ALBERT

Description: Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. ALX148 is a fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In combination with anti-tumor antibodies, ALX148 enhances the innate and adaptive immune response against cancer. ALX148 has previously been shown to be well tolerated both as a single agent and in combination with pembrolizumab or trastuzumab in a range of solid tumors with no maximum tolerated dose (MTD) identified (SITC 2018 #P335, ASCO 2019 #2514). Characterization of ALX148's safety profile and antitumor activity in combination with rituximab are reported in patients (pts) with both aggressive and indolent histologies of non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety confirmation population was first cycle dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Preliminary clinical data from the fully enrolled cohort is reported as of July 15, 2019. Results: Twenty pts (15 males, 5 females) with NHL were administered ALX148 in combination with rituximab (DLBCL, n=11; mantle cell lymphoma, n=4; follicular lymphoma, n=3; and marginal zone lymphoma, n=2). The pts median age was 66 years (range 32-80) and ECOG PS 0/1 was 7/13. Patients had a median of 3 prior lines of therapy (range 1-7) with 50% having rituximab-refractory tumors. There were no dose limiting toxicities reported and the MTD of ALX148 in combination with rituximab was not reached. The maximum administered dose was 10 mg/kg QW. Sixteen pts experienced any AE, while 11 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (20%, n=4); anemia, fatigue, nausea, neutropenia and decreased platelets (10%, n=2 each). One TRAE ≥ G3 of neutropenia occurred in more than 1 patient (1G3, 1G4). As of the data cut off with a median follow-up time of 3 (0.3-14) months, preliminary tumor response was assessed in 17 evaluable pts using the Lugano Classification, 2014. The ORR was 35% across all tumor histologies, with a 50% ORR reported in indolent (FL+MZL), and 31% ORR reported in aggressive (DLBCL+MCL) histologies. The overall DCR was 41%. Six pts achieved partial response [(2) follicular, (2) DLBCL, (2) mantle cell]. Four pts achieved SD [(1) each of follicular, marginal zone, DLBCL(〉1yr), and mantle cell]. Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with favorable PK/PD characteristics in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity in combination with rituximab was observed with objective responses reported in heavily pretreated and rituximab-refractory patients. Clinical trial information: NCT03013218 Disclosures Kim: AstraZeneca: Consultancy, Research Funding; Novartis: Consultancy; Sanofi: Consultancy; Bayer: Consultancy; Takeda: Consultancy. Lakhani:ALX Oncology Inc.: Research Funding; Ascentage Pharma: Research Funding; Asana Biosciences: Research Funding; BeiGene: Research Funding; Constellation Pharmaceuticals: Research Funding; Alexion Pharma: Research Funding; Cerulean Pharma: Research Funding; Forty Seven: Research Funding; Loxo: Research Funding; Macrogenics: Research Funding; Merck: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; TaiRx: Research Funding; Apexian: Research Funding; Formation Biologics: Research Funding; Coordination Therapeutics: Research Funding; Symphogen: Research Funding; CytomX: Research Funding; InhbRx: Research Funding; Incyte: Research Funding; Jounce Therapeutics: Research Funding; Livzon: Research Funding; Northern Biologics: Research Funding; Tesaro: Research Funding; Innovent Biologics: Research Funding. Gainor:BMS: Research Funding; Genentech/Roche: Other: grant; Takeda: Other: grant, personal fees; Blueprint: Research Funding; Loxo: Research Funding; Oncorus: Other: grant , personal fees; Regeneron: Other: grant,personal fees; Pfizer: Other: grant personal fees; Incyte: Other: grant personal fees; Novartis: Other: grant, personal fees; Merck: Other: grant personal fees; Agios: Other: personal fees; Amgen: Other: personal fees; Array: Research Funding; Tesaro: Research Funding; Moderna: Other: grant; Adaptimmune: Other: grant; ALX Oncology: Other: grant; Ironwood Pharma: Equity Ownership. Kamdar:AstraZeneca: Consultancy; Pharmacyclics: Consultancy; Genentech: Consultancy; Seattle Genetics: Speakers Bureau. Fanning:ALX Oncology Inc: Employment, Equity Ownership. Squifflet:IDDI: Employment; ALX Oncology Inc: Consultancy. Jin:ALX Oncology Inc.: Consultancy. Wan:ALX Oncology Inc.: Employment, Equity Ownership. Pons:ALX Oncology Inc.: Employment, Equity Ownership; venBio: Employment, Membership on an entity's Board of Directors or advisory committees. Randolph:ALX Oncology Inc: Employment, Equity Ownership; venVio: Consultancy; Carrick: Equity Ownership. Kim:Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Celltrion: Research Funding.

Description: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug–related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.

