Chemotherapy With Liposomal Cytarabine CNS Prophylaxis for Adult Acute Lymphoblastic Leukemia & Lymphoblastic Lymphoma

Acute Lymphocytic Leukemia Clinical Trial

Official title:

A Phase II Study of Punctual, Cyclic, and Intensive Chemotherapy With Liposomal Cytarabine (Depocyt®) CNS Prophylaxis for Adults With Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02043587
• Other study ID #: 130934
• Status: Terminated
• Phase: Phase 2
• Start date: January 2014
• Est. completion date: April 14, 2022

Study information

• Verified date: April 2022
• Source: University of California, San Diego
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this protocol is to improve survival for adults with acute lymphoblastic leukemia or acute lymphoblastic lymphoma by reducing systemic and central nervous system (CNS) relapse with acceptable toxicity using intensive chemotherapy with liposomal cytarabine (Depocyt®) CNS prophylaxis.

Description:

This treatment regimen builds on the "Linker" regimen/UCSF Protocol 8707 ALL regimen backbone with the goal of improved efficacy and acceptable toxicity by substituting pegylated asparaginase for native L-asparaginase, the addition of rituximab for pre-B-cell ALL, and the addition of dasatinib for Philadelphia chromosome/BCR-ABL positive ALL, and the addition of cyclophosphamide for younger adults. In addition, the study regimen aims to reduce CNS relapse through the use of intrathecal liposomal cytarabine in place of intrathecal methotrexate for CNS relapse prophylaxis and The regimen uses 3 modules of therapy with non-cross-resistant chemotherapy agents. Rituximab is added for a total of 8 doses for patients with pre-B-cell ALL. Dasatinib is added for patients with Ph+ ALL. Course 1A (Induction): Daunorubicin, vincristine, PEG-asparaginase, and prednisone for all patients with the addition of cyclophosphamide for patients 18-39 years of age. Treatment is intensified for patients with disease present on a day 14 bone marrow biopsies during Induction Course 1A. In addition to standard analyses, minimal residual disease will be assessed on day 14 and remission bone marrow aspirates and correlated with outcomes. Course 1B: High-dose methotrexate, oral 6-mercaptopurine, and PEG-asparaginase. Course 1C: High-dose cytarabine and etoposide. The 3 courses then repeat (2A (Intensification), 2B, 2C) followed by a final "B" cycle (3B) of high-dose methotrexate, 6-mercaptopurine, and PEG-asparaginase. After completion of Course 3B, patients proceed to maintenance chemotherapy with monthly methotrexate, vincristine, 6-mercaptopurine, and prednisone cycles for 24 months with a single dose PEG-asparaginase given in month 1 of Maintenance. CNS prophylaxis: Intrathecal liposomal cytarabine replaces intrathecal methotrexate CNS prophylaxis and is given every 2 weeks during the "A" Induction and Intensification courses then every 3 months during Maintenance for a total of 8 doses. Given the presence of CNS penetrating chemotherapy in the "B" and "C" cycles, intrathecal liposomal cytarabine is not given due to risk of excessive CNS toxicity. There is a randomization to hydrocortisone or placebo premedication prior to PEG-asparaginase.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 31
• Est. completion date: April 14, 2022
• Est. primary completion date: April 14, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• Ability to understand and the willingness to sign a written informed consent.
• Diagnosis of acute lymphoblastic leukemia or lymphoblastic lymphoma as defined by the World Health Organization [94]
• Untreated disease EXCEPT for corticosteroids, hydroxyurea, leukapheresis, and/or tyrosine kinase inhibitors for up to 2 weeks prior to initiation of study therapy.
• Age 18 through 60 years
• ECOG performance status 0,1, or 2 (see Appendix A)
• Adequate organ function defined as:
• Total bilirubin < 2 mg/dL (unless due to ALL)
• AST(SGOT)/ALT(SGPT) < 3 times institutional upper limit of normal (unless due to ALL)
• Serum creatinine < 2 mg/dL (unless elevated creatinine felt by investigator to be acute and reversible) OR creatinine clearance >60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
• Left ventricular ejection fraction =50%
• Women of child-bearing potential and men with partners of child- bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 90 days following completion of therapy. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.
• A woman of child-bearing potential is any female (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the

following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)

Exclusion Criteria:

