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Ibrutinib in Preventing Acute Leukemia in Patients After Reduced-Intensity Conditioning and Stem Cell Transplant

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ClinicalTrials.gov Identifier: NCT03267186
Recruitment Status : Recruiting
First Posted : August 30, 2017
Last Update Posted : February 12, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
Pharmacyclics LLC.
Information provided by (Responsible Party):
Andrew Rezvani, Stanford University

Brief Summary:
This phase II trial studies how well ibrutinib works in preventing acute leukemia in patients after reduced-intensity conditioning and stem cell transplant. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Acute Biphenotypic Leukemia Acute Lymphoblastic Leukemia Acute Myeloid Leukemia Chronic Myelogenous Leukemia, BCR-ABL1 Positive Hematopoietic Cell Transplantation Recipient Drug: Ibrutinib Other: Laboratory Biomarker Analysis Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To reduce the incidence of relapse at 18 months after reduced-intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myeloid leukemia (CML) in blast crisis from a historical baseline of 45% to 25%, using ibrutinib maintenance therapy.

SECONDARY OBJECTIVES:

I. To study the incidence and severity of post-transplant complications in subjects receiving ibrutinib maintenance after allogeneic HCT.

II. To study the incidence of infectious complications in subjects receiving maintenance ibrutinib after allogeneic HCT.

III. To study the impact of ibrutinib maintenance on minimal residual disease after RIC and allogeneic HCT.

IV. To study the impact of maintenance ibrutinib on immune reconstitution and alloreactivity after allogeneic HCT, specifically on Th1/ Th2 polarization, T follicular cell number, T and B cell repertoire, serum immunoglobulin levels, and alloantibody formation.

OUTLINE:

Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib orally (PO) once daily (QD) for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 2 years.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 2 Study of Ibrutinib Maintenance After Reduced-Intensity Conditioning and Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia
Actual Study Start Date : September 12, 2017
Estimated Primary Completion Date : September 2019
Estimated Study Completion Date : March 2020


Arm Intervention/treatment
Experimental: Prevention (ibrutinib)
Beginning 60-90 days after allogeneic HCT, patients receive ibrutinib PO QD for up to 18 months post-transplant in the absence of disease progression or unacceptable toxicity.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Other: Laboratory Biomarker Analysis
Correlative studies




Primary Outcome Measures :
  1. Incidence of relapsed leukemia [ Time Frame: Up to 18 months ]
    Incidence of relapsed leukemia defined as > 5% leukemic blasts detected in bone marrow or peripheral blood. Participants will also be considered to have relapsed leukemia if they receive any active treatment for progressive leukemia after allogeneic HCT, even if they have < 5% leukemic blasts. Withdrawal of immunosuppression alone is not considered an active treatment for progressive disease.


Secondary Outcome Measures :
  1. Incidence of acute GVHD grades II-IV and III-IV [ Time Frame: At 180 days ]

    Incidence of acute GVHD grades II-IV and III-IV will be evaluated according following criteria.

    Stage of Acute GvHD was assessed as follows.

    • Stage 1: Skin: rash < 25% of skin. Liver: bilirubin 2 to 3 mg/dL. Gut: diarrhea >500 mL/day or upper-gut symptoms with positive histology
    • Stage 2: Skin: rash 25 to 50% of skin. Liver: bilirubin 3 to 6 mg/dL. Gut: diarrhea >1000 mL/day.
    • Stage 3: Skin: rash > 50% of skin. Liver: bilirubin 6 to 15 mg/dL. Gut: diarrhea > 1500 mL/day.
    • Stage 4: Skin: generalized erythroderma with bulla formation. Liver: bilirubin > 15 mg/dL. Gut: diarrhea > 2500 mL/day or severe abdominal pain with or without ileus

    Grade of Acute GvHD was determined as follows.

    • Grade 1: Stage 1-2 Skin + No Liver stage + No Gut stage
    • Grade 2: Stage 3 Skin OR Stage 1 Liver or Stage 1 Gut
    • Grade 3: No Skin stage + Stage 2 to 3 Liver Stage 2 to 4 Gut
    • Grade 4: Stage 4 Skin + or Stage 2 to 3 Liver + No Gut stage

  2. Incidence of chronic GVHD [ Time Frame: At 18 months ]
    Assessment of chronic GvHD will be performed using the 2015 NIH consensus criteria

  3. Incidence of detectable minimal residual disease [ Time Frame: At 1 year ]
    Incidence of detectable minimal residual disease will be assessed using high-throughput sequencing (ClonoSEQ) and high-sensitivity flow cytometry. Minimal residual disease will be considered present if > 1 x 10^-6 leukemic clones are detected by ClonoSEQ, or if any aberrant blasts matching the original leukemic immunophenotype are detected by high-sensitivity flow cytometry.



