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

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 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 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 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 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 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. Both issues may be addressed by the addition of anti-CD20
monoclonal antibody (Mab) rituximab to Moxetumomab pasudotox.

Objective:

-To determine the safety and toxicity of Moxetumomab pasudotox 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-year
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 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 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 6L/day.

- 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,

hydroxyzine, and/or acetaminophen.

- Dexamethasone 4 mg orally will be given to treat nausea or fever associated with
Moxetumomab pasudotox, which might prevent adequate water intake

-Statistical design:

- Up to 13 patients are intended to be treated in the trial using the following plan; if a
higher dose of Moxetumomab pasudotox 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 na(SqrRoot) ve.

- HCL or HCLv with at least 1 prior purine analog, and, for HCL patients with >2-year
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 and rituximab on the developing human fetus are
unknown therefore participants must use effective methods of contraception as directed
below.

- Females of childbearing potential 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 4 months after completion of moxetumomab pasudotox
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 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 and rituximab,
breastfeeding should be discontinued if the mother is treated with moxetumomab
pasudotox 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
Lamivudine 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.