Breakthrough Clinical Results
ImCheck Therapeutics announced positive interim data from its Phase I/II EVICTION study evaluating ICT01, a γ9δ2 T-cell activator, in combination with azacitidine and venetoclax (Aza-Ven) for newly diagnosed acute myeloid leukemia (AML) patients unfit for intensive chemotherapy. The study showed a 96% composite complete remission (CRc) rate, including 74% complete remissions (CR), across molecular subtypes, even in patients with adverse- or intermediate-risk mutations. A 10mg dose of ICT01 showed an 83% 9-month overall survival rate. The favorable safety profile supports further clinical development of this triple combination therapy.
Key Highlights
- 96% composite complete remission (CRc) rate and 74% complete remission (CR) rate observed with ICT01 + Aza-Ven in newly diagnosed AML patients.
- High response rates achieved even in patients with adverse- or intermediate-risk mutations.
- Favorable safety profile with Grade ≥3 adverse events consistent with Aza-Ven hematological toxicity.
- 10 mg ICT01 proposed dose for further clinical development.
Incidence and Prevalence
Global Incidence and Prevalence of Acute Myeloid Leukemia
Regional Incidence Rates
In European populations (2000-2002), acute myeloid leukemia (AML) was among the commonest myeloid malignancies with an age-standardized incidence rate of 2.96 per 100,000.
Data from Hong Kong (2014-2016) shows an age-adjusted incidence rate for AML of 2.23 cases per 100,000 person-years. Overall rates of AML were lower in Hong Kong compared to white and Asian individuals in the U.S., with rates in U.S. Asians being intermediate to those in Hong Kong and white individuals in the U.S.
In Fujian Province (China), the annual incidence of acute myeloid leukemia (excluding acute promyelocytic leukemia) was 1.179 per 100,000, while acute promyelocytic leukemia was 0.309 per 100,000. AML incidence was slightly higher in men (1.307 per 100,000) than in women (1.044 per 100,000) in this region.
Pediatric Incidence
Myeloid leukemia incidence rates in children varied about fivefold globally, with highest rates in the Philippines and Korea (exceeding 14.0 per million person-years) and lowest in Eastern Europe and Uganda.
Global Distribution
According to GLOBOCAN reports, Asia accounts for 48.6% of leukemia cases, and India reports approximately 10.2% of all leukemia cases worldwide.
Proportion of Leukemia Cases
In various studies, AML represented a significant proportion of acute leukemia cases: 34% in Oman, 68.9% in an Egyptian study, and was the predominant type in Fujian Province with a ratio of AML:ALL:APL being 3.82:1.84:1.
Emerging Mechanism of Action
Emerging Mechanisms of Action for Acute Myeloid Leukemia
Key Mechanisms of Action (MoA)
Epigenetic Therapy Approaches
Epigenetic dysregulation is an essential driver of leukemogenesis in AML. While non-selective hypomethylating agents (HMAs) currently form the backbone of non-intensive treatment, more selective second-generation inhibitors targeting specific chromatin regulators have demonstrated promising preclinical activity. These drugs commonly cause leukemia cell differentiation and potentially sensitize AML to immune-based treatments.
Immunotherapy Approaches
Several immunotherapy strategies are showing promise in AML treatment. Checkpoint inhibition has shown modest efficacy, but combination approaches appear more promising. For example, anti-CD47 antibody was substantially more efficient against AML when combined with azacitidine. Research on CAR-T, CAR-NK, adaptor CAR-T, and allogeneic NK-cells is progressing. Ipilimumab (checkpoint inhibitor) holds promise in impacting local control for AML-related extramedullary manifestations. Clinical investigations are underway combining bispecific antibodies or cellular treatments with HMAs.
Antibody-based Therapies
Monoclonal antibodies targeting CD33, CD45, and CD66 have been used in AML treatment. These antibodies have been used unlabeled or conjugated to radioisotopes or cytotoxic agents. Gemtuzumab ozogamicin, an anti-CD33 antibody linked to calicheamicin, has shown activity both alone and combined with conventional chemotherapy. Radiolabeled anti-CD45 antibodies have shown promising results for conditioning before stem cell transplantation.
RNA Modification Approaches
Epitranscriptomics is an emerging field targeting RNA modifications in AML. M6A modification has large therapeutic implications in this disease. RNA m6A-modification machineries represent potential druggable candidates, including: - Editor/writer: Mettl3, Mettl14 - Eraser/remover: FTO, ALKBH5 - Effector/reader: YTHDF-1/2
MicroRNAs like miR-498 can effectively suppress TIM-3 expression in AML cell lines, inhibiting malignant cell proliferation and inducing apoptosis.
