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Title A Phase IB Study of the Safety and Pharmacology of MPDL3280A (Anti-Pd-L1 Antibody) Administered Alone or in Combination with Azacitidine in Patients with Myelodysplastic Syndromes

IRB ROCH1915

CC 15-767

Hospital Main Campus

Phase Phase 1

Disease Myelodisplastic Syndrome (MDS)

Drug MPDL3280A

Description

PRIMARY OBJECTIVES

• To establish the safety and tolerability of MPDL3280A monotherapy in high-risk MDS patients who are relapsed or refractory to hypomethylating agents (HMA)
• To determine the safety and tolerability of the combination of MPDL3280A and azacitidine in high-risk MDS patients who are either na�ve to HMAs or relapsed/refractory to prior HMA therapy
• To determine the recommended Phase II dose of MPDL3280A in combination with azacitidine

SECONDARY OBJECTIVES

• To characterize the pharmacokinetics of MPDL3280A when given alone or in combination with azacitidine
• To characterize the immunogenicity of MPDL3280A when administered alone and in combination with azacitidine
• To make a preliminary assessment of the anti-neoplastic activity of MPDL3280A alone and in combination with azacitidine in MDS patients

EXPLORATORY OBJECTIVES

• To assess biomarkers related to disease biology, mechanism(s) of action of MPDL3280A alone and in combination with azacitidine, potential mechanism(s) of resistance to MPDL3280A alone and in combination with azacitidine, prediction of response, prognosis, and improvement of diagnostic assays

Inclusion Criteria

1. Signed Informed Consent Form
2. Age≥ 18 years
3. Ability to comply with the study protocol
4. Diagnosis of MDS according to WHO 2008 criteria (patients with therapy-related MDS are eligible)
5. Eastern Cooperative Oncology Group (ECOG) performance status score≤ 2
6. For patients in Cohorts A and B:
   • Progression (according to 2006 IWG criteria; see Appendix 4) at any time after initiation of azacitidine or decitabine treatment
   • Failure to achieve complete or partial response or hematological improvement (according to 2006 IWG criteria) after at least six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine
   • Relapse after initial complete or partial response or hematological improvement (2006 IWG criteria) after six 4-week cycles of azacitidine or either four 4-week or four 6-week cycles of decitabine administered within the past 2 years
7. Adequate end-organ function, defined by the following laboratory parameters obtained within 28 days prior to the first dose of study drug:
   • AST, ALT, and ALP≤ 2.5xULN
   • Serum bilirubin ≤ 1.5xULN (patients with known Gilbert's disease who have serum bilirubin ≤ 3xULN may be enrolled)
   • INR and aPTT≤ 1.5xULN (this applies only to patients who are not receiving therapeutic anti-coagulation)
   • Serum creatinine ≤ 1.5xULN
8. For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception (i.e., one that results in a failure rate of <1% per year, when used consistently and correctly) and to continue its use for 90 days after the last dose of MPDL3280A.
9. Willing and able to undergo a pre-treatment bone marrow biopsy and subsequent on treatment bone marrow biopsies

Exclusion Criteria

1. Patients who have a diagnosis of hypoplastic MDS or MDS secondary to paroxysmal nocturnal hemoglobinuria (PNH), aplastic anemia, or another inherited bone marrow failure disorder (e.g., dyskeratosis congenita, Fanconi anemia, or Schwachman-Bodian-Diamond syndrome)
2. Prior allogeneic stem cell transplant or solid organ transplant
3. Pregnant or lactating, or intending to become pregnant during the study
4. Women who are not postmenopausal (≥12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 28 days prior to initiation of study drug.
5. Investigational therapy within 28 days prior to initiation of study treatment
   • Immunosuppressive therapy (not limited to but including azathioprine, mycophenolate mofetil (MMF), cyclosporine, tacrolimus, methotrexate, and anti-TNF agents) within 6 weeks of Cycle 1, Day 1
6. Daily requirement for corticosteroids (>10 mg prednisone daily or equivalent) (except for inhalation corticosteroids) within 2 weeks prior to Cycle 1, Day 1.
7. Active or latent tuberculosis (TB). Patients suspected of harboring latent TB should undergo confirmatory interferon-? release assay (QuantiFERON®) testing and chest imaging (X-ray or computed tomography [CT] scan depending on clinical context) if deemed clinically necessary
8. Any approved MDS related therapy within 28 days prior to enrollment (includes erythropoietin-stimulating agents within 2 weeks of Cycle 1, Day1; granulocyte colony-stimulating factor (G-CSF) to treat infections associated with neutropenic fever is permitted)
9. Clinically significant cardiovascular disease (e.g., uncontrolled or any New York Heart Association (NYHA) Class III or IV congestive heart failure, uncontrolled angina, history of myocardial infarction or stroke within 6 months of study entry, uncontrolled hypertension or clinically significant arrhythmias not controlled by medication)
10. Planned major surgery during the study
11. Administration of a live, attenuated vaccine within 4 weeks of Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study (Influenza vaccination should only be given during influenza season - approximately October to March)
12. Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cells or any component of the MPDL3280A or azacitidine formulations
13. History of severe allergic, anaphylactic or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
14. History of autoimmune disease (see Appendix 5 for a comprehensive list)
    • Patients with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement may be eligible for this study
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen may be eligible for this study
15. Positive for hepatitis C antibody at screening
16. Positive for hepatitis B surface antigen at screening
17. Known HIV infection
18. History of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment
19. Prior treatment with immune checkpoint blockade therapies (anti-CTLA-4, anti-PD-1 or anti-PD-L1) or immune agonists (anti-CD137, anti-CD40, anti-OX40)
20. Treatment with systemic immunostimulatory agents (including but not limited to IFN and IL-2) within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to Cycle 1, Day 1
21. Treatment with denosumab (or other RANKL inhibitor) 4 weeks before the first dose and for 10 weeks after the last dose of MPDL3280A. Patients on denosumab therapy must be willing to be treated with a bisphosphonate, while on study treatment.
22. Serious infection requiring oral or IV antibiotics/antifungals/antivirals within 28 days prior to screening
    • Patients on prophylactic oral antibiotics, antifungals and antivirals due to prolonged neutropenia in the absence of documented infection are eligible
23. Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the patient's safe participation in and completion of the study
24. History or presence of an abnormal ECG that is clinically significant in the investigator's opinion, including complete left bundle branch block, second- or third-degree heart block, evidence of prior myocardial infarction
25. History of other malignancy within 2 years prior to screening, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, low-grade, localized prostate cancer (Gleason score≤ 7) not requiring treatment or Stage I uterine cancer
26. History of idiopathic pulmonary fibrosis, organizing pneumonitis (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis