ALBERT

Description: Introduction Low molecular weight heparin (LMWH) is currently the preferred anticoagulant for malignancy-associated venous thromboembolism (VTE) given improved outcomes compared to warfarin. However, recurrent thrombosis still occurs in up to 9% of patients despite use of this preferred agent. Data to guide clinical decisions-making in the setting of recurrent thrombosis despite use of LMWH is lacking. Unlike warfarin or unfractionated heparin (UFH), LMWH typically does not require monitoring to determine efficacy or safety. However, many providers will still check a LMWH anti-Xa level, despite little clinical validation on how these values should be interpreted and how they correspond with patient outcome. Therefore, the levels have the potential to be used or interpreted incorrectly. The aim of this study was to evaluate how LMWH anti-Xa levels are currently incorporated into clinical practice, with emphasis on whether the lab was drawn correctly, the indication for checking the level, and whether testing impacted clinical decision making. Methods This is a single-institution, retrospective study. Cases of malignancy-associated thrombosis occurring between 1/1/2006 and 12/31/2011 were identified using current procedural terminology (CPT) codes and the Northwestern University Electronic Data Warehouse. This cohort was then screened for those who had a LMWH anti-Xa level checked at any point in that time frame. All resultant cases had charts reviewed by 2 independent investigators to confirm active malignancy, treatment with LMWH, and history of VTE. Patients were excluded from analysis if the anti-Xa level was checked while on unfractionated heparin and if the last dose of anticoagulation was given as an outpatient. Results An anti-Xa level was checked 447 times in patients with malignancy-associated thrombosis in the specified time frame. Analysis thus far was limited to the 247 patients with malignancy-associated VTE who had only one LMWH anti-Xa level checked during the study period. After reviewing for exclusion criteria, 167 cases were eligible. LMWH anti-Xa testing was sent most frequently in those with hematologic malignancy (25%) and lung cancer (13%). The indication for testing was not documented or was unclear in 88 (53%) of cases. Impaired renal function (10%), documented or suspected recurrent thrombosis despite anticoagulation (9%), and bleeding (6%) were among the more common reasons that LMWH anti-Xa levels were checked. 40% of the patients had a body mass index (BMI) ≥30. Optimal timing for testing is 4-6 hours after the third dose. In this study, the timing of the lab draw was correct in only 55% of cases, leading to potentially imprecise results in the remaining 45%. Of those drawn correctly, 76% were in the reported “therapeutic target range.” In the majority of cases, there was no change in the type or dose of anticoagulation in the 24 hours after the anti-Xa level was drawn. Conclusions Despite widespread use in routine clinical practice, the role for checking LMWH anti-Xa levels in those with malignancy-associated thrombosis being treated with LMWH is not clear. Our data indicate that providers may not be aware of how the lab should be drawn, with regard to peak levels. In addition, a majority of anti-Xa levels were checked in overweight and obese patients, despite no definitive evidence that these patients require extra monitoring. Finally, when tested correctly, the majority of patients were already in what is reported to be the therapeutic range, bringing to question if the level needed to be checked at all. This strongly suggests a role for provider education if testing is felt to be clinically indicated. At present, though testing is widely available, it is not yet clear in which clinical contexts (if any) providers should send LMWH anti-Xa levels. Prospective studies are needed to better clarify whether anti-Xa levels correlate with clinical outcomes in those with malignancy-associated thrombosis, and how the results should be incorporated clinical practice. Disclosures: No relevant conflicts of interest to declare.

Description: Background While inferior vena cava (IVC) filter placements continue to exponentially increase, the long-term complications from these devices are progressively more recognized. Randomized data on the efficacy of filters is sparse and focuses mainly on outcomes following permanent filter placement; however, the majority of filters placed currently are retrievable. Placement and removal of these filters are more expensive than permanent filters and have more long-term complications. In this study, we analyzed the use of retrievable filters in the cancer population, a group at very high risk for incident and recurrent venous thromboembolism (VTE). Methods This is a single-institution study. All patients with a history of malignancy or active malignancy that received an interventional radiology (IR) placed temporary IVC filter from 2009 to 2013 were logged into a database. Patients were followed prospectively from time of device placement. Recorded data included demographics, type of malignancy, indication for filter placement, time to filter retrieval, complications of placement/retrieval, rates of VTE recurrence and cause of death (if applicable). Final data analysis (n=179 filter placements) was only performed on patients that had an active malignancy or were receiving adjuvant therapy for a recent active malignancy. Results The most common indications cited for filter placement included a contraindication to anticoagulation (69%), surgical prophylaxis (17%) and concern for cardiopulmonary collapse from a pulmonary embolism (PE) (6%). IVC filters were most frequently placed in patients with underlying hematologic malignancies (28%), gastrointestinal malignancies (17%) and gynecologic malignancies (15%). The majority of patients had stage III or IV cancer (61%). Internal medicine providers were most likely to order filter placements (36%) followed by hematologists/oncologists (26%) and gynecologic oncologists (17%). 35% of filters were not placed due to a contraindication to anticoagulation or failure of anticoagulation, and of these filters placed, 20% were not removed. Of the 179 temporary filters placed, 60% remained permanent. The most common reasons stated for failure of filter removal included: progressive disease/clinical deterioration (51%), continued contraindication to anticoagulation (23%) and loss of follow-up (7%). Only 2% of filters were unable to be removed because of mechanical reasons. Of the 81 attempted filter removals, 5 had in-filter thrombus, 4 had surrounding fiber sheaths, 4 had filter tilt, 1 had IVC in-growth, 1 had a procedure related infection and 1 had broken struts. The rate of recurrent VTE in all patients studied was 20% (predominantly deep vein thromboses), with the majority of recurrences occurring in patients that had the filter in place and were not maintained on anticoagulation. By the end of the study, 59% of patients had died, most commonly due to progressive cancer. Median time from filter placement to death was 5.25 months. Additionally, we gathered data on filter costs. Costs were attributable to the device ($1576.00), placement ($10,983.00) and removal ($8,824.00), totaling over $2 million dollars for placement of IVC filters in this cohort. Conclusions A significant number of cancer patients who have an IVC filter placed have no contraindication to anticoagulation or evidence of recurrent VTE on anticoagulation. Better prospective data is needed regarding the safety and efficacy of IVC filter placement for prophylactic purposes or in the setting of a large VTE burden as these are commonly cited indications for placement. Additionally, consideration for permanent filter placement should be made in cancer patients as the majority of temporary filters are not removed and may carry higher risks of complications. Notably, our filter removal rate was significantly higher than the retrieval rate at most centers (

Description: Background: ALRN-6924, the first-ever clinical stage stapled peptide, has been structurally stabilized ("stapled") in an α-helical configuration, to mimic the inhibitor-binding region of the intracellular tumor suppressor protein, p53. By mimicking this region, ALRN-6924 binds the two most important endogenous inhibitors of p53, murine double minute-X (MDMX) and murine double minute-2 (MDM2), thereby restoring p53's ability to induce cell cycle arrest and apoptosis in TP53 wild-type (WT) cancer cells. ALRN-6924 is the first known synthetic agent to simultaneously target both of these important p53 inhibitors. In preclinical studies, ALRN-6924 inhibited the proliferation of AML cell lines and primary human AML cells alone and in combination with cytarabine. Preclinical data (Carvajal et al, 2018) demonstrated antiproliferative effects against leukemic stem cells, and complete responses that translated into cures in approximately 40% of mice in xenotransplantation studies. These data also suggested that more frequent dosing may enhance efficacy, and this hypothesis is now being evaluated in the ongoing clinical trial. Methods: ALRN-6924 is being evaluated alone and in combination with cytarabine, using a 3+3 dose escalation design. Using the previously determined RP2D for solid tumors (Meric-Bernstam et al., 2017), the initial cohorts receive 3.1 mg/kg of ALRN-6924 IV over 1 hour on Days 1, 8, and 15 of