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

Leukemia Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03066648
• Other study ID #: CPDR001X2105
• Secondary ID: 2016-005060-33
• Status: Completed
• Phase: Phase 1
• Start date: July 6, 2017
• Est. completion date: September 8, 2023

Study information

• Verified date: September 2023
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 241
• Est. completion date: September 8, 2023
• Est. primary completion date: September 8, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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:

• 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)

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.

6. 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 = 2.

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.

Related Conditions & MeSH terms

• Bone Marrow Diseases
• Chronic Myelomonocytic Leukemia
• Hematologic Diseases
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Decitabine
Decitabine is a cytidine deoxynucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation.
• 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.
• MBG453
MBG453 is a high-affinity, humanized anti-TIM-3 IgG4 monoclonal antibody which blocks the binding of TIM-3 to phosphatidylserine (PtdSer).
• Azacitidine
Azacitidine (5-azacytidine) is a cytidine nucleoside analogue that selectively inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Finland	Novartis Investigative Site	Helsinki
France	Novartis Investigative Site	Marseille
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Jena
Netherlands	Novartis Investigative Site	Amsterdam
Spain	Novartis Investigative Site	Barcelona	Catalunya
United Kingdom	Novartis Investigative Site	Cardiff
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	MD Anderson Cancer Center	Houston	Texas
United States	Oregon Health Sciences University Main Center	Portland	Oregon

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Finland,  France,  Germany,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine or azacitidine.	Incidence and severity of AEs and SAEs	24 months
Primary	Incidence of Dose Limiting Toxicities (DLTs)	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.	2 months
Primary	Incidence of Dose Limiting Toxicities (DLTs)	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.	1 month
Primary	Tolerability of MBG453 single agent treatment or MBG453 in combination with PDR001 or PDR001 and/or MBG453 in combination with decitabine or azacitidine.	Incidence and severity of AEs and SAEs	24 months
Secondary	AUC of PDR001, MBG453, decitabine and azacitidine.	AUC	24 months
Secondary	Cmax of PDR001, MBG453, decitabine and azacitidine	Cmax	24 months
Secondary	Tmax of PDR001, MBG453, decitabine and azacitidine	Tmax	24 months
Secondary	Half-life of PDR001, MBG453, decitabine and azacitidine	Half-life	24 months
Secondary	Overall Response Rate (ORR)	Determine ORR in each arm of the study	24 months
Secondary	Best Overall Response (BOR)	Determine BOR in each arm of the study	24 months
Secondary	Progression Free Survival (PFS)	Determine PFS in each arm of the study	24 months
Secondary	Time to Progression (TTP)	Determine TTP in each arm of the study	24 months
Secondary	Duration of Response (DOR)	Determine DOR in each arm of the study	24 months
Secondary	Number of participants with anti-PDR001 and anti-MBG453 antibodies	Presence of anti-PDR001 and anti-MBG453 antibodies.	24 months