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Recurrent B Acute Lymphoblastic LeukemiaPhase 1NCT02879695

Blinatumomab and Nivolumab With or Without Ipilimumab in Treating Patients With Poor-Risk Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

A Phase 1 study testing Biospecimen Collection, Blinatumomab and Bone Marrow Aspiration and Biopsy in people with Recurrent B Acute Lymphoblastic Leukemia and Recurrent Mixed Phenotype Acute Leukemia, run by National Cancer Institute (NCI) at 7 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record

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Trial summary

This phase I trial studies the side effects and best dose of blinatumomab when given with nivolumab alone or nivolumab and ipilimumab in treating patients with poor-risk CD19+ precursor B-lymphoblastic leukemia that has come back after a period of improvement (relapsed) or has not responded to treatment (refractory). Read more about this study

Who is it for?
Ages 16 years and older
What is being tested?
Biospecimen Collection, Blinatumomab and Bone Marrow Aspiration and Biopsy
Could I receive a placebo?
No, everyone receives an active treatment
How many people
28 participants
Where
7 sitesUnited States
Study dates
25 Oct 2017to 18 Jul 2027
Phase
Phase 1

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 16 years and older
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • PRE-REGISTRATION ELIGIBILITY CRITERIA
  • Patients must have suspected refractory or relapsed pre-B cell ALL or mixed phenotype acute leukemia (MPAL), or if newly diagnosed, the patient must be 60 years of age or older
  • Bone marrow and/or peripheral blood specimens will be submitted for correlative studies; patients who have a dry tap will still be eligible
  • REGISTRATION ELIGIBILITY CRITERIA
  • Patients must have histologically or cytologically confirmed by the local institution CD19+ precursor B-acute lymphoblastic leukemia (pre-B cell ALL) OR CD19+ mixed phenotype acute leukemia (MPAL): a) with relapse following or refractory to at least one prior line of therapy if older than 21 years; b) in second or higher relapse or refractory to at least two prior lines of therapy if 21 years old and younger (16-21); c) or they must have a new diagnosis of pre-B cell ALL or CD19+ MPAL but are >= 60 years old and are either not a candidate for or do not wish to receive traditional induction chemotherapy
  • The evidence of CD19+ expression on leukemia cells must be confirmed by pathology review of the bone marrow and/or peripheral blood specimens (flow cytometry and/or immunohistochemistry) collected at the time of current relapse and prior to the initiation of therapy
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  • Patients with Philadelphia chromosome (Ph) positive (+) pre-B cell ALL OR Ph+ MPAL will be eligible if they have been refractory to or intolerant of treatment with at least 1 second-generation or third-generation tyrosine kinase inhibitor (TKI)
  • Patients who were treated with blinatumomab in the past will be allowed on the study as long as they have persistent CD19 expression on leukemia cells and did not experience unacceptable toxicities with prior blinatumomab administration; patients who were treated with chimeric antigen receptor (CAR)-modified T cells targeting CD19 in the past will be allowed on the study as long as they have persistent CD19 expression on leukemia cells
  • Patients with a history of allogeneic hematopoietic stem cell transplantation (HSCT) will be eligible if they are more than 90 days removed from the date of stem cell infusion, have no evidence of acute graft-versus-host disease (GVHD) or active chronic (grade 2-4) GVHD, and are off of all transplant-related immunosuppression for at least 2 weeks
  • Age >= 16 years. Because no dosing or adverse event data are currently available on the use of blinatumomab in combination with nivolumab ± ipilimumab in pediatric patients, children are excluded from this study, but will be eligible for future pediatric trials.
  • Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status of 0-2 (Karnofsky >= 60%)
  • Life expectancy of greater than 12 weeks
  • Total bilirubin =< 2.0 mg/dL (except patients with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x upper limit of normal (ULN)
  • Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula)
  • The effects of nivolumab, ipilimumab, and blinatumomab on the developing human fetus are unknown; for this reason, women of child-bearing potential (WOCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; WOCBP should use an adequate method to avoid pregnancy for 23 weeks after the last dose of investigational drug; women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of treatment on the study; women must not be breastfeeding; men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year; men receiving nivolumab +/- ipilimumab and blinatumomab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product; women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception
  • Note: Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal; menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes; in addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level less than 40 mIU/mL
  • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she (or the participating partner) should inform the treating physician immediately
  • Adequate pulmonary function as assessed by oxygen saturation >= 90% when ambulating and not requiring supplemental oxygen
  • Patients with a known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) will be eligible if:
  • They are generally healthy from an HIV perspective and on a stable anti-retroviral regimen for > 6 months
  • They have had no AIDS-defining conditions in the past 12 months other than historically low CD4+ cell counts
  • They have an undetectable viral load on standard assays
  • Patients with a known history of hepatitis C (HCV) will be eligible if they have an undetectable viral load; if the patient received treatment for HCV, then that treatment must have been completed at least three weeks prior to enrollment
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Patients who have had chemotherapy or other systemic therapy or radiotherapy, or those who have not recovered from adverse events due to prior administered agents as follows: chemotherapy, radiotherapy or surgery =< 3 weeks prior to entering the study, targeted therapy (e.g., TKI) =< 1 week prior to entering the study; autologous HSCT =< 6 weeks prior to entering the study; investigational drug or immunotherapy (e.g. rituximab) =< 4 weeks prior to entering the study; prophylactic intrathecal chemotherapy within one week of enrollment allowed; patients will be allowed to receive cytoreduction with hydroxyurea, 6-mercaptopurine, corticosteroids (dexamethasone, prednisone or similar) or cyclophosphamide provided that it is discontinued at least 24 hours prior to the initiation of study treatment; pre-phase treatment with dexamethasone 10 mg/m^2 (maximum total 24 mg per day) for up to 5 days is required for patients with bone marrow blasts more than 50%, peripheral blood blasts of 15,000/uL or higher, or elevated lactate dehydrogenase suggesting rapidly progressing disease as per investigator's assessment; pre-phase treatment must be stopped at least 24 hours prior to the initiation of blinatumomab
  • Patients who are receiving any other investigational agents
  • Patients should be excluded if they have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways
  • Patients with active central nervous system leukemia are excluded from this clinical trial because they may develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; patients with a history of central nervous system (CNS) leukemia but no active disease at the time of enrollment are eligible; the absence of CNS disease must be confirmed by flow cytometric and cytologic examination of the cerebrospinal fluid (CSF) within 7 days of study enrollment
  • Active leukemia in the testes or isolated extramedullary relapse; patients with a history of treated leukemia in testes but no active disease at the time of enrollment are eligible
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab, ipilimumab, or blinatumomab
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  • History of severe hypersensitivity reaction to any monoclonal antibody
  • Uncontrolled intercurrent illness including, but not limited to, active, uncontrolled infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements; patients with infection under treatment and controlled with antibiotics are eligible
  • Pregnant women are excluded from this study because nivolumab and ipilimumab have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with nivolumab and ipilimumab, breastfeeding should be discontinued if the mother is treated with nivolumab and ipilimumab; these potential risks may also apply to blinatumomab
  • History of any chronic hepatitis including alcoholic, non-alcoholic steatohepatitis (NASH), drug related, autoimmune, chronic viral positive tests for hepatitis B virus surface antigen (HBsAg), hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antibody (anti-HBs), or a positive hepatitis C (HCV) viral load; these patients are excluded due to the risk for autoimmune hepatitis with immune checkpoint inhibitors exacerbating their known liver disease as well as the unknown risk for hepatitis B and/or C reactivation with blinatumomab and immune checkpoint inhibitors
  • Subjects with active autoimmune disease, a history of known or suspected autoimmune disease or a history of a syndrome requiring systemic corticosteroids (> 10 mg daily of prednisone equivalent) except for the treatment of malignancy with the exception of:
  • Isolated vitiligo
  • Resolved childhood atopy
  • History of a positive antinuclear antibody (ANA) titer without associated symptoms or history of symptoms of an autoimmune disorder
  • Controlled thyroid disorders
  • Type I diabetes mellitus
  • Psoriasis, Sjogren's syndrome, and arthropathies not requiring systemic treatment
  • Autoimmune diseases: these include but are not limited to patients with a history of immune related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), connective tissue diseases, scleroderma, autoimmune vasculitis, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
  • Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids and adrenal replacement doses =< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease; patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen), or as pre-phase treatment for cytoreduction; patients will receive steroids with blinatumomab to reduce cytokine release syndrome (CRS) as specified in the protocol
  • Patients who have had evidence of active or acute diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction and abdominal carcinomatosis which are known risk factors for bowel perforation should be evaluated for the potential need for additional treatment before coming on study
  • Patients who have a history of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, psychosis, or other significant CNS abnormalities; a history of treated CNS leukemia will be allowed if recent CNS studies confirm the absence of active CNS disease at the time of study entry (screening)
  • Patients with a known concurrent malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or carcinoma in situ of the cervix
  • Subjects with interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity

Trial locations and contacts

7 sites in 1 country.

7 sites in 1 country

United States7 sites

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

  • Yale University

    New Haven, Connecticut, 06520

  • UPMC Hillman Cancer Center

    Pittsburgh, Pennsylvania, 15232

  • Huntsman Cancer Institute/University of Utah

    Salt Lake City, Utah, 84112

Other trials in United States

About this study

Official title: A Phase 1 Study of Blinatumomab in Combination With Checkpoint Inhibitor(s) of PD-1 (Nivolumab) or Both PD-1 (Nivolumab) and CTLA-4 (Ipilimumab) in Patients With Poor-Risk, Relapsed or Refractory CD19+ Precursor B-Lymphoblastic Leukemia

This phase I trial studies the side effects and best dose of blinatumomab when given with nivolumab alone or nivolumab and ipilimumab in treating patients with poor-risk CD19+ precursor B-lymphoblastic leukemia that has come back after a period of improvement (relapsed) or has not responded to treatment (refractory). Immunotherapy with monoclonal antibodies, such as blinatumomab, nivolumab, and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To evaluate the safety and tolerability of the blinatumomab given in combination with nivolumab alone, or in combination with both nivolumab and ipilimumab in subjects with poor-risk, relapsed or refractory CD19+ pre-B cell acute lymphoblastic leukemia (ALL) or CD19+ mixed phenotype acute leukemia (MPAL).

II. To determine the maximum tolerated dose (MTD) of the combination of blinatumomab plus nivolumab, and blinatumomab plus both nivolumab and ipilimumab and to further confirm the safety of the combination therapy in subjects with poor-risk, relapsed or refractory CD19+ pre-B cell ALL or CD19+ mixed phenotype acute leukemia (MPAL).

SECONDARY OBJECTIVES:

  1. To observe and record anti-leukemia activity of blinatumomab and nivolumab, and blinatumomab plus both nivolumab and ipilimumab, including the effects on minimal residual disease (MRD).

II. To assess preliminary anti-leukemia activity in expansion cohorts of patients with poor-risk, relapsed or refractory CD19+ precursor B-lymphoblastic leukemia, or CD19+ mixed phenotype acute leukemia (MPAL).

EXPLORATORY OBJECTIVES:

  1. To examine changes in absolute lymphocyte count and distribution of T cell subsets (CD4+, CD8+, regulatory T cells [Tregs], effector T cells [Teffs]) and their differentiation status, natural killer (NK) cells, and B cells before and post-blinatumomab, and immune checkpoint inhibitor(s) therapy in both peripheral blood and the bone marrow microenvironment.

II. To explore changes in T cell co-signaling receptors expression in defined T cell subpopulations and their canonic transcription factor expression in both peripheral blood and bone marrow before and post-blinatumomab, and immune checkpoint inhibitor(s) therapy.

III. To examine changes in expression of co-signaling molecules on leukemia blasts (CD10+/CD19+/CD34+) before and after treatment with blinatumomab and checkpoint inhibitors.

IV. To examine the serum levels of cytokines before and after treatment with blinatumomab and checkpoint inhibitors, including the levels of sCTLA-4.

  1. To perform immune profiling of T cell repertoire and characterize T cell transcriptional signature before and after treatment.

OUTLINE: This is a safety and tolerability study of blinatumomab given in combination with nivolumab alone, or in combination with both nivolumab and ipilimumab.

Patients receive blinatumomab intravenously (IV) continuously on days 1-28. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then every 6 weeks for up to 1 year. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 3 months for up to 2 years.

Being tested
Biospecimen Collection, Blinatumomab, Bone Marrow Aspiration and Biopsy, Ipilimumab, Nivolumab
Medical subject headings
Burkitt Lymphoma, Leukemia, Biphenotypic, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biospecimen CollectionProcedure or surgery

    Also called Biological Sample Collection, Biospecimen Collected, Sample Collection, Specimen Collection

    Undergo blood sample collection

  • BlinatumomabBiological

    Also called AMG 103, AMG-103, AMG103, Anti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody

    Given IV

  • Bone Marrow Aspiration and BiopsyProcedure or surgery

    Undergo bone marrow aspiration and biopsy

  • IpilimumabBiological

    Also called Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS 734016, BMS-734016, BMS734016

    Given IV

  • NivolumabBiological

    Also called ABP 206, BCD-263, BMS 936558, BMS-936558

    Given IV

Study groups in NCT02879695
Study groupRoleWhat they receive
Treatment (blinatumomab, nivolumab, ipilimumab)ExperimentalPatients receive blinatumomab IV continuously on days 1-28. Treatment repeats every 42 days for up to 5 cycles in the absence of disease progression or unacceptable toxicity. Patients also receive nivolumab IV over 30 minutes on day 11 and then every 2 weeks for up to year. Some patients also receive ipilimumab IV over 90 minutes on day 11 and then every 6 weeks for up to 1 year. Patients also undergo bone marrow aspiration and biopsy and blood sample collection throughout the study.
Receives: Procedure: Biospecimen Collection; Biological: Blinatumomab; Procedure: Bone Marrow Aspiration and Biopsy; Biological: Ipilimumab; Biological: Nivolumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants Experiencing Grade 3, 4, or 5 Adverse Events

    Defined by Common Terminology Criteria for Adverse Events, version 5.0. The highest grade experienced by the participant will be reported.

    Measured: Up to 5.5 years

  2. Number of Participants With Dose Limiting Toxicities

    Maximum tolerated dose was determined by the absence of dose limiting toxicity in each patient assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Dose Limiting Toxicities were evaluated during treatment; therefore, the time frame is from the first participant starting treatment to the last participant completing treatment.

    Measured: Up to 5.5 years

Secondary outcomes (4)

  1. Count of Participants Responders With Minimal Residual Disease

    Will be assessed by flow cytometry. Participants who have a clinical response (responders) were evaluated for minimal residual disease negative versus minimal residual disease positive. These are the participants with remission as provided in the Secondary Outcome #4.

    Measured: Up to 5.5 years

  2. Number of Participants Achieving Remission

    Remission includes participants achieving complete remission or complete remission with incomplete blood count recovery by standard leukemia outcome measures.

    Measured: Up to 5.5 years

  3. Duration of Response

    Will be analyzed using the Kaplan Meier method. A sensitivity analysis may be performed to evaluate duration of response while excluding patients who go on to have an allogeneic-hematopoietic stem cell transplantation. Time from measured response to progressive disease, death, or study end, assessed up to 2 years after treatment

    Measured: Up to 5.5 years

  4. Overall Survival

    Determined from the first day of treatment on the study until death or last known follow up, assessed up to 2 years after completing treatment.

    Measured: Up to 5.5 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Aug 2016 (estimated)
  2. Study start25 Oct 2017
  3. Primary completion22 May 2023
  4. Study completion18 Jul 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
28 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02879695
Sponsor's protocol ID
NCI-2016-01300
Other IDs
NCI-2016-01300, ETCTN10030, 10030, 10030, UM1CA186691
Status last verified
Aug 2026
First submitted
23 Aug 2016
Last updated
20 Aug 2026
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Shi Z, Zhu Y, Zhang J, Chen B. Monoclonal antibodies: new chance in the management of B-cell acute lymphoblastic leukemia. Hematology. 2022 Dec;27(1):642-652. doi: 10.1080/16078454.2022.2074704.

    PubMed 35622074

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