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

 ...
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 to keep a hydration diary to record daily fluid
 consumption.

 -  To prevent rituximab toxicity, patients will receive prophylactic dexamethasone
 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, famotidine, and acetaminophen.

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

 -  Statistical design:

 -  Up to 10-16 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.
-  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 3 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. 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.