial is designed to investigate the role of gemcitabine, cisplatin and CPI-613 in pts with advanced BTC. CPI-613 is a stable intermediate of a lipoate analog that inhibits pyruvate dehydrogenase and a-ketoglutarate dehydrogenase enzymes of the tricarboxylic (TCA) cycle preferentially within the mitochondria of cancer cells. Methods: Key eligibility criteria include histologically confirmed, metastatic or unresectable BTC (intra- or extra-hepatic and gallbladder) without prior systemic treatment, measurable disease per RECIST v1.1, and ECOG PS 0-1. Primary objective of the phase 1b portion (n = 20 pts; TiTE-CRM methodology) is to determine the recommended phase 2 dose of the combination, and for the phase 2 portion, ORR (n = 48-58 pts; 2:1 randomization). Assuming a null hypothesis ORR of 25% and an alternative hypothesis of 43%, this ongoing trial has at least 80% power with a one-sided alpha of 0.05 to identify treatment efficacy of the study arm. Secondary objectives include evaluation of progression-free survival, overall survival, and safety in this patient population. Exploratory objectives include identification of molecular markers of response and resistance in tumor samples and serially collected blood (pre-, on-, and post-therapy), including whole exome/transcriptomic analysis, and immunohistochemical staining (PDK, PDH, KGDH, SOD2 and CD79a). Gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 with or without CPI-613 (dose levels: 500 mg/m2, 1000 mg/m2, 1500 mg/m2, and 2000 mg/m2) will be given IV on days 1 and 8 every 21 days. In the absence of disease progression, pts may continue therapy for up to 2 years. Total accrual goal is 68-78 evaluable pts. To date, 5 of planned 20 pts enrolled on the phase 1b portion are without dose limiting toxicity. Clinical trial information: NCT04203160.

TPS7051 Background: The prognosis for adults with relapsed or refractory BCP-ALL is poor. MRD+ is the strongest predictor of relapse. Blinatumomab, a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule, is an effective treatment for patients with MRD+.1 Blinatumomab is administered as a continuous intravenous infusion (cIV) 28 days per cycle. Severe adverse events (AEs) such as cytokine release syndrome (CRS) and neurologic toxicity (NT) may occur; thus, hospitalization is recommended for the first 3 days of cycle 1 and the first 2 days of cycle 2 for MRD+ patients. However, the incidence of severe AEs is low in MRD+ BCP-ALL patients (CRS: 2%, NT: 13%).1 We believe that with the use of effective digital monitoring devices, blinatumomab can be safely administered for the entire 28-day cIV cycle as an outpatient. Methods: Adult patients (n = 45) with BCP-ALL in complete remission and MRD+ (≥0.1% blasts) are being enrolled at 25 planned treatment sites, endpoint: grade ≥3 AE during monitoring (Amgen NCT04506086). Patient suitability for blinatumomab and outpatient monitoring is established. Patients will receive 2-4 cycles of blinatumomab. Cycles are initiated in the outpatient setting, digital monitoring devices activated and attached, and patients sent home. Once home, patients set up the home hub and real-time remote data transfer to the healthcare professional (HCP) begins. The devices are worn continuously, 24 hours a day for the first 3 days of cycle 1 and the first 2 days of cycle 2 only. Devices: Current Health’s Wearable Monitoring System (CHWMS) is an FDA-cleared platform for wireless and wearable health monitoring of patients at home. The CHWMS provides continuous oxygen saturation, respiratory rate, and heart rate; an axillary temperature sensor is worn and provides continuous temperature. Patients manually measure blood pressure every 3-6 hours around the clock. Patients have an integrated mobile device (tablet) to initiate contact with the HCP if needed. HCP/designee has a mobile device (smart phone) and receives vital signs as a constant live feed transmitted from the CHWMS device. The CHWMS platform generates a loud audible alert based on pre-specified vital sign alarming thresholds or if there is an interruption in data transfer. HCP may initiate direct audio and video contact with the patient, assess the patient’s condition, and make an appropriate intervention. HCP may also initiate patient contact in the absence of an alert. Patients are required to have a caregiver present during the entire period of outpatient monitoring. Patients have a full set of replacement devices as well as a 24/7 hotline for device support. Trial enrollment is underway. This study may generate feasibility data on the effectiveness of home monitoring during blinatumomab infusion in patients with MRD+ BCP-ALL. 1Gökbuget, Blood, 2018. Clinical trial information: NCT04506086.

