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

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Active, not recruiting
CT.gov ID
NCT03066648
Collaborator
(none)
243
Enrollment
11
Locations
6
Arms
59.8
Anticipated Duration (Months)
22.1
Patients Per Site
0.4
Patients Per Site Per Month

Study Details

Study Description

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 or azacitidine in AML and intermediate or high- risk MDS patients, and to identify recommended doses for future studies.

Study Design

Study Type:
Interventional
Actual Enrollment :
243 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Intervention Model Description:
The study is comprised of six 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 (Arm 4) Evaluation of a fixed dose of PDR001 in combination with an escalating dose of MBG453 (Arm 5) Evaluation of a fixed dose of the standard of care agent azacitidine in combination with an escalating dose of MBG453 (Arm 6) 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.The study is comprised of six 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 (Arm 4) Evaluation of a fixed dose of PDR001 in combination with an escalating dose of MBG453 (Arm 5) Evaluation of a fixed dose of the standard of care agent azacitidine in combination with an escalating dose of MBG453 (Arm 6) 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 :
Jul 6, 2017
Anticipated Primary Completion Date :
Jun 30, 2022
Anticipated Study Completion Date :
Jun 30, 2022

Arms and Interventions

ArmIntervention/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 Names:
  • 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 Names:
  • 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 Names:
  • 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).

    Experimental: Azacitidine and MBG453

    Azacitidine in combination with MBG453

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

    Drug: Azacitidine
    Azacitidine (5-azacytidine) is a cytidine nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation

    Outcome Measures

    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 or azacitidine. [24 months]

      Incidence and severity of AEs and SAEs

    2. Incidence of Dose Limiting Toxicities (DLTs) [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) [1 month]

      The incidence of DLTs during the first cycle of MBG453 single agent treatment or during the first two cycles of treatment with MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine.

    4. Tolerability of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine or azacitidine. [24 months]

      Incidence and severity of AEs and SAEs

    Secondary Outcome Measures

    1. AUC of PDR001, MBG453, decitabine and azacitidine. [24 months]

      AUC

    2. Cmax of PDR001, MBG453, decitabine and azacitidine [24 months]

      Cmax

    3. Tmax of PDR001, MBG453, decitabine and azacitidine [24 months]

      Tmax

    4. Half-life of PDR001, MBG453, decitabine and azacitidine [24 months]

      Half-life

    5. Overall Response Rate (ORR) [24 months]

      Determine ORR in each arm of the study

    6. Best Overall Response (BOR) [24 months]

      Determine BOR in each arm of the study

    7. Progression Free Survival (PFS) [24 months]

      Determine PFS in each arm of the study

    8. Time to Progression (TTP) [24 months]

      Determine TTP in each arm of the study

    9. Duration of Response (DOR) [24 months]

      Determine DOR in each arm of the study

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion 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)

    • Newly diagnosed 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)

    • Intermediate or high risk MDS or MDS/MPN including CMML (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)

    • Intermediate or high risk MDS or MDS/MPN including CMML 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.)

    Arm 6:
    • Newly diagnosed AML patients who are suitable for treatment with azacitidine (patients who are suitable for standard induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded) (Arm 6a)

    • Intermediate or high-risk MDS or MDS/MPN including CMML (patients who are suitable for standard induction chemotherapy or hematopoietic stem cell transplantation and willing to receive it are excluded) (Arm 6b)

    1. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

    2. 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.

    3. Arms 1-3: Patients must be fit for standard treatment with decitabine as determined by the investigator and as per local decitabine package insert.

    4. Arm 6: Patients must be fit for standard treatment with azacitidine as determined by the investigator and as per the local azacitidine package insert.

    Exclusion Criteria:
    1. Arms 1-3 or Arm 6: Patients who have received prior hypomethylating agent treatment for AML or MDS.

    2. Patients with active, known or suspected autoimmune disease. Patients with vitiligo, type I diabetes, residual hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur should not be excluded.

    3. History of, or current drug-induced interstitial lung disease or pneumonitis grade ≥

    4. Patients who discontinued prior PD-1 or PD-L1 directed therapy due to a treatment related toxicity should not be included in the PDR001 containing arms of the study. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin rash or with replacement therapy for endocrinopathies should not be excluded.

    5. Systemic antineoplastic therapy (including cytotoxic chemotherapy, alphainterferon, kinase inhibitors or other targeted small molecules, and toxinimmunoconjugates) or any experimental therapy within 14 days or 5 half-lives, whichever is shorter, before the first dose of study treatment.

    6. Systemic chronic corticosteroid therapy (>10 mg/day prednisone or equivalent) or any immunosuppressive therapy within 7 days of first dose of study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.

    Other protocol-defined inclusion/exclusion criteria may apply.

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Massachusetts General HospitalBostonMassachusettsUnited States02114
    2Oregon Health and Science UniversityPortlandOregonUnited States97239
    3MD Anderson Cancer CenterHoustonTexasUnited States77030
    4Novartis Investigative SiteMelbourneVictoriaAustralia3004
    5Novartis Investigative SiteHelsinkiFinlandFIN 00290
    6Novartis Investigative SiteMarseilleFrance13273
    7Novartis Investigative SiteDresdenGermany01307
    8Novartis Investigative SiteJenaGermany07740
    9Novartis Investigative SiteAmsterdamNetherlands1081 HV
    10Novartis Investigative SiteBarcelonaCatalunyaSpain08036
    11Novartis Investigative SiteCardiffUnited KingdomCF4 4XN

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT03066648
    Other Study ID Numbers:
    • CPDR001X2105
    First Posted:
    Feb 28, 2017
    Last Update Posted:
    Oct 15, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Oct 15, 2021