Clinical Trials /

Title: Moxetumomab Pasudotox-tdfk (Lumoxiti ) and Rituximab (Rituxan ) for Relapsed Hairy Cell Leukemia

NCT03805932

Description:

Background: Hairy cell leukemia (HCL) is a rare, slow-growing blood cancer in which the bone marrow makes too many of certain white blood cells. The antibody Rituximab binds to a protein in cancerous white blood cells and is often used to treat HCL. Researchers want to see if combining it with the drug Moxetumomab pasudotox-tdfk (also called Lumoxiti) can fight HCL better. Objective: To test the safety of Moxetumomab pasudotox taken with Rituximab for people with HCL or HCL variant. Eligibility: People age 18 years and older with HCL or HCL variant that has not responded to standard therapy Design: Participants will be screened with: Medical history Physical exam Blood, heart, and urine tests Test of blood oxygen levels Review of bone marrow. This can be from previous test results or a new sample. Scans Exercise test Participants will get the study drugs in up to 8 cycles. A cycle will last about 28 days. Both drugs will be given through a plastic tube in a vein. In the first week of cycle 1, participants will have: 1 visit to get Rituximab for 7.5 hours 3 visits to get Lumoxiti for 30 minutes per infusion In the first week of cycles 2-8, participants will have: 1. visit to get Rituximab for 2-4 hours and Lumoxiti for 30 minutes 2. visits to get Lumoxiti for 30 minutes per infusion Participants will be asked to drink lots of water and take aspirin during the cycles. They will get drugs to minimize allergic reactions. Participants will repeat screening tests at visits throughout the cycles and 1 follow-up visit. They may have an eye exam. Sponsoring Institute: National Cancer Institute ...

Related Conditions:
  • Hairy Cell Leukemia
  • Hairy Cell Leukemia Variant
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Title: Moxetumomab Pasudotox-tdfk (Lumoxiti ) and Rituximab (Rituxan ) for Relapsed Hairy Cell Leukemia
  • Official Title: A Phase I Study of Moxetumomab Pasudotox-tdfk (Lumoxiti (TM)) and Rituximab (Rituxan (R)) for Relapsed Hairy Cell Leukemia

Clinical Trial IDs

  • ORG STUDY ID: 190042
  • SECONDARY ID: 19-C-0042
  • NCT ID: NCT03805932

Conditions

  • Hairy Cell Leukemia

Interventions

DrugSynonymsArms
Moxetumomab Pasudotox-tdfk1
Rituximab1

Purpose

Background: Hairy cell leukemia (HCL) is a rare, slow-growing blood cancer in which the bone marrow makes too many of certain white blood cells. The antibody Rituximab binds to a protein in cancerous white blood cells and is often used to treat HCL. Researchers want to see if combining it with the drug Moxetumomab pasudotox-tdfk (also called Lumoxiti) can fight HCL better. Objective: To test the safety of Moxetumomab pasudotox taken with Rituximab for people with HCL or HCL variant. Eligibility: People age 18 years and older with HCL or HCL variant that has not responded to standard therapy Design: Participants will be screened with: Medical history Physical exam Blood, heart, and urine tests Test of blood oxygen levels Review of bone marrow. This can be from previous test results or a new sample. Scans Exercise test Participants will get the study drugs in up to 8 cycles. A cycle will last about 28 days. Both drugs will be given through a plastic tube in a vein. In the first week of cycle 1, participants will have: 1 visit to get Rituximab for 7.5 hours 3 visits to get Lumoxiti for 30 minutes per infusion In the first week of cycles 2-8, participants will have: 1. visit to get Rituximab for 2-4 hours and Lumoxiti for 30 minutes 2. visits to get Lumoxiti for 30 minutes per infusion Participants will be asked to drink lots of water and take aspirin during the cycles. They will get drugs to minimize allergic reactions. Participants will repeat screening tests at visits throughout the cycles and 1 follow-up visit. They may have an eye exam. Sponsoring Institute: National Cancer Institute ...