12009 Background: Older adults are at risk for physical function decline during therapy for AML. Impaired physical function after induction therapy is associated with shorter survival Interventions designed to maintain function may improve treatment outcomes. We piloted a physical activity (PA) intervention among older adults receiving intensive chemotherapy for AML designed to prevent functional decline. Methods: Single institution randomized pilot study of PA vs. usual care. Eligibility included age ≥60 years, newly-diagnosed AML, ambulatory, planned intensive induction chemotherapy. Intervention participants were offered a PA session five days/week tailored daily to symptoms and conditions during the induction hospitalization. Session options were: 1) Standard (ward-based), walking + balance trahining + resistance exercises; 2) Intermediate (room-based), upper-body ergometer + balance training + resistance exercises; 3) Low-intensity (bed-based), upper-body ergometer + resistance exercises. Behavioral counseling sessions to establish PA goals and overcome barriers were conducted weekly during hospitalization and continued monthly by phone for 6 months. Assessment of physical function occurred at baseline, weekly during hospitalization (approximately 4-6 weeks), 3 months, and 6 months. The primary functional outcome of interest was the Short Physical Performance Battery (SPPB; 5 repeat chair stands, gait speed, balance tests; score 0-12 higher indicates better function). Clinically significant change in physical function was defined as ≥1.0 on the SPPB. Proportions of those that declined, remained stable, or improved on the SPPB were compared by group using an exact test for trend. Results: Among 96 eligible patients 70 enrolled (recruitment rate 73%, average participation 3 sessions/week). The mean age was 72.1±6.3 years, 70% were male. Mean baseline SPPB score was 7.0±3.8. In the surviving intention to treat population (N = 66), more intervention participants, compared to controls, maintained or improved their SPPB score (38% vs. 25%) during induction hospitalization (p = 0.278). Among those who achieved remission (N = 42), function was maintained or improved in a greater proportion of intervention participants (55%) compared to controls (23%), p = 0.047. Maintenance or improvement in SPPB from baseline to last follow-up (3 or 6 months post enrollment) was 62% vs 54% for intervention versus control among the intention to treat cohort (N = 50) and 67% vs. 55% among those who achieved remission (N = 40). Conclusions: A symptom adapted PA intervention with behavioral counseling during induction chemotherapy shows promise in preventing clinically meaningful decline in physical function among older adults with AML who achieve remission. Continued maintenance intervention may sustain benefits. Clinical trial information: NCT01519596.

The azanucleotide decitabine is used in the treatment of acute myeloid leukemia (AML). Studies have shown conflicting results with 10-day regimens used in previously untreated AML patients. Additionally, there is little data on 10-day decitabine regimens in the relapsed setting. This study investigated outcomes of 108 adult patients with AML in the upfront and relapsed setting treated with a 10-day decitabine regimen. In the upfront group, the overall response rate (ORR, CR + CRi) was 36.1% and the median overall survival (OS) was 6.6 months, while the relapsed/refractory group had an ORR of 25% with an OS of 4.8 months. When analyzed with respect to cytogenetics, the upfront group featured an ORR of 28.1% with an OS of 9.4 months in the intermediate cytogenetic cohort compared to a 40.5% ORR and an OS of 5.4 months in the unfavorable cytogenetic cohort. An analysis of the relapsed/refractory group demonstrated an ORR of 26.3% with an OS of 7.9 months for intermediate cytogenetics versus 25.0% with an OS of 1.8 months in the unfavorable cohort. While these response rates are similar to previously published data, the median OS appears shorter.