a 28-day cycle (QW mono-therapy). In separate cohorts, ALRN-6924 is combined with cytarabine IV over 1 hour (initially 100 mg/m2, later 200 mg/m2 ; QW combo-therapy). Later monotherapy cohorts receive more frequent ALRN-6924 administration on Days 1, 3, 5, 8, 10, and 12 of a 21-day cycle (TIW mono-therapy), with an initial dose level of 2.7 mg/kg. Adverse events (AEs) are assessed per CTCAE V4.03; responses are evaluated by the investigators according to IWG (Cheson 2006) and AML Response Criteria (Dohner 2010), for MDS and AML, respectively. Results: Preliminary results are being presented for 13 pts on QW mono- and 19 pts on QW combo-therapy. As of 13 July 2018, 32 QW pts have enrolled, with a median age of 75 years (38-90), 18 pts with de novo or secondary AML and 14 pts with MDS who failed hypomethylating agents. Thus far, pts have received 1-14 cycles. No DLTs have been observed and no MTD has been reached for QW mono-therapy (3.1-5.8 mg/kg) or QW combo-therapy (3.1-4.4 mg/kg ALRN-6924 and 100-200 mg/m2 cytarabine). For QW-treated pts (mono and combo), AEs related to treatment with ALRN-6924 have been reported in 62.5% of pts; most frequent are nausea (25.0%), thrombocytopenia (25.0%), vomiting (25.0%), fatigue (15.6%), and diarrhea (15.6%). Hyperbilirubinemia was reported in 18.8% of pts, representing a known transient effect of ALRN-6924 clearance that has not been associated with liver injury. Thrombocytopenia is the only ≥ grade 3 hematologic AE related to treatment with ALRN-6924 that was reported in ≥5% of pts, with all cases being grade 4 thrombocytopenia (7 pts, 21.9%). SAEs related to treatment with ALRN-6924 have been reported in 2 pts (grade 3 extremity pain and grade 4 angioedema while on concomitant lisinopril). The AE profiles for pts receiving ALRN-6924 QW mono- or QW combo-therapy were not significantly different. Including all QW cohorts (mono and combo), twenty-seven pts are efficacy-evaluable as of July 13, 2018. In preliminary efficacy results across all cohorts, marrow CR was reported in two out of four MDS pts treated with 4.4 mg/kg ALRN-6924 + 200 mg/m2 cytarabine, one of whom went on to transplant. An additional three MDS pts achieved SD. Among AML pts, 1 had a 〉50% reduction in bone marrow blasts while receiving 3.1 and then 4.4 mg/kg ALRN-6924 plus 100 mg/m2 cytarabine QW. This was durable until the pt succumbed to pneumonia that was unrelated to study drug in cycle 7. For QW-treated pts (mono and combo), main reasons for treatment discontinuation include treatment failure (31.2%), consent withdrawn (25.0%), death (9.4%), MDS transformed to AML (6.2%), and adverse event (6.2%). Accrual to QW combo-therapy with cytarabine in MDS and TIW mono-therapy in AML and MDS continues; updated data for QW mono-, QW-combo as well as TIW mono-therapy will be presented at the meeting. Conclusion: ALRN-6924 has shown clinical activity and an acceptable safety profile in AML and MDS. Continued development of ALRN-6924 for AML and MDS treatment is warranted. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau. Borate:Agios: Consultancy; Novartis: Consultancy. Cull:Celgene: Speakers Bureau. Komrokji:Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Steidl:Aileron: Consultancy, Research Funding. Corvez:Aileron Therapeutics Inc.: Employment, Equity Ownership. Payton:Aileron Therapeutics: Employment, Equity Ownership. Annis:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties. Pinchasik:Aileron Therapeutics Inc.: Employment, Equity Ownership. Aivado:Aileron Therapeutics Inc.: Employment, Equity Ownership, Patents & Royalties.

Description: Background: Despite numerous treatment (Tx) options, follicular lymphoma (FL) remains incurable, and established common treatments such as chemoimmunotherapy combinations and kinase inhibitors can have significant morbidity, especially in older patients or in those with comorbidities. G100 is a TLR4 (toll-like receptor 4) agonist that activates both the innate and adaptive arms of the immune system. When given intratumorally (IT), G100 triggers an anti-tumor immune response that leads to systemic tumor shrinkage (Flowers ASCO 2017). Initial data from a randomized study of the combination of G100 and pembrolizumab (P) demonstrated that the addition of P resulted in more PRs, abscopal tumor shrinkage, and a trend to a better PFS than G100 alone. In addition, an association between baseline tumor TLR4 expression by immunohistochemistry (IHC) and clinical response was observed (Flowers ASH 2017). We now present updated response data and long-term follow-up of this randomized study. Methods: Previously treated or Tx naïve FL pts with ≥2 tumor sites were eligible. Pts received 6-9 doses of IT G100 (G) weekly to a site treated with low dose radiation (RT, 2 Gy x2 doses). A 2nd course of G could be given without additional RT to an additional site. Pts were randomized to IT G (10 µg/dose) or IT G + P 200mg IV on Day 14 then q3wks for up to 2 years. Responses were evaluated by IrRC criteria based on bidimensional measurements (Wolchok ClCanRes 2009). Untreated sites were followed for abscopal response. Results: As of 3July2018, 26 FL pts were treated (13, G vs. 13, G + P). 