Cancer Vaccines
Systemic multifunctional nanovaccines using NOD2 and TLR9 agonists with tumor cell lysate as antigens have shown promise in AML treatment. These nanovaccines demonstrated complementary stimulation of dendritic cells and primed homing to lymphoid organs. In mouse models, intravenous administration cured 78% of AML mice and elicited long-term immune memory.
Promising Therapeutic Targets
The most promising therapeutic targets related to these emerging MoAs include: - Chromatin regulators for epigenetic approaches - Immune checkpoints and CD47 for immunotherapy - CD33, CD45, and CD66 for antibody therapies - RNA modification enzymes including Mettl3, Mettl14, FTO, ALKBH5, and YTHDF-1/2 - TIM-3 as a target for microRNA approaches - NOD2 and TLR9 pathways for vaccine development
Recent Studies
Recent Studies for Acute Myeloid Leukemia
NCT02937662 Trial
- Study: NCT02937662
- Intervention: Idarubicin, cytarabine, and cyclophosphamide (IAC) regimen
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Key Outcomes:
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Efficacy: IAC group showed 71.4% objective response rate and 66.7% complete remission rate versus 40% in control group
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Survival: Median overall survival of 14.1 months in IAC group versus 9.9 months in control group
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Safety: Main hematologic adverse events were anemia, thrombocytopenia, and neutropenia with 100% incidence of grade 3-4 hematologic AEs in IAC group
Elderly AML Standard-Dose vs. Attenuated Chemotherapy Study
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Intervention: Two regimens compared:
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Standard-dose: Daunorubicin 45 mg/m² × 3 days with cytarabine 100 mg/m² × 7 days
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Attenuated therapy: Daunorubicin 30 mg/m² × 3 days with cytarabine 75 mg/m² × 7 days
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Key Outcomes:
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Efficacy: Similar complete remission rates (56.6% overall), but attenuated chemotherapy showed improved OS (39 vs 24 months)
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Safety: Agranulocytosis was most common adverse effect (98.3%), with significantly lower early mortality in the attenuated group (0.64% vs 7.1%)
Amonafide Phase I Trials
- Intervention: Amonafide-l-malate (amonafide) studied as monotherapy and in combination with cytarabine
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Key Outcomes:
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Efficacy: 3/17 patients achieved complete remission in monotherapy trial and 10/26 in combination trial
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Safety: Both trials demonstrated acceptable safety profiles and significant antileukemic activity in poor-risk AML
BRIGHT AML 1003 Trial
- Study: BRIGHT AML 1003
- Intervention: Glasdegib + low-dose cytarabine (LDAC) versus LDAC alone
- Patient Population: AML patients ineligible for intensive chemotherapy
ALLG MDS4 Trial
- Study: ALLG MDS4
- Intervention: Standard azacitidine or combination azacitidine with lenalidomide
- Patient Population: Higher risk myelodysplastic syndromes, chronic myelomonocytic leukemia and low blast AML patients
Venetoclax Combination Therapy Study
- Intervention: Venetoclax combination therapy
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Key Outcomes:
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Efficacy:
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For initially treated AML: 67.4% complete remission rate and median OS of 17.3 months
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For R/R AML: 38.7% complete remission rate and median OS of 7.1 months
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Safety: Reported as "safe and efficacious"
FLAG-IDA with Treosulfan-Based Conditioning Study
- Intervention: FLAG-IDA protocol followed by treosulfan-based conditioning
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Key Outcomes:
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Efficacy: 96% achieved complete hematologic remission with OS rates of 50% at 1 year
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Safety: 17% of patients had grade 3-4 toxicities and 20% died within 30 post-transplant days
ATRA-TCP Combination Study
- Intervention: ATRA-TCP combination
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Key Outcomes:
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Efficacy: Overall response rate of 23.5% and clinical benefit rate of 35.3%
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Safety: Acceptable safety profile with MTD of TCP at 20 mg twice daily
Drug used in other indications
Based on the provided context, I cannot provide information about ICT01 in combination with azacitidine and venetoclax being trialed for indications other than Acute myeloid leukemia (AML). The context does not contain any specific data about:
- ICT01 being trialed for indications other than AML
- ICT01 in combination with azacitidine and venetoclax for any indication
- Intervention models for trials involving ICT01 with azacitidine and venetoclax
The context only mentions information about: - Treatment of AML with venetoclax combined with azacitidine - Treatment of Mixed phenotype acute leukemia (MPAL) with azacitidine and venetoclax - Various AML treatment approaches including antibody-drug conjugates and CDK9 inhibitors - A phase 1b study investigating alvocidib (a CDK9 inhibitor) in combination with venetoclax for relapsed/refractory AML
None of these references include information about ICT01 specifically or its use in combination therapy for indications beyond AML.