F10 is a novel polymeric fluoropyrimidine drug candidate with strong anticancer activity in multiple preclinical models. F10 has strong potential for impacting cancer treatment because it displays high cytotoxicity toward proliferating malignant cells with minimal systemic toxicities thus providing an improved therapeutic window relative to traditional fluoropyrimidine drugs, such as 5-fluorouracil. F10 has a unique mechanism that involves dual targeting of thymidylate synthase and Top1. In this review, the authors provide an overview of the studies that revealed the novel aspects of F10's cytotoxic mechanism and summarize results obtained in preclinical models of acute myeloid leukemia, acute lymphocytic leukemia, glioblastoma and prostate cancer that demonstrate the strong potential of F10 to improve treatment outcomes.

In the past few decades, nucleoside analog drugs have been used to treat a large variety of cancers. These anti-metabolite drugs mimic nucleosides and interfere with chain lengthening upon incorporation into the DNA or RNA of actively replicating cells. However, efficient delivery of these drugs is limited due to their pharmacokinetic properties, and tumors often develop drug resistance. In addition, nucleoside analogs are generally hydrophilic, resulting in poor bioavailability and impaired blood-brain barrier penetration. Conjugating these drugs to lipids modifies their pharmacokinetic properties and may improve in vivo efficacy. This review will cover recent advances in the field of conjugation of phospholipids to nucleoside analogs. This includes conjugation of myristic acid, 12-thioethyldodecanoic acid, 5-elaidic acid esters, phosphoramidate, and self-emulsifying formulations. Relevant in vitro and in vivo data will be discussed for each drug, as well as any available data from clinical trials.

Background: Acute myeloid leukemia (AML) remains an agressive malignancy with poor clinical outcomes, particularly in older patients. Dysregulated metabolism has long presented a promising target for cancer therapeutics; however, the development of clinical-stage therapies targeting cancer cell metabolism has been limited and faces challenges to achieve both efficacy and acceptable toxicity. As an exception, the lipoic acid analogue devimistat has shown positive clinical outcomes in numerous early-phase clinical trials including for relapsed and refractory AML patients. While inhibition of lipoic acid-dependent ketoacid dehydrogenase (KADH) enzymes has been proposed as the mechanism of these antineoplastic effects, the mechanisms underlying the efficacy devimistat and its possible relation to metabolism in patients has not been established. Methods: Samples of bone marrow and blood plasma from patients with relapsed or refractory AML before and after treatment with devimistat were collected. The samples were analyzed using liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) methods to profile ~400 polar metabolites. Kinetic flux profiling in cultured cancer cell lines treated with devimistat was also performed. Results: Analysis of blood plasma samples collected following devimistat treatment revealed detectable levels of drug, consistent with clinically therapeutic concentrations. Comprehensive metabolite profiling of pretreatment and posttreatment blood plasma samples revealed distinct metabolic alterations induced by devimistat administration. Devimistat is thought to inhibit ketoacid dehydrogenase (KADH) enzyme, and consistent with this proposed mechanism of action, accumulations of KADH substrates were observed in the posttreatment samples. Local metabolism in the tumor microenvironment was also altered by devimistat therapy, with robust reductions of TCA intermediates measured in bone marrow plasma samples collected after treatment. Interestingly, quantification of these metabolites revealed an association between overall clinical outcomes and changes in concentrations of bone marrow metabolites. Kinetic flux tracing demonstrated an expected reduction of mitochondrial metabolic flux in cultured tumor cells following treatment with devimistat. Conclusions: Comprehensive metabolite profiling reveals that devimistat targets KADH enzymes and reduces mitochondrial metabolism in humans. Furthermore, these metabolic changes are quantitatively associated with clinical outcomes, posing a potential opportunity for biomarker development and precision metabolic therapy. Citation Format: Michael A. Reid, Shree Bose, Zhengtao Xiao, Peter G. Mikhael, Juan Liu, Jason W. Locasale, Timothy S. Pardee. Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5709.

Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and chemotherapy resistance. Devimistat (CPI-613 ®) is a novel agent that inhibits two key tricarboxylic acid (TCA) cycle enzymes, pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes (KGDH). Our lab has shown that genetic and pharmacologic inhibition of PDH sensitizes cells to chemotherapy and recent clinical trials of chemotherapy plus devimistat have been promising. However, the means by which AML cells adapt to PDH loss during devimistat treatment is unknown. AML cells with PDH deleted by CRISPR-Cas9 (PDH KO) show decreased mitochondrial oxygen consumption, membrane potential and altered mitochondrial morphology. Surprisingly, PDH KO cells also showed decreased glycolytic rates. In order to explore this mechanism we assessed glucose uptake and found PDH KO cells had significantly less glucose uptake. We next assessed expression of hexokinase II, a key enzyme that commits glucose retention in the cell, in PDH KO and devimistat treated cells. Strikingly, we found that hexokinase II expression was decreased in PDH KO cells, which was rescued with proteasomal inhibition. Consistent with disruption of the protective interaction between mitochondrial membrane channel VDAC1 and HKII. However, PDH KO and devimistat treated cells are more sensitive to the glycolytic inhibitor 2-deoxy-D-glucose. This indicates that even though TCA cycle inhibition decreases glycolysis through loss of HKII, the cells are still reliant on the activity that remains. Cells can supplement TCA cycle intermediates through amino acid metabolism. Two key amino acids, asparagine and glutamate, were reintroduced to devimistat treated, amino acid starved, AML cells and asparagine significantly rescued the cells. Asparaginase, which converts asparagine into aspartic acid and ammonia, significantly increased sensitivity to genetic and pharmacological inhibition of PDH in AML cells. This indicates that glycolysis inhibition and amino acid deprivation in combination with devimistat-mediated PDH inhibition should be further explored in clinical trials. Citation Format: Rebecca Anderson, Kristin M. Pladna, Timothy S. Pardee. Pyruvate dehydrogenase inhibition leads to decreased glycolysis and increased reliance on asparagine in acute myeloid leukemia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4800.

4635 Background: Glycolic and mitochondrial metabolism are aberrant in pancreatic cancer and translate into chemoresistance. Inhibition of glutamine metabolism can potentially synergize with therapies that increase intracellular reactive oxygen species, such as nab-paclitaxel. CPI- 613 is a novel antimitochondrial agent developed by Rafael Pharmaceuticals that showed promising clinical activity in combination with modified FOLFIRINOX in patients with stage IV pancreatic cancer. Preclinical data suggested possible synergy of CPI-613 with nab-paclitaxel. Methods: Single arm, open-label, phase I study of CPI-613 with gemcitabine and nab-paclitaxel in patients with locally advanced or metastatic pancreatic cancer to determine MTD, safety, and preliminary efficacy of CPI-613 in combination with chemotherapy. Key eligibility criteria included: histologically documented and measurable locally-advanced or metastatic, PDAC. ECOG performance status 0-2; and first line systemic treatment. CPI-613 was infused intravenously with a starting dose of 500 mg/m2 followed by modified dose nab-paclitaxel (100mg/m2) and gemcitabine ( 800 mg/m2) on Days 1, 8, and 15 of a 28-day cycle. The the primary endpoint, the MTD of CPI-613 was determined by a two-stage, dose-escalation schema, with 6-month treatment duration for patients exhibiting treatment response. Secondary endpoints were treatment-related adverse events, complete response (CR) and partial response (PR). Results: From February 2018 to 2020, 26 patients were screened, (23 metastatic and 3 locally advanced), 22 patients enrolled and 18 patients underwent a restaging scan. As of the time of submission 3 patients are still on active treatment. Patient demographics were: median age of 65, ECOG was 0-1, The MTD of CPI- 613 was determined to be 1500 mg/m2. The dose limiting toxicities were not achieved. Overall the treatment was well tolerated with toxicities mainly related to chemotherapy; most common grade 3 and 4 toxicities were hematologic toxicity and neuropathy. 1 patient achieved CR, 9 PR, 8 stable disease and 1 progressive disease for an objective response rate of 50% with a CR rate of 5.5%. Conclusions: The results demonstrate that CPI 613 can be safely administered with gemcitabine and nab-paclitaxel at doses up to 1,500 m/g2. Efficacy data suggest synergy with chemotherapy. Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Clinical trial information: NCT03435289 .