| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CD123 positive Acute Myeloid Leukemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Acute Myeloid Leukemia (AML) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | SOC |
| E.1.2 | Classification code | 10029104 |
| E.1.2 | Term | Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. Dose Escalation Cohorts:
Evaluate the safety and tolerability and identify a recommended Phase 2 dose (RP2D) of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with relapsed or refractory CD123-positive AML.
2. Dose Expansion Cohorts:
a. Assess preliminary anti-leukemia activity of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B), azacitidine+venetoclax (Regimen C) in patients with either relapsed or untreated AML and assess MRD levels.
b. Regimen D (IMGN632 monotherapy in MRD + maintenance): Assess preliminary anti-leukemia activity of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit AML (Cohort D2) patient populations and assess MRD levels. |
|
| E.2.2 | Secondary objectives of the trial |
Regimens A-C:
1. Evaluate the safety and tolerability of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C) in patients with AML (Dose Expansion Phase).
2. Characterize the pharmacokinetics (PK) of IMGN632 when used in combination with azacitidine and/or venetoclax.
3. Evaluate concentrations of azacitidine, venetoclax and azacitidine + venetoclax when administered in combination with IMGN632.
4. Characterize the immunogenicity of IMGN632.
5. Assess MRD levels (Dose Escalation Phase).
Regimen D: (Cohort D1 and D2):
1. Evaluate the safety and tolerability of IMGN632 as monotherapy in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
2. Characterize the PK of IMGN632.
3. Characterize the immunogenicity of IMGN632. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient must be ≥ 18 years of age.
2. Patients must have confirmed diagnosis of AML (excluding acute promyelocytic leukemia) based on World Health Organization classification.
3. Disease characteristics and allowable prior therapy:
a. Patients must be evaluated for any available standard of care therapies (including induction, consolidation chemotherapy and/or transplant) and, in the opinion of the treating physician, be deemed appropriate for this experimental therapy.
b. Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for Regimens A (IMGN632 + azacitidine) and C (Triplet) (IMGN632 + azacitidine + venetoclax) in separate cohorts. No prior treatments with hypomethylating agents (HMAs) for MDS are allowed.
Note: Patients who are MRD+ following frontline treatment are eligible for the Regimen D Cohorts D1 and D2 (Expansion Phase).
c. Patients must have CD123-positive AML as confirmed by local flow cytometry (or immunohistochemistry [IHC]).
d. Patients may have received prior CD123-targeted therapies, except IMGN632, as long as CD123 remains detectable during screening.
e. Relapsed or refractory CD123-positive AML patients will be allowed to enroll in the Escalation Phase of Regimens A, B, and C (Triplet)
(IMGN632 + azacitidine, venetoclax, or azacitidine + venetoclax, respectively) and relapsed CD123-positive AML patients will be allowed to enroll the Expansion Phase of Regimens A-C.
Note: Patients may also have received up to 2 prior lines of therapy, eg, frontline treatment (induction, consolidation [including transplant], and maintenance) and 1 salvage regimen.
f. Patients enrolling in Regimen D must be in CR (CR/CRh/CRp/CRi) for no more than 6 months and be MRD+ at the time of screening, confirmed
by central laboratory testing, after induction/consolidation therapy (which may include stem cell transplant).
Note: Fit patients who previously received intensive treatment (eg 3+7, HiDAC, etc.) are eligible for Regimen D Cohort D1. Unfit patients who previously received nonintensive treatment (eg, HMA, low dose cytarabine, etc.) are eligible for Regimen D Cohort D2.
4. Eastern Cooperative Oncology Group performance status ≤ 1. If nonambulatory due to a chronic disability, must be Karnofsky
performance status > 70.
5. Previous treatment-related toxicities must have resolved to Grade 1 or baseline (excluding alopecia).
6. Total white blood cell count must be less than 25 × 10e9 cells/L. Hydroxyurea may be used to control blood counts before Cycle 1 Day 1, at the discretion of the treating physician, according to institutional practice. During the Escalation Phase in Regimens A-C, hydroxyurea may also be used during Cycle 1.
7. Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).
8. Total bilirubin ≤ 1.5 × the ULN within 14 days of enrollment.
9. Serum creatinine ≤ 1.5 mg/dL within 14 days of enrollment.
10. Left ventricular ejection fraction (LVEF) ≥ 45% based on locally available assessment, eg, ECHO or other modality.
11. Patients with prior autologous and allogeneic bone marrow transplant are eligible. Patients with an allogeneic transplant must meet
the following conditions: The transplant must have been performed more than 120 days before the date of dosing on this study, the patient must
not have active ≥ Grade 2 graft versus host disease, and the patient must be off potent systemic immunosuppression for at least 2 weeks
before dosing.
12. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care.