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • INCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT)
  • Diagnosis of acute myeloid leukemia (AML), acute biphenotypic leukemia, or acute lymphoblastic leukemia (ALL); CML transformed to blast crisis is eligible
  • Planned allogeneic HCT using fludarabine phosphate (FLU)/melphalan hydrochloride (MEL) or FLU/busulfan (BU) conditioning
  • Planned graft versus host disease (GVHD) prophylaxis consisting of tacrolimus (TAC)/methotrexate (MTX) or TAC/sirolimus (SRL)
  • Human leukocyte antigen (HLA) identical sibling donor, HLA matched unrelated donor, or donor mismatched at 1 HLA allele or antigen
  • Less than or equal to 5% blasts on bone marrow examination within 60 days of starting conditioning
  • Age >= 18 years and =< 70 years
  • Able to give informed consent
  • Subjects will be eligible if their planned conditioning regimen for allogeneic HCT consists of one of the two following standard reduced intensity conditioning regimens:

    • FLU/MEL: fludarabine phosphate (fludarabine) 120 to 180 mg/m^2; melphalan hydrochloride (melphalan) =< 150 mg/m^2
    • FLU/BU: fludarabine 120 to 180 mg/m^2; busulfan =< 8 mg/kg orally or =< 6.4 mg/kg intravenously
  • Subjects will be eligible if their planned post grafting immunosuppression consists of one of the two following regimens:

    • TAC/MTX: tacrolimus (oral or intravenous) and intravenous methotrexate administered according to institutional standard practice.
    • TAC/SRL: tacrolimus (oral or intravenous) and oral sirolimus, administered according to institutional standards of care
  • INCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION)
  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
  • Absolute neutrophil count (ANC) > 0.75 x 10^9/L
  • Platelet count > 50 x 10^9/L
  • Hemoglobin > 8.0 g/dL without transfusion or growth factor support for at least 7 days prior to screening (with the exception of pegylated granulocyte-colony stimulating factor [G-CSF] and darbopoietin, which require at least 14 days of abstinence prior to screening)
  • Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x upper limit of normal
  • Estimated creatinine clearance >= 30 mL/min via Cockroft-Gault formula
  • Bilirubin =< 1.5 x upper limit of normal (unless elevated bilirubin is due to Gilbert's syndrome or of non-hepatic origin)
  • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) (activated partial thromboplastin time [aPTT]) =< 1.5 x upper limit of normal
  • Female subjects who are of non-reproductive potential (ie, post-menopausal by history - no menses for >= 1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy); female subjects of childbearing potential must have a negative serum pregnancy test upon screening
  • Male and female subjects who agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], sexual abstinence, or sterilized partner) and a barrier method (eg, condoms, vaginal ring, sponge, etc) during the period of therapy and for 30 days after the last dose of study drug for females and 90 days after the last dose of the study drug for males
  • Between day +60 and day +90 after allogeneic HCT

Exclusion Criteria:

  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Active involvement of the central nervous system with malignancy (previous central nervous system [CNS] involvement is allowed if clearance of CNS disease has been documented prior to enrollment)
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Pregnant or breastfeeding
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Karnofsky performance status < 60%
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Active leukemia (> 5% leukemic blasts in peripheral blood or bone marrow)
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Non-hematologic malignancy with a life expectancy of < 5 years
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Known history of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or hepatitis B virus (HBV) infection; subjects who are positive for hepatitis B core antibody or hepatitis B surface antigen must have a negative polymerase chain reaction (PCR) result before enrollment; those who are PCR positive will be excluded
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
  • EXCLUSION CRITERIA FOR ENROLLMENT (PRE-TRANSPLANT): History of other malignancies, except:

    • Malignancy treated with curative intent and with no known active disease present for >= 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease Adequately treated carcinoma in situ without evidence of disease
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Active and uncontrolled acute GVHD grades III or IV
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Use of secondary therapy for acute GVHD at any time (defined as any systemic therapy intended to treat acute GVHD besides corticosteroids)
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Requirement for anticoagulation with warfarin or other vitamin K antagonists (concomitant use of other anticoagulants is permitted)
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Relapsed leukemia (> 5% leukemic blasts in peripheral blood or bone marrow after allogeneic HCT)
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Karnofsky performance status < 60%
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Chemotherapy =< 21 days prior to first administration of study treatment and/or monoclonal antibody =< 6 weeks prior to first administration of study treatment
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): History of stroke or intracranial hemorrhage within 6 months prior to screening
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Any life threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Major surgery within 4 weeks of first dose of study drug
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Any uncontrolled active systemic infection
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Unresolved toxicities from prior anti cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4), grade =< 1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Requires treatment with a strong cytochrome P450 (CYP) 3A4/5 inhibitor
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Unwilling or unable to participate in all required study evaluations and procedures
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations)
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Currently active, clinically significant hepatic impairment (Child-Pugh class B or C)
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Lactating or pregnant
  • EXCLUSION CRITERIA (PRIOR TO IBRUTINIB ADMINISTRATION): Uncontrolled cardiac arrhythmias

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03267186


Contacts
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Contact: Janet Mcdowell 650-725-1647 janetm2@stanford.edu

Locations
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United States, California
Stanford University, School of Medicine Recruiting
Palo Alto, California, United States, 94304
Contact: Janet McDowell    650-725-1647    janetm2@stanford.edu   
Principal Investigator: Andrew Rezvani, MD         
Sponsors and Collaborators
Andrew Rezvani
National Institutes of Health (NIH)
Pharmacyclics LLC.
Investigators
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Principal Investigator: Andrew Rezvani Stanford University

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Responsible Party: Andrew Rezvani, Assistant Professor of Medicine, Stanford University
ClinicalTrials.gov Identifier: NCT03267186     History of Changes
Other Study ID Numbers: IRB-38934
NCI-2017-00125 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
IRB-38934 ( Other Identifier: Stanford IRB )
BMT302 ( Other Identifier: OnCore )
First Posted: August 30, 2017    Key Record Dates
Last Update Posted: February 12, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Biphenotypic, Acute
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Leukemia, Lymphoid
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases