New safety and efficacy findings from the dose escalation and expansion of the first-in-human trial of IMGN632 in patients with relapsed/refractory acute myeloid leukemia (AML), a cancer of the bone marrow cells that produce white blood cells, and blastic plasmacytoid dendritic cell neoplasm (BPDCN), a rare form of blood cancer that has features of both leukemia and lymphoma, with characteristic skin lesions, lymph node involvement, and frequent spread to the bone marrow, were presented in an oral session at the 61st annual meeting of the American Society of Hematology (ASH) held December 7 – 10, 2019 in Orlando, Florida. [1][2]
Preclinical data related to IMGN632, a CD123-targeting antibody-drug conjugate, in combination with azacitidine (Vidaza®; Celgene, now part of Bristol-Myers Squibb) and venetoclax (Venclexta®; Genentech/AbbVie), and two “trial in progress” posters were also presented at the conference.
CD123, the alpha subunit of the IL-3 receptor, regulates the proliferation, survival and differentiation of hematopoietic cells. Studies have indicated that abnormalities of the alpha-chain of the interleukin-3 receptor, also known as IL-3RA, are frequently observed in some leukemic disorders and may contribute to the proliferative advantage of leukemic cells.
IMGN632 includes a monoclonal antibody conjugated, via a cleavable linker, to a cytotoxic, DNA-alkylatingan, indolino-benzodiazepine dimer (IGN) containing an imine moiety, which alkylate DNA without crosslinking. Following administration of anti-CD123 antibody-drug conjugate, the antibody part targets the cell surface antigen CD123.
After antibody/antigen binding, internalization, and lysosome uptake, the cytotoxic moiety is released, and covalently binds to and alkylates DNA with its imine moiety. This results in cell cycle arrest in S-phase, which leads to apoptosis and inhibition of cell growth in cells overexpressing CD123.
The novel indolino-benzodiazepine payload have been designed to have high potency against AML blasts, while demonstrating less toxicity to normal marrow progenitors than other DNA-targeting payloads.
Potential
“The data presented at ASH demonstrate the potential of IMGN632 to offer a new treatment option for patients with AML and BPDCN,” said Anna Berkenblit, MD, Senior Vice President and Chief Medical Officer of ImmunoGen.
“With the benefit of a comprehensive assessment of IMGN632’s safety and efficacy across a wide range of doses and two schedules, we have selected a dose and schedule that demonstrate significant anti-tumor activity, favorable tolerability, and the convenience of a short infusion that can be administered in an outpatient setting,” Berkenblit noted.
“Together with the preclinical data on combining IMGN632 with azacitidine and venetoclax presented by our collaborators from MD Anderson, these updated clinical results provide a strong foundation for our ongoing expansion of IMGN632 monotherapy studies in BPDCN, AML, and ALL, and the recent initiation of our trial to evaluate IMGN632 combinations with azacitidine and venetoclax in relapsed and frontline AML, as well as IMGN632 as a monotherapy in minimal residual disease positive AML patients,” she concluded.
Encouraging activity
“We are particularly encouraged by the activity and tolerability of IMGN632 in heavily pre-treated patients, including a 40% ORR in relapsed and refractory de novo AML patients treated at the recommended phase II dose, and the responses in relapsed or refractory BPDCN patients previously treated with tagraxofusp-erzs (Elzonris®; Stemline Therapeutics) and intensive chemotherapy,” said Naval Daver, MD, Associate Professor in the Department of Leukemia at MD Anderson Cancer Center.
“We look forward to continuing to evaluate IMGN632 as a monotherapy and in combination with azacitidine and venetoclax in doublet and triplet regimens in relapsed/refractory AML and frontline older AML,” Daver added.
