Clinical Trials /

OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT03390296

Description:

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.

Related Conditions:
  • Acute Myeloid Leukemia
  • Acute Myeloid Leukemia Arising from Previous Myelodysplastic Syndrome
  • Secondary Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: OX40, Venetoclax, Avelumab, Glasdegib, Gemtuzumab Ozogamicin, and Azacitidine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 2017-0337
  • SECONDARY ID: NCI-2018-00972
  • SECONDARY ID: 2017-0337
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT03390296

Conditions

  • Recurrent Acute Myeloid Leukemia
  • Refractory Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
Anti-OX40 Agonist Monoclonal Antibody PF-04518600PF-04518600, PF04518600Arm A (anti-OX40 antibody PF-04518600)
AvelumabBavencio, MSB-0010718C, MSB0010718CArm C (azacitidine, GO, avelumab)
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, VidazaArm B (azacitidine, venetoclax, GO)
Gemtuzumab OzogamicinCalicheamicin-Conjugated Humanized Anti-CD33 Monoclonal Antibody, CDP-771, CMA-676, gemtuzumab, hP67.6-Calicheamicin, Mylotarg, WAY-CMA-676Arm B (azacitidine, venetoclax, GO)
GlasdegibPF 04449913, PF-04449913, PF04449913Arm F (GO, glasdegib)
Glasdegib MaleateDaurismo, PF 04449913 MaleateArm F (GO, glasdegib)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoArm B (azacitidine, venetoclax, GO)
Azacitidine5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496Arm C (azacitidine, GO, avelumab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (anti-OX40 antibody PF-04518600)ExperimentalPatients 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.
  • Anti-OX40 Agonist Monoclonal Antibody PF-04518600
Arm B (azacitidine, venetoclax, GO)ExperimentalPatients 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.
  • Azacitidine
  • Gemtuzumab Ozogamicin
  • Venetoclax
Arm C (azacitidine, GO, avelumab)ExperimentalPatients 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.
  • Avelumab
  • Gemtuzumab Ozogamicin
  • Azacitidine
Arm D (azacitidine, venetoclax, avelumab)ExperimentalPatients 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.
  • Avelumab
  • Azacitidine
  • Venetoclax
Arm E (azacitidine, avelumab, anti-OX40 antibody PF-04518600)ExperimentalPatients 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.
  • Anti-OX40 Agonist Monoclonal Antibody PF-04518600
  • Avelumab
  • Azacitidine
Arm F (GO, glasdegib)ExperimentalPatients 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.
  • Gemtuzumab Ozogamicin
  • Glasdegib
  • Glasdegib Maleate

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 =< 2.

          -  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.

          -  Women of childbearing potential must agree to use an adequate method of contraception
             during the study and until 3 months after the last treatment. Males must be surgically
             or biologically sterile or agree to use an adequate method of contraception during the
             study until 3 months after the last treatment. Adequate methods of contraception
             include:

               -  Total abstinence when this is in line with the preferred and usual lifestyle of
                  the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
                  post-ovulation methods) and withdrawal are not acceptable methods of
                  contraception.

               -  Female sterilization (have had surgical bilateral oophorectomy with or without
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment.
                  In case of oophorectomy alone, only when the reproductive status of the woman has
                  been confirmed by follow up hormone level assessment.

               -  Male sterilization (at least 6 months prior to screening). For female patients on
                  the study, the vasectomized male partner should be the sole partner for that
                  patient.

               -  Combination of any of the two following:

                    -  Use of oral, injected or implanted hormonal methods of contraception or
                       other forms of hormonal contraception that have comparable efficacy (failure
                       rate < 1%), for example hormone vaginal ring or transdermal hormone
                       contraception.

                    -  Placement of an intrauterine device (IUD) or intrauterine system (IUS).

                    -  Barrier methods of contraception: condom or occlusive cap (diaphragm or
                       cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal
                       suppository in case of use of oral contraception, women should have been
                       stable on the same pill before taking study treatment.

               -  Note: Oral contraceptives are allowed but should be used in conjunction with a
                  barrier method of contraception due to unknown effect of drug-drug interaction.
                  Women are considered post-menopausal and not of child bearing potential if they
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have
                  had surgical bilateral oophorectomy (with or without hysterectomy) or tubal
                  ligation at least six weeks ago. In the case of oophorectomy alone, only when the
                  reproductive status of the woman has been confirmed by follow up hormone level
                  assessment is she considered not of child bearing potential.

        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).

          -  Prior organ transplantation including allogenic stem-cell transplantation within 3
             months prior to planned enrollment.

          -  Patients with symptomatic CNS leukemia or patients with poorly controlled CNS
             leukemia.

          -  Active and uncontrolled disease (active infection requiring systemic therapy, fever
             likely secondary to infection within prior 48 hours, uncontrolled hypertension despite
             adequate medical therapy as judged by the treating physician.

          -  Known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome.

          -  Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at
             screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test
             positive.

          -  Vaccination within 4 weeks of the first dose of avelumab and while on trials is
             prohibited except for administration of inactivated vaccines.

          -  Other severe acute or chronic medical conditions that is active and not well
             controlled including colitis, inflammatory bowel disease, or psychiatric conditions
             including recent (within the past year) or active suicidal ideation or behavior; or
             laboratory abnormalities that may increase the risk associated with study
             participation or study treatment administration or may interfere with the
             interpretation of study results and, in the judgment of the investigator, would make
             the patient inappropriate for entry into this study.

          -  Patients unwilling or unable to comply with the protocol.

          -  Pregnant or breastfeeding.

          -  Known alcohol or drug abuse within the last 1 year.

          -  Acute promyelocytic leukemia (APL).

          -  Cardiac exclusions specific to glasdegib and OX40 containing arms: Any one of the
             following ongoing or in the previous 6 months: congenital long QT syndrome, torsades
             de pointes or any clinically significant ventricular fibrillation, sustained
             ventricular tachyarrhythmia requiring medical intervention, right bundle branch block
             + left anterior hemiblock (i.e. bifascicular block): isolated RBBB without a
             bifascicular block will not be an exclusion criterion; complete left bundle branch
             block, unstable angina or myocardial infarction, coronary/peripheral artery bypass
             graft, cerebrovascular accident (CVA), transient ischemic attack or symptomatic
             pulmonary emboli, as well as bradycardia defined as < 50 bpms on screening or day 1
             electrocardiography (EKG). Known history of second or third degree heart block (may be
             eligible if the patient currently has a pacemaker). Active cardiac dysrhythmias of NCI
             CTCAE grade >= 2 (eg, atrial fibrillation) or corrected QT interval by Fridericia's
             correction formula (QTcF) interval > 470 msec within 4 weeks prior to starting the
             study drug
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (Arms A-F)
Time Frame:Up to 5 years
Safety Issue:
Description:The method of Thall, Simon and Estey (1995) will be used to monitor efficacy and safety.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

March 19, 2020