Clinical Trials /

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

NCT02879695

Description:

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 or has not responded to treatment. 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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
  • Mixed Phenotype Acute Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01300
  • SECONDARY ID: NCI-2016-01300
  • SECONDARY ID: ETCTN10030
  • SECONDARY ID: 10030
  • SECONDARY ID: 10030
  • SECONDARY ID: UM1CA186691
  • NCT ID: NCT02879695

Conditions

  • Allogeneic Hematopoietic Stem Cell Transplant Recipient
  • B Acute Lymphoblastic Leukemia
  • B Acute Lymphoblastic Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
  • CD19-Positive Neoplastic Cells Present
  • Mixed Phenotype Acute Leukemia With t(9;22)(q34.1;q11.2); BCR-ABL1
  • Recurrent B Acute Lymphoblastic Leukemia
  • Recurrent Mixed Phenotype Acute Leukemia
  • Refractory B Acute Lymphoblastic Leukemia
  • Refractory Mixed Phenotype Acute Leukemia

Interventions

DrugSynonymsArms
BlinatumomabAnti-CD19 x Anti-CD3 Bispecific Monoclonal Antibody, Anti-CD19/Anti-CD3 Recombinant Bispecific Monoclonal Antibody MT103, Blincyto, MEDI-538, MT-103Treatment (blinatumomab, nivolumab, ipilimumab)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyTreatment (blinatumomab, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (blinatumomab, nivolumab, ipilimumab)

Purpose

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 or has not responded to treatment. 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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. 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:

      I. 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 an expansion cohort of patients with
      poor-risk, relapsed or refractory CD19+ precursor B-lymphoblastic leukemia, or CD19+ mixed
      phenotype acute leukemia (MPAL).

      EXPLORATORY OBJECTIVES:

      I. 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.

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

      OUTLINE: This is a dose-escalation study of blinatumomab.

      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 60 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.

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

Trial Arms

NameTypeDescriptionInterventions
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 60 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.
  • Blinatumomab
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  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

          -  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

        Exclusion Criteria:

          -  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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:16 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years
Safety Issue:
Description:Incidence of adverse events will be graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. All adverse events and toxicities will be tabulated and reported by type and grade for all dose levels of all treatment combinations and the proportions reported with exact 95% binomial confidence intervals.

Secondary Outcome Measures

Measure:Minimal residual disease
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by flow cytometry. For patients who have a clinical response, the frequency of minimal residual disease positive versus minimal residual disease negative responses will be reported by treatment arm and dose level for all patients on study.
Measure:Anti-leukemia activity
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Complete remission
Time Frame:Up to 2 years
Safety Issue:
Description:The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.
Measure:Complete remission with incomplete blood count recovery
Time Frame:Up to 2 years
Safety Issue:
Description:The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.
Measure:Progressive disease
Time Frame:Up to 2 years
Safety Issue:
Description:The frequency distribution of responses, including complete remission, complete remission with incomplete blood count recovery or progressive disease will be reported by treatment arm and dose level for all patients on study and reported with exact 95% confidence intervals.
Measure:Duration of response
Time Frame:Time from measured response to progressive disease, death, or study end, assessed up to 2 years
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:From the first day of treatment on the study until death or last known follow up, assessed up to 2 years
Safety Issue:
Description:Will be measured using the Kaplan Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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