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

Sponsor

Masonic Cancer Center, University of Minnesota (Other)

Overall Status

Completed

CT.gov ID

NCT00889408

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Locations

Arm

7.6

Actual Duration (Months)

8.3

Patients Per Site

1.1

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Leukemia Lymphoma	Biological: DT2219ARL	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Dec 2, 2013

Actual Primary Completion Date :

Jul 21, 2014

Actual Study Completion Date :

Jul 21, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment DT2219ARL at assigned dose IV over 4 hours in the outpatient setting on day 1, 3, 5, and 8	Biological: DT2219ARL anti-CD19/CD22 bispecific ligand-directed toxin DT2219ARL

Arm

Intervention/Treatment

Experimental: Treatment

DT2219ARL at assigned dose IV over 4 hours in the outpatient setting on day 1, 3, 5, and 8

Biological: DT2219ARL

anti-CD19/CD22 bispecific ligand-directed toxin DT2219ARL

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose [29 days]
This phase I study will use Continual Reassessment method (CRM) method to establish a maximum tolerated dose (MTD) of DT2219ARL when the maximum desired level of toxicity is 33% (defined as grade 3 or 4 capillary leak syndrome toxicities and any grade 3 or greater adverse event attributed to DT2219ARL based on CTCAE v 4).

Secondary Outcome Measures

Therapeutic activity of DT2219ARL [2 years]
Determined by the change in percentage of blasts in bone marrow and peripheral blood and recovery of normal hematopoiesis and by change in size of lymph nodes/tumor involved by lymphoma

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Masonic Cancer Center at University of Minnesota	Minneapolis	Minnesota	United States	55455
2	M. D. Anderson Cancer Center at University of Texas	Houston	Texas	United States	77030-4009
3	Scott and White Cancer Institute	Temple	Texas	United States	76508