Montag, 14. Juni 2021
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JOURNAL ONKOLOGIE – STUDIE
STIMULUS-MDS2

Study of Efficacy and Safety of MBG453 in Combination With Azacitidine in Subjects With Intermediate, High or Very High Risk Myelodysplastic Syndrome (MDS) as Per IPSS-R, or Chronic Myelomonocytic Leukemia-2 (CMML-2)

Rekrutierend

NCT-Nummer:
NCT04266301

Studienbeginn:
Juni 2020

Letztes Update:
03.06.2021

Wirkstoff:
MBG453, azacitidine, Placebo

Indikation (Clinical Trials):
Leukemia, Preleukemia, Leukemia, Myelomonocytic, Chronic, Leukemia, Myelomonocytic, Juvenile, Myelodysplastic Syndromes, Syndrome

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 3

Sponsor:
Novartis Pharmaceuticals

Collaborator:
-

Studienleiter

Novartis Pharmaceuticals
Study Director
Novartis Pharmaceuticals

Kontakt

Studienlocations
(3 von 130)

Novartis Investigative Site
42551 Velbert
(Nordrhein-Westfalen)
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01307 Dresden
(Sachsen)
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86179 Augsburg
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40479 Duesseldorf
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60590 Frankfurt
(Hessen)
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37075 Gottingen
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24116 Kiel
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89081 Ulm
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Yale University School of Medicine Smilow Cancer Hospital
06520 New Haven
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Ansprechpartner:
Cindy Medina
Phone: 203-737-1906
E-Mail: cindy.medina@yale.edu
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Studien-Informationen

Detailed Description:

This is a Phase III multi-center, randomized, two-arm parallel-group, double-blind, placebo

controlled study of MBG453 or placebo added to azacitidine in adult subjects with

intermediate, high or very high risk myelodysplastic syndrome (MDS) as per IPSS-R, or Chronic

Myelomonocytic Leukemia-2 (CMML-2).

The primary objective of this study is to compare overall survival (OS) in the MBG453 plus

azacitidine arm versus placebo plus azacitidine arm where OS is the time from randomization

until death due to any cause.

Subjects will be randomized in a 1:1 ratio to treatment arms as follow: MBG453 800 mg IV Q4W

plus azacytidine, Placebo IV Q4W plus azacitidine The randomization will be stratified into 4

groups: intermediate risk MDS, high risk MDS, very high risk MDS and CMML-2.

All subjects who discontinue both study treatments will enter a long-term post-treatment

follow-up including response and PRO assessments, and/or survival follow-up for up to 5 years

after the last subject was randomized.

Subjects will be treated until they experience progression of disease (including

transformation to acute leukemia per WHO 2016 classification), experience unacceptable

toxicity or discontinue the study treatment for other reasons.

Continuation of study treatment beyond progression (excluding transformation to acute

leukemia: continuation in this case is not possible) may be possible in selected subjects.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Signed informed consent must be obtained prior to participation in the study

- Age ≥ 18 years at the date of signing the informed consent form

- Morphologically confirmed diagnosis of myelodysplastic syndrome (MDS) based on WHO

2016 classification (Arber et al 2016) by local investigator assessment with one of

the following Prognostic Risk Categories, based on the revised International

Prognostic Scoring System (IPSS-R):

- Very high (> 6 points)

- High (> 4.5 - ≤ 6 points)

- Intermediate (> 3 - ≤ 4.5 points) Or Morphologically confirmed diagnosis of

Chronic Myelomonocytic Leukemia -2 based on WHO 2016 classification (Arber et al

2016) by local investigator assessment with WBC < 13 x 109/L

- Indication for azacitidine treatment according to the investigator, based on local

standard medical practice and institutional guidelines for treatment decisions

- Not eligible at time of screening for intensive chemotherapy according to the

investigator, based on local standard medical practice and institutional guidelines

for treatment decisions, including assessment of individual clinical factors such as

age, comorbidities and performance status

- Not eligible at time of screening for hematopoietic stem cell transplantation (HSCT)

according to the investigator, based on local standard medical practice and

institutional guidelines for treatment decisions, including assessment of individual

clinical factors such as age, comorbidities, performance status, and donor

availability

- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2

Exclusion Criteria:

- Prior exposure to TIM-3 directed therapy at any time. Prior therapy with immune

checkpoint inhibitors (e.g, anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2), cancer

vaccines is allowed except if the drug was administered within 4 months prior to

randomization

- Previous first-line treatment for intermediate, high, very high risk myelodysplastic

syndromes (based on IPSS-R) or CMML with any antineoplastic agents including for

example chemotherapy, lenalidomide and hypomethylating agents (HMAs) such as

decitibine and azacitidine. However, previous treatment with hydroxyurea or

leukopheresis to reduce WBC count is allowed prior to randomization.

- Investigational treatment received within 4 weeks or 5 half-lives of this

investigational treatment, whatever is longer, prior to randomization. In case of a

checkpoint inhibitor: a minimal interval of 4 months prior to randomization is

necessary to allow randomization.

- Subjects with Myelodysplastic syndrome (MDS) based on 2016 WHO classification (Arber

et al 2016) with revised International Prognostic Scoring System (IPSS-R) ≤ 3

- Diagnosis of acute myeloid leukemia (AML) including acute promyelocytic leukemia and

extra-medullary acute myeloid leukemia, primary or secondary myelofibrosis based on

WHO 2016 classification (Arber et al 2016)

- Diagnosis of therapy related myeloid neoplasms based on WHO 2016 classification (Arber

et al 2016)

- History of organ or allogeneic hematopoietic stem cell transplant

Other protocol-defined Inclusion/Exclusion Criteria may apply.

Studien-Rationale

Primary outcome:

1. Overall Survival (Time Frame - Up to 5 years after last patient randomized):
Time from randomization until death due to any cause



Secondary outcome:

1. Key secondary endpoint 1: Time to definitive deterioration of fatigue using Functional Assessment of Cancer Therapy (FACIT)-Fatigue score (Time Frame - Up to 5 years after last patient randomized):
FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer patients. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Time from randomization to at least 3 points worsening from baseline will be presented.

2. Key secondary endpoint 2: Red Blood Cell transfusion-free intervals (Time Frame - Up to 5 years after last patient randomized):
Cumulative times of intervals with no evidence of Red Blood Cell (RBC) transfusion for at least 8 weeks after randomization

3. Key secondary endpoint: Percent of subjects with at least 3 point confirmed improvement from baseline in FACIT-fatigue scoresscore (Time Frame - Up to 5 years after last patient randomized):
FACIT-Fatigue score is a 13-item questionnaire designed to assess fatigue in cancer patients. All items use a 5-point scale ranging from 0 to 4 (0=Not at All to 4=Very Much). The total score ranges from 0 to 52 with higher values representing better quality of life. Percentage of subjects with at least 3 point confirmed improvement from baseline will be presented.

4. Key secondary endpoint 4: Percent of subjects with at least 10 point confirmed improvement from baseline in physical functioning using European Or ganization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC QLQ-C30) (Time Frame - Up to 5 years after last patient randomized):
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 5 questions about their physical functioning (Items 1-5) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. Percentage of subjects with at least 10 point confirmed improvement from baseline in physical functioning will be presented.

5. Key secondary endpoint 5: Percent of subjects with at least 10 point confirmed improvement from baseline in emotional functioning using EORTC-QLQ-C30 (Time Frame - Up to 5 years after last patient randomized):
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 4 questions about their emotional functioning (Items 21-24) are scored on a 4-point scale (1=Not at All to 4=Very Much). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A high score indicates a high / healthy level of functioning. Percentage of subjects with at least 10 point confirmed improvement from baseline in emotional functioning will be presented.

6. Percentage of subjects with either CR, or mCR, or PR, or HI in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment (Time Frame - Up to 5 years after last patient randomized):
Response rate of subjects with complete remission (CR), or marrow remission (mCR), or partial remission (PR), or hematologic improvement (HI)

7. Percentage of subjects with SD in each treatment arm according to International Working Group for MDS (IWG-MDS) as per investigator assessment (Time Frame - Up to 5 years after last patient randomized):
Response rate of subjects with stable disease (SD)

8. Progression Free Survival (PFS) (Time Frame - Up to 5 years after last patient randomized):
Time from randomization to disease progression (including transformation to acute leukemia per WHO 2016 classification), relapse from CR according to International Working Group for MDS (IWG-MDS), or death due to any cause, whichever occurs first, as per investigator assessment

9. Leukemia-free survival (Time Frame - Up to 5 years after last patient randomized):
Time from randomization to ≥ 20% blasts in bone marrow/peripheral blood (per WHO 2016 classification) or diagnosis of extramedullary acute leukemia, or death due to any cause

10. Number of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization (Time Frame - Up to 5 years after last patient randomized as per IWG-MDS criteria):
Improvement in RBC/Platelets transfusion independence as per International Working Group for MDS (IWG-MDS) criteria

11. Percentage of transfusion dependent subjects at baseline who become Red Blood Cells/platelets transfusion independent after randomization (Time Frame - Up to 5 years after last patient randomized):
Improvement in RBC/Platelets transfusion Independence as per International Working Group for MDS (IWG-MDS) criteria

12. Pharmacokinetics of MBG453 (parameter Cmax) (Time Frame - At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug):
Maximum (peak) MBG453 concentration [Cmax]

13. Pharmacokinetics of MBG453 (parameter AUC) (Time Frame - At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug):
Area Under the Curve [AUC]

14. Anti-drug Antibody (ADA) prevalence at baseline and ADA incidence on-treatment (Time Frame - At Day 8 of each cycle (1 cycle = 28 days) until cycle 9, at day 8 of cycle 12 and every 6 cycles thereafter up to 150 day after end of study drug):
Immunogenicity of MBG453

15. Change from baseline in the European Quality of Life (EuroQol) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) score over time (Time Frame - Up to 5 years after last patient randomized):
The EQ-5D-5L comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. For each of the 5 dimensions, subject's responses are scored on a 5-point scale (1=no problem to 5=extreme problems). Change from baseline will be presented.

16. Change from baseline in the European Quality of Life (EuroQoL) - 5 Dimensions, 5 Level Questionnaire (EQ-5D-5L) Visual Analogue Scale over time (Time Frame - Up to 5 years after last patient randomized):
The EQ-5D-5L VAS records the subject's self-rated health on a visual analogue scale numbered from 0 to 100, with 0 being "the worst health you can imagine" and 100 being "the best health you can imagine". Change from baseline will be presented.

17. Change from baseline to C12D1 of Global Health Status/Quality of Life scores using European Organization for Research and Treatment of Cancer's Core Quality of Life Questionnaire (EORTC-QLQ-C30) (Time Frame - Up to cycle 12 day 1 (C12D1)(1 cycle = 28 days)):
EORTC-QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of cancer patients. Subject's responses to 2 questions (Items 29+30: "How would you rate your overall health during the past week?" and "How would you rate your overall quality of life during the past week?") are scored on a 7-point scale (1=Very Poor to 7=Excellent). Using linear transformation, raw scores are standardized, so that scores range from 0 to 100. A higher score indicates a better overall outcome. Change from baseline to Cycle 12 Day 1 will be presented.

Studien-Arme

  • Experimental: MBG453 + Azacitidine
    Participants will receive MBG453 plus Azacitidine
  • Placebo Comparator: Placebo + Azacitidine
    Participants will receive Placebo plus Azacitidine

Geprüfte Regime

  • MBG453:
    A dose of MBG453 800 mg will be administered intravenously (IV) every 4 weeks (Q4W).
  • Azacitidine:
    A dose of Azacitidine 75 mg/m2 will be administered IV or subcutaneously (SC) on Day 1-7, or Day 1-5, 8 and 9.
  • Placebo:
    A dose of Placebo 800 mg will be administered intravenously every 4 weeks (Q4W).

Quelle: ClinicalTrials.gov


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