Chemoimmunotherapy With Epratuzumab in Relapsed Acute Lymphoblastic Leukemia (ALL)

Recurrent Childhood Acute Lymphoblastic Leukemia Clinical Trial

Official title:

A Feasibility Pilot and Phase II Study Of Chemoimmunotherapy With Epratuzumab (IND #12034) for Children With Relapsed CD22-Positive Acute Lymphoblastic Leukemia (ALL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00098839
• Other study ID #: ADVL04P2
• Secondary ID: NCI-2011-01624CO
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: December 8, 2004
• Last updated: November 14, 2017
• Start date: February 2005
• Est. completion date: April 2011

Study information

• Verified date: November 2017
• Source: Children's Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This Phase II trial is studying how well giving epratuzumab together with an established chemotherapy platform works in treating young patients with relapsed acute lymphoblastic leukemia. Monoclonal antibodies, such as epratuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Chemotherapy drugs work in different ways to stop the growth of cancer cells, either by killing them or by stopping them from dividing. Giving monoclonal antibody therapy in combination chemotherapy may kill cancer cells more effectively.

Description:

PRIMARY OBJECTIVES:

I. Determine the feasibility of epratuzumab administered alone and in combination with re-induction combination chemotherapy in pediatric patients with relapsed CD22-positive acute lymphoblastic leukemia.

II. Determine the toxic effects of this regimen in these patients.

III. Determine the antitumor activity of this regimen in these patients.

IV. To estimate the remission re-induction rate and four-month event-free survival (EFS) for patients with early first relapse ALL who receive epratuzumab in combination with cytotoxic thermotherapy.

SECONDARY OBJECTIVES:

I. Determine the pharmacokinetics of epratuzumab in these patients. II. Determine the biologic activity of epratuzumab using measurements of minimal residual disease in these patients.

III. Determine the human anti-human antibody (HAHA) response in patients treated with this regimen.

OUTLINE: This is a multicenter study comprising a feasibility part A (closed to accrual as of 10/30/06) followed by a pilot part B study. A Simon's two stage design was initially used to evaluate the efficacy of the once weekly dosing schedule for part B patients (called B1 cohort), which planned to accrue a total of 112 patients with 56 to be enrolled at the first stage. After completion the accrual of stage 1, i.e. after 56 patients were enrolled, the design of part B was revised to evaluate a modified doing schedule (twice weekly doing, called B2 cohort) using a stratified two-stage design by London and Chang (2005), where patients enrolled to B2 were stratified according to relapse (first early marrow relapsed occurring < 18 months from initial diagnosis vs 18-36 months from initial diagnosis).

PART A (CLOSED TO ACCRUAL 10/30/06):

REDUCTION THERAPY: Patients receive epratuzumab IV over several hours on days -14, -10, -6, and -2 and cytarabine intrathecally (IT) on day -14*.

NOTE: *Patients who receive IT chemotherapy within 7 days of study entry as prior maintenance chemotherapy (e.g., before the diagnosis of relapse) did not receive this first dose of IT cytarabine.

RE-INDUCTION THERAPY (BLOCK 1): Patients received vincristine IV on days 1, 8, 15, and 22; oral prednisone two or three times daily on days 1-29; pegaspargase intramuscularly (IM) on days 2, 9, 16, and 23; dexrazoxane IV followed by doxorubicin IV over 15 minutes on day 1; methotrexate IT on days 15 and 29 for CNS-negative disease; and epratuzumab IV over 1 hour on days 8, 15, 22, and 29. Patients with CNS-positive disease also received triple IT therapy (ITT) consisting of methotrexate, cytarabine, hydrocortisone on days -10, -6, 1 and 15.

RE-INDUCTION THERAPY (BLOCK 2): Beginning at least 7 days after the last dose of IT chemotherapy, patients received etoposide IV over 2 hours and cyclophosphamide IV over 30 minutes on days 1-5. Patients also received high-dose methotrexate IV continuously over 24 hours on day 22. Beginning 42 hours after the start of the methotrexate infusion (day 24), patients received leucovorin calcium IV every 6 hours for a minimum of 3 doses. Patients with CNS-negative disease also receive methotrexate IT on days 1 and 22. Patients with CNS-positive disease will receive triple IT as in re-induction therapy (block 1) on days 1 and 22. Patients received filgrastim (G-CSF) subcutaneously (SC) once daily beginning on day 6 and continuing until blood counts recover.

RE-INDUCTION THERAPY (PART 3): Beginning at least 7 days after the last dose of IT chemotherapy, patients received cytarabine IV over 3 hours twice daily on days 1, 2, 8, and 9 and native E. Coli asparaginase IM on days 2 and 9. Patients receive G-CSF SC once daily beginning on day 10 and continuing until blood counts recovered.

PART B:

RE-INDUCTION THERAPY (BLOCK 1): Patients received vincristine, prednisone, pegaspargase, doxorubicin, cytarabine, methotrexate, and epratuzumab as in phase I re-induction therapy (block 1). Epratuzumab was given on Days 1, 8, 15 and 22 before amendment 5 (B1 cohort) and on Days 1, 4, 8, 11, 15, 18, 22 and 25 after amendment 5 (B2 cohort) Patients with CNS-negative disease received methotrexate IT on days 1 and 22. Patients with CNS-positive disease received triple IT therapy comprising methotrexate, cytarabine, and hydrocortisone on days 8, 15, 22, and 29.

RE-INDUCTION THERAPY (BLOCKS 2 AND 3): Patients received re-induction therapy blocks 2 and 3 as in the part A re-induction therapy (blocks 2 and 3) portion of the study.

Patients are followed annually.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 134
• Est. completion date: April 2011
• Est. primary completion date: April 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 2 Years to 31 Years

Eligibility

Inclusion Criteria:

• Diagnosis of B lymphoblastic leukemia (B-ALL)

• At least 25% expression of CD22 by immunophenotyping

• In marrow relapse (M3 bone marrow) with or without associated extramedullary disease as defined by 1 of the following:

• In first or later marrow relapse occurring any time after initial diagnosis (part A [closed to accrual as of 10/30/06] or B)

• In first, early marrow relapse with or without associated extramedullary disease occurring < 36 months from the time of initial diagnosis (part B only)

• No B-cell L3 morphology OR evidence of a regulator gene that codes for a transcription factor (MYC) translocation by molecular or cytogenetic analysis

• No Down syndrome

• Patients with CNS or other extramedullary site involvement are allowed

• Performance status - Karnofsky 50-100% (for patients > 10 years of age)

• Performance status - Lansky 50-100% (for patients = 10 years of age)

• White Blood Count (WBC) = 50,000/mm^3 (part A only [closed to accrual as of 10/30/06])

• Bilirubin = 1.5 times upper limit of normal unless disease-related (ULN)

• Alanine aminotransferase (ALT) = 5 times ULN

• Albumin = 2 g/dL

• Creatinine clearance OR radioisotope glomerular filtration rate = 70 mL/min

• Creatinine as defined by age as follows:

• = 0.5 mg/dL (for patients < 1 year old)

• = 0.8 mg/dL (for patients 1 to 5 years old)

• = 1.0 mg/dL (for patients 6 to 10 years old)

• = 1.2 mg/dL (for patients 11 to 15 years old)

• = 1.5 mg/dL (for patients > 15 years old)

• Shortening fraction = 27% by echocardiogram

• Ejection fraction = 45% by Multi Gated Acquisition Scan (MUGA)

• No dyspnea at rest

• No exercise intolerance

• Pulse oximetry > 94%

• No active or uncontrolled infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• Recovered from prior immunotherapy

• At least 4 months since prior stem cell transplantation or rescue AND no evidence of active graft-vs-host disease

• At least 7 days since prior hematopoietic growth factors

• At least 7 days since prior biologic therapy*

• No other concurrent immunotherapy

• No other concurrent biologic therapy

• Recovered from prior chemotherapy

• No waiting period for children who relapse while receiving standard ALL maintenance therapy

• No prior cumulative anthracycline exposure > 400 mg/m^2*

• No concurrent chemotherapy

• Recovered from prior radiotherapy

• No concurrent radiotherapy

• At least 2 days since prior hydroxyurea

• No other concurrent investigational drugs

• No other concurrent anticancer agents

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Lymphoid
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Recurrent Childhood Acute Lymphoblastic Leukemia

Intervention

Drug:
• L-asparaginase
Given IM
• doxorubicin hydrochloride
Given IV
• therapeutic hydrocortisone
40 mg/m2/day PO divided BID or TID
• vincristine sulfate
Given IV

Biological:
• epratuzumab
Given IV

Drug:
• cytarabine
Given IT
• prednisone
Given orally
• pegaspargase
Given IM
• dexrazoxane hydrochloride
Given IV
• methotrexate
Given IT
• etoposide
Given IV
• cyclophosphamide
Given IV
• leucovorin calcium
Given IV

Biological:
• filgrastim
Given SC

Locations

Country	Name	City	State
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	The Children's Hospital at Westmead	Sydney	New South Wales
Canada	Hospital Sainte-Justine	Montreal	Quebec
Puerto Rico	San Jorge Children's Hospital	Santurce
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University	Baltimore	Maryland
United States	Eastern Maine Medical Center	Bangor	Maine
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Wayne State University	Detroit	Michigan
United States	University of California San Francisco Medical Center-Parnassus	Frisco	California
United States	Baylor College of Medicine	Houston	Texas
United States	M D Anderson Cancer Center	Houston	Texas
United States	Indiana University Medical Center	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	University of Kentucky	Lexington	Kentucky
United States	Loma Linda University Medical Center	Loma Linda	California
United States	Miller Children's Hospital	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Children's Hospital Central California	Madera	California
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Vanderbilt-Ingram Cancer Center	Nashville	Tennessee
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	New York University Langone Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Kaiser Permanente-Oakland	Oakland	California
United States	Childrens Hospital of Orange County	Orange	California
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Primary Children's Medical Center	Salt Lake City	Utah
United States	Seattle Children's Hospital	Seattle	Washington
United States	Saint Joseph Children's Hospital of Tampa	Tampa	Florida
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
Children's Oncology Group	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Remission Re-induction (CR2) Rate	The proportion of patients who achieved complete response at the end Block 1 of re-induction therapy. Complete Remission (CR) - Attainment of M1 bone marrow (<5% blasts) with no evidence of circulating blasts or extramedullary disease and with recovery of peripheral counts (ANC >1000/uL and platelet count >100,000/uL). Partial Remission (PR) - Complete disappearance of circulating blasts and achievement of M2 marrow status (5% or < 25% blast cells and adequate cellularity). Partial Remission Cytolytic (PRCL) - Complete disappearance of circulating blasts and achievement of at least 50% reduction from baseline in bone marrow blast count. Minimal Response Cytolytic (MRCL) - 50% reduction in the peripheral blast count with no increase in peripheral white blood cell count.	At the end of Block 1 of re-induction therapy (day 36)
Primary	Event-free Survival Rate	Proportion of patients who were event free at 4 months	At 4 months after enrollment
Primary	Rate of Minimal Residual Disease (MRD) < 0.01%	Proportion of patients (evaluable and had MRD measured at the end of Block 1) who had MRD < 0.01%.	At the end of Block 1 of re-induction therapy (day 36)
Secondary	Pharmacokinetics	Mean trough serum concentration measured before final dose of epratuzumab.	Up to day 36