ICT01 Plus Azacitidine and Venetoclax Shows Early Evidence of Antitumor Activity in AML

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Transient γ9δ2 T-cell (γ9δ2TC) activation with a low dose of ICT01 (ICT01low) plus azacitidine and venetoclax (Venclexta; ICT01low-aza-ven) augmented responses without sacrificing tolerability in patients with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard intensive chemotherapy and hematopoietic stem cell transplant, according to data from the phase 1 ENVISION trial presented at the 2025 AACR Annual Meeting.1

Early onset and higher responses were seen with ICT01low-aza-ven compared with ICT01high-aza-ven. Within the ICT01low-aza-ven cohort (n = 23) the respective complete remission (CR) and CR, CR with partial hematological recovery, or CR with incomplete hematological recovery (CRc) rates were 39% and 52% in cycle 1, 57% and 83% in cycle 2, 70% and 90% in cycle 3, and 74% and 91% in cycle 4. Within the ICT01high-aza-ven cohort (n = 16) the respective CR and CRc rates were 13% and 38% in cycle 1, 44% and 63% in cycle 2, 44% and 69% in cycle 3, and 44% and 69% in cycle 4.

Investigators provided a side-by-side comparison of responses from the phase 3 VIALE-E trial (NCT02993523) with azacitidine and venetoclax, showing CRc rates of 40% in cycle 1, 47% in cycle 2, 50% in cycle 3, and 67% in cycle 4.

Efficacy in both cohorts was also evaluated according to the revised European LeukemiaNet (ELN) classification. Within the ICT01low-aza-ven favorable, intermediate, and adverse risk groups, the respective CR/CRc rates were 75% and 100%; 72% and 100%; and 60% and 80%.

“ICT01low-aza-ven generated very high CR and CR/CRi rates across molecular AML subtypes. Although survival analysis is not informative to date, a differential median overall survival [OS] is assessed for ICT01low as compared with ICT01high,” Abhishek Maiti, MD, an assistant professor in the Department of Leukemia, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center in Houston, and coauthors, wrote in the poster.

Preclinical Basis and Study Enrollment Criteria

AML damages immunosurveillance by evading target recognition and cytotoxic T-cell responses, which is partly offset by immunomodulatory effects of azacitidine and venetoclax. γ9δ2TC is known to drive graft-vs-leukemia efficacy.

ICT01 is a first-in-class, anti-butyrophilin 3A monoclonal antibody that selectively activates γ9δ2TCs leading to direct antileukemic cytotoxicity and immunomodulation. ICT01-mediated γ9δ2TC activation is dose dependent, safe, and tolerable but has minimal activity as a single agent in immunocompromised settings in dose-escalation trials. However, in vivo, ICT01-mediated γ9δ2TC activation is upheld under azacitidine and venetoclax co-administration resulting in synergistic antileukemic efficacy and positive immunomodulatory effects.

To be eligible for enrollment patients needed to have received a diagnosis of newly diagnosed AML that was ineligible for induction chemotherapy and be without translocation t(15;17), t(8;21), t(16;16), or inversion (16). Patients would be excluded from enrollment if they had history of myeloproliferative neoplasms, polycythemia vera, chronic myeloid leukemia with or without BCR-ABL1 translocation, or AML with BCR-ABL1 translocation.

Trial Protocol and Patient Demographics

Following screening, patients were randomly assigned to received permanent γ9δ2TC activation with 75 mg of ICT01high-aza-ven every 4 weeks (Q4W; n = 16) or transient γ9δ2TC activation with 10 mg of ICT01low-aza-ven Q4W (n = 29).

Azacitidine was administered intravenously or subcutaneously at 75 mg/m2 on days 1 through 7 Q4W and venetoclax was given at 100 mg, 200 mg, and 400 mg on days 1, 2, and 3 of cycle 1 and at the target dose of 400 mg once daily Q4W.

The first cohort was stopped after dose selection at the end of 2024, and the data cutoff was January 20, 2025.

With respect to the pooled cohorts (n = 45) the median age was 76 years (range, 51-87) and most patients were male (53%) and had an ECOG performance status of 0 or 1 (71%). The median bone marrow blast percentage was 40% (range, 7%-98%). Revised ELN 2024 risk status was predominantly intermediate (44%) or adverse (29%) as opposed to favorable (27%).

The primary end point was CR rate according to the ELN 2022 criteria.

Additional Efficacy and Safety Data

“At a median follow-up of 7.8 months [95% CI, 4.3-not reached], differential CR and CRi/CRh rates for ICT01low and ICT01high appear to translate into differential median duration of response (DOR) and OS outcomes,” the authors wrote.

The median DOR was not evaluable (NE) in the ICT01low-aza-ven cohort (n = 21) vs 6.6 months (95% CI, 3.2-NE) in the ICT01high-aza-ven cohort (n = 11; HR, 0.2; 95% CI, 0.1-0.7; log-rank P = .032). The median OS in the ICT01low-aza-ven (n = 29) and ICT01high-aza-ven (n = 16) cohorts was NE (95% CI, 10.2-NE) and 10.9 months (95% CI, 3.1-NE), respectively (HR, 0.3; 95% CI, 0.1-0.9; log-rank P = .028). However, the authors noted that these data are immature with 67% of 45 patients ongoing treatment.

Investigators also presented data supporting the relationship between the agent’s proposed mechanism of action and the aforementioned clinical data. Specifically, investigators reported rapid induction of IFNγ and TNFα with bystander activation of NK and CD8 T cells. “ICT01low induced rapid γ9δ2TC activation and immune cascade, indicating the contribution of ICT01 to azacitidine and venetoclax efficacy,” the authors noted.

Investigators were also able to conclude that non-responders had low baseline γ9δ2TC counts and low-level IFNγ response. Moreover, the modest efficacy seen in the ICT01high-aza-ven cohort was associated with lack of γ9δ2TC recovery.

“Continued dosing of ICT01high leads to sustained depletion of γ9δ2TCs, suggesting over(activation)-induced cell death,” the authors wrote.

With respect to safety, treatment-emergent adverse effects (TEAEs) within the ICT01low and ICT01low cohorts, respectively, were neutropenia (66%; 81%), thrombocytopenia (48%; 56%), hypokalemia (48%; 50%), anemia (41%; 44%), febrile neutropenia (38%; 50%), constipation (34%; 56%), nausea (34%; 50%), asthenia/fatigue (31%; 44%), diarrhea (31%; 25%), oedema (24%; 31%), musculoskeletal pain (21%; 38%), vomiting (21%; 25%), sepsis (21%; 19%), urinary tract infection (17%; 25%), bleeding events (17%; 25%), rash (17%; 19%), abdominal pain (17%; 12%), alanine aminotransferase increase (17%; 12%), anorexia (14%; 31%), cardiac arrhythmia (14%; 25%), aspartate aminotransferase increase (14%; 12%), pneumonia (10%; 25%), pyrexia (10%; 19%), hyperuricemia (10%; 19%), headache (10%; 19%), infusion-related reaction (IRR)/cytokine release syndrome (CRS; 10%; 12%), hypertension (10%; 6%), hepatocellular injury (10%), hyperphosphatemia (7%; 19%), cholestasis (7%; 6%), bilirubin increase (7%; 6%), hyperglycemia (7%), pain (3%; 6%), nephrolithiasis (3%), lipase increase (3%), gastrointestinal (GI) obstruction (3%), GI infection (3%), Escherichia infection (3%), cardiac failure (3%), and anal abscess (3%).

Additional TEAEs within the ICT01high cohort were pleural effusion (25%), gout (12%), tumor lysis syndrome (6%), LV dysfunction (6%), fibrinogen decrease (6%), failure to thrive (6%), encephalopathy (6%), and cellulitis (6%).

“ICT01low shows less neutropenia and less febrile neutropenia with potential ICT01-induced MCL1-mediated protection of granulocytes,” the authors wrote.

Low rates of IRR/CRS were also seen with dexamethasone prophylaxis and only 1 event of TLS was seen and was managed clinically without sequelae.

“Safety of ICT01-aza-ven is clinically well manageable with typical aza-ven hematotoxicity and [a] low 30-day mortality [rate of 3%],” the authors explained. “Overall, 4 deaths [occurred] due to pneumonia and sepsis, and 1 death due to preexisting chronic kidney disease; all deaths were unlikely or not related to ICT01.”

“ICT01low-aza-ven exhibited a favorable benefit-risk profile, and the recommended phase 2 dose of ICT01 is 10 mg Q4W in combination with azacitidine and venetoclax,” the authors concluded.

Disclosures: No disclosures were listed for Maiti.

Reference

Maiti A, Peterlin P, Morillo D, et al. γ9δ2 T-cell (γδTC) activation and azacitidine-venetoclax (AV) for older/unfit adults with newly diagnosed (ND) acute myeloid leukemia (AML) induces high rates of complete remission (CR): Preliminary efficacy, safety, pharmacodynamics (PD) and dose selection of ICT01 in the phase 1 study EVICTION. Presented at: 2025 AACR Annual Meeting; April 25-30, 2025; Chicago, IL. Abstract CT024.