Clinical trials
| Abstract | Title | Type | Presented by |
| #734 | Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) | Oral Presentation | Naval Daver, MD, an Associate Professor in the Department of Leukemia at MD Anderson Cancer Center. |
Description
In this trial, 74 patients (67 AML, 7 BPDCN) with a median age of 69 years (range 33-83), received IMGN632 across nine dose-escalation cohorts on two different schedules. Doses escalated on schedule A (n=61) was 0.015 to 0.45 mg/kg. On schedule B (n=13) doses escalated from 0.015 to 0.06 mg/kg on days 1, 4, and 8.
Forty-four percent of the patients had secondary AML and 70% of classifiable AML patients were ELN adverse risk (32/46). A total of Twenty-six percent were primary refractory to frontline therapy, 32% were enrolled in first relapse, and 41% had other relapsed-refractory disease. Sixty-eight percent of patients had received prior intense therapy. This included 19% of patients with stem cell transplant.
Adverse events
The most common treatment-emergent adverse events (AEs) observed by the investigators was diarrhea (30%; all ≤ grade 2), febrile neutropenia (27%; all grade 3), nausea (26%; one grade 3), chills (23%; all ≤ grade 2), and lung infection (22%; ≥ grade 2).
The principal treatment-related adverse events were infusion-related reactions (16%; four grade 3), including chills, nausea, diarrhea and tachycardia. These adverse events did not require treatment discontinuation. The majority of participating patients received premedication with dexamethasone. In this study, a total of 3 dose limiting toxicities at dose levels ≥ 0.18 mg/kg (all in schedule A) occurred. Toxicities included one prolonged case of neutropenia and two reversible cases of veno-occlusive disease. The investigators did not observe patterns of hepatotoxicity or cytopenias with doses below 0.18 mg/kg, which are doses being evaluated for combinations.
This phase I trial demonstrated ama nageable safety profile and broad therapeutic window of IMGN632 in high risk R/R AML and BPDCN patients. The single agent activity and safety profile, along with supporting preclinical efficacy studies, have led to the subsequent development of IMGN632 as a monotherapy in patients with R/R BPDCN and MRD+ AML, and in combination with azacitidine and/or venetoclax in patients with R/R and untreated AML.
| Abstract | Title | Type | Presented by |
| # 1375 | IMGN632, a CD123-Alkylating ADC Bearing a DNA-Alkylating IGN Payload, Combines Effectively with Azacitidine and Venetoclax In Vivo, Prolonging Survival in Preclinical Models of Human Acute Myeloid Leukemia (AML) | Oral Presentation | Vinitha Mary Kuruvilla, MSc, Department of Leukemia, The University of Texas MD Anderson Cancer Center. |
Description
In this study, IMGN632 was evaluated in combination with azacitidine, and as a triplet with azacitidine and venetoclax in AML models, including patient derived xenografts (PDX). The addition of IMGN632 to azacitidine alone or to azacitidine plus venetoclax consistently led to reductions in tumor burden and to improved survival in these murine models. These data support clinical testing of the addition of IMGN632 to standard of care therapy including azacitidine, and azacitidine plus venetoclax in AML patients.
Reference
[1] Daver NG, Montesinos P, DeAngelo DJ, Wang ES, Papadantonakis N, Deconinck E, MD, PhD6*, Harry P. Erba HP, Pemmaraju N, et al. Clinical Profile of IMGN632, a Novel CD123-Targeting Antibody-Drug Conjugate (ADC), in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML) or Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN).Blood (2019) 134 (Supplement_1): 734.[Abstract]
[2] Kuruvilla VM, McCarthy R, Zhang Q, Sloss CM, Zweidler-McKay PA, Romanelli A, Adams S, Konopleva MY. IMGN632, a CD123-Alkylating ADC Bearing a DNA-Alkylating IGN Payload, Combines Effectively with Azacitidine and Venetoclax In Vivo, Prolonging Survival in Preclinical Models of Human Acute Myeloid Leukemia (AML). Blood (2019) 134 (Supplement_1): 1375. [Abstract]
