CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Disease Characteristics:

   a. Confirmation of CD123 positivity by flow cytometry or IHC. Participants who received prior CD123-targeting agents will be allowed as long as the blasts still have detectable CD123 expression.
2. Expansion inclusion:

   * Cohort 1 - Participants with relapsed or refractory blastic plasmacytoid dendritic cell neoplasm (BPDCN) with 1-3 prior lines of therapy
   * Cohort 2 - Participants with relapsed AML
   * Cohort 3 - Participants with relapsed relapsed or refractory ALL (including any subtypes: B-cell, T-cell, Ph+ and Ph-)
   * Cohort 4 - Participants with relapsed or refractory other hematologic malignancies not included in the cohorts above (eg, high risk/very high-risk MDS, MPN, CMML, BP-CML).
   * Cohort 5 - Participants with relapsed relapsed or refractory (to nonintense therapies) CD123+ AML.
   * Cohort 6 - Participants with frontline de novo BPDCN at screening who have not received prior systemic therapy and participants with frontline BPDCN who have PCHM and have not received prior systemic therapy.

Note: Participants in Cohort 6 may have received local therapy (radiotherapy, surgical excision, photodynamic therapy). Eligible participants must have a recurrence or progression in the field of local therapy OR disease outside the field of local therapy.

Exclusion Criteria:

1. Participants who, in the judgment of their treating physician, have appropriate standard of care therapies will be excluded from Cohorts 1 through 5.
2. Frontline BPDCN participants with central nervous system (CNS) disease will be excluded. A lumbar puncture must be performed during the 28-day screening period, prior to drug administration. Relapsed or refractory BPDCN participants with a known history of CNS disease must have been treated locally, have at least 1 lumbar puncture with no evidence of CNS disease, and must be clinically stable prior to first dose. Concurrent therapy for CNS prophylaxis or continuation of therapy for controlled CNS disease is permitted with the approval of the Sponsor.
3. Participants with a history of veno-occlusive disease (sinusoidal obstruction syndrome) of the liver.
4. Participants with a history of Grade 4 capillary leak syndrome, or non-cardiac Grade 4 edema are ineligible, eg, related to tagraxofusp-erzs or other etiology.
5. Interval from prior cancer therapy: 1. For frontline BPDCN participants with prior local therapy (eg, radiotherapy), participants must not have received treatment within 14 days prior to drug administration on this study. 2. Relapsed or refractory BPDCN participants must not have received any anti-cancer therapy including chemotherapy, immunotherapy, radiotherapy, hormonal, biologic, or any investigational agents within 14 days prior to drug administration on this study. Participants must have recovered to baseline from all acute toxicity from this prior therapy.

Note: the exception that participants who have received a checkpoint inhibitor must not have received that therapy within 28 days prior to drug administration on this study.

主要终点：Composite Complete Remission/Response (CCR) Rate As Assessed by Investigator in Frontline De Novo Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Participants · CCR rate was defined as percentage of participants with complete remission/response (CR) and clinical complete remission (CRc). CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/microliter \[μL\]) and platelet count (≥ 100,000/μL); absence of leukemic blasts; 100% clearance of all skin lesions from baseline; no new lesions in participants without lesions at baseline; nodal masses regression to normal size on computed tomography (CT); and spleen and liver not palpable and nodules disappeared. CRc was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/μL) and platelet count (≥ 100,000/μL); absence of leukemic blasts; marked clearance of all skin lesions from baseline, residual hyperpigmentation or abnormality with BPDCN identified on biopsy (or no biopsy performed); nodal masses regression to normal size on CT; and spleen and liver not palpable and nodules disappeared. · Up to approximately 81 months
次要终点：Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)；Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs)；Maximum Plasma Concentration (Cmax) of IMGN632 (Antibody Drug Conjugate [ADC]) and Total Antibody；Cmax of FGN849；Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of IMGN632 (ADC) and Total Antibody；AUC0-last of FGN849；Number of Participants With Anti-drug Antibodies (ADAs) at Any Post-baseline Visit；Dose Escalation Phase: Overall Response Rate (ORR), As Assessed by Investigator in Participants With AML

• Escalation and Expansion · EXPERIMENTAL · Escalation: IMGN632 was administered by IV on 2 different schedules for participants with relapsed/refractory AML, ALL, or BPDCN. Expansion: IMGN632 was administered by IV: * Cohort 1: Relapsed or refractory BPDCN participants who have received 1-3 prior systemic therapies (incl. tagraxofusp-erzs and/or any other systemic therapy deemed appropriate for the treatment of BPDCN) * Cohort 2: Relapsed AML * Cohort 3: Relapsed or refractory ALL * Cohort 4: Other relapsed or refractory hematologic malignancies * Cohort 5: Relapsed or refractory AML at alternate dose or schedule * Cohort 6: Pivotal cohort for frontline BPDCN participants who have not received prior systemic therapy and participants with frontline BPDCN who have prior or concomitant hematologic malignancy (PCHM) and have not received prior systemic therapy.

This is an open-label, multi-center, Phase 1/2 study to determine the MTD and assess the safety, tolerability, PK, immunogenicity, and anti-leukemia activity of IMGN632 when administered as monotherapy to patients with CD123+ disease.