13. Women of childbearing potential (WCBP), defined as sexually mature women who have not undergone surgical sterilization or who have not been naturally postmenopausal for at least 12 consecutive months (ie, who have had menses any time in the preceding 12 consecutive months), must agree to use acceptable contraceptive methods while on study drug and for at least 7 months after the last dose of IMGN632.
14. WCBP must have a negative pregnancy test within 3 days before the first dose of study drug.
15. Male patients who are able to father children must agree to use acceptable methods of contraception throughout the study and for at least 4 months after the last dose of IMGN632.
16. Patients with prior malignancy are eligible; however, the patient must be in remission from the prior malignancy and have completed all
chemotherapy and radiotherapy for the prior malignancy at least 6 months before enrollment, and all treatment-related toxicities must have resolved to Grade 1 or less.
Note: patients with prostate cancer or breast cancer on adjuvant hormonal therapy are eligible. |
|
| E.4 | Principal exclusion criteria |
1. Patients who have received any anticancer therapy, including investigational agents, within 14 days (or within 28 days for checkpoint inhibitors) before drug administration on this study (hydroxyurea is allowed before beginning study treatment). Patients must have recovered to baseline from all acute toxicity from this prior therapy.
2. Patients who have been previously treated with IMGN632.
3. Patients with myeloproliferative neoplasm–related secondary AML are excluded from the Dose Expansion Phase of the study.
4. Patients with active central nervous system (CNS) AML will be excluded. A lumbar puncture does not need to be performed unless there
is clinical suspicion of CNS involvement per investigator judgement. Concurrent therapy for CNS prophylaxis or continuation of therapy for
controlled CNS AML is allowed with the approval of the sponsor.
5. Patients with a history of sinusoidal obstruction syndrome/venous occlusive disease of the liver.
6. Myocardial infarction within 6 months before enrollment or New York Heart Association Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities before study entry.
7. Clinically relevant active infection including known active hepatitis B or C, HIV infection, or cytomegalovirus or any other known concurrent infectious disease that, in the judgment of the investigator, would make a patient inappropriate for enrollment into this study (testing not required).
8. Patients who have undergone a major surgery within 4 weeks (or longer if not fully recovered) before study enrollment.
9. Serious or poorly controlled medical conditions that could be exacerbated by treatment or that would seriously compromise safety assessment or compliance with the protocol, in the judgment of the investigator.
10. Women who are pregnant or breastfeeding.
11. Prior known hypersensitivity reactions to monoclonal antibodies (≥Grade 3).
12. Prior known hypersensitivity reactions to study drugs and/or any of their excipients.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Dose Escalation (Regimens A-C):
a. RP2D of IMGN632 when administered in combination with azacitidine (Regimen A) or venetoclax (Regimen B) or azacitidine + venetoclax (Regimen C).
b. Treatment-emergent adverse events (TEAEs), laboratory test results, physical examination, and vital signs.
2. Dose Expansion Cohorts:
a. (Regimens A-C):
i. Composite CR rate (CRMRD-, CR, CRh, CRp, CRi).
ii. Overall response rate (ORR) (CRMRD-, CR, CRh, CRp, CRi, MLFS, PR).
iii. Duration of remission (DOR).
iv. MRD levels using central flow cytometry–based testing.
b. Regimen D (Cohort D1 and D2):
i. MRD+ to MRD- conversion rate and relapse-free survival (RFS) in MRD+ Fit (Cohort D1) and MRD+ Unfit (Cohort D2) AML patients.
ii. MRD levels using central flow cytometry–based testing. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Safety and Tolerability are assessed throughout the study and at the end of the treatment and end of the study
2. Anti-tumor activity data will be collected at the end of each cycle until a response or progression has reached. |
|
| E.5.2 | Secondary end point(s) |
a. Regimens A-C:
i. Treatment-emergent adverse events (TEAEs) (Expansion Cohort).
ii. IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs (tmax).
iii. Blood concentration of azacitidine, venetoclax, and azacitidine + venetoclax measured before and after their administration.
iv. Anti-drug antibody (ADA) response.
v. MRD levels using central flow cytometry-based testing (Dose Escalation Phase).
b. Regimen D (Cohort D1 and D2):
i. TEAEs.
ii. IMGN632 PK parameters for intact ADC, total antibody, and free payload (FGN849) include, but are not limited to, Cycle 1 and Cycle 3 maximum plasma concentration (Cmax), area under the time concentration curve (AUC), terminal half-life (t½), clearance (CL), volume of distribution at steady state (Vss), and time that Cmax occurs
(tmax).
iii. ADA response. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Safety and Tolerability are assessed throughout the study and at the end of the treatment and end of the study
2. Anti-tumor activity data will be collected at the end of each cycle until a response or progression has reached. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Phase 1b/2 safety and tolerability |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| Italy |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study will be defined as the latter of the completion of the safety follow-up visit for the last patient remaining on treatment or 1 year from the last accrued patient’s first visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 29 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 2 |
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