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Study of PDR001 and/or MBG453 in Combination With Decitabine in Patients With AML or High Risk MDS

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ClinicalTrials.gov Identifier: NCT03066648
Recruitment Status : Recruiting
First Posted : February 28, 2017
Last Update Posted : July 17, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Study Description
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Brief Summary:
To characterize the safety and tolerability of 1) MBG453 as a single agent or in combination with PDR001 or 2) PDR001 and/or MBG453 in combination with decitabine in AML and high risk MDS patients, and to identify recommended doses for future studies.

Condition or disease Intervention/treatment Phase
Leukemia Leukemia, Myeloid Leukemia, Myeloid, Acute Myelodysplastic Syndromes Preleukemia Bone Marrow Diseases Hematologic Diseases Drug: Decitabine Drug: PDR001 Drug: MBG453 Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 235 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study is comprised of five combination arms:

  • Evaluation of a fixed dose of the standard of care agent decitabine, in combination with fixed dose PDR001 (Arm 1)
  • Evaluation of a fixed dose of the standard of care agent decitabine in combination with escalating dose MBG453 (Arm 2)
  • Evaluation of a fixed dose of the standard of care agent decitabine in combination with fixed dose of PDR001 and escalating dose of MBG453 (Arm 3) *
  • Evaluation of an escalating dose of MBG453

  • Evaluation of a fixed dose of PDR001 in combination with an escalating dose of MBG453

    • The evaluation of decitabine with the combination of PDR001 and MBG453 (Arm 3) will start after Novartis and Investigator's review of the available safety and tolerability data from each of the first two cohorts in Arm 1 and Arm 2.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1b, Multi-arm, Open-label Study of PDR001 and/or MBG453 in Combination With Decitabine in Patients With Acute Myeloid Leukemia or High Risk Myelodysplastic Syndrome
Actual Study Start Date : July 6, 2017
Estimated Primary Completion Date : April 1, 2020
Estimated Study Completion Date : April 1, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Decitabine

Arms and Interventions
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Arm Intervention/treatment
Experimental: Decitabine and PDR001
Decitabine in combination with PDR001
 Drug: Decitabine
Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Name: 5-aza-2'-deoxycytidine

Drug: PDR001
PDR001 is a high-affinity, ligand-blocking, humanized IgG4 monoclonal antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2.
Experimental: Decitabine and MBG453
Decitabine in combination with MBG453
 Drug: Decitabine
Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Name: 5-aza-2'-deoxycytidine

Drug: MBG453
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Experimental: Decitabine, PDR001 and MBG453
Decitabine in combination with PDR001 and MBG453
 Drug: Decitabine
Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Name: 5-aza-2'-deoxycytidine

Drug: PDR001
PDR001 is a high-affinity, ligand-blocking, humanized IgG4 monoclonal antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2.

Drug: MBG453
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Experimental: MBG453
MBG453 alone
 Drug: MBG453
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Experimental: MBG453 and PDR001
MBG453 in combination with PDR001
 Drug: PDR001
PDR001 is a high-affinity, ligand-blocking, humanized IgG4 monoclonal antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2.

Drug: MBG453
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).


Outcome Measures
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Primary Outcome Measures :
  1. Safety of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine. [ Time Frame: 24 months ]
    Incidence and severity of AEs and SAEs

  2. Incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: 2 months ]
    The incidence of DLTs during the first two cycles of treatment with MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine.

  3. Incidence of Dose Limiting Toxicities (DLTs) [ Time Frame: 1 month ]
    The incidence of DLTs during the first cycle of treatment with MBG453.

