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

• ClinicalTrials.gov Identifier: NCT03825367
• Recruitment Status: Active, not recruiting
• First Posted: January 31, 2019
• Last Update Posted: October 12, 2022
• Sponsor: Therapeutic Advances in Childhood Leukemia Consortium
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Therapeutic Advances in Childhood Leukemia Consortium

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
AML, Childhood	Drug: Nivolumab; Drug: 5-azacytidine	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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)
• Actual Study Start Date: November 29, 2019
• Estimated Primary Completion Date: May 31, 2023
• Estimated Study Completion Date: March 30, 2024

Arms and Interventions

Arm	Intervention/treatment
Open label design; Nivolumab and 5-azacytidine,	Drug: Nivolumab; The dose of Nivolumab will be 3 mg/kg which is the adult recommended dose and is the recommended dose in children in the phase 2 portion of COG ADVL1412. If 3 mg/kg is not tolerated in combination with 5-azacytidine, the dose will be stepped down to 1 mg/kg.; Drug: 5-azacytidine; 75mg/m2 subcutaneously will be given daily for 7 days on days 1 to 7.

Outcome Measures

Primary Outcome Measures :

1. Dose Toxicity [ Time Frame: 4 weeks ]
   Occurrence of dose limiting toxicity (DLT) during Cycle 1 of therapy (Phase I)
2. Remission [ Time Frame: 4 weeks ]
   Achievement of complete remission (CR/CRp/CRi) at the end of cycle 1

Eligibility Criteria

• Ages Eligible for Study: 1 Year to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

United States, California

Children's Hospital of Los Angeles

Los Angeles, California, United States, 90027

United States, Georgia

Children's Healthcare of Atlanta

Atlanta, Georgia, United States, 30322

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21287

United States, New York

Columbia University Medical Center

New York, New York, United States, 10032

United States, North Carolina

Levine Cancer Institute

Charlotte, North Carolina, United States, 28204

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Tennessee

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

Children's Health

Dallas, Texas, United States, 75235

Cook Children's Medical Center

Fort Worth, Texas, United States, 76104

Texas Children's Hospital/Baylor College of Medicine

Houston, Texas, United States, 77030

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84108

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98101

Sponsors and Collaborators

Therapeutic Advances in Childhood Leukemia Consortium

Bristol-Myers Squibb

More Information

• Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
• ClinicalTrials.gov Identifier: NCT03825367
• Other Study ID Numbers: T2016-002
• First Posted: January 31, 2019
• Last Update Posted: October 12, 2022
• Last Verified: October 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:

Relapse; Refractory; Leukemia; Acute; Pediatric; nivolumab; azacytidine

Additional relevant MeSH terms:

Nivolumab; Azacitidine; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Enzyme Inhibitors