Detailed Description

      Background:

        -  Hairy cell leukemia (HCL) is an indolent CD22+ B-cell leukemia comprising 2% of all
           leukemias, or approximately 1200 of the 62,130 new cases of leukemia/year in the US. HCL
           variant (HCLv), also CD22+, is 10-20% as common as HCL, but more common in the
           relapsed/refractory population due to its poor prognosis and response to standard purine
           analog chemotherapy. HCLv cells are CD25-negative and wild type for BRAF, so HCLv
           patients are not candidates for BRAF inhibitors. CD25+ classic-appearing HCL-cells that
           express unmutated IGHV4-34 are wild-type for BRAF, remain brightly CD22 positive, and
           confer a poor prognosis when treated with chemotherapy.

        -  Moxetumomab pasudotox-tdfk is a recombinant immunotoxin containing a variable domain
           (Fv) fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin,
           which kills CD22+ cells by binding to CD22 via the Fv fragment, and induction of
           apoptotic cell death catalytic inhibition of protein synthesis in the cytosol.

        -  Moxetumomab pasudotox-tdfk in phase 1 testing demonstrated a high complete response (CR)
           rate in patients with chemoresistant HCL, without dose-limiting toxicity (DLT), but with
           reversible grade 2 hemolytic uremic syndrome (HUS) not requiring plasmapheresis.

        -  Moxetumomab pasudotox-tdfk completed multicenter phase 3 testing in 80 patients, meeting
           its CR endpoint, with 8.8% incidence each of capillary leak syndrome (CLS, grade 3-4
           2.5%), and HUS (grade 3-4 6.3%), both reversible.

        -  Moxetumomab pasudotox-tdfk is the only known non-chemotherapy-containing regimen for HCL
           which can consistently eradicate minimal residual disease (MRD), and this is associated
           with prolonged CR durations. Recently, US Food and Drug Administration (FDA) has
           accepted the Biologics License Application (BLA) for moxetumomab pasudotox-tdfk as the
           treatment of adult patients with HCL.

        -  Patients who did not achieve CR, or CR with MRD, often made neutralizing antibodies to
           the bacterial-based toxin, and/or had collections of HCL cells not completely eradicated
           by moxetumomab pasudotox-tdfk. Both issues may be addressed by the addition of anti-CD20
           monoclonal antibody (Mab) rituximab to Moxetumomab pasudotox-tdfk.

      Objective:

      -To determine the safety and toxicity of Moxetumomab pasudotox-tdfk and rituximab used at the
      planned dose level, in patients with HCL and HCLv.

      Eligibility:

        -  HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years 1
           month response, at least 1 other therapy.

        -  Need for treatment, either 1) ANC <1/nL, 2) Hgb <10g/dL, 3) Plt <100/nL, 4) symptomatic
           splenomegaly, or enlarging HCL mass > 2cm in short axis

        -  Serum creatinine < 1.5 mg/dL, or creatinine clearance greater than or equal to 60 mL/min
           by Cockcroft-Gault equation, where creatinine clearance = (140 age)(Kg weight)/(72 times
           Creatinine).

        -  No uncontrolled infection or cardiopulmonary dysfunction

      Design:

        -  Phase I trial, single arm, non-randomized, dose escalation

        -  Administration:

             -  Doses: Moxetumomab pasudotox-tdfk 30-40 mcg/kg intravenous (iv) over 30 min,
                rituximab 375 mg/m(2) iv, 50-400 mg/hr.

             -  Rituximab day 1 (begin day -2 on cycle 1), Moxetumomab pasudotox-tdfk days 1, 3,
                and 5.

             -  Patients will receive up 4 cycles past documentation of CR without MRD, maximum 8.

             -  To prevent renal toxicity and hypovolemia, patients will be encouraged to drink
                water gradually, approximately 1 cup/hour or 6L/day, not going >3 hours without
                drinking from days 1 to 8 and .will keep a hydration diary to record daily fluid
                consumption.

             -  To prevent rituximab toxicity, patients will receive prophylactic dexamethasone 12
                mg orally 0.5-2 hours before the 1st dose of rituximab, and before subsequent doses
                until rituximab infusion reactions are not seen. Patients will also receive
                diphenhydramine, and acetaminophen.

             -  Dexamethasone 4 mg orally (maximum 2 doses/day) will be given to treat nausea or
                fever associated with Moxetumomab pasudotox-tdfk, which might prevent adequate
                water intake

        -  Statistical design:

             -  Up to 13 patients are intended to be treated in the trial; if a higher dose of
                Moxetumomab pasudotox-tdfk is used, total 16 evaluable subjects may be required.
    

Trial Arms

NameTypeDescriptionInterventions
1ExperimentalMoxetumomab Pasudotox-tdfk + Rituximab
  • Moxetumomab Pasudotox-tdfk
  • Rituximab

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Diagnosis of HCL or HCLv.

          -  Treatment required for either 1) Absolute neutrophil count (ANC) <1/nL, 2) Hemoglobin
             <10g/dL, 3) Platelets<100/nL, 4) symptomatic splenomegaly, or 5) enlarging HCL mass >
             2cm in short axis. Patients who have eligible blood counts within 4 weeks from the
             initiation of study will not be considered ineligible if subsequent blood counts prior
             to enrollment fluctuate and become ineligible up until the time of enrollment.

          -  Patients must be Pseudomonas-immunotoxin naive.

          -  HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >=2-years
             1 month response, at least 1 other therapy. Age greater than or equal to 18 years as
             the disease under study, HCL/HCLv, has not been reported in children < age 18.

          -  ECOG performance status less than or equal to2 (Karnofsky greater than or equal to
             60%)

          -  Patients must have adequate organ and marrow function as defined below:

               -  Total bilirubin less than or equal to 1.5 mg/dL, unless consistent with Gilbert s
                  (ratio between total and direct bilirubin > 5)

               -  AST and ALT less than or equal to 3x upper limit of normal (ULN)

               -  Alkaline phosphatase < 2.5 ULN

               -  Serum creatinine less than or equal to 1.5 mg/dL or creatinine clearance greater
                  than or equal to 60 mL/min by Cockcroft-Gault equation, where creatinine
                  clearance = (140-age)(Kg weight)/(72 x Creatinine)

               -  Serum albumin greater than or equal to 2 g/dL

               -  Partial thromboplastin time (PTT) or Prothrombin time (PT)/International
                  Normalized Ratio < 2.5x ULN (If on warfarin, PT/INR < 3.5x ULN; If on any other
                  anticoagulation, Prothrombin time (PT) < 2.5x baseline)

               -  Fibrinogen greater than or equal to 0.5 lower limit of normal

          -  The effects of moxetumomab pasudotox-tdfk and rituximab on the developing human fetus
             are unknown therefore participants must use effective methods of contraception as
             directed below.

               -  Females of childbearing potential (<50 years) who are sexually active with a
                  non-sterilized male partner must use a highly effective method of contraception
                  prior to study entry and or the duration of study participation and must agree to
                  continue using such precautions for 12 months after completion of Rituximab
                  administration. Contraception after this point should be discussed with a
                  responsible physician. Periodic abstinence, the rhythm method, and the withdrawal
                  method are not acceptable methods of contraception. Females of childbearing
                  potential are defined as those who are not surgically sterile (i.e., bilateral
                  tubal ligation, bilateral oophorectomy, or complete hysterectomy) or those who
                  are premenarchal or postmenopausal (defined as 12 months with no menses without
                  an alternative medical cause). A highly effective method of contraception is
                  defined as one that results in a low failure rate (i.e., less than 1% per year)
                  when used consistently and correctly. Not all methods of contraception are highly
                  effective. Female subjects must use a hormonal method in addition to a barrier
                  method alone, to minimize the chance of pregnancy. Should a woman become pregnant
                  or suspect she is pregnant while she or her partner is participating in this
                  study, she should inform her treating physician immediately.