7 and 5 pts were Relapsed/Refractory (R/R) in G and G+P, respectively. Median number of prior therapies were 3 for G and 4 for G+P and included 5pts previously Tx with auto-SCT. Median duration of observation was 14.3 and 16.6 mos for the G and G+P, respectively. G was well tolerated; related AEs were all grade (Gr) 1/ 2 with no G-related DLTs or SAEs. For G+P, 1 pt experienced Gr 2 hypothyroidism and 1pt, Gr 3 colitis/lab abnormalities/adrenal insufficiency (SAE). No deaths were reported. Overall best responses (PRs) were: 23% in pts on G and 54% in pts on G+P. In the R/R population, PRs occurred in 29% of pts on G and in 80% of pts on G+P. Median time to response was 2.3 mos (range 1.7-18.1) for G and 3.7 mos (range 2.2-17.1) for G+P, and included delayed responses at ≥18mos. Among pts with baseline TLR4high (≥50%) tumor expression, ORR was 17% for G (n=6) vs 75% for G+P (n=8). Within the GELF high tumor burden pts, PRs occurred in 0% of pts in G and in 33% of pts in G+P. Likewise, in pts failing R-Chemo

Description: Background The use of both temporary and permanent inferior vena cava (IVC) filters continues to rise yet randomized data regarding efficacy and complication rates are limited, especially in cancer patients. Temporary IVC filters are associated with higher costs and can have more long-term complications than permanent IVC filters. In this study, we examined the use of temporary and permanent IVC filters in the cancer population, a group at high risk for venous thromboembolism (VTE) as well as complications of anticoagulation. Methods This single-institution study included patients with active malignancy receiving adjuvant chemotherapy or considered for future chemotherapy that received an interventional radiology (IR) placed temporary (N=179) or permanent (N=207) IVC filter from 2009 to 2013. Patients were followed prospectively from the time of filter placement. The database included patient demographics, type of malignancy, indication for filter placement, time to filter retrieval, complications of placement/retrieval, rates of VTE recurrence and cause of death (if applicable). Results Patient demographic information is shown in Table 1. The most common reasons cited for filter placement included a contraindication to anticoagulation from bleeding (36%), recent or upcoming procedure (19%), thrombocytopenia (17%), and surgical prophylaxis (8%). 21% of filters were placed in patients with no contraindication to anticoagulation or failure of anticoagulation. Of these, 35% of the temporary filters were not removed. IVC filters were most frequently placed in patients with underlying hematologic malignancies (22%), gastrointestinal malignancies (22%) and lung cancer (16%). The majority of patients had stage III or IV cancer (62%). Of the 179 temporary filters placed, 60% were not retrieved. The most common reasons for failure of filter retrieval included: progressive disease/clinical deterioration (51%), continued contraindication to anticoagulation (23%) and loss of follow-up (8%). Only 2% of filters could not be removed because of mechanical reasons. Of the 81 attempted filter removals, 5 had in-filter thrombus, 4 had surrounding fibrin sheaths, 4 had filter tilt, 1 had IVC in-growth, 1 had broken struts and 1 had a procedure-related infection. The rate of recurrent VTE in all patients studied was 23% (21% in temporary filter group, 24% in permanent filter group), including 20 pulmonary emboli (PE) and 14 thromboses within the IVC filter. The majority of recurrences occurred off of anticoagulation (58%). Only 34% could be maintained on therapeutic anticoagulation. By study end, 72% of patients had died, most commonly due to progressive cancer. Median time from filter placement to death was 2.9 months (range: 0.1-64.7 months). Seventy-five patients (19%) died within 30 days of filter placement. They were more likely to have stage IV disease (78% vs. 54%). Of these 75 patients, three experienced recurrent VTE, two with lower extremity DVTs and one with an IVC thrombus. Data on filter costs were also collected. Costs were attributable to the placement and retrieval procedures when applicable ($10,983.00 and $8,824.00, respectively) as well as the device itself ($1,576.00). Conclusions Malignancy-associated thrombosis is common and associated with a high rate of recurrence. While most recurrent VTE after IVC filter placement were deep vein thromboses, a relatively large number of PE's occurred after filter placement as well. A significant number of patients with malignancy-associated thrombosis who underwent IVC filter placement had no contraindication to anticoagulation or recurrent VTE while on anticoagulation. Better prospective studies are needed to assess the safety and efficacy of IVC filters in the setting of hemodynamic compromise, extensive clot burden or for surgical prophylaxis, especially in the oncology population. In this cohort, the majority of filters were placed in patients with advanced cancer with likely short life expectancies, suggesting the patient selection for filter placement could be optimized. Finally, the cost of filter placement and retrieval is substantial, further emphasizing the need for better prospective data to identify the subset of patients who will derive the most benefit from filter use. Disclosures Stein: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lewandowski:Cook Medical: Consultancy; Boston Scientific: Membership on an entity's Board of Directors or advisory committees.

Description: Prior studies have reported that adolescent and young adult (AYA) patients are specifically vulnerable to distress because of the intersection of disease and age. Compared to older cancer patients, AYA cancer patients indicate a more negative psychosocial outcome. Recent studies have focused on improving the quality of life of AYA patients by providing adjunctive non-pharmacological interventions. Popular methods adopted include cognitive behavioral therapy, hypnosis, video games and virtual reality (VR) exposure. Although VR has been tested among other cancer populations, to our knowledge, no studies have focused on the efficacy of VR for mitigating mental distress in the AYA population. Additionally, no studies have focused on what specific virtual-based experiences are efficacious without causing cybersickness in cancer patients. Research has found that up to 25% of healthy patients exposed to VR experience some form of cybersickness. This longitudinal study analyzed the efficacy of VR in the AYA population and sought to understand their preferences in virtual environments. The study included eight AYA cancer patients admitted to our institution receiving inpatient chemotherapy. Seven patients had acute leukemia and the 8th patient had medulloblastoma. Patients were offered the VR intervention every other day during the hospital stay. On average, patients were enlisted in the study for 19 days, and were provided with 27 different virtual environments to choose from. Subject scores were collected using validated survey instruments, including the Numeric Rating Scale (NRS) for pain, State Trait Anxiety Inventory (STAI) for anxiety, and Hospital Anxiety and Depression Scale (HADS-D) for depression. Objective measures were also collected including heart rate and electrodermal response. Additional qualitative data were collected via patient interviews to better understand the patient's attitudes and behaviors regarding their virtual reality experience. Responses collected from patients using HADS-D, STAI showed that, on average, there was a 15% decrease in depression and 13% decrease in general anxiety after receiving the VR intervention. Additionally, the response from the NRS showed that their perception of pain decreased by 18%. Moreover, these results were supported by the objective measures, where the frequency domain metric of heart rate variability, LF/HF (Low frequency to High Frequency power) ratio decreased by 42% displaying a high parasympathetic nervous system activity during the intervention and decrease in the number of bursts in skin conductance response by 7%. It was also observed from the survey that AYA patients preferred environments with more interaction and presence rather than simply exploring. Although no participants reported significant cybersickness, it was observed that 50% of the population reported fatigue at least once during the period of study. Hence, the design consideration of the VR environment is a crucial factor, especially while providing intervention for cancer patients. This proof of concept study affirms the capability of VR to be used as an adjunct therapy to help manage pain, anxiety and depression in AYA patients and provides design consideration for VR environments to be used in AYAs. Future work includes the development and testing of adaptive environments using affective computing techniques where the virtual environment changes according to the patient's mood. Disclosures Cull: Celgene: Speakers Bureau; ADC Therapeutics: Research Funding.

Description: Background: CLR 131 is a novel targeted radiotherapeutic that exploits the selective uptake and retention of phospholipid ethers (PLEs) by malignant cells. Based on initial preclinical and clinical experience and the radiosensitivity of MM, fractionated dosing of CLR 131 is being examined in RRMM in a Phase 1 trial (NCT02278315) and a Phase 2 trial, CLOVER-1 (NCT02952508). Methods: Both the Phase 1 and Phase 2 trials of CLR 131 aim to determine efficacy and safety in RRMM. Eligibility criteria include progressive or relapsed MM that is refractory to at least 1 proteasome inhibitor (PI) and 1 immunomodulatory (IMiD) drug with no upper limit to the number of prior lines of therapy. Prior autologous stem cell transplant (ASCT) and external beam radiation therapy are allowed (〈 20% of total marrow irradiated). The Phase 1 trial was a single and fractionated ascending dose escalation safety study and the Phase 2 trial is evaluating 3 doses: a bolus dose and 2 fractionated doses. The fractionated doses of CLR 131 included infusion of either 31.25 mCi/m2 CLR 131 or 37.5 mCi/m2 CLR 131 (administered as 15.625 mCi/m2 or 18.75 mCi/m2, respectively, on day 1 and day 7 (± 1 day)) administered as a 30-minute intravenous infusion is reported here. Adverse events (AEs) are graded by NCI-CTCAE v4.03. Responses were determined using IMWG criteria as assessed by the investigator. Results: As of 30Jul2019, 10 subjects have received fractionated 31.25 mCi/m2 and 6 subjects fractionated 37.5 mCi/m2 CLR 131. In addition, 1 subject was scheduled to receive fractionated 37.5 mCi/m2 CLR 131 but died due to progressive disease prior to administration of the second dose; this subject is not included in the analyses below as they did not receive both fractionated doses. There is no upper age limit for enrollment and the median age for the 16 RRMM patients was 71 (range 51-83), including 6 females and 10 males with a median of 4 prior therapies (range 2 to 13). Seven patients had prior ASCT. CLR 131 demonstrated 100% disease control rate in subjects receiving either fractionated dose of CLR 131. The overall response rate (ORR) in the fractionated 37.5 mCi/m2 cohort is 50%. Three subjects in the cohort experienced a partial responses (PR), median time to response 43 days, and the other three had minimal responses (MR) with an average 39% reduction in m-protein. In this cohort, 80% of the subjects were either quad- or penta-refractory; all 80% were refractory to daratumumab. There were two subjects in the 31.25 mCi/m2 cohort with non-secretory disease and their status was followed by FDG-PET imaging. Both have been excluded from the evaluation of efficacy as their disease does not meet with IMWG criteria for response. No patients in this cohort achieved a PR or better however a majority of the subjects experienced a minimal response. The primary AEs include thrombocytopenia, anemia, neutropenia, and fatigue (Table 2). The hematologic AEs were expected, manageable and followed a predictable timeline to nadir (average. 40 days) and subsequent recovery (average 17 days post nadir). Conclusions: CLR 131 is a unique, first in class targeted radiotherapeutic for RRMM. Preliminary data for CLR 131 administered as a fractionated dose shows an acceptable and expected safety profile in this patient population. Fractionated dosing at 37.5 mCi/m2 has shown an efficacy signal and has been adopted as the standard for CLR 131 dosing in ongoing and future trials. Dose escalation to determine the highest tolerated dose is ongoing in the Phase 1 study and is currently examining a fractionated infusion of 40 mCi/m2 administered as 20 mCi/m2 CLR 131 on day 1 and day 7 (± 1 day). Based upon these data enrollment to the fractionated 37.5 mCi/m2 cohort of the Phase 2 trial continues. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Stiff:Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Ibrahim:Cellectar: Honoraria, Research Funding; Incyte: Research Funding; Pfeizer: Research Funding; Puma: Research Funding; Eli Lilly: Research Funding; Hoffman-LaRoche: Research Funding; Spectrum: Research Funding; Takeda: Research Funding. Cull:Celgene: Speakers Bureau; ADC Therapeutics: Research Funding. Green:GSK: Consultancy; Seattle Genetics: Research Funding; Juno Therapeutics: Consultancy, Patents & Royalties, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Oliver:Cellectar Biosciences: Employment. Longcor:Cellectar Biosciences: Employment, Equity Ownership.

Description: Introduction: Patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after hematopoietic cell transplant or chimeric antigen receptor T-cell therapy, or those who are ineligible for such therapies, need more treatment options. Loncastuximab tesirine (ADCT-402; Lonca) is an antibody-drug conjugate (ADC) comprising a humanized antibody directed against human CD19 conjugated to a pyrrolobenzodiazepine dimer toxin. Its target, the human CD19 antigen, is a classic B-cell marker expressed at normal-to-high levels on the majority of malignant B-cells. Preliminary data from a Phase 1 dose-escalation and dose-expansion trial of Lonca in R/R B-cell non-Hodgkin lymphoma showed significant clinical activity in DLBCL, with an acceptable safety profile, and the recommended Phase 2 dose of 150 μg/kg was identified. Here, we present the planned interim analysis for futility on the first 52 pts with R/R DLBCL treated with Lonca in Phase 2. Methods: This single-arm, multi-center, open-label, two-stage, Phase 2 trial is currently enrolling pts ≥18 years of age with R/R DLBCL following ≥2 multi-agent systemic treatment regimens and without bulky disease (tumor ≥10 cm). The primary objective is to evaluate the efficacy of single-agent Lonca by overall response rate (ORR). The secondary objectives are to further evaluate efficacy (including duration of response [DOR], progression-free survival [PFS], and overall survival [OS]), to characterize the safety, pharmacokinetics and immunogenicity profile of Lonca, and to evaluate the impact of Lonca on health-related quality-of-life. Pts received 30-minute intravenous infusions of Lonca once every 3 weeks (1 cycle) at a dose of 150 μg/kg for the first 2 cycles, then 75 μg/kg for subsequent cycles, for up to 1 year or until disease progression, unacceptable toxicity, or other discontinuation criteria, whichever occurs first. A preplanned interim analysis for futility was conducted when the 52nd pt would have had 2 tumor assessments (approximately 12 weeks after the start of study drug), with the study planned to proceed to full enrollment if ≥10 of the first 52 pts responded to Lonca. ORR (complete response [CR] + partial response [PR]) was determined by an independent reviewer. Results: 52 pts with DLBCL were included in the interim analysis. Pts had a median age of 62.5 years [range 24-84] and had received a median of 3 previous therapies (range 2-7; Table 1). As of the data cut-off of May 01, 2019, pts had received a median of 2.5 (range 1-9) cycles of Lonca. ORR among the futility analysis population (52) was 44.2%, meeting futility requirements. A total of 10/52 (19.2%) and 13/52 (25.0%) pts attained CR and PR, respectively. In addition, 11 pts (21.2%) had stable disease (Figure 1). All (100%) pts had at least 1 treatment-emergent adverse event (TEAE), and 37 (71.2%) pts had grade ≥3 TEAEs. The most common all-grade non-hematological TEAEs, regardless of relationship to study treatment, were gamma-glutamyltransferase (GGT) increase (24 [46.2%]), pyrexia (18 [34.6%]) and hypokalemia (15 [28.8%]); pleural effusions and peripheral edema were reported in 5/52 pts (9.6%) and 6/52 pts (11.5%), respectively; 1 of these pts had a grade ≥3 event (pleural effusion). The most common grade ≥3 TEAEs were GGT increase (11 [21.2%]), hypercalcemia (4 [7.7%]) and hypokalemia (3 [5.8%]). No grade ≥3 skin-related TEAEs have been reported. The most common all-grade hematological abnormalities were platelet count decreased* (34 [65.4%]), neutrophil count decreased* (27 [51.9%]) and anemia (14 [26.9%]), and the most common grade ≥3 hematological abnormalities were neutrophil count decreased* (15 [28.8%]), platelet count decreased* (10 [19.2%]) and anemia (6 [11.5%]). Overall, 26 (50%) pts had TEAEs leading to dose reductions/delays and 10 (19.2%) pts had TEAEs leading to treatment discontinuation. Conclusions: Lonca has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in pts with R/R DLBCL. Futility requirements were met and pts are now enrolling in stage 2 of the trial. Updated efficacy results will be presented at the meeting. *Laboratory abnormality data are reported for platelet count decreased and neutrophil count decreased to avoid under-reporting of these events. Study sponsored by ADC Therapeutics SA. http://clinicaltrials.gov/show/NCT03589469 Disclosures Carlo-Stella: Amgen: Honoraria; Boehringer Ingelheim: Consultancy; AstraZeneca: Honoraria; Novartis: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Sanofi: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Takeda: Other: Travel, accommodations; Celgene: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Genenta Science srl: Consultancy; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Janssen: Other: Travel, accommodations; Janssen Oncology: Honoraria; BMS: Honoraria; MSD: Honoraria. Zinzani:VERASTEM: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PORTOLA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELLTRION: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GILEAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN-CILAG: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KYOWA KIRIN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANOFI: Consultancy; IMMUNE DESIGN: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSAPHARMA: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SANDOZ: Membership on an entity's Board of Directors or advisory committees. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Caimi:ADC Therapeutics: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau. Solh:ADC Therapeutics: Research Funding; Amgen: Speakers Bureau; Celgene: Speakers Bureau. Townsend:Roche: Consultancy, Honoraria. Stathis:PharmaMar: Other: Renumeration; Roche: Other: Institutional research funding; Pfizer: Other: Institutional research funding; MEI-Pharma: Other: Institutional research funding; Novartis: Other: Institutional research funding; Merck: Other: Institutional research funding; Bayer: Other: Institutional research funding; Abbvie: Other: Renumeration; ADC Therapeutics: Other: Institutional research funding. Cull:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau. Hamadani:Otsuka: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Takeda: Research Funding; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Merck: Research Funding. Spira:Novartis: Research Funding; Roche: Research Funding; Boehringer Ingelheim: Research Funding; ADC Therapeutics: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Incyte: Research Funding; AstraZeneca: Research Funding; Newlink Genetics: Research Funding; BMS: Consultancy; Virginia Cancer Specialists: Employment; MedImmune: Research Funding. Feingold:ADC Therapeutics: Employment, Other: Potential equity interest. Ungar:ADC Therapeutics: Employment, Other: Stock options. equity interest. He:ADC Therapeutics: Employment, Other: Potential equity interest. Qin:ADC Therapeutics: Consultancy, Other: Potential equity interest. Radford:AstraZeneca: Equity Ownership, Research Funding; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Research Funding; GSK: Equity Ownership; Seattle Genetics: Consultancy, Honoraria.

Description: Abstract 942 Background: Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration. Methods: To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel's largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration. Results: We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC 〉10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later. Conclusions: (1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Immunotherapy offers the promise of a new paradigm for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). CD123, the IL-3 receptor alpha-chain, represents an attractive target for antibody therapies because of its high expression on AML/MDS blasts and leukemic stem cells compared to normal hematopoietic stem and progenitor cells. APVO436, a novel bispecific anti-CD123 x anti-CD3 ADAPTIR™ molecule, depleted CD123+ cells in AML patient samples ex vivo (Godwin et al. ASH 2017), reduced leukemia engraftment in a systemic AML xenograft model (Comeau et al. AACR 2018), and transiently reduced peripheral CD123+ cells in non-human primates with minimal cytokine release and in a dose-dependent fashion (Comeau et al. AACR 2019). These data provide a basis for the clinical application of APVO436 as a treatment in AML and MDS. Here, we report preliminary data from a first-in-human dose-escalation study of APVO436 in patients with R/R AML and high-risk MDS. Study Design/Methods This ongoing Phase 1/1b study (ClinicalTrials.gov: NCT03647800) was initiated to determine the safety, immunogenicity, pharmacokinetics, pharmacodynamics, and clinical activity of APVO436 as a single agent. Major inclusion criteria were: R/R AML with no other standard treatment option available, R/R MDS with 〉 5% marrow blasts or any peripheral blasts and failure of a hypomethylating agent, ECOG performance status ≤ 2, life expectancy 〉 2 months, white blood cells ≤ 25,000 cells/mm3, creatinine ≤ 2 x upper limit of normal (ULN), INR and PTT 〈 1.5 x ULN and alanine aminotransferase 〈 3 x ULN. Patients were not restricted from treatment due to cytogenetic or mutational status. Intravenous doses of APVO436 were administered weekly for up to six 28-day cycles (24 doses) with the option to continue dosing for up to 36 total cycles (144 doses). Flat and step dosing regimens were escalated using a safety-driven modified 3 + 3 design. Pre-medication with diphenhydramine, acetaminophen, and dexamethasone was administered starting with dose 1 to mitigate infusion related reactions (IRR) and cytokine release syndrome (CRS). First doses and increasing step doses of APVO436 were infused over 20-24 hours followed by an observation period of 24 hours or more. Bone marrow biopsies were performed every other cycle with responses assessed by European Leukemia Net 2017 criteria for AML or International Working Group (IWG) 2006 criteria for MDS. Results The data cut-off for this interim analysis was July 9, 2020. Twenty-eight patients with primary R/R AML (n=19), therapy-related R/R AML (n=3), or high-risk MDS (n=6) have been enrolled and received a cumulative total of 186 doses. The number of doses received per patient ranged from 1 to 43 (mean of 6.4 doses). Most patients discontinued treatment due to progressive disease; however, blast reduction was achieved in 2 patients, with one patient with MDS maintaining a durable response for 11 cycles before progressing. APVO436 was tolerated across all dose regimens in all cohorts tested. The most common adverse events (AEs), regardless of causality, were edema (32%), diarrhea (29%), febrile neutropenia (29%), fever (25%), hypokalemia (25%), IRR (21%), CRS (18%), chills (18%), and fatigue (18%). AEs ≥ Grade 3 occurring in more than one patient were: febrile neutropenia (25%), anemia (18%), hyperglycemia (14%), decreased platelet count (11%), CRS (11%), IRR (7%), and hypertension (7%). After observing a single dose limiting toxicity (DLT) at a flat dose of 9 µg, step dosing was implemented and no DLTs have been observed thereafter. No treatment-related anti-drug antibodies (ADA) were observed. Transient serum cytokine elevations occurred after several reported IRR and CRS events, with IL-6 most consistently elevated. Conclusions Preliminary results indicate that APVO436 is tolerated in patients with R/R AML and MDS at the doses and schedules tested to date, with a manageable safety profile. Dose escalation continues and the results will be updated for this ongoing study. Disclosures Watts: BMS: Membership on an entity's Board of Directors or advisory committees; Aptevo Therapeutics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees. Lin:Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Aptevo: Research Funding; Celgene: Research Funding; Genetech-Roche: Research Funding; Celyad: Research Funding; Prescient Therapeutics: Research Funding; Seattle Genetics: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Incyte: Research Funding; Gilead Sciences: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding. Wang:Abbvie: Consultancy; Macrogenics: Consultancy; Astellas: Consultancy; Jazz Pharmaceuticals: Consultancy; Bristol Meyers Squibb (Celgene): Consultancy; PTC Therapeutics: Consultancy; Stemline: Speakers Bureau; Genentech: Consultancy; Pfizer: Speakers Bureau. Mims:Leukemia and Lymphoma Society: Other: Senior Medical Director for Beat AML Study; Syndax Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Agios: Consultancy; Jazz Pharmaceuticals: Other: Data Safety Monitoring Board; Abbvie: Membership on an entity's Board of Directors or advisory committees. Cull:Aptevo Therapeutics: Research Funding. Patel:Agios: Consultancy; Celgene: Consultancy, Speakers Bureau; DAVA Pharmaceuticals: Honoraria; France Foundation: Honoraria. Shami:Aptevo Therapeutics: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Cogle:Aptevo Therapeutics: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Chenault:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Macpherson:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Chunyk:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. McMahan:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Gross:Aptevo Therapeutics: Current Employment, Current equity holder in publicly-traded company. Stromatt:Aptevo Therapeutics: Current equity holder in publicly-traded company.