An Open-Label Phase Ib/II Multi-Arm Study of OX40 Agonist Monoclonal Antibody (mAb), Anti-PDL1 mAb, Smoothened Inhibitor, Anti-CD33 mAb, Bcl-2 Inhibitor and Azacitidine as Single-Agents and/or Combinations for the Treatment of Patients With Acute Myeloid Leukemia (AML)
Overview
- Phase
- Phase 1
- Intervention
- Anti-OX40 Agonist Monoclonal Antibody PF-04518600
- Conditions
- Recurrent Acute Myeloid Leukemia
- Sponsor
- M.D. Anderson Cancer Center
- Enrollment
- 50
- Locations
- 1
- Primary Endpoint
- Number of Participants With a Response
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase Ib/II trial studies the side effects and best dose of anti-OX40 antibody PF-04518600 (OX40) and how well it works alone or in combination with venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine in treating patients with acute myeloid leukemia that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as OX40, avelumab, and gemtuzumab ozogamicin, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Glasdegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as venetoclax and azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving OX40, venetoclax, avelumab, glasdegib, gemtuzumab ozogamicin, and azacitidine may work better in treating patients with acute myeloid leukemia.
Detailed Description
PRIMARY OBJECTIVES: I. To evaluate the safety of multiple combination regimens of IO-agents (PF04518600 \[Ox40 agonist monoclonal antibody (mAb)\], avelumab \[PD-L1 antagonist mAb\], hypomethylator therapy (azacitidine), anti CD33 mAb (gemtuzumab ozogamycin, GO), Bcl-2 inhibitor (venetoclax) and smoothened pathway inhibitor (glasdegib) in patients with relapsed/refractory (RR) acute myeloid leukemia (AML). II. To evaluate the composite complete response (CRc) defined as complete response (CR) + complete response with incomplete recovery of platelets (CRp) + complete response with incomplete recovery of counts (CRi) within 3 months of therapy initiation in patients with RR AML of: Arm A. PF-04518600 alone, Arm B. azacitidine + venetoclax + GO, Arm C. azacitidine + aveluma + GO, Arm D. azacitidine + venetoclax + avelumab, Arm E. Azacitidine + avelumab + PF-04518600, Arm F. GO + glasdegib. SECONDARY OBJECTIVES: I. To assess the morphologic leukemia free survival (MLFS), partial response (PR), hematologic improvement (HI) rate of patients with RR AML treated on arms A-F. II. To assess relapse-free survival (RFS), time to next therapy (TNT), 4-week and 8-week mortality, and overall survival (OS) of patients with RR AML treated on arms A-F. III. To assess minimal residual disease (MRD) by multiparametric flow-cytometry at response (+/- 1 month) and assess correlation of MRD to OS in arms A-F. EXPLORATORY OBJECTIVES: I. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include quantification of immune ligand expression by the AML/myelodysplastic syndrome (MDS) blasts and AML/MDS stromal components (myeloid-derived suppressor cell \[MDSC\]s, monocytes and mesenchymal stem cell \[MSC\]s) including galectin 9, 4-1BBL, ICOSL, PD-L1, PD-L2, OX-40L, CD137L, others. II. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include determination of the quantitative expression of positive and negative co-stimulatory molecules including 4-1BB, CTLA-4, ICOS, PD-1, OX40, LAG-3, TIM-3, HLA-DR, Ki67, others on T-lymphocyte subsets. III. To study immunological and molecular features at baseline and at predefined time-points on-therapy with each combination in the peripheral blood and bone marrow to include identification of the immunophenotype of tumor-infiltrating T-lymphocytes (TILs) pre- and post-therapy including CD8+, CD4+ effector, CD4+ regulatory TILs and central memory, effector memory, and naive T-cell subsets among the CD4 and CD8 populations. IV. To develop a micro-array based gene expression profile (GEP) predictor of response to the immune combinations using either baseline ribonucleic acid (RNA) sequencing and/or nanostring. V. To perform a validated next generation sequencing (NGS)-based analysis for the detection of somatic mutations in the coding sequences of 28 genes commonly mutated in AML at baseline and on treatment to identify baseline predictors and clonal evolution on treatment and/or whole exome sequencing (WES) in selected cases. VI. To identify clonal T-cells by performing T-cell repertoire analysis at baseline and longitudinally on therapy on the peripheral blood and/o bone marrow samples. VII. To assess levels of cytokines at baseline and longitudinally on therapy in peripheral blood and/or bone marrow. OUTLINE: This is a phase I, dose escalation study of anti-OX40 antibody PF-04518600 followed by a phase II study. Patients are assigned to 1 of 6 arms. ARM A: Patients receive anti-OX40 antibody PF-04518600 intravenously (IV) over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive azacitidine IV over 10-40 minutes or via injection subcutaneously (SC) on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax orally (PO) on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM C: Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM D: Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM E: Patientss receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM F: Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After conclusion of study treatment, patients are followed up at 30 days, then every 3-6 months for up to 5 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •ARMS A-G: RR AML: Patients with AML who are refractory or relapsed (any salvage) with no available therapies or not candidates for available therapies. For patients with prior MDS or chronic myelomonocytic leukemia (CMML) or myeloproliferative neoplasm (MPN) who transformed to AML, therapy received for MDS, CMML, or MPN is NOT considered as prior therapy for AML with the exception of MDS or CMML treated with hypomethylating agents (HMAs). Patients with MDS or CMML treated with HMA therapies who progress to AML, and have no available therapies or are not candidates for available therapies, will be eligible at the time of progression to AML.
- •Prior therapy with hydroxyurea, chemotherapy, biological or targeted therapy (e.g. FLT3 inhibitors, other kinase inhibitors), or hematopoietic growth factors is permitted.
- •Eastern Cooperative Oncology Group (ECOG) performance status =\<
- •Total bilirubin =\< 2.0 times upper limit of normal (x ULN).
- •Aspartate aminotransferase or alanine aminotransferase =\< 2.5 x ULN (aspartate aminotransferase or alanine aminotransferase =\< 5.0 x ULN if deemed related to leukemia by the treating physician).
- •Adequate renal function defined by an estimated creatinine clearance \>= 40 mL/min according to the Cockcroft-Gault formula (or local institutional standard method).
- •Patients must provide written informed consent.
- •In the absence of rapidly progressive disease, the interval from prior treatment to the time of initiation of protocol therapy will be at least 14 days for prior anti-leukemic therapy, with the exception of hydroxyurea as noted below, OR at least 5 half-lives for cytotoxic/noncytotoxic agents, whichever is shorter. The half-life for the therapy in question will be based on published pharmacokinetic literature (abstracts, manuscripts, investigator brochure's, or drug-administration manuals) and will be documented in the protocol eligibility document. The toxicity from prior therapy should have resolved to grade =\< 1, however alopecia and sensory neuropathy grade =\< 2 not constituting a safety risk based on investigators judgement is acceptable. Since the effect of most IO-agents, HMA-therapies, SMO-inhibitors, venetoclax may be delayed, use of hydroxyurea for patients with rapidly proliferative disease is allowed before the start of study therapy and will not require a washout.
- •Concurrent therapy for central nervous system (CNS) prophylaxis or continuation of therapy for controlled CNS disease is permitted. Patients with a known history of CNS disease or leukemic brain metastasis must have been treated locally, have at least 3 consecutive lumbar punctures (LPs) with no evidence of CNS leukemia, and must be clinically stable for at least 4 weeks prior to enrollment and have no ongoing neurological symptoms that in the opinion of the treating physician are related to the CNS disease (sequelae that are a consequence of the treatment of the CNS disease are acceptable).
- •Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.
Exclusion Criteria
- •Patients with a known allergy or hypersensitivity to the protocol therapies or any of their components to be used in the arm the patient is to be enrolled on. Known severe hypersensitivity reactions to monoclonal antibodies (grade \>= 3 National Cancer Institute \[NCI\] Common Terminology Criteria for Adverse Events \[CTCAE\] version \[v\] 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma).
- •Patients with a known history of severe interstitial lung disease or severe pneumonitis or active pneumonitis/pneumonia or pulmonary pathology that is not well controlled in the opinion of the treating physician and/or principal investigator (PI).
- •Clinically significant (i.e., active) cardiovascular disease: acute cerebral vascular accident/stroke (\< 6 months prior to enrollment) excluding transient ischemic attack (TIA), myocardial infarction (\< 6 months prior to enrollment), unstable angina, congestive heart failure (\>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication.
- •Ejection fraction \< 50% on screening echocardiography (ECHO) or multigated acquisition scan (MUGA).
- •Persisting toxicity related to prior therapy of grade \> 1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy grade =\< 2 is acceptable.
- •Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: \* Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible
- •Current use of immunosuppressive medication, EXCEPT for the following:
- •Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection);
- •Systemic corticosteroids at physiologic doses =\< 10 mg/day of prednisone or equivalent;
- •Steroids as premedication for hypersensitivity reactions (e.g., computed tomography \[CT\] scan premedication).
Arms & Interventions
Arm A (anti-OX40 antibody PF-04518600)
Patients receive anti-OX40 antibody PF-04518600 IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Anti-OX40 Agonist Monoclonal Antibody PF-04518600
Arm B (azacitidine, venetoclax, GO)
Patients receive azacitidine IV over 10-40 minutes or via injection SC on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax PO on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm B (azacitidine, venetoclax, GO)
Patients receive azacitidine IV over 10-40 minutes or via injection SC on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax PO on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Gemtuzumab Ozogamicin
Arm B (azacitidine, venetoclax, GO)
Patients receive azacitidine IV over 10-40 minutes or via injection SC on days 1-7 or 1-5 and 8-9. Patients also receive venetoclax PO on days 1-28 and GO IV over 2 hours on day 8. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Arm C (azacitidine, GO, avelumab)
Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Avelumab
Arm C (azacitidine, GO, avelumab)
Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Gemtuzumab Ozogamicin
Arm C (azacitidine, GO, avelumab)
Patients receive azacitidine and GO as in Arm B. Patients also receive avelumab IV over 60 minutes on days 1 and 14. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm D (azacitidine, venetoclax, avelumab)
Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Avelumab
Arm D (azacitidine, venetoclax, avelumab)
Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm D (azacitidine, venetoclax, avelumab)
Patients receive azacitidine and venetoclax as in Arm A and avelumab as in Arm C. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Venetoclax
Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)
Patients receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Anti-OX40 Agonist Monoclonal Antibody PF-04518600
Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)
Patients receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Avelumab
Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)
Patients receive azacitidine and avelumab as in Arm C and anti-OX40 antibody PF-04518600 as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Azacitidine
Arm F (GO, glasdegib)
Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Gemtuzumab Ozogamicin
Arm F (GO, glasdegib)
Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Glasdegib
Arm F (GO, glasdegib)
Patients receive GO IV over 2 hours on days 1, 4, and 7, and glasdegib PO on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Intervention: Glasdegib Maleate
Outcomes
Primary Outcomes
Number of Participants With a Response
Time Frame: within 3 months of initiation of therapy
Response is: CR + complete response with incomplete recovery of platelets (CRp) + complete response with incomplete recovery of counts (CRi) within 3 months. CR: Bone Marrow blasts \</= 5%, Absolute neutrophil count \>/= 1,000, Platelets \>/= 100 and no extra medullary disease.CRp: Bone Marrow blasts \</= 5%, Absolute neutrophil count \>/= 1,000 and no extra medullary disease. CRi: Bone Marrow blasts \</= 5%
Secondary Outcomes
- Overall Survival(Up to 4 years)