Description: Male recipients of transplants from female (F→M) hematopoietic stem cell donors represent a special group in whom donor T cells that are specific for recipient minor histocompatibility antigens encoded by Y-chromosome genes may contribute to a graft-versus-leukemia (GVL) effect and to graft-versus-host disease (GVHD). We examined the contribution of donor/patient sex to the risk for relapse and GVHD in 3238 patients who underwent HLA-identical sibling hematopoietic stem cell transplantation (HSCT) for hematopoietic malignancies at a single institution. Compared with other sex combinations, male recipients of female transplants had the lowest risk for relapse and the greatest odds for GVHD. Remarkably, after controlling for GVHD as a time-dependent covariate, F→M HSCT still exhibited a lower risk for relapse than other sex combinations, demonstrating a selective GVL effect distinct from that contributed by GVHD. A reduction in relapse after F→M HSCT was observed in patients with chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), and acute lymphoblastic leukemia (ALL). Taken together, these data suggest that minor H antigens encoded or regulated by genes on the Y chromosome contribute to a selective GVL effect against myeloid and lymphoid leukemias after F→M HSCT.

Description: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with most patients relapsing even after initial therapies. Despite recent advances in treatment, the development of efficacious novel treatments remains an unmet need. CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host immune response, and its blockade enhances anti-tumor immunity (Weiskopf, 2017). Recently, pre-clinical and clinical studies that explored the use of CD47 targeting agents in combination with azacitidine, a hypomethylating chemotherapeutic, demonstrated robust anti-cancer activity (Feng, ASH 2018 and Sallman, ASH 2019). ALX148 is an engineered fusion protein comprised of a high affinity CD47 blocker linked to an inactive human immunoglobulin Fc region. In preclinical studies, ALX148 bridges innate and adaptive immunity by promoting macrophage phagocytosis, dendritic cell activation and a shift of tumor-associated macrophages towards an inflammatory phenotype, leading to increased anti-tumor activity when combined with various anti-cancer therapeutics (Kauder, 2018). ALX148 has previously been shown to be well tolerated in patients with both solid tumor and hematological malignancies with encouraging anti-tumor responses reported in combination with anti-cancer therapeutics (EHA 2020, #EP1247 and ASCO 2020, #3056). Recently, the combination of azacitidine with venetoclax, a BCL2 inhibitor, has shown increased efficacy compared to azacitidine alone in patients with AML (EHA 2020, #LB2601). We observed in vitro treatment with azacitidine or venetoclax increased the cell surface expression of both CD47 and calreticulin, a pro-phagocytic marker, in multiple AML cell lines. We thereby hypothesize that combining ALX148 with either azacitidine or venetoclax would enhance the therapeutic efficacy against AML and report our preclinical findings here. In vitro treatment with ALX148 led to enhanced phagocytic engulfment by human monocyte-derived macrophages across multiple AML cell lines treated with azacitidine or venetoclax, including those harboring TP53 and FLT3 mutations, compared to either treatment alone. Our in vitro findings correlated with enhanced in vivo antileukemic activity in several murine AML xenograft models. Mice were inoculated via tail vein or implanted subcutaneously with AML cells, and when tumors reached exponential growth, mice were randomized to receive the following: vehicle control, azacitidine, venetoclax, ALX148 alone or ALX148 in combination. Cohorts receiving ALX148 combination therapies demonstrated significantly greater inhibition of tumor progression with evidence of tumor eradication, leading to markedly enhanced survival over any single agent therapy. Together, these in vitro and in vivo results provide rationale that ALX148 combinations may benefit AML and MDS patients. Clinical trials with ALX148 in patients with MDS (NCT04417517) and AML are currently planned. Disclosures Chen: ALX Oncology: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Harrabi:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Fong:ALX Oncology Inc: Current Employment, Current equity holder in publicly-traded company. Ruffner:ALX Oncology Inc: Current Employment, Current equity holder in publicly-traded company. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Sim:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kuo:ALX Oncology Inc: Consultancy, Current equity holder in publicly-traded company, Ended employment in the past 24 months; Tallac Therapeutics: Current Employment, Current equity holder in private company.

Description: Background: CD47 is a myeloid checkpoint upregulated by tumor cells to evade the host's immune response. The high affinity CD47 blocker fusion protein, ALX148, is linked to an inactive immunoglobulin Fc region to minimize toxicity. ALX148 is half the size of an antibody, has been well tolerated, and enhances the innate and adaptive immune response against cancer in combination with anticancer therapeutics across solid and hematologic tumors (ASCO 2020 #3056, EHA 2020 #EP1247). Characterization of ALX148's tolerability profile and antitumor activity in combination with rituximab are reported in patients (pts) with non-Hodgkin Lymphoma (NHL). Methods: Patients with relapsed or refractory CD20-positive B-cell NHL for which no curative therapy was available received ALX148 (10 mg/kg QW or 15 mg/kg QW) in combination with rituximab (375 mg/m2 weekly for 4 doses followed by once monthly for 8 doses). The primary endpoint for the safety population was dose limiting toxicity (DLT). Tumor response, pharmacokinetic (PK), and pharmacodynamic (PD) markers were assessed in all pts. Data are reported as of 30Jun2020 in these fully enrolled cohorts with final data to be updated at the time of presentation. Results: A total of 33 patients with NHL were administered ALX148 in combination with rituximab. Twenty-two pts with median age of 66 years (range 32-80) were administered ALX148, 10 mg/kg QW (ALX10), in combination with rituximab [DLBCL, n=11; mantle cell lymphoma (MCL), n=4; follicular lymphoma (FL), n=5; and marginal zone lymphoma (MZL), n=2]. Eleven pts with median age of 64 years (range 53-78) were administered ALX148, 15 mg/kg QW (ALX15), in combination with rituximab (DLBCL, n=6; MCL, n=1; FL, n=3; and MZL, n=1). There have been no DLTs reported in the fully enrolled safety cohorts, and the MTD of ALX148 in combination with rituximab has not been reached. The maximum ALX148 administered dose is 15 mg/kg QW. Twenty-eight pts experienced any AE, while 16 pts reported mostly low grade treatment-related adverse events (TRAE). The most common TRAEs were rash (21%, n=7), fatigue (9%, n=3), anemia, nausea, neutropenia, and pruritus (6%, n=2 each). With a median follow up of 14 months, objective responses were observed across all histologies in response-evaluable ALX10 pts: 40.9% ORR (4CR,5PR, 6SD, n=22 total) and with a median follow up of 9 months in ALX15 pts: 63.6% ORR (3CR, 4PR, 1SD, n=11 total). Preliminary results indicate favorable ALX148 PK and near complete CD47 receptor occupancy across the dosing interval. Final results will be updated at time of presentation. Conclusions: ALX148 demonstrates excellent tolerability with durable responses in combination with rituximab in patients with relapsed/refractory NHL. The MTD of ALX148 in combination with rituximab was not reached. Encouraging preliminary activity and favorable PK/PD characteristics in combination with rituximab were observed at all dose levels with greater objective response rates reported at the MAD of 15 mg/kg QW. Disclosures Kim: Boryung: Consultancy; Voronoi: Consultancy; F. Hoffmann-La Roche Ltd/Genentech, Inc.: Consultancy; Sanofi: Consultancy; Novartis: Consultancy; Takeda: Consultancy; AstraZeneca and Korea Health Industry Development Institute: Research Funding; AstraZeneca: Consultancy. Lakhani:incyte: Research Funding; merck: Research Funding; mersana: Research Funding; northern biologics: Research Funding; odonate: Research Funding; pfizer: Research Funding; ikena: Research Funding; symphogen: Research Funding; taiRx: Research Funding; tesaro: Research Funding; livzon: Research Funding; loxo: Research Funding; macrogenics: Research Funding; inhibRx: Research Funding; cytomx: Research Funding; formation biologics: Research Funding; forty seven inc: Research Funding; alexion Pharmaceuticals: Research Funding; Alpine Biosciences: Research Funding; ALX Oncology Inc.: Research Funding; Apexian: Research Funding; asana biosciences: Research Funding; ascentage pharma: Research Funding; beigene: Research Funding; celgene: Research Funding; cerulean pharma: Research Funding; constellation pharma: Research Funding; coordination therapeutics: Research Funding; regeneron: Research Funding; sapience therapeutics: Research Funding; shattuck labs: Research Funding; innovent bio: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; jounce therapeutics: Research Funding. Gainor:theravance: Consultancy; adaptimmune: Research Funding; ariad: Research Funding; astrazeneka: Research Funding; blueprint medicines: Research Funding; lily: Consultancy; gilead sciences: Consultancy; merck: Consultancy, Research Funding; moderna therapeutics: Consultancy, Research Funding; tesaro: Research Funding; blueprint medicines: Consultancy; novartis: Research Funding; oncorus: Consultancy; regeneron: Consultancy; bristol-myers Squibb: Consultancy, Research Funding; amgen: Consultancy; array biopharma: Consultancy, Research Funding; agios: Consultancy; ironwood pharmaceuticals: Consultancy; takeda: Consultancy; genentech: Consultancy, Research Funding; jounce therapeutics: Consultancy, Research Funding. Kamdar:Roche: Research Funding. Fanning:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Squifflet:ALX Oncology Inc.: Consultancy; IDDI: Current Employment. Jin:ALX Oncology Inc.: Current Employment. Forgie:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company; Pfizer Inc.: Ended employment in the past 24 months. Wan:Tallac Therapeutics: Current Employment, Current equity holder in private company; ALX Oncology Inc.: Consultancy, Current equity holder in publicly-traded company. Pons:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Randolph:ALX Oncology Inc.: Current Employment, Current equity holder in publicly-traded company. Kim:F. Hoffmann-La Roche: Research Funding; Pfizer: Research Funding; JJ: Research Funding; Celltrion: Research Funding; Kyowa Kirn: Research Funding; Donga: Research Funding; Mundipharma: Research Funding.