P1/2, N=65, Recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Aug 2026 | Trial primary completion date: Dec 2025 --> Aug 2026

P1/2, N=218, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting | Phase classification: P1b/2 --> P1/2

P1, N=100, Not yet recruiting, Byondis B.V.

Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia.

Ongoing developments with SL-401, IMGN632, CD123 chimeric antigen receptor (CAR) T-cells, and bispecific antibodies (BsAb) show promising advancements. The exploration of combinations such as CD123-targeted immunotherapies with azacitidine and venetoclax is suggested to enhance antineoplastic responses and improve survival rates in BPDCN patients. In conclusion, this multifaceted approach offers hope for more effective and tailored therapeutic interventions against this challenging hematologic malignancy.

P1/2, N=60, Recruiting, AstraZeneca | Not yet recruiting --> Recruiting

P1/2, N=79, Not yet recruiting, AstraZeneca

P1, N=30, Recruiting, Fred Hutchinson Cancer Center | Not yet recruiting --> Recruiting

Furthermore, AZD9829 demonstrated durable blast reduction at day 28 after the first dose with leukemic blast reduction in blood (7/13 models) and in bone marrow (5/13 models). Safety studies in cynomolgus monkey support the clinical development of AZD9829, a promising therapeutic candidate for the treatment of AML across the spectrum of CD123-expression and genetic mutations.

P1, N=30, Not yet recruiting, Fred Hutchinson Cancer Center | Initiation date: Nov 2023 --> Feb 2024

Importantly, we previously showed high synergy of IMGN632 combination with BCL-2 inhibitor venetoclax (VEN) and DNA hypomethylating azacytidine (AZA) in AML cell lines and xenograft models (ASH 2020, #617). Together, these results suggest that VEN, apart from its canonical inhibitory effect on anti-apoptotic BCL-2, exerts previously unrecognized ability to suppress DDR program in AML and augments activity of DNA damaging IMGN632. Failure of cells to sustain DDR in the presence of VEN constitutes a key aspect of high efficacy of IMGN/VEN/AZA combination in AML.

In sum, BYON4413 shows great potential to be an effective targeted therapy against AML, MDS, and other CD123+ hematological malignancies such as blastic plasmacytoid dendritic cell neoplasm (BPDCN). Readied with these promising pre-clinical results, we have designed a first-in-human dose-escalation and expansion trial enrolling AML and high-risk MDS patients scheduled to begin in Q12024.

Standard of care treatments for BPDCN patients are intense chemotherapy or tagraxofusp (Elzonris®)...Pivekimab sunirine was granted orphan drug and Breakthrough Therapy designation and is currently being tested for the treatment of BPDCN patients as monotherapy and, as a triplet therapy in combination with azacitidine and venetoclax for the treatment of AML patients...Pivekimab sunirine is a potent ADC targeting CD123 and is highly efficacious against an aggressive BPDCN cell line model. This finding reinforces the importance of its use for the treatment of BPDCN patients.

Encouraging CCRMRD- rates were observed across cytogenetic/molecular subsets, and the majority of responding pts achieved early and deep remissions, which may translate to improved clinical outcomes. The regimen was well tolerated with no new safety signals, and the addition of PVEK to the AZA-VEN backbone did not appear to meaningfully prolong count recovery.

The freshly prepared mixture was then incubated VIP716 and ispinesib, a clinical stage KSPi. Additionally, toxicology in non-human primates and in vivo TK studies confirm safety, favorable drug exposures, and little non-specific release of the payload. Based on these data, evaluation of VIP943 in human clinical trials is warranted.

P1b/2, N=292, Recruiting, ImmunoGen, Inc. | Trial completion date: Jun 2024 --> Dec 2024 | Trial primary completion date: Jun 2024 --> Dec 2024

P1, N=36, Recruiting, Vincerx Pharma, Inc. | Not yet recruiting --> Recruiting

P1, N=36, Not yet recruiting, Vincerx Pharma, Inc.

P1, N=30, Not yet recruiting, Fred Hutchinson Cancer Center

P1/2, N=0, Withdrawn, Children's Oncology Group | N=38 --> 0 | Not yet recruiting --> Withdrawn

P1/2, N=179, Active, not recruiting, ImmunoGen, Inc. | Recruiting --> Active, not recruiting

P1b/2, N=242, Recruiting, ImmunoGen, Inc. | Trial completion date: Jun 2022 --> Jun 2024 | Trial primary completion date: Jun 2022 --> Jun 2024

Capillary leak syndrome is an important adverse effect of tagraxofusp that requires close monitoring. Several clinical trials are underway to study other regimens for the treatment of BPDCN, including IMGN632 (pivekimab sunirine), venetoclax (alone and in combination with hypomethylating agents), CAR-T cells, and bispecific monoclonal antibodies.

The PVEK+AZA+VEN triplet (Regimen C) is currently enrolling frontline unfit patients across sites in France, Germany, Italy, Spain, UK and USA. The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264.

