Clinical Trials /

Nivolumab in Combination With 5-azacytidine in Childhood Relapsed/Refractory AML

NCT03825367

Description:

This is a phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric patients with relapsed/refractory acute myeloid leukemia

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab in Combination With 5-azacytidine in Childhood Relapsed/Refractory AML
  • Official Title: A Phase I/II Study of Nivolumab in Combination With 5-azacytidine in Pediatric Patients With Relapsed/Refractory Acute Myeloid Leukemia (BMS Reference CA209-9JY)

Clinical Trial IDs

  • ORG STUDY ID: T2016-002
  • NCT ID: NCT03825367

Conditions

  • AML, Childhood

Interventions

DrugSynonymsArms
NivolumabOpen label design
5-azacytidineOpen label design

Purpose

This is a phase I/II Study of Nivolumab in Combination with 5-azacytidine in pediatric patients with relapsed/refractory acute myeloid leukemia

Detailed Description

      This proposed study will be the first to test nivolumab in combination with AZA in pediatric
      patients with hematologic malignancies. Patients will receive the first dose of nivolumab on
      day 1 along with AZA. After "chemotherapy priming", a second dose of nivolumab will be given
      at day 15 which will enhance the effect of nivolumab on the regenerating CD4+ and CD8+ memory
      T cells.

      To establish a recommended Phase II dose (RP2D)of nivolumab in combination with 5-azacytidine
      in children with relapsed or refractory AML. To assess the clinical activity of Nivolumab in
      combination with 5-azacytidine in AML patients with M2/M3 disease at study entry.
    

Trial Arms

NameTypeDescriptionInterventions
Open label designOtherNivolumab and 5-azacytidine,
  • Nivolumab
  • 5-azacytidine

Eligibility Criteria

        Inclusion Criteria:

        Age Patients must be ≥ 1 and ≤30 years of age.

        Diagnosis

          1. Relapsed or refractory AML with ≥5% blasts (by morphology) in the bone marrow.

               -  1st or greater relapse, OR

               -  Failed to go into remission (i.e. refractory) after first or greater relapse, OR

               -  Failed to go into remission from original diagnosis after two or more induction
                  attempts.

          2. Relapsed or refractory AML with ≤ 5% blasts (by morphology) and MRD positive disease
             (M1/MRD+): Two serial marrows demonstrating stable or rising MRD ≥ 0.1 % (i.e. not
             declining). MRD will be determined by multiparameter flow cytometry using
             AML-associated phenotype markers, or real-time quantitative PCR for AML-associated
             genetic lesions

          3. Patients may have CNS 1 or 2 or other sites of extramedullary disease. No cranial
             irradiation is allowed during the protocol therapy.

          4. Patients with secondary AML are eligible.

          5. Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
             excluded.

          6. Patients with Down Syndrome will be eligible and will be included as an observation
             cohort

        Performance Level Karnofsky > 50% for patients > 16 years of age and Lansky > 50% for
        patients ≤ 16 years of age.

        Prior Therapy Patients must have fully recovered from the acute toxic effects of all prior
        chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

        A. Myelosuppressive chemotherapy

          1. Prior chemotherapy Patients must have fully recovered from the acute toxic effects of
             all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
             At least 14 days must have elapsed since the completion of the cytotoxic therapy,
             except Intrathecal chemotherapy.

          2. Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 24
             hours prior to the start of day 1 nivolumab and azacytidine. It is recommended to use
             hydroxyurea in patients with significant leukocytosis (WBC > 50,000/L) to control
             blast count before initiation of systemic protocol therapy.

        B. Hematopoietic stem cell transplant: Patients who have experienced their relapse after a
        HSCT are eligible provided they have no evidence of active GVHD, no past history of grade 3
        or greater GVHD, and are at least 100 days post-transplant at the time of enrollment.
        Patients should be off immune suppression for at least 2 weeks (excluding physiologic
        replacement steroids).

        C. Hematopoietic growth factors: It must have been at least 7 days since the completion of
        therapy with GCSF or other growth factors at the time of enrollment. It must have been at
        least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).

        D. Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic
        agent. For agents that have known adverse events occurring beyond 7 days after
        administration, this period must be extended beyond the time during which adverse events
        are known to occur. The duration of this interval must be discussed with the study chair

        E. Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the
        last dose of monoclonal antibody. (i.e. Gemtuzumab = 36 days)

        F. Immunotherapy: At least 42 days after the completion of any type of immunotherapy, e.g.
        tumor vaccines or CAR T-cells.

        G. XRT: XRT is prohibited during protocol therapy. No washout period is necessary for
        radiation given to non-CNS chloromas; ≥ 90 days must have elapsed if prior TBI or
        craniospinal XRT.

        Renal and hepatic function

        Patients must have adequate renal and hepatic functions as indicated by the following
        laboratory values:

        A. Adequate renal function defined as: Patient must have a calculated creatinine clearance
        or radioisotope GFR ≥ 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender in
        the chart below:

        B. Adequate Liver Function Defined as: Direct bilirubin < 1.5 x upper limit of normal (ULN)
        for age or normal, AND alanine transaminase (ALT) < 5 x ULN for age. The hepatic
        requirements are waived for patients with known or suspected liver involvement by leukemia.
        This must be reviewed by and approved by the study chair or vice chair.

        Adequate Cardiac Function Defined as: Shortening fraction of ≥ 27% OR ejection fraction of
        ≥ 50%.

        Reproductive Function A. Female patients of childbearing potential must have a negative
        urine or serum pregnancy test confirmed within 24 hours prior to first dose.

        B. Female patients with infants must agree not to breastfeed their infants while on this
        study.

        C. Male and female patients of child-bearing potential must agree to use an effective
        method of contraception approved by the investigator during the study and for a minimum of
        7 months after study treatment. Women of childbearing potential (WOCBP) receiving nivolumab
        will be instructed to adhere to contraception for a period of 5 months after the last dose
        of nivolumab. Men receiving nivolumab and who are sexually active with WOCBP will be
        instructed to adhere to contraception for a period of 7 months after the last dose of
        nivolumab.

        Informed Consent Patients and/or their parents or legal guardians must be capable of
        understanding the investigational nature, potential risks and benefits of the study. All
        patients and/or their parents or legal guardians must sign a written informed consent. Age
        appropriate assent will be obtained per institutional guidelines. To allow non-English
        speaking patients to participate in this study, bilingual health services will be provided
        in the appropriate language when feasible.

        Protocol Approval All institutional, FDA, and OHRP requirements for human studies must be
        met.

        Exclusion Criteria:

        Patients will be excluded if they have a known allergy or hypersensitivity to nivolumab or
        AZA used in the study.

        Patients will be excluded if they have a systemic fungal, bacterial, viral or other
        infection that is exhibiting ongoing signs/symptoms related to the infection without
        improvement despite appropriate antibiotics or other treatment. The patient needs to be off
        pressors and have negative blood cultures for 48 hours.

        Patients will be excluded if there is a plan to administer non-protocol chemotherapy,
        radiation therapy, or immunotherapy during the study period.

        Patients will be excluded if they have significant concurrent disease, illness, psychiatric
        disorder or social issue that would compromise patient safety or compliance with the
        protocol treatment or procedures, interfere with consent, study participation, follow up,
        or interpretation of study results.

        Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are
        excluded.

        Patients with a known history of severe interstitial lung disease or severe pneumonitis or
        active pneumonitis that is uncontrolled in the opinion of the treating physician.

        Patients who have previously been treated with nivolumab will be excluded.

        Patients with a known history of any of the following autoimmune diseases are excluded: (a)
        patients with a history of inflammatory bowel disease (including Crohn's disease and
        ulcerative colitis) (b) patients with a history of rheumatoid arthritis, systemic
        progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis
        [e.g., Wegener's Granulomatosis]).

        Patients with organ allografts (such as renal transplant) are excluded.

        Patients with known Human Immunodeficiency Virus seropositivity will be excluded.

        Known to be positive for hepatitis B by surface antigen expression. Known to have active
        hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for
        hepatitis C within the last 6 months).

        Pregnant or breastfeeding.

        Acute promyelocytic leukemia (APL).

        CNS 3 disease.

        Patients who have experienced their relapse after a HSCT and are less than 100 days
        post-transplant at the time of enrollment, have active GVHD at time of enrollment, have
        past history of grade 3 or greater GVHD, Patients on immune suppression (excluding
        physiologic replacement steroids).
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:1 Year
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose Toxicity
Time Frame:4 weeks
Safety Issue:
Description:Occurrence of dose limiting toxicity (DLT) during Cycle 1 of therapy (Phase I)

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Therapeutic Advances in Childhood Leukemia Consortium

Trial Keywords

  • Relapse
  • Refractory
  • Leukemia
  • Acute
  • Pediatric
  • nivolumab
  • azacytidine

Last Updated

May 21, 2019