Clinical trial NCT00382109: Tacrolimus and Methotrexate With or Without Sirolimus in Preventing Graft-Versus-Host Disease in Young Patients Undergoing Donor Stem Cell Transplant for Acute Lymphoblastic Leukemia in Complete Remission
Official title: A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: B-cell Childhood Acute Lymphoblastic Leukemia
Childhood Acute Lymphoblastic Leukemia in Remission
Graft Versus Host Disease
L1 Childhood Acute Lymphoblastic Leukemia
L2 Childhood Acute Lymphoblastic Leukemia
T-cell Childhood Acute Lymphoblastic Leukemia
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-09-28
Enrollment: 146
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase III trial is studying tacrolimus, methotrexate, and sirolimus to see how well they work compared to tacrolimus and methotrexate in preventing graft-versus-host disease in young patients who are undergoing donor stem cell transplant for intermediate-risk or high-risk acute lymphoblastic leukemia in second complete remission and high risk acute lymphoblastic leukemia in first remission. Giving chemotherapy, such as thiotepa and cyclophosphamide, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. The donated stem cells may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus, methotrexate, and sirolimus after the transplant may stop this from happening. It is not yet known whether tacrolimus and methotrexate are more effective with or without sirolimus in preventing graft-versus-host disease.

Detailed description: PRIMARY OBJECTIVES:

I. Compare the post-transplant 2-year event-free survival of pediatric patients with intermediate-risk or high-risk acute lymphoblastic leukemia (ALL) in second complete remission or high risk ALL in first remission undergoing allogeneic hematopoietic stem cell transplantation treated with graft-versus-host disease (GVHD) prophylaxis comprising tacrolimus and methotrexate with or without sirolimus.

SECONDARY OBJECTIVES:

I. Compare rates of relapses, transplant-related mortality, and acute and chronic GVHD in these patients.

II. Evaluate the relative contribution of resistance by ALL blasts to cytolytic therapy (e.g., chemotherapy/irradiation) as a cause of relapse post-transplantation by correlating ALL in vivo blast resistance with in vivo sirolimus, inhibition levels of the mTOR pathway in patients treated with sirolimus, and altered resistance pathways in ALL blasts measured by microarray analysis.

III. Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post-transplantation by correlating the development of donor anti-ALL T-cell response, the development of acute and/or chronic GVHD, and the detection of altered ALL blast immunogenicity after transplant with increased minimal residual disease, persistent recipient chimerism, and relapse.

OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to specific combinations of risk (intermediate CR2 vs high CR2 vs high CR1), donor type (matched sibling vs unrelated or other related), and stem cell source (filgrastim \[G-CSF\]-primed bone marrow vs unprimed bone marrow vs bone marrow vs peripheral blood vs umbilical cord blood).

PREPARATIVE REGIMEN: Patients undergo total-body irradiation twice daily on days -8 to -6 and receive thiotepa IV on days -5 and -4 and cyclophosphamide IV on days -3 and -2.

ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: Patients undergo allogeneic hematopoietic stem cell transplantation on day 0.

GRAFT-VERSUS-HOST DISEASE (GVHD) PROPHYLAXIS: Patients are randomized to 1 of 2 treatment arms.

ARM I: (experimental) Patients receive tacrolimus IV continuously or orally (when able) daily beginning on day -2 followed by a taper beginning on day 42 and continuing until day 98 (for patients undergoing matched sibling donor transplantation) OR tacrolimus IV continuously or orally daily beginning on day -2 followed by a taper beginning on day 100 and continuing until day 180 (for patients undergoing related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV on days 1, 3, and 6 (for patients with matched sibling and umbilical cord blood donors) OR days 1, 3, 6, and 11 (for patients with unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus daily beginning on day 0 followed by a taper beginning on day 180 and continuing until day 207.

ARM II: (control) Patients receive tacrolimus and methotrexate as in arm I.

After completion of study treatment, patients are followed periodically for approximately 5 years.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed acute lymphoblastic leukemia (ALL) in second complete remission (CR2) (M1 bone marrow, \< 5% blasts by morphology) meeting the following criteria:

  * Intermediate risk relapsed ALL in CR2 (may receive matched sibling transplantation only) meeting 1 of the following criteria:

    * B-lineage ALL in CR2 after a late first bone marrow (BM) relapse (≥ 36 months after the initiation of primary chemotherapy) with or without associated extramedullary disease
    * B-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy)
  * High risk relapsed ALL in CR2 (may receive other related donor, unrelated donor, or matched sibling transplantation) meeting 1 of the following criteria:

    * In CR2 after an early first BM relapse (\< 36 months from initiation of primary chemotherapy)
    * T-lineage ALL in CR2 after a first BM relapse occurring at any time after initiation of primary chemotherapy
    * Philadelphia chromosome-positive ALL in CR2 after a first BM relapse occurring at any time after the initiation of primary chemotherapy
    * T-lineage ALL in CR2 after a very early isolated extramedullary relapse (\<18 months from the initiation of primary chemotherapy)
  * High risk de novo ALL in CR1 (may receive matched sibling, other related/unrelated BM/PBSC or unrelated CB transplantation) meeting 1 of the following criteria:

    * Patients with the presence of t(9;22) translocation (Ph+) detected by cytogenetic or PCR analysis at initial diagnosis. For patients on AALL0622, the criteria for transplant are 1) any patient with Ph+ ALL with an available matched sibling donor or 2) any patient with Ph+ ALL that is defined as high risk (MRD \> 1% Day 29 or MRD \> 0.01% end-Consolidation Block 2) with any available donor, related or unrelated. Patients enrolled on AALL0622 are only eligible if they follow this algorithm.
    * Patients with the presence of extreme hypodiploidy (\< 44 chromosomes or DNA index of \< 0.81) detected by cytogenetic/ploidy analysis at initial diagnosis.
    * Patients with the presence of 11q23 (MLL) rearrangements detected by cytogenetic or PCR analysis at initial diagnosis who are slow early responders (M2/M3 at Day 14 or MRD \> 0.1% at Day 29).
* Enrolled on an appropriate COG relapsed ALL clinical trial after completing the required study therapy (i.e., minimum 1 re-induction course (4-6 weeks) and 1 round of intensive consolidation chemotherapy (3-6 weeks). Patients with high risk ALL in CR1 are eligible as soon as they have achieved a CR.

  * Patients not on a COG relapsed ALL clinical trial are eligible provided they have received ≥ 1 round of re-induction lasting 4-6 weeks and 1 round of intensive consolidation chemotherapy lasting 3-6 weeks
* No B-cell ALL L3 morphology with evidence of myc translocation by molecular or cytogenetic technique
* No Down syndrome
* No evidence of active CNS or other extramedullary disease (i.e., no CNS2)
* Karnofsky performance status (PS) 60-100% (for patients \> 16 years of age) OR Lansky PS 60-100% (for patients ≤ 16 years of age)
* Shortening fraction ≥ 27% by echocardiogram OR ejection fraction ≥ 50% by radionuclide angiogram
* ALT or AST \< 5 times upper limit of normal
* Bilirubin \< 2.5 mg/dL (unless an increase is attributable to Gilbert's syndrome)
* Creatinine clearance OR radioisotope glomerular filtration rate ≥ 70 mL/min
* FEV_1 ≥ 60% by pulmonary function tests (PFTs)
* FVC ≥ 60% by PFTs
* DLCO ≥ 60% by PFTs
* For children who are unable to cooperate for PFTs all of the following criteria must be met:

  * No evidence of dyspnea at rest
  * No exercise intolerance
  * No requirement for supplemental oxygen therapy
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No HIV or uncontrolled fungal, bacterial, or viral infection

  * Fungal infection acquired during induction therapy allowed provided there is a significant response to antifungal therapy with minimal or no evidence of disease by CT scan
* Other concurrent immunosuppressants allowed
* No prior allogeneic or autologous stem cell transplantation
* No prior or concurrent voriconazole unless prior voriconazole therapy is completed or a different agent is substituted for voriconazole prior to study entry
* No concurrent grapefruit juice during sirolimus administration

Primary outcomes:
measure: Estimated Percentage of Participants With Event Free Survival
timeFrame: at 2 years
Secondary outcomes:
measure: Rate of Relapses
timeFrame: At 2 years
measure: Estimated Transplant Related Mortality Percentage
timeFrame: 100 days
measure: Estimated Rate of Acute Graft VS Host Disease (GVHD)
timeFrame: At 200 days
measure: Estimated Rate of Overall Chronic Graft VS Host Disease
timeFrame: At 2 years
measure: Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation
timeFrame: Up to 1 year
measure: Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)
timeFrame: At 1 year
measure: Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)
timeFrame: At 2 months
measure: Chimerism
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Oakland
country: United States
facility: Children's Hospital and Research Center at Oakland
state: California
city: Orange
country: United States
facility: Childrens Hospital of Orange County
state: California
city: San Diego
country: United States
facility: Rady Children's Hospital - San Diego
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center-Parnassus
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Saint Petersburg
country: United States
facility: All Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Chicago
country: United States
facility: Childrens Memorial Hospital
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Louisville
country: United States
facility: Kosair Children's Hospital
state: Kentucky
city: New Orleans
country: United States
facility: Children's Hospital-Main Campus
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Kansas City
country: United States
facility: The Childrens Mercy Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Valhalla
country: United States
facility: New York Medical College
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Hershey
country: United States
facility: Penn State Hershey Children's Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
city: Fort Worth
country: United States
facility: Cook Children's Medical Center
state: Texas
city: San Antonio
country: United States
facility: Methodist Children's Hospital of South Texas
state: Texas
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Midwest Children's Cancer Center
state: Wisconsin
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
state: Queensland
city: Perth
country: Australia
facility: Princess Margaret Hospital for Children
state: Western Australia
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: The Montreal Children's Hospital of the MUHC
state: Quebec
Study officials:
affiliation: Children's Oncology Group
name: Michael Pulsipher, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Pulsipher MA, Carlson C, Langholz B, Wall DA, Schultz KR, Bunin N, Kirsch I, Gastier-Foster JM, Borowitz M, Desmarais C, Williamson D, Kalos M, Grupp SA. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. 2015 May 28;125(22):3501-8. doi: 10.1182/blood-2014-12-615757. Epub 2015 Apr 10.
citation: Pulsipher MA, Langholz B, Wall DA, Schultz KR, Bunin N, Carroll WