Clinical Trials /

Phase I Study to Assess the Tolerability and Efficacy of Nivolumab in Patients With Hematologic Malignancies

NCT02985554

Description:

This is an open-label, dose escalation Phase I study to evaluate the tolerability and efficacy of single agent of Nivolumab as maintenance treatment to prevent relapse in patients with hematologic malignancies after allogeneic stem cell transplantation. Approximately 29 patients will be enrolled, where about 6-12 patients will be included on the dose escalation phase and 20 patients will be on the expansion cohort at maximal tolerated dose.

Related Conditions:
  • Hematopoietic and Lymphoid Malignancy
Recruiting Status:

Terminated

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Phase I Study to Assess the Tolerability and Efficacy of Nivolumab in Patients With Hematologic Malignancies
  • Official Title: Phase I Study to Assess the Tolerability and Efficacy of Nivolumab as Single Agent to Eliminate Minimal Residual Disease and Maintain Remission in Patients With Hematologic Malignancies After Allogeneic Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: IRB16-0888
  • NCT ID: NCT02985554

Conditions

  • Hematologic Malignancies

Interventions

DrugSynonymsArms
NivolumabOpdivoNivolumab

Purpose

This is an open-label, dose escalation Phase I study to evaluate the tolerability and efficacy of single agent of Nivolumab as maintenance treatment to prevent relapse in patients with hematologic malignancies after allogeneic stem cell transplantation. Approximately 29 patients will be enrolled, where about 6-12 patients will be included on the dose escalation phase and 20 patients will be on the expansion cohort at maximal tolerated dose.

Detailed Description

      Nivolumab will be administrated intravenously. Standard dose escalation will be used for the
      intensification phase with starting dose at 1m/kg every 2 weeks for 4 doses. The DLT
      observation period is 29 days starting with the first dose taken on Day 1, The study
      treatment will continue until one of the discontinuation criteria is met. Each dose level
      (1-2) will be tested using the 3+3 design. If level 2 of 3mg/kg is reached without DLTs,
      3mg/kg will be used for the dose expansion cohort. After the intensification phase, patients
      will start Nivolumab every 12 weeks maintenance phase till 2 years post allo-SCT. Patients
      will also receive best supportive care (BSC), including blood product transfusions,
      antimicrobials, and (as appropriate) granulocyte colony stimulating factors for neutropenic
      infection or poor graft function.
    

Trial Arms

NameTypeDescriptionInterventions
NivolumabExperimentalNivolumab will be administrated intravenously. Standard dose escalation will be used for the intensification phase with starting dose at 1m/kg every 2 weeks for 4 doses.
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with hematologic malignancies status post allogeneic SCT without evidence of
             disease relapse, active GVHD or history of more than Stage I skin acute GVHD; and off
             immunosuppression for at least 4 weeks. At least 60 days after allo-SCT.

          -  Patients with high risk myeloid or lymphoid malignancies at stem cell transplant
             following ASBMT criteria
             (http://www.asbmt.org/displaycommon.cfm?an=1&subarticlenbr=35, under disease
             classification), including but not limited to conditions listed. Refractory acute
             myelogenous or lymphoid leukemia Relapsed acute myelogenous or lymphoid leukemia
             Myelodysplastic syndromes with 5% or more blasts Chronic myelogenous leukemia in
             chronic phase 3 or more, blast phase presently, or second accelerated phase, Recurrent
             or refractory malignant lymphoma or Hodgkin's disease with less than a partial
             response at transplant High risk chronic lymphocytic leukemia defined as no response
             or stable disease to the most recent treatment regimen.

          -  Age ≥18 years. Because no dosing or adverse event data are currently available on the
             use of nivolumab in patients <18 years of age, children are excluded from this study,
             but will be eligible for future pediatric trials.

          -  ECOG/Karnofsky performance status of 0 or 1 (Karnofsky ≥70%, see Appendix A).

          -  Screening laboratory values must meet the following criteria and should be obtained
             within 14 days prior to treatment.

          -  leukocytes ≥2000/mcL

          -  absolute neutrophil count ≥1,000/mcL(In the absence of growth factor support)

          -  platelets ≥50,000/mcL or recovery to the baseline count(in the absence of
             transfusion)Hgb >9.0g/dL

          -  total bilirubin ≤1.5× institutional upper limit of normal (ULN) (except patients with
             Gilbert Syndrome, who can have total bilirubin <3.0 mg/dL)

          -  AST(SGOT)/ALT(SGPT) ≤3 × ULN 17

          -  Serum creatinine ≤1.5× ULN OR

          -  creatinine clearance (CrCl) ≥40 mL/min (if using the Cockcroft-Gault formula below):
             Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum creatinine in
             mg/dL Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine in
             mg/dL

          -  The effects of nivolumab 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
             Nivolumab. Women of childbearing potential must have a negative serum or urine
             pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24
             hours prior to the start of nivolumab. 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 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. 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. WOCBP receiving nivolumab will be instructed
             to adhere to contraception for a period of 23 weeks (30 days plus the time required
             for nivolumab to undergo five half-lives) after the last dose of investigational
             product. Men receiving nivolumab 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. These durations have been calculated using the upper limit of
             the half-life for nivolumab (25 days) and are based on the protocol requirement that
             WOCBP use contraception for 5 half-lives plus 30 days and men who are sexually active
             with WOCBP use contraception for 5 half-lives plus 90 days. 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. 18

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  History of allergy to study drug components.

          -  Patients who have disease relapse, active GVHD or history of more than Stage 1 skin
             acute GVHD, history of cGVHD.

          -  Patients with active infection, un-resolving more than grade 2 transplant-related
             toxicities.

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
             nitrosoureas or mitomycin C) prior to entering the study or those who have not
             recovered from adverse events (AEs) due to agents administered more than 4 weeks
             earlier.

          -  Patients who are receiving any other investigational agents.

          -  Patients with known CNS involvement may be excluded because of poor prognosis and
             concerns regarding progressive neurologic dysfunction that would confound the
             evaluation of neurologic and other adverse events. However, if CNS disease is cleared
             before the treatment with Nivolumab, patients could be allowed if no permanent CNS
             damage.

          -  History of severe hypersensitivity reaction to any monoclonal antibody.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Pregnant women are excluded from this study because Nivolumab is an agent with 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, breastfeeding should be discontinued if the mother is treated
             with Nivolumab.

          -  Patients with known history of testing positive for human immunodeficiency virus (HIV)
             or known acquired immunodeficiency syndrome (AIDS) might be enrolled if the viral load
             by PCR is undetectable with/without active treatment and absolute lymphocyte count >=
             350/ul. Patients with a positive test for hepatitis B virus surface antigen (HBV sAg)
             or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic
             infection might be enrolled if the viral load by PCR is undetectable with/without
             active treatment.

          -  Patients with active autoimmune disease or history of autoimmune disease that might
             recur, which may affect vital organ function or require immune suppressive treatment
             including systemic corticosteroids, should be excluded. 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 SLE, connective tissue diseases,
             scleroderma, 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 with vitiligo, endocrine deficiencies
             including thyroiditis managed with replacement hormones including physiologic
             corticosteroids are eligible. Patients with rheumatoid arthritis and other
             arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and
             patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
             antibodies should be evaluated for the presence of target organ involvement and
             potential need for systemic treatment but should otherwise be eligible.

          -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
             residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger (precipitating event).

          -  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, intraarticular, 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) is permitted.

          -  Patients who have had evidence of active or acute diverticulitis, intra-abdominal
             abscess, 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.eligible. Patients with rheumatoid arthritis and other
             arthropathies, Sjögren's syndrome and psoriasis controlled with topical medication and
             patients with positive serology, such as antinuclear antibodies (ANA), anti-thyroid
             antibodies should be evaluated for the presence of target organ involvement and
             potential need for systemic treatment but should otherwise be eligible.

          -  Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus,
             residual hypothyroidism due to autoimmune condition only requiring hormone
             replacement, psoriasis not requiring systemic treatment, or conditions not expected to
             recur in the absence of an external trigger (precipitating event).

          -  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, intraarticular, 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) is permitted.

          -  Patients who have had evidence of active or acute diverticulitis, intra-abdominal
             abscess, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of Nivolumab
Time Frame:24 months
Safety Issue:
Description:The maximum tolerated dose (MTD) of Nivolumab in patients with hematologic malignancies after allo-SCT.

Secondary Outcome Measures

Measure:Number of type of adverse events
Time Frame:24 months
Safety Issue:
Description:To evaluate the toxicities of Nivolumab as maintenance treatment after allogeneic stem cell transplantation (allo-SCT).
Measure:Incidence of non-relapse mortality
Time Frame:From the date of therapy to the date of non-relapse death, whichever came first, assessed up to 100 months
Safety Issue:
Description:
Measure:Time until progression free survival
Time Frame:From start date of therapy to the first documented disease relapse or death from any cause, whichever may come first, assessed up to 100 months
Safety Issue:
Description:
Measure:Time until overall survival
Time Frame:From start date of therapy to death from any cause, whichever may come first, assessed up to 100 months
Safety Issue:
Description:

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Chicago

Trial Keywords

  • hematologic malignancies
  • allogeneic stem cell transplantation (allo-SCT)

Last Updated

October 12, 2018