• Current or anticipated use of other investigational agents during the study
• Known central nervous system mass lesion
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to liposomal cytarabine or other agents used in study inclusive of known allergy to polyethylene glycol.
• History of unprovoked venous thrombosis/thromboembolism
• Recurrent or chronic pancreatitis
• Uncontrolled diabetes mellitus
• Uncontrolled intercurrent illness that would limit compliance with study requirements including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or nursing.
• Any condition, in the opinion of the investigator, that compromises compliance with study requirements
• Known HIV positivity

Related Conditions & MeSH terms

• Acute Lymphocytic Leukemia
• Adult Lymphoblastic Lymphoma
• Leukemia
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• DNR
Daunorubicin 60 mg/m2 IV (in the vein) daily 1,2,3 Courses 1A, 2A
• VCR
1.4 mg/m2 IV, days 1, 8, 15, 22 (cap at 2mg for ages >50) during Courses 1A, 2A; Maintenance: Day 1 during months 2-12
• PEG-asp
2,000 IU/m2 IV for ages </= 50, age > 50, 1000 IU/m2 IV Day 16, Courses 1A & 2A; Day 18, Course 1B; Day 17, Course 2B; Day 16, Maintenance, Month 1
• CTX
750 mg/m2 IV, days 1 &15 for subjects <40 year of age, substitute cyclophosphamide 500 mg/m2 IV over 60 minutes every 12 hours for 4 doses on days 15 & 16 for subjects < 40 years of age if day 14 bone marrow M2 or M3; Courses 1A & 2A
• Prednisone
60 mg/m2 orally once daily on days 1-28 during Courses 1A & 2A; Maintenance: Monthly, days 1-5
• Liposomal AraC
25 mg intrathecal (IT), on days 1 & 15 during Courses 1A & 2A; 50 mg intrathecal on day 1 during Maintenance Months 1 through 4
• MTX
220 mg/m2 IV bolus over 15 minutes then 60 mg/m2/hour for 36 hours once on days 2-3 and 16-17 during Courses 1B & 2B; 20 mg/m2 orally one day per week every 7 days during Maintenance Months
• LCV
50 mg/m2 IV over 15-30 minutes every 6 hours for 3 doses to begin immediately after completion of methotrexate infusion, then 10 mg/m2 orally or IV over 15-30 minutes every 6 hours until methotrexate level less than 0.1 micromolar during Courses 1B & 2B
• AraC
2,000 mg/m2 IV, days 1-4 during Courses 1C & 2C
• Etoposide
500 mg/m2 IV over 3 hours once daily on days 1-4 during Courses 1C & 2C
• Dasatinib
140 mg orally daily if BCR/ABL positive and/or Ph+
• Rituximab
375 mg/m2 IV once daily on days 1 & 15 (precursor B-cell ALL only, administer per institutional protocol) during Courses 1A, 1B, 1C & 2A
• Hydrocortisone
Randomize patients proceeding to Course 1B to hydrocortisone versus placebo prior to PEG-asparaginase treatments in Courses 1B, 2B, 3B, and Maintenance month 1

Locations

Country	Name	City	State
United States	UCSD, Division of Blood and Marrow Transplantation, Moores Cancer Center	La Jolla	California
United States	Hematological Malignancies/Stem Cell Transplantation Unit, David Geffen School of Medicine at UCLA	Los Angeles	California
United States	University of California Davis Comprehensive Cancer Center	Sacramento	California
United States	UCSF Comprehensive Cancer Center	San Francisco	California

Sponsors (2)

Lead Sponsor	Collaborator
University of California, San Diego	Leadiant Biosciences, Inc.

Country where clinical trial is conducted

United States, 

References & Publications (1)

Linker C, Damon L, Ries C, Navarro W. Intensified and shortened cyclical chemotherapy for adult acute lymphoblastic leukemia. J Clin Oncol. 2002 May 15;20(10):2464-71. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Minimal residual disease and outcomes		3 years
Other	Asparaginase antibodies and asparaginase activity		3 years
Primary	Event-free survival		3-year
Secondary	Liposomal cytarabine toxicity		3 years
Secondary	CNS relapse rate		3-year
Secondary	Overall survival		3-year
Secondary	Leukemia-free survival		3-year
Secondary	Efficacy of hydrocortisone premedication for reduced PEG-asparaginase allergic reactions		3 years
Secondary	PEG-asparaginase toxicities		3 years
Secondary	Complete and overall response rates		3 years
Secondary	Non-relapse mortality		3-year