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

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.

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.

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.