Clinical trial NCT00889408: DT2219ARL for Relapsed or Refractory CD19 (+), CD 22 (+) B-Lineage Leukemia Or Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Leukemia
Lymphoma
Keywords: refractory chronic lymphocytic leukemia
childhood diffuse large cell lymphoma
childhood grade III lymphomatoid granulomatosis
childhood immunoblastic large cell lymphoma
B-cell adult acute lymphoblastic leukemia
recurrent adult acute lymphoblastic leukemia
B-cell childhood acute lymphoblastic leukemia
recurrent childhood acute lymphoblastic leukemia
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
recurrent adult acute myeloid leukemia
recurrent childhood acute myeloid leukemia
secondary acute myeloid leukemia
B-cell chronic lymphocytic leukemia
relapsing chronic myelogenous leukemia
childhood chronic myelogenous leukemia
cutaneous B-cell non-Hodgkin lymphoma
recurrent adult grade III lymphomatoid granulomatosis
Waldenström macroglobulinemia
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
recurrent childhood grade III lymphomatoid granulomatosis
recurrent childhood large cell lymphoma
recurrent childhood lymphoblastic lymphoma
recurrent childhood small noncleaved cell lymphoma
childhood Burkitt lymphoma
intraocular lymphoma
noncutaneous extranodal lymphoma
prolymphocytic leukemia
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-04-28
Enrollment: 25
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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).

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Maximum tolerated dose
timeFrame: 29 days
Secondary outcomes:
measure: Therapeutic activity of DT2219ARL
timeFrame: 2 years
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Temple
country: United States
facility: Scott and White Cancer Institute
state: Texas
Study officials:
affiliation: University of Minnesota
name: Verokina Bachanova, MD
role: PRINCIPAL_INVESTIGATOR
References: