DT2219ARL for Relapsed or Refractory CD19 (+), CD 22 (+) B-Lineage Leukemia Or Lymphoma

A Phase I Study of DT2219ARL, A Bispecific Singe Chain Immunotoxin for the Treatment of Relapsed or Refractory CD19(+), CD22(+) B-Lineage Leukemia or Lymphoma

This is a phase I dose escalation study of DT2219ARL for the treatment of relapsed or refractory B-lineage leukemia and lymphoma. Patients will receive a single course of DT2219ARL as a 4 hour infusion on days 1, 3, 5, and 8. Weekly follow-up will continue through day 29, at which time a disease reassessment will be done. For patients in remission, follow-up will continue monthly until disease progression or start of a new treatment. Otherwise day 29 will be the final study visit if there is no ongoing toxicity.

This phase I study will use Continual Reassessment Method (CRM) to establish a maximum tolerated dose (MTD) of DT2219ARL. Up to 3 dose levels will be tested with an additional dose level (-1) if dose level 1 proves too toxic. The goal of CRM is to identify the dose level which correspondences to a desired toxicity rate of 33% or less using grade 3 or 4 capillary leak syndrome and any grade 3 or greater toxicity attributed to DT2219ARL as the targeted toxicity (based on CTCAE version 4).

The current study was initially conducted at University of Texas and the Scott and White Cancer Institute (A. Frankel, MD - PI) and M. D. Anderson Cancer Center with 15 evaluable patients enrolled by the end of 2011 (table 1). The 3rd patient enrolled in the 40 μg/kg dose cohort was the first to experience dose limiting toxicity (grade 3 neurological: lower extremity weakness) receiving only 3 of the 4 planned doses. Per study design, the 40 μg/kg would enroll an additional 3 patients to confirm dose limiting toxicity. It is at this point the Texas centers discontinued involvement in the study.

Approximately 15 months after the last patient was enrolled under the original study plan, the protocol was redesigned by the Masonic Cancer Center at the University of Minnesota, building on the experience of the 1st 15 patients enrolled through the Texas centers. To increase efficiency, the study design was changed from the standard 3 x 3 dose escalation to a Continuous Reassessment Method (CRM) model testing 3 doses levels (40, 60, and 80 ug/kg) with an added feature of a dose level -1 (30 ug/kg) in the event dose level 1 proves too toxic. The maximum tolerated dose will be identified once 20 evaluable patients are enrolled.

Inclusion Criteria:

• Histologic verification of B-cell lineage leukemia or B cell non-Hodgkin lymphoma and evidence of relapse/refractory disease with the presence of CD19 and/or CD22 by flow cytometry or immunohistochemistry of bone marrow aspirate, peripheral blood or node biopsy

• Disease refractory to conventional therapy and other therapies of higher priority

• Age ≥ 12 years

• Karnofsky Performance status of ≥ 60% or, if less than 16 years of age, Lansky Play Score of ≥ 60 (appendix II)

• Patients must have recovered from effects of prior therapy - at least 2 weeks should have elapsed since the last dose of chemotherapy; however patients who have recovered from the effects of previous treatment and have a >50% rise in peripheral blast count (confirmed twice) or > 50% growth of lymph nodes are immediately eligible - Patients who have relapsed following autologous or allogeneic BMT are eligible

• In order to prevent tumor lysis syndrome, leukemia patients must have a peripheral blast count under 50 x 109/L. This should be achieved with hydroxyurea cytoreduction, prior to starting DT2219ARL as follows - patients with peripheral blasts and a WBC >50 x 109/L, give hydroxyurea 1-5 g daily for up to 5 days to reduce WBC below 50 x 109/L

• Adequate organ function within 14 days (30 days for cardiac and pulmonary) of treatment start defined as:

  • Creatinine: ≤ 1.5 x upper limit of institutional normal (ULN)
  • Hepatic: SGOT (AST) or SGPT (ALT) < 2.5 x ULN and total bilirubin </= 1.5 x ULN
  • General health: Serum albumin ≥ 3.0g/dL
  • Pulmonary: PFTs > 50% if symptomatic or prior known impairment
  • Cardiac: LVEF by ECHO or MUGA ≥ 40%

• Agrees to stay within the Twin Cities metropolitan area (i.e. within 30 miles of the study center) for the duration of the treatment (at least 24 hours after the last dose) and 2) have a capable caregiver

• Women of childbearing potential and men should be advised and agree to practice effective methods of contraception during the course of study

• Voluntary written consent

Exclusion Criteria:

• Presence of leukemic or infectious pulmonary parenchymal disease
• Presence of active CNS leukemia. CSF with <5 WBC/uL will not exclude the patient
• Presence of any uncontrolled systemic infection
• Documented uncontrolled seizure disorder or abnormal neurological examination - a seizure disorder controlled with medication (i.e. no seizures in the previous 6 months) will not exclude a patient
• Documented penicillin or cephalosporin allergies
• Pregnant or lactating - Women of child bearing potential must have a negative pregnancy test within 14 days of study treatment start