Clinical trial NCT02043587: Chemotherapy With Liposomal Cytarabine CNS Prophylaxis for Adult Acute Lymphoblastic Leukemia & Lymphoblastic Lymphoma
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Acute Lymphocytic Leukemia
Adult Lymphoblastic Lymphoma
Keywords: Acute lymphoblastic leukemia
Lymphoblastic leukemia
Lymphoblastic lymphoma
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: Leadiant Biosciences, Inc.
First posted: 2014-01-23
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Event-free survival
timeFrame: 3-year
Secondary outcomes:
measure: Liposomal cytarabine toxicity
timeFrame: 3 years
measure: CNS relapse rate
timeFrame: 3-year
measure: Overall survival
timeFrame: 3-year
measure: Leukemia-free survival
timeFrame: 3-year
measure: Efficacy of hydrocortisone premedication for reduced PEG-asparaginase allergic reactions
timeFrame: 3 years
measure: PEG-asparaginase toxicities
timeFrame: 3 years
measure: Complete and overall response rates
timeFrame: 3 years
measure: Non-relapse mortality
timeFrame: 3-year
Other outcomes:
measure: Minimal residual disease and outcomes
timeFrame: 3 years
measure: Asparaginase antibodies and asparaginase activity
timeFrame: 3 years
Locations:
city: La Jolla
country: United States
facility: UCSD, Division of Blood and Marrow Transplantation, Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: Hematological Malignancies/Stem Cell Transplantation Unit, David Geffen School of Medicine at UCLA
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: San Francisco
country: United States
facility: UCSF Comprehensive Cancer Center
state: California
Study officials:
affiliation: UC San Diego, Division of Blood and Marrow Transplantation
name: James K Mangan, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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. doi: 10.1200/JCO.2002.07.116.