  4. Tolerability of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine. [ Time Frame: 24 months ]
    Incidence and severity of AEs and SAEs


Secondary Outcome Measures :
  1. AUC of PDR001, MBG453 and decitabine. [ Time Frame: 24 months ]
    AUC

  2. Cmax of PDR001, MBG453 and decitabine [ Time Frame: 24 months ]
    Cmax

  3. Tmax of PDR001, MBG453 and decitabine [ Time Frame: 24 months ]
    Tmax

  4. Half-life of PDR001, MBG453 and decitabine [ Time Frame: 24 months ]
    Half-life

  5. Concentration vs time profile of PDR001, MBG453 and decitabine [ Time Frame: 24 months ]
    Concentration vs. time

  6. Overall Response Rate (ORR) [ Time Frame: 24 months ]
    Determine ORR in each arm of the study

  7. Best Overall Response (BOR) [ Time Frame: 24 months ]
    Determine BOR in each arm of the study

  8. Progression Free Survival (PFS) [ Time Frame: 24 months ]
    Determine PFS in each arm of the study

  9. Time to Progression (TTP) [ Time Frame: 24 months ]
    Determine TTP in each arm of the study

  10. Duration of Response (DOR) [ Time Frame: 24 months ]
    Determine DOR in each arm of the study


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  1. Written informed consent must be obtained prior to any screening procedures

  2. Male or female patients ≥ 18 years of age who present with one of the following:

    Arms 1-3:

    • Refractory/relapsed AML following ≥1 prior therapies and are deemed by the investigator not to be candidates for standard therapy, including re-induction with cytarabine or other established chemotherapy regimens for patients with AML (patients who are suitable for standard re-induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded)
    • De novo AML patients who are suitable for treatment with decitabine (patients who are suitable for standard induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded)
    • High risk MDS (patients who are suitable for standard re-induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded)

    Arms 4-5:

    • Refractory / relapsed AML following ≥1 prior therapies (Arms 4a & 5a)
    • High risk MDS who have failed hypomethylating agent therapy (Arms 4b & 5b) (Note: hypomethylating agent failure is defined as progressive disease on hypomethylating agent therapy or lack of clinically meaningful response as deemed by investigator after at least 4 cycles of hypomethylating agent therapy.)
  3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  4. Patient must be a candidate for serial bone marrow aspirate and/or biopsy according to the institutions guidelines and be willing to undergo a bone marrow aspirate and/biopsy at screening, during and at the end of therapy on this study. Exceptions may be considered after documented discussion with Novartis.
  5. Arms 1-3: Patients must be fit for standard treatment with decitabine as determined by the investigator and as per local decitabine package insert.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03066648


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111

Locations
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United States, Massachusetts
Novartis Investigative Site Recruiting
Boston, Massachusetts, United States, 02114
Contact: Meghan Burke    617-726-5131    Mburke19@partners.org   
Principal Investigator: Andrew M. Brunner         
United States, Oregon
Novartis Investigative Site Recruiting
Portland, Oregon, United States, 97239
United States, Texas
Novartis Investigative Site Recruiting
Houston, Texas, United States, 77030
Australia, Victoria
Novartis Investigative Site Recruiting
Melbourne, Victoria, Australia, 3004
Finland
Novartis Investigative Site Recruiting
Helsinki, Finland, FIN 00290
France
Novartis Investigative Site Recruiting
Marseille, France, 13273
Germany
Novartis Investigative Site Recruiting
Dresden, Germany, 01307
Novartis Investigative Site Recruiting
Jena, Germany, 07740
Netherlands
Novartis Investigative Site Recruiting
Amsterdam, Netherlands, 1081 HV
Spain
Novartis Investigative Site Recruiting
Barcelona, Catalunya, Spain, 08036
United Kingdom
Novartis Investigative Site Recruiting
Cardiff, United Kingdom, CF4 4XN
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
More Information
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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03066648     History of Changes
Other Study ID Numbers: CPDR001X2105
First Posted: February 28, 2017    Key Record Dates
Last Update Posted: July 17, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Acute Myeloid Leukemia
Myelodysplastic syndromes
Additional relevant MeSH terms:
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Leukemia
Preleukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Hematologic Diseases
Bone Marrow Diseases
Syndrome
Disease
Pathologic Processes
 Neoplasms by Histologic Type
Neoplasms
Precancerous Conditions
Decitabine
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors