Retreatment Protocol for BL22 Immunotherapy in Relapsed or Refractory Hairy Cell Leukemia
Retreatment Protocol for BL22 Immunotherapy in Relapsed or Refractory Hairy Cell Leukemia
BL22 is a type of protein that scientists have created to interact with certain cancer cells.
 Experiments have shown that BL22 can bind with cancer cells that have a particular kind of
 protein (called CD22 ) on their surface, and can kill those cells. CD22 is present on certain
 types of hairy cell leukemia (HCL) cancer cells, and researchers have been working on
 treatments that will use BL22 and other related proteins to interact with and kill these
 kinds of cancer cells. The primary purpose of this study will be to provide access to and
 treatment with BL22 for patients who have HCL in order to determine their response to the
 treatment. In addition, the study will assess potential side effects of BL22 and examine why
 some patients respond better than others to treatment with BL22 and related therapies.

 This study will include about 21 to 25 adults who have been diagnosed with forms of HCL that
 have not responded well to standard treatments such as surgery, chemotherapy, or radiation
 therapy. These adults also will have received anti-CD22 therapies before, potentially
 including treatments with BL22, and have not developed immunity or resistance to these
 treatments.

 Prior to the study, patients will undergo a 1- to 2-week screening period to assess their
 eligibility for treatment. Eligible patients will participate in the study for up to 16
 cycles of treatment, with each cycle lasting approximately 4 weeks. For each cycle, patients
 will receive 1 prescribed dose of BL22 every other day for a total of 3 doses per cycle, and
 will be assessed after every cycle to evaluate the success of the treatment. During the
 evaluation visits, patients will be required to have a brief physical examination, give blood
 and urine samples for testing, and undergo other tests as need to check heart and kidney
 function and assess the state of the leukemia. Patients who agree will give additional blood,
 urine, or bone marrow samples for future research purposes.
Background:

 BL22, also called CAT-3888 or RFB4(dsFv)-PE38, is a recombinant immunotoxin containing an Fv
 fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin (PE).

 In Phase 1 and 2 trials in patients with chemoresistant hairy cell leukemia (HCL), BL22
 showed 47-61% complete remission (CR) rates and 12% of HCL patients had a completely
 reversible hemolytic uremic syndrome (HUS).

 A mutant of BL22, termed CAT-8015 or HA22, differs by 3 amino acids and has higher binding
 affinity to CD22 compared to BL22 (15-fold greater). CAT-8015 is currently undergoing Phase 1
 testing in HCL and other diseases.

 HCL patients who have previously received recombinant anti-CD22 immunotoxin (BL22, CAT-8015,
 or LMB-2) may benefit from additional BL22 administration.

 Objectives:

 The primary objective is to provide access to BL22 for HCL patients who have previously
 received BL22, CAT-8015, or LMB-2, or are ineligible for CAT-8015, but may benefit from BL22.
 The primary outcome will be response to treatment.

 Secondary objectives:

 -  Determine immunogenicity and safety profiles of BL22 in patients with prior immunotoxin,
 using aspirin/enoxaparin to prevent HUS.

 -  To correlate response to ex vivo sensitivity of HCL cells, obtained from blood with or
 without apheresis, to BL22 and to other recombinant anti-CD22 immunotoxins such as
 CAT-8015, and to tumor markers.

 -  To correlate neutralizing antibodies with number of cycles of BL22, type and number of
 prior systemic therapies, and time since prior purine analog.

 -  To correlate CR by bone marrow biopsy with improvement in bone marrow as assessed by
 magnetic resonance imaging (MRI) of the spine.

 Eligibility:

 Patient must have received prior recombinant anti-CD22 immunotoxin (i.e. BL22, CAT-8015, or
 LMB-2 treatment) or be ineligible for CAT-8015.

 HCL with cytopenia, high malignant count or symptomatic splenomegaly.

 Patients must have had at least 2 prior systemic therapies. There must have been at least 2
 prior courses of purine analog, or 1 if the response to this course lasted < 2 years, or if
 the patient had unacceptable toxicity to purine analog.