BPDCN currently has 1 approved therapy, tagraxofusp (TAG), with a median age of 68, CR/CRc rate of 57% and mOS of 15.8 mos (n=65; Pemmaraju JCO 2022). PVEK demonstrates compelling activity in frontline and R/R BPDCN pts, including durable responses in the R/R setting for pts who received prior TAG. PVEK safety was manageable with primarily low-grade IRRs and edema and no new safety signals were observed. Enrollment continues in the pivotal de novo frontline BPDCN cohort (NCT03386513) Antibody targeting, Monoclonal antibody, Myeloid malignancies

Recent advances in molecular biology and genetics have led to the development of targeted agents, such as tagraxofusp (a recombinant fusion protein targeting CD123), anti-CD123 CAR-T cells, XmAb14045, and IMGN632. Lastly, this review provides a comprehensive overview of pDC neoplasms.

The PVEK+Magro doublet (Regimen E) is planned to be open for enrollment mid-2023 at sites in the USA. Clinical trial information: NCT04086264.

Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers...In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms. Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.

Encouraging efficacy data were presented from first-in-human studies of two investigational menin inhibitors, SNDX-5613 and KO-539, in relapsed and refractory (R/R) acute myeloid leukemia (AML) with KMT2A rearrangement or mutant NPM1, with overall response rates (ORR) of 53% (32/60) and 40% (8/20), respectively. The addition of the novel drug pivekimab sunirine, a first-in-class antibody-drug conjugate targeting CD123, to azacitidine and venetoclax in R/R AML resulted in an ORR of 45% (41/91), which rose to 53% in those who were venetoclax naïve. Additional novel triplet treatment combinations included the addition of magrolimab, an anti-CD47 antibody, to azacitidine and venetoclax, with an ORR of 81% (35/43) in newly diagnosed AML, including an ORR of 74% (20/27) in TP53 mutated AML. The addition of the FLT3 inhibitor gilteritinib to azacitidine/venetoclax was also featured, with an ORR of 100% (27/27) in newly diagnosed AML and an ORR of 70% (14/20) in R/R AML.

Some of these agents have shown promising results at the clinical level, including tagraxofusp (CD123 conjugated with diphtheria toxin) for the treatment of BPDCN and IMGN632 (anti-CD123 drug-conjugate), and flotetuzumab (bispecific anti-CD123 and anti-CD3 monoclonal antibody) for the treatment of AML. However, the therapeutic efficacy of CD123-targeting treatments is still unsatisfactory and must be improved through new therapeutic strategies and combined treatments with other antileukemic drugs.

IMGN632 exerted profound in vivo activity against pediatric ALL PDXs with varying CD123 expression levels, particularly those of B-lineage, inducing prolonged remissions at doses as low as 60 µg/kg. The significant difference in CD123 expression between B- and T-lineage ALL could have contributed to the difference in IMGN632 activity between the B-ALL and T-ALL models. These data strongly support the clinical evaluation of IMGN632 in B-lineage pediatric ALL.

Background: Current treatment options (cytarabine with anthracyclines) for patients with acute myeloid leukemia (AML) are often associated with severe and barely tolerable toxicities...An in vivo patient-derived AML PDX mouse model was treated with VIP943 (5 mg/kg IV every 7 days) or in combination with 5-azacytidine (2.5 mg/kg SC days 1-5 x 3) and venetoclax (50 mg/kg PO days 1-5 x 3)... VIP943 is a next-generation ADC with a differentiated safety profile from currently approved ADCs, including lack of in vitro cytokine release. In vitro and in vivo studies using patient-derived AML cells show VIP943 has favorable monotherapy and combination efficacy including targeting of leukemic stem cells, which drive relapse. These findings warrant evaluating VIP943 in clinical trials.

All patients received either azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5 with Ven dose adjusted based on azole antifungal prophylaxis...After Ven+HMA failure, therapy was pursued in 11 of 71 (15%) patients with gilteritinib (n=6), ivosidenib (n=2), Ven+Gilteritinib (n=1), CPX-351 (n=1), and IMGN 632 clinical trial (n=1)...Conclusion The current study identifies presence of TP53 and K/NRAS mutations as predictors of inferior survival in patients with AML relapsed or refractory to front-line Ven+HMA. Additionally, we propose a practical three-tiered survival model based on TP53 and K/NRAS mutations and refractoriness to Ven+HMA.

With a manageable safety profile in patients with R/R AML, the higher-intensity cohorts of the novel PVEK triplet demonstrated anti-leukemia activity across several difficult-to-treat subsets of patients. Enrollment and follow-up in both relapsed and frontline patients are ongoing (NCT04086264). Additional and updated safety and efficacy data will be presented at ASH.

The PVEK triplet with AZA+VEN demonstrates anti-leukemic activity across multiple high-risk genetic subsets of relapsed/refractory AML. Prophylactic steroids added on day -1 have significantly reduced IRRs. Expansion cohorts are now enrolling for untreated and relapsed AML patients (NCT04086264).

Results N/A Conclusion Phase 2 expansion cohorts for patients with untreated /frontline and relapsed AML are enrolling to further characterize the safety profile and assess the antileukemic activity. NCT04086264

Results N/A Conclusion Enrollment continues in the pivotal cohort for frontline/untreated BPDCN patients. CADENZA, https:// BPDCNtrial.com, NCT03386513

In addition, IMGN632 monotherapy is being explored in expansion cohorts of MRD-positive patients to assess conversion rate from MRD+ to MRD- and RFS in both fit and unfit AML subpopulations (NCT04086264). IMGN632 is also being tested as a monotherapy in a pivotal cohort for adults with frontline BPDCN (NCT03386513, https://BPDCNtrial.com).