Moxetumomab Pasudotox-tdfk (Lumoxiti(TM)) and Either Rituximab (Rituxan(R)) or Ruxience for Relapsed Hairy Cell Leukemia
Condition: Hairy Cell Leukemia
MeSH terms: Leukemia; Leukemia, Hairy Cell
Intervention: Moxetumomab Pasudotox-tdfk; Rituximab; Ruxience; Dexamethasone; Acetaminophen; Diphenhydramine; Famotidine; Aspirin
Intervention description: Moxetumomab pasudotox-tdfk is administered at 30-40 ug/Kg intravenous (iv) over 30 min given on days 1, 3, 5 of each cycle.; Rituximab will be administered at 375mg/m^2 intravenous (iv), 50-400 mg/hour (hr). On cycle 1, Rituximab is given on day -2, on subsequent cycles, Rituximab is given on day 1.; Ruxience will be administered at 375mg/m^2 intravenous (iv), 50-400 mg/hour (hr). On cycle 1, Ruxience is given on day -2, on subsequent cycles, Ruxience is given on day 1 (Delta); 12 mg Cycle 1, Day -2; Cycles 2-8, Day 1. Administer 0.5-2 hours before rituximab/Ruxience. If participant has previous reaction to rituximab/Ruxience, give 12mg. If participants tolerate rituximab/Ruxience without problems, may hold at discretion of provider. Pre-medications are given prior to rituximab/Ruxience on day 1.; 650 mg Cycle 1, Day -2, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and recommended every 6 hours x 4 after the end of infusion; Cycles 2-8, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and recommended every 6 hours x 4 after the end of infusion. Pre-medications are given prior to rituximab/Ruxience on day 1.; 25-50 mg Cycle 1, Day -2; Cycles 2-8, Day 1. Pre-medications are given prior to rituximab/Ruxience on day 1. May be given prior to moxetumomab pasudotox-tdfk at discretion of principal investigator.; 20-40 mg Cycle 1, Day -2; Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and is recommended every 12 hours x 2 after the end of infusion; Cycles 2-8, Day 1, Day 3, Day 5. To be given 30-90 minutes prior to every moxetumomab pasudotox-tdfk infusion and is recommended every 12 hours x 2 after the end of infusion. Pre-medications are given prior to rituximab/Ruxience on day 1.; 81 mg Cycle 1, Days 1-8; Cycles 2-8, Days 1-8. Only if platelet counts ≥ 100 x 109/L.
Intervention MeSH terms: Aspirin; Acetaminophen; Diphenhydramine; Promethazine; Dexamethasone; Rituximab; Immunotoxin HA22; Famotidine
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Sequential Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HCL Variant; Recombinant Immunotoxin; Monoclonal Antibody; Targeted Therapy; Biologic Therapy

Summary:

      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/Ruxience 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/Ruxience 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.

      The study 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 or Ruxience 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/Ruxience 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.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Diagnosis of hairy cell leukemia (HCL) or Hairy cell leukemia variant (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.

          -  Eastern Cooperative Oncology Group (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)

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (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/Ruxience 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/Ruxience 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. 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 investigators 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/Ruxience within last 3 months prior to initiation of
             treatment.

          -  Patients who are receiving any other investigational agents.

          -  Breastfeeding within the projected duration of the study, starting with the screening
             visit through 6 months after the last dose of rituximab/Ruxience. Pregnant women are
             excluded from this study because moxetumomab pasudotox-tdfk and rituximab/Ruxience 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/Ruxience,
             breastfeeding should be discontinued if the mother is treated with moxetumomab
             pasudotox-tdfk and rituximab/Ruxience.

          -  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 cluster of differentiation 4 (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/hemolytic uremic syndrome (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 partial pressure of
             oxygen (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.