               -  Non-sterilized males who are sexually active with a female partner of
                  childbearing potential must use an effective method of contraception from Day 1
                  until 90 days after receipt of the final dose of investigational product. It is
                  required that a female partner of a male subject also use an effective method of
                  contraception throughout this period.

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

          -  Patients must be willing to co-enroll in the investigator s companion protocol
             10C-0066 titled Collection of Human Samples to Study Hairy Cell and other Leukemias,
             and to Develop Recombinant Immunotoxins for Cancer Treatment.

        EXCLUSION CRITIERIA:

          -  Patients who have had chemotherapy, immunotherapy or radiotherapy within 4 weeks or
             treatment with rituximab within last 3 months prior to initiation of treatment.

          -  Patients who are receiving any other investigational agents.

          -  Is pregnant or breastfeeding or expecting to conceive within the projected duration of
             the study, starting with the screening visit through 4 months after the last dose of
             trial treatment. Pregnant women are excluded from this study because moxetumomab
             pasudotox-tdfk and rituximab are agents 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 moxetumomab
             pasudotox-tdfk and rituximab, breastfeeding should be discontinued if the mother is
             treated with moxetumomab pasudotox-tdfk and rituximab.

          -  Patients with known brain metastases should be excluded from this clinical trial
             because of their poor prognosis and because they often develop progressive neurologic
             dysfunction that would confound the evaluation of neurologic and other adverse events.

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

          -  Patients with retinal or choroidal detachment.

          -  Positive for Hepatitis B core antibody or surface antigen unless the patient is on
             Tenofovir or Entecavir and Hepatitis B Viral deoxyribonucleic acid (DNA) load is <2000
             IU/mL

          -  Active second malignancy requiring treatment other than minor resection of indolent
             cancers like basal cell and squamous skin cancers.

          -  Human immunodeficiency virus (HIV)-positive patients unless taking appropriate
             anti-HIV medications with a CD4 count of > 200. Otherwise, there may be an increased
             risk of lethal infections when temporarily suppressing normal B-cells.

          -  History of an allogeneic bone marrow transplant.

          -  Patients with a history of both thromboembolism and known congenital hypercoagulable
             conditions.

          -  Radioimmunotherapy within 2 years prior to enrollment in the study.

          -  Patients with history of thrombotic microangiopathy or thrombotic microangiopathy
             /HUS.

          -  Patients with corrected QT interval (Frederica) elevation > 500 msec (manually
             over-read by medically qualified person) based on at least two separate 12-lead ECGs.

          -  Patients on high dose estrogen (defined as > 0.625 mg/day of an estrogen compound).

          -  Oxygen saturation at rest < 88% measured by pulse oximetry or PaO2 less than or equal
             to 55 mm Hg.

          -  Patients with life expectancy of less than 6 months.

          -  Patients with clinical evidence of disseminated intravascular coagulation (Grade 3-4).

          -  Patients with < 50% of predicted forced expiratory volume (FEV1) or < 50% of predicted
             diffusing capacity for carbon monoxide, corrected for hemoglobin concentration and
             alveolar volume (DLCO). Note: Patients with no prior history of pulmonary illness are
             not required to have pulmonary function testing (PFT). Forced expiratory volume will
             be assessed after bronchodilator therapy.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Toxicity
Time Frame:4 weeks
Safety Issue:
Description:Response rate and duration of response

Details

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

Trial Keywords

  • HCL Variant
  • Recombinant Immunotoxin
  • Monoclonal Antibody
  • Targeted Therapy
  • Biologic Therapy

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