Phase II Trial of LMB-2, Fludarabine and Cyclophosphamide for Adult T-Cell Leukemia

BACKGROUND:

- Cluster of differentiation 25 (CD25) (p55, Tac or interleukin receptor 2 (IL2Ra) is
strongly expressed in virtually 100 % of patients with adult T-cell leukemia/lymphoma
(ATL), a highly aggressive human T-lymphotropic virus type 1 (HTLV-1) related malignancy
responding poorly to chemotherapy.

- In adult T-cell leukemia (ATL), the humanized anti-CD25 monoclonal antibody (Mab)
daclizumab produced 13-14 % responses, and the anti-CD52 Mab Alemtuzumab (Campath- 1H)
produced response lasting > 8 weeks in of 30 % of 23 patients.

- LMB-2 is an anti-CD25 recombinant immunotoxin containing variable domains of murine MAb
anti-Tac and truncated Pseudomonas exotoxin.

- In a phase I trial at National Cancer Institute (NCI), the maximum tolerated dose (MTD)
of LMB-2 was 40 mcg/Kg dose intravenous (IV) given every other day for 3 doses (every
other day (QOD) x3). LMB-2 induced > 90 % tumor reduction rapidly in all 3 ATL patients
on protocol, but achieved only 1 partial response due to rapid tumor progression and/or
immunogenicity.

- In preclinical models, response from recombinant immunotoxins is limited by high
concentrations of soluble receptor in the blood and especially in the interstitial space
of the tumor. Synergism was observed with chemotherapy and immunotoxins, possibly due
reduction of soluble receptor in tumor interstitium.

OBJECTIVES:

- To determine, in nonrandomized fashion, if after verifying its safety, fludarabine and
cyclophosphamide (FC) prior to LMB2 for ATL can result in low immunogenicity and a rate
of major response lasting > 8 weeks which may be an improvement over that demonstrated
previously from Alemtuzumab (CAMPATH).

- Secondary objectives

- To determine the effect of 1 cycle of FC alone in ATL.

- To examine progression-free and overall survival in ATL after FC/LMB-2.

- Evaluate pharmacokinetics, toxicity, and monitor soluble CD25 and other tumor
marker levels in the serum.

- To study the effects of LMB-2 +FC on normal B- and T-cell subsets by FACS.

ELIGIBILITY:

- CD25+ ATL, untreated or with prior therapy, leukemic type without malignant masses > 4
cm.

- Eastern Cooperative Oncology Group (ECOG) 0-2, absolute neutrophil count (ANC),
platelets and albumin at least 1000, 75,000, and 3.0 respectively.

DESIGN:

- IV fludarabine and cyclophosphamide (FC) days 1-3 (doses listed respectively)

- Patients 1-7 and 10-14, and >18: 25 and 250 mg/m^2/day

- Patients 8-9: 30 and 300 mg/m^2/day

- Patients 15-17: 20 and 200 mg/m^2/day

- LMB-2 dose: Begin with 30 mcg/Kg IV on days 3,5 and 7. Escalate to 40 mcg/Kg if dose
limiting toxicity (DLT) in 0/3 or 1/6 at 30 mcg/Kg. Continue at 40 mcg/Kg if 0-1 of 6
have DLT at 40 mcg/Kg.

- Administer cycle 1 with FC alone. Two weeks after starting cycle 1, begin up to 6 cycles
of FC plus LMB-2 at minimum 20 day intervals.

- Accrual goals: 29-37 patients, which includes 4 replacements.

- INCLUSION CRITERIA:

1. Diagnosis of acute or lymphomatous adult T-cell leukemia (ATL) by flow cytometry
of blood or immunohistochemistry of biopsy tissue, confirmed by National Cancer
Institute (NCI) Laboratory of Pathology, and previously treated unless the
patient is ineligible for or refuses other protocols or treatments for ATL.

2. Neutralizing antibodies less than or equal to 75% neutralization of 200 ng/ml of
LMB-2.

3. At least 18 years old.

4. Eastern Cooperative Oncology Group (ECOG) 0-2.

5. Able to understand and give informed consent.

6. Negative pregnancy test for females of childbearing potential.

7. The transaminases alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) must each be less than or equal to 3-times the upper limits of normal (UNL)
or less than or equal to 10-times normal if due to ATL. Albumin must be greater
than or equal to 3.0 gm/dL. Total bilirubin must be less than or equal to 1.5
mg/dL except in patients with Gilberts syndrome (as defined by greater than 80
percent unconjugated bilirubin) it must be less than 5mg/dl.

8. Creatinine less than 2.0 mg/dL.

9. Absolute neutrophil count (ANC) greater than or equal to 1000/uL and platelets
greater than or equal to 50,000/uL.

10. Current or prior features of acute ( corrected calcium (Ca)++ > 2.73 or lactate
dehydrogenase (LDH) 2- fold above ULN) or chronic (LDH 1.5-2-fold above ULN or
absolute lymphocyte count >4 x10^9/L with T-cells >3.5 x10^9/L) ATL. Patients
with smoldering ATL (no acute or chronic features) and symptomatic ATL skin
lesions are also eligible.

EXCLUSION CRITERIA:

1. Prior therapy with LMB-2.

2. Central nervous system disease as evidenced by clinical symptomatology.

3. Cytotoxic chemotherapy, steroids or monoclonal antibody (Mab) within 3 weeks of
enrollment, except anti Tac Mab (i.e. daclizumab), which cannot be used within 12
weeks of enrollment. Hydroxyurea is considered different from cytotoxic chemotherapy
and may be used up to the day before enrollment providing it is not increased during
the week prior to enrollment and that patients disease burden is not decreasing during
that time.

4. Uncontrolled infection.

5. Untreated or uncontrolled 2nd malignancy.

6. Patients who are pregnant or breast-feeding.

7. Patients who have human immunodeficiency virus (HIV) or hepatitis C, since in these
patients reductions in normal T- or B-cells would increase the risk of exacerbation of
their underlying disease. Patients would not be excluded for hepatitis B surface
antigen positivity if on Lamivudine or Entecavir.

8. Patients receiving warfarin (Coumadin [R])

9. Patients with a left ventricular ejection fraction of less than 45%.

10. Patients with a diffusing capacity of the lungs for carbon monoxide (DLCO) less than
50% of normal or an forced expiratory volume 1 (FEV1) less than 50% of normal.

11. No concomitant use of alternative complimentary therapies or over the counter (OTC)
agents allowed without prior approval of the principal investigator (PI).

12. Tumor or lymph node masses > 4 cm.