Blastic Plasmacytoid Dendritic Cell Neoplasm, Myeloproliferative Neoplasm
Conditions
Keywords
Antibody Drug Conjugate, Other Hematologic Malignancies, Myeloproliferative Neoplasms, CD123, MDS, Relapsed, Refractory, Acute Lymphocytic Leukaemia, Blastic Plasmacytoid Dendritic Cell Neoplasm, Acute Myeloid Leukemia
Brief summary
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.
Detailed description
IMGN632 is administered by IV on Day 1 of each cycle, with cycles repeating every 21 days.
Interventions
DRUGIMGN632
CD123-targeted ADC
Sponsors
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission/Response (CCR) Rate As Assessed by Investigator in Frontline De Novo Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) Participants | Up to approximately 81 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Up to approximately 81 months | An adverse event (AE) was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered study drug related. This included an exacerbation of a pre-existing condition. SAEs included death, a life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. TEAEs were defined as any new AEs that begin or any pre-existing conditions that worsen in severity from the first dose of study drug through 30 days after the last dose or prior to the subsequent therapy, whichever occurs first. |
| Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) | Up to approximately 81 months | DLT was defined as all treatment-emergent adverse events (TEAEs) or abnormal laboratory values that met the protocol-defined DLT criteria, including those TEAEs and abnormal laboratory values that resulted in a failure to meet the criteria for re-treatment. A summary of all SAEs and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Maximum Plasma Concentration (Cmax) of IMGN632 (Antibody Drug Conjugate [ADC]) and Total Antibody | Cycle 1 and Cycle 3 (each cycle length = 21 days) | — |
| Cmax of FGN849 | Cycle 1 and Cycle 3 (each cycle length = 21 days) | — |
| Area Under the Curve From Time Zero to the Last Quantifiable Concentration (AUC0-last) of IMGN632 (ADC) and Total Antibody | Cycle 1 and Cycle 3 (each cycle length = 21 days) | — |
| AUC0-last of FGN849 | Cycle 1 and Cycle 3 (each cycle length = 21 days) | — |
| Number of Participants With Anti-drug Antibodies (ADAs) at Any Post-baseline Visit | Up to approximately 81 months | — |
| Dose Escalation Phase: Overall Response Rate (ORR), As Assessed by Investigator in Participants With AML | Up to approximately 81 months | ORR was defined as percentage of participants with CR without minimal residual disease (CRMRD-), CR, CR with partial hematologic recovery (CRh), CR with incomplete recovery (CRi), morphologic leukemia-free state (MLFS), or partial response (PR). CRMRD-: CR with negativity for a genetic marker. CR: Morphologic CR \<5% blasts; Absolute neutrophil count (ANC) \>1000/μL; Platelets ≥100,000/μL; Participant independent of transfusions; No residual evidence of active extramedullary disease; MRD+ or unknown. CRh: Met requirements for CR except ANC \>500/μL and platelets \>50,000/μL. CRi: Met requirements for CR except either ANC \<1000/μL or platelets \<100,000/μL. MLFS: Bone marrow \<5% blasts in an aspirate with spicules; No blasts with Auer rods or persistence of extramedullary disease; Marrow not "aplastic"; ≥200 cells should be enumerated or cellularity should be ≥10%. PR: Decrease of ≥50% in percentage of blasts to 5% to 25% in bone marrow aspirate (BMA) and normalization of blood counts. |
| Dose Escalation Phase: CR+CRh Rate, As Assessed by Investigator in Participants With AML | Up to approximately 81 months | CR+CRh rate was defined as percentage of participants with CR, and CRh. CR: Morphologic CR \<5% blasts; Absolute neutrophil count (ANC) \>1000/μL; Platelets ≥100,000/μL; Participant independent of transfusions; No residual evidence of active extramedullary disease; MRD+ or unknown. CRh: Met requirements for CR except ANC \>500/μL and platelets \>50,000/μL. |
| Dose Escalation Phase: CR+CRh+CRi Rate, As Assessed by Investigator in Participants With AML | Up to approximately 81 months | CR+CRh+CRi rate was defined as percentage of participants with CR, CRh, or CRi. CR: Morphologic CR \<5% blasts; Absolute neutrophil count (ANC) \>1000/μL; Platelets ≥100,000/μL; Participant independent of transfusions; No residual evidence of active extramedullary disease; MRD+ or unknown. CRh: Met requirements for CR except ANC \>500/μL and platelets \>50,000/μL. CRi: Met requirements for CR except either ANC \<1000/μL or platelets \<100,000/μL. |
| CCR Rate As Assessed by Investigator in Participants With Relapsed/Refractory (R/R) BPDCN | Up to approximately 81 months | CCR rate was defined as percentage of participants with CR and CRc. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. |
| Duration of CCR (DOCR) As Assessed by Investigator in Frontline De Novo BPDCN Participants With CR or CRc | Up to approximately 81 months | DOCR was defined from the first response (CR or CRc) to the time of relapse or death from any cause, whichever came first. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. Median and 95% CI were calculated by Kaplan-Meier estimation. |
| DOCR As Assessed by Investigator in R/R BPDCN Participants With CR or CRc | Up to approximately 81 months | DOCR was defined from the first response (CR or CRc) to the time of relapse or death from any cause, whichever comes first. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. |
| DOCR As Assessed by Investigator in Total Frontline BPDCN Participants With CR or CRc | Up to approximately 81 months | DOCR was defined from the first response (CR or CRc) to the time of relapse or death from any cause, whichever comes first. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. |
| Number of Participants With TEAEs in Participants Who Received IMGN632 As a Single Agent at the RP2D Level (0.045 mg/kg) | Up to approximately 81 months | An AE was defined as any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in any phase of a clinical study, whether or not considered study drug related. This included an exacerbation of a pre-existing condition. TEAEs were defined as any new AEs that began or any pre-existing conditions that worsen in severity from the first dose of study drug through 30 days after the last dose or prior to the subsequent therapy, whichever occurs first.. A summary of all SAEs and Other Adverse Events (nonserious) regardless of causality is located in the 'Reported Adverse Events' Section. |
| Rate of CR+CRc+CRh As Assessed by Investigator in Total R/R BPDCN Participants | Up to approximately 81 months | Rate of CR+CRc+CRh: percentage of participants with CR, CRc, and CRh. CR: normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥1000/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 CT; and spleen and liver not palpable and nodules disappeared. CRc: 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. CRh: normalization of neutrophil count (≥ 500/μL) and platelet count (≥ 50,000/μL); other criteria same as defined for CRc. |
| Duration of CR+CRc+CRh As Assessed by Investigator in Total R/R BPDCN Participants | Up to approximately 81 months | Duration of CR+CRc+CRh was defined as time from first response to time of relapse or death from any cause, whichever came first. CR: normalization of blast percentage (≤5%); normalization of neutrophil count (≥1000/μL) and platelet count (≥100,000/μL); absence of leukemic blasts; 100% clearance of all skin lesions from baseline; no new lesions; nodal masses regression to normal size on CT; and spleen and liver not palpable and nodules disappeared. CRc: 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. CRh: normalization of neutrophil count (≥ 500/μL) and platelet count (≥ 50,000/μL); other criteria same as defined for CRc. |
| ORR As Assessed by Investigator in Total R/R BPDCN Participants | Up to approximately 81 months | ORR: percentage of participants with CR, CRc, CRh, CRi, and PR. CR, CRc, and CRh as defined in Outcome Measure 20 above. CRi: normalization of blast percentage (≤5%); normalization of neutrophil count (≥1000/μL) or 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. PR: Decreased by \> 50% in blast percentage to 5%-25%; 50% to \<100% clearance of all skin lesions from baseline; no new lesions in participants without lesions at baseline; ≥50% decrease in the sum of the product of the diameters (SPD) of up to 6 largest dominant masses, no increase in size of other nodes; ≥ 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter), no increase in size of liver of spleen. |
| Duration of Overall Response As Assessed by Investigator in Total R/R BPDCN Participants | Up to approximately 81 months | Duration of overall response (CR, CRc, CRh, CRi, and PR) was defined as time from first response to time of relapse or death from any cause, whichever came first. CR, CRc, and CRh, CRi, and PR as defined in Outcome Measure 21 above. |
| Overall Survival in Total R/R BPDCN Participants | Up to approximately 81 months | Overall survival was defined as date of first dose until death from any cause. |
| CCR Rate As Assessed by Investigator in All Frontline BPDCN Participants With Post-Treatment Consolidative Stem Cell Transplant (SCT) | Up to approximately 81 months | CCR rate was defined as percentage of participants with CR and CRc. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. |
| CCR Rate As Assessed by Investigator in All R/R BPDCN Participants With Post-Treatment Consolidative SCT | Up to approximately 81 months | CCR rate was defined as percentage of participants with CR and CRc. CR was defined as normalization of blast percentage (≤ 5%); normalization of neutrophil count (≥ 1000/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 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. |
| Percentage of Participants With Post-baseline Transfusion Independence in BPDCN Participants | Up to approximately 81 months | Post-baseline transfusion independence (red blood cell \[RBC\] and platelet transfusion independence) was defined as any 56-day period after Cycle 1 Day 1 in which the participant did not receive either a RBC or platelet transfusion. |
Countries
France, Germany, Italy, Spain, United Kingdom, United States
Contacts
STUDY_DIRECTORABBVIE INC.
AbbVie
Participant flow
Pre-assignment details
The study is ongoing and reports data up to the primary analysis data cut-off date (up to approximately 81 months).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 121 Participants |
| Age, Categorical Between 18 and 65 years | 58 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 154 Participants |
| Sex: Female, Male Female | 53 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 10 / 12 | 12 / 13 | 7 / 7 | 5 / 5 | 2 / 2 | 3 / 3 | 6 / 6 | 12 / 14 | 76 / 104 | 9 / 10 |
| other Total, other adverse events | 3 / 3 | 12 / 12 | 13 / 13 | 7 / 7 | 5 / 5 | 2 / 2 | 3 / 3 | 5 / 6 | 12 / 14 | 102 / 104 | 10 / 10 |
| serious Total, serious adverse events | 2 / 3 | 8 / 12 | 11 / 13 | 7 / 7 | 5 / 5 | 2 / 2 | 2 / 3 | 6 / 6 | 12 / 14 | 66 / 104 | 10 / 10 |
Outcome results
None listed