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JOURNAL ONKOLOGIE – STUDIE

IMGN632 as Monotherapy or With Venetoclax and/or Azacitidine for Patients With CD123-Positive Acute Myeloid Leukemia

Rekrutierend

NCT-Nummer:
NCT04086264

Studienbeginn:
November 2019

Letztes Update:
27.05.2021

Wirkstoff:
azacitidine, IMGN632, Venetoclax

Indikation (Clinical Trials):
Leukemia, Leukemia, Myeloid, Leukemia, Myeloid, Acute

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
ImmunoGen, Inc.

Collaborator:
Jazz Pharmaceuticals

Studienleiter

Patrick Zweidler-McKay, MD
Study Director
ImmunoGen, Inc.

Kontakt

Studienlocations
(3 von 20)

University Hospital Leipzig
04103 Leipzig
(Sachsen)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Karolin Hubert
Phone: +49 341 97-20363
E-Mail: karolin.hubert@medizin.uni-leipzig.de

Jana Heinrichs-Knopf
Phone: +49 341 97 12634
» Ansprechpartner anzeigen
University Hospital of Ulm
89081 Ulm
(Baden-Württemberg)
GermanyNoch nicht rekrutierend» Google-Maps
Ansprechpartner:
Ayten Sagir
Phone: 0731-45927
E-Mail: ayten.sagir@uniklinik-ulm.de

Tobias Glöggler
Phone: 0731-45746
E-Mail: tobias.gloeggler@uniklinik-ulm.de
» Ansprechpartner anzeigen
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
60611 Chicago
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Tony Tran
Phone: 312-695-0503
E-Mail: tony.tran1@northwestern.edu
» Ansprechpartner anzeigen
Roswell Park Comprehensive Cancer Center
14203 Buffalo
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Stephanie Halliwell
Phone: 716-845-4971


E-Mail: Stephanie.Halliwell@roswellpark.org
» Ansprechpartner anzeigen
Centre Antoine Lacassagne
06100 Nice
FranceRekrutierend» Google-Maps
Ansprechpartner:
Anasthasia Gama
Phone: + 33 (0) 4 92 03 10 35
E-Mail: anasthasia.gama@nice.unicancer.fr

Lauris Gastaud, MD
Phone: + 33 (0) 492031221
E-Mail: Lauris.GASTAUD@nice.unicancer.fr
» Ansprechpartner anzeigen
Istituto di Ematologia "Lorenzo e A. Seragnoli" - Policlinco S. Orsola - Malpighi
40138 Bologna
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Antonio Curti, MD
Phone: +390512144074
E-Mail: antonio.curti@unibo.it
» Ansprechpartner anzeigen
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST)
47014 Meldola
ItalyRekrutierend» Google-Maps
Ansprechpartner:
Federica Frabetti
Phone: 0039 0543 739292
E-Mail: federica.frabetti@irst.emr.it
» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

This is an open-label, multicenter, Phase 1b/2 study to determine the safety and tolerability

of IMGN632 and assess the antileukemia activity of IMGN632 when administered in combination

with azacitidine and/or venetoclax in patients with relapsed and frontline CD123-positive

AML, and antileukemia activity of IMGN632 when administered as monotherapy in patients with

MRD+ AML after frontline treatment.

This study explores multiple IMGN632 doses in combination and monotherapy Regimens, including

(A) azacitidine, (B) venetoclax, (C) azacitidine+venetoclax, and (D) monotherapy in MRD+ AML.

For combination Regimens A-C, a Phase 1b Dose Escalation Cohort will determine the

recommended Phase 2 dose (RP2D) of IMGN632 in that specific combination Regimen, followed by

a Phase 2 Dose Expansion Cohort for each combination Regimen to further characterize the

safety profile and assess the antileukemia activity of the different combination Regimens.

Regimen D will open with a Dose Expansion Cohort using the IMGN632 monotherapy dose and

schedule based on safety data from the initial Phase 2 study (IMGN632-0801) and will not have

a Dose Escalation Phase.

Ein-/Ausschlusskriterien

Patient 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 (Arber 2016).

3. Disease characteristics and allowable prior therapy:

1. Patients must be evaluated for any available standard of care therapies and, in

the opinion of the treating physician, be deemed appropriate for this

experimental therapy.

2. Treatment-naïve (untreated) patients will be allowed in the Expansion Phase for

Regimens A (IMGN632 + azacitidine) and C (IMGN632 + azacitidine + venetoclax). No

prior treatments with 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).

3. Patients must have CD123-positive AML as confirmed by local flow cytometry (or

immunohistochemistry [IHC]).

4. Patients may have received prior CD123-targeted therapies, except IMGN632, as

long as CD123 remains detectable during screening.

5. 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.

6. Patients enrolling in Regimen D must be in CR (CR/CRi) for no more than 6 months

and be MRD+, confirmed by central laboratory testing, after intensive

induction/consolidation therapy. 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 non-intensive treatment (eg, HMA, low dose

cytarabine, etc.) are eligible for Regimen D Cohort D2.

4. Patients enrolling on Regimen D (MRD+ AML), must first have an evaluable screening

bone marrow sample confirmed as MRD+ by central flow testing of MRD.

5. Eastern Cooperative Oncology Group performance status ≤ 1. If nonambulatory due to a

chronic disability, must be Karnofsky performance status > 70.

6. Previous treatment-related toxicities must have resolved to Grade 1 or baseline

(excluding alopecia).

7. Total white blood cell count must be less than 25 x 10^9 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.

8. Liver enzymes (AST and ALT) ≤ 3 × the upper limit of normal (ULN).

9. Total bilirubin ≤ 1.5 × the ULN within 14 days of enrollment.

10. Serum creatinine ≤ 1.5 mg/dL within 14 days of enrollment.

11. Echocardiogram or other modality demonstrating an ejection fraction ≥ 45%.

12. 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 all systemic immunosuppression for at least 2 weeks before

dosing.

13. Voluntary written informed consent before performance of any study-related procedure

not part of normal medical care.

14. 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 highly effective contraceptive methods

(examples include oral, parenteral, or implantable hormonal contraceptive,

intrauterine device, barrier contraceptive with spermicide, partner's latex condom or

vasectomy) while on study drug and for at least 7 months after the last dose of study

drug.

15. WCBP must have a negative pregnancy test within 3 days before the first dose of study

drug.

16. A male patient must agree to use a latex condom even if he has had a successful

vasectomy and must continue to follow these requirements for at least 12 weeks after

the last dose of study drug.

17. 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.

Patient 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

Studien-Rationale

Primary outcome:

1. Safety and Tolerability (Time Frame - approximately 7 months):
Evaluate the safety and tolerability and identify an RP2D of IMGN632 when administered in combination with azacitidine, with venetoclax, and with azacitidine and venetoclax, in patients with relapsed or refractory CD123-positive AML through review of Treatment Emergent Adverse Events and abnormal laboratory values that result in a failure to meet the criteria for re-treatment

2. Preliminary antileukeumia activity (Time Frame - approximately 20 months):
Assess preliminary antileukemia activity of IMGN632 when administered as a monotherapy in MRD+ Fit and MRD+ Unfit AML patient populations, and in combination with azacitidine, with venetoclax, and with azacitidine and venetoclax in patients with relapsed or untreated AML as assessed by complete response, complete remission with partial hematologic recovery, complete remission with incomplete platelet recovery, morphologic leukemia-free state, partial response, and duration of remission

3. Minimal Residual Disease Levels (Time Frame - approximately 18 months):
Assess Minimal Residual Disease Levels using central flow cytometry-based testing

Studien-Arme

  • Experimental: Regimen A
    IMGN632, administered intravenously on Day 7 of a 28 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with azacitidine, administered subcutaneously or intravenously daily at 75 mg/m2 on Days 1 to 7 of a 28 day cycle. Cycle 1 azaciditine dose in subsequent cohorts may be reduced.
  • Experimental: Regimen B
    IMGN632, administered intravenously on Day 7 of a 21 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with venetoclax, administered orally daily at 100 mg on Day 1, 200mg on Day 2, and 400 mg on the day 3 up to Day 21 of a 21 day cycle. Alternate schedules with reduced venetoclax administration may be explored.
  • Experimental: Regimen C
    IMGN632, administered intravenously on Day 7 of a 28 day cycle at 0.015 mg/kg, 0.045 mg/kg, or 0.09 mg/kg, in combination with azacitidine, administered subcutaneously or intravenously daily at 35-75 mg/m2 given for Days 1 to 7 of a 28 day cycle and venetoclax, administered orally daily at 100 mg on Day 1, 200mg on Day 2, and 400 mg on Day 3 up to Day 28 of a 28 day cycle. Alternate schedules with reduced venetoclax administration or reduced azacitidine dose or administration may be explored.
  • Experimental: Regimen D
    IMGN632, administered intravenously on Day 1 of a 21 day cycle at 0.045 mg/kg, as a monotherapy for Fit and Unfit MRD+ patients

Geprüfte Regime

  • Azacitidine (Vidaza / Decitabine / ):
    IMGN632 in combination with azacitidine
  • IMGN632 (CD123-targeted ADC):
    IMGN632 in combination with azacitidine
  • Venetoclax (Venclexta / Venclyxto / ):
    IMGN632 in combination with venetoclax

Quelle: ClinicalTrials.gov


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