 Design:

 This is a single institution, expanded access protocol accruing 21-25 patients.

 Patients will be administered BL22 at 30 microg/kg every other day for 3 doses (QOD times 3)
 per 4-week cycle (at least 26 days) for a maximum of 16 cycles.

 Patients in CR may receive up to 2 more cycles if without minimal residual disease (MRD), or
 4 more cycles if in CR with MRD, but no more than 16 cycles total.

 No retreatment if high levels of neutralizing antibodies or progressive disease.

 Patients who have been off treatment and relapse after greater than 2 months of a CR or
 partial response may be retreated if eligibility criteria are still met.

 If any HUS, accrual to the study will be suspended for discussion with FDA.
-  INCLUSION CRITERIA:

 One of the following:

 1. Patients who previously received CAT-3888 and did not have unacceptable toxicity

 2. Patients who received CAT 8015 in study CAT 8015-1001 and have progression of disease
 or relapse. These patients must be considered off-study for CAT-8015 protocol
 specified follow-up

 Patient must have histopathological evidence of HCL as confirmed by the Laboratory of
 Pathology, NCI.

 At least one of the following indications for treatment:

 1. Neutropenia (absolute neutrophil count (ANC) less than 1000 cells/microL).

 2. Anemia (hemoglobin (Hgb) less than 10 g/dL).

 3. Thrombocytopenia (platelet (Plt) less than 100,000/microL).

 4. Absolute lymphocyte count of greater than 5000 cells/microL

 5. Symptomatic splenomegaly.

 6. Enlarging lymph nodes greater than 2cm.

 Patient must have had at least 2 prior systemic therapies. There must have been at least 2
 prior courses of purine analog, or 1 if the response to this course lasted less than 2
 years, or if the patient had unacceptable toxicity to purine analog.

 Patient must have Eastern Cooperative Oncology Group (ECOG) performance status of 0-2,
 unless due to potentially reversible active uncontrolled infection.

 Patient must be greater than or equal to 18 years old.

 Patient can understand and give informed consent.

 Patient must have adequate liver and renal function, as defined by the following criteria:

 1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) less than or equal
 to 2.5-times the upper limits of normal.

 2. Albumin greater than or equal to 3.0 g/dL.

 3. Total bilirubin less than or equal to 2.2 mg/dL.

 4. Creatinine less than or equal to 1.4 mg/dL or creatinine clearance greater than or
 equal to 50 mL/min.

 Patient must agree to using adequate contraception (hormonal or barrier method of birth
 control; abstinence) prior to study entry and for the duration of the study.

 EXCLUSION CRITERIA:

 Patients who are pregnant or nursing. A negative pregnancy test (urine or serum) must be
 documented within one week prior to starting BL22 in women of child-bearing potential.

 Patient has developed antibody titer that neutralizes greater than 75% of the activity of 1
 microg/mL of BL22 using a bioassay.

 Patients who had systemic cytotoxic chemotherapy, immunotherapy, recombinant anti-CD22
 immunotoxin (ie, CAT-8015, BL22, or LMB-2) or systemic steroid (with the exception of
 stable doses of Prednisone less than or equal to 20 mg/day) treatment within 4 weeks of
 enrollment. Patients receiving a limited number of doses (less than 5) of steroid for
 non-treatment reasons (eg, allergy prophylaxis connected with medical testing) may not
 receive any steroid within one week of enrollment and may not have had any evidence of
 disease response to steroid. Subjects who are receiving steroids for other conditions
 (e.g., autoimmune disorders) are eligible, as long as there is no increase in the dose or
 change in steroid type within 1 week of treatment. Subjects who are using a chronic steroid
 must wait for 4 weeks before starting the trial.

 Patient had monoclonal antibody therapy (with the exception of BL22 or CAT-8015 or LMB-2)
 within 4 weeks of enrollment.

 Patient is receiving any other investigational agent.

 Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive
 heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
 situations that would limit compliance with study requirements.

 Patients who discontinued from CAT-8015 or BL22 studies due to toxicity or dose-limiting
 toxicity.

 Dose limiting toxicity to CAT-8015