- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03066648
Study of PDR001 and/or MBG453 in Combination With Decitabine in Patients With AML or High Risk MDS
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
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This is a phase 1b, multi-arm, open-label study in patients with acute myeloid leukemia (AML) or intermediate or high risk myelodysplastic syndrome (MDS). Patients with myelodysplastic-myeloproliferative neoplasms (MDS/MPN), including chronic myelomonocytic leukemia (CMML) could also be enrolled.
The study was comprised of six arms as described below. Arms 1-3 enrolled patients with newly diagnosed AML who were planned for non-intensive chemotherapy, relapsed/refractory (R/R) AML, or intermediate or high-risk MDS.
- Arm 1: Evaluation of a fixed dose of the standard of care agent decitabine in combination with fixed dose PDR001.
- Arm 2: Evaluation of a fixed dose of the standard of care agent decitabine in combination with escalating dose MBG453.
- Arm 3: Evaluation of a fixed dose of the standard of care agent decitabine in combination with fixed dose PDR001 and escalating dose MBG453.
Arms 4-5 enrolled patients with R/R AML or intermediate or high-risk MDS who had failed hypomethylating agent therapy.
- Arm 4: Evaluation of an escalating dose of MBG453
- Arm 5: Evaluation of an escalating dose of MBG453 in combination with fixed dose PDR001 Arm 6 enrolled patients with newly diagnosed AML who were planned for non-intensive chemotherapy, or intermediate or high-risk MDS.
- Arm 6: Evaluation of a fixed dose of the standard of care agent azacitidine in combination with an escalating dose of MBG453.
Patients received the assigned treatment until disease progression, unacceptable toxicity, start of a new anti-neoplastic therapy, discontinuation at the discretion of the investigator or patient, lost to follow-up, death, or the study termination, whichever occurred first.
Study Type
Enrollment (Actual)
Phase
- Phase 1
Contacts and Locations
Study Locations
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Victoria
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Melbourne, Victoria, Australia, 3004
- Novartis Investigative Site
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Helsinki, Finland, FIN 00290
- Novartis Investigative Site
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Marseille, France, 13273
- Novartis Investigative Site
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Dresden, Germany, 01307
- Novartis Investigative Site
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Jena, Germany, 07740
- Novartis Investigative Site
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Amsterdam, Netherlands, 1081 HV
- Novartis Investigative Site
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Catalunya
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Barcelona, Catalunya, Spain, 08036
- Novartis Investigative Site
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Cardiff, United Kingdom, CF4 4XN
- Novartis Investigative Site
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Massachusetts
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Boston, Massachusetts, United States, 02114
- Massachusetts General Hospital
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Oregon
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Portland, Oregon, United States, 97239
- Oregon Health Sciences University Main Center
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Texas
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Houston, Texas, United States, 77030
- MD Anderson Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Written informed consent must be obtained prior to any screening procedures
Male or female patients ≥ 18 years of age who present with one of the following:
Arms 1-3:
- Relapsed/refractory AML following ≥1 prior therapies who have relapsed or exhibited refractory disease (primary failure) 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)
- Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 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.
- Arms 1-3: Patients must be fit for standard treatment with decitabine as determined by the investigator and as per local decitabine package insert.
- 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:
- Arms 1-3 or Arm 6: Patients who have received prior hypomethylating agent treatment for AML or MDS.
- 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.
- History of, or current drug-induced interstitial lung disease or pneumonitis grade ≥ 2.
- 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.
- 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.
- 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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
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Experimental: Decitabine and PDR001
Decitabine in combination with PDR001
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Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Names:
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.
Other Names:
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Experimental: Decitabine and MBG453
Decitabine in combination with MBG453
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Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Names:
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Other Names:
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Experimental: Decitabine, PDR001 and MBG453
Decitabine in combination with PDR001 and MBG453
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Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
Other Names:
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.
Other Names:
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Other Names:
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Experimental: MBG453
MBG453 alone
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MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Other Names:
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Experimental: MBG453 and PDR001
MBG453 in combination with PDR001
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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.
Other Names:
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Other Names:
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Experimental: Azacitidine and MBG453
Azacitidine in combination with MBG453
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MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
Other Names:
Azacitidine (5-azacytidine) is a cytidine nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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Safety of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine or azacitidine.
Time Frame: 24 months
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Incidence and severity of AEs and SAEs
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24 months
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Incidence of Dose Limiting Toxicities (DLTs)
Time Frame: 2 months
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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.
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2 months
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Incidence of Dose Limiting Toxicities (DLTs)
Time Frame: 1 month
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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.
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1 month
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Tolerability of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine or azacitidine.
Time Frame: 24 months
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Incidence and severity of AEs and SAEs
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24 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
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AUC of PDR001, MBG453, decitabine and azacitidine.
Time Frame: 24 months
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AUC
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24 months
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Cmax of PDR001, MBG453, decitabine and azacitidine
Time Frame: 24 months
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Cmax
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24 months
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Tmax of PDR001, MBG453, decitabine and azacitidine
Time Frame: 24 months
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Tmax
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24 months
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Half-life of PDR001, MBG453, decitabine and azacitidine
Time Frame: 24 months
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Half-life
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24 months
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Overall Response Rate (ORR)
Time Frame: 24 months
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Determine ORR in each arm of the study
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24 months
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Best Overall Response (BOR)
Time Frame: 24 months
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Determine BOR in each arm of the study
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24 months
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Progression Free Survival (PFS)
Time Frame: 24 months
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Determine PFS in each arm of the study
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24 months
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Time to Progression (TTP)
Time Frame: 24 months
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Determine TTP in each arm of the study
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24 months
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Duration of Response (DOR)
Time Frame: 24 months
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Determine DOR in each arm of the study
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24 months
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Number of participants with anti-PDR001 and anti-MBG453 antibodies
Time Frame: 24 months
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Presence of anti-PDR001 and anti-MBG453 antibodies.
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24 months
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Disease
- Precancerous Conditions
- Myelodysplastic-Myeloproliferative Diseases
- Chronic Disease
- Syndrome
- Myelodysplastic Syndromes
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Preleukemia
- Leukemia, Myelomonocytic, Chronic
- Leukemia, Myelomonocytic, Juvenile
- Hematologic Diseases
- Bone Marrow Diseases
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Antineoplastic Agents, Immunological
- Immune Checkpoint Inhibitors
- Decitabine
- Azacitidine
- Spartalizumab
Other Study ID Numbers
- CPDR001X2105
- 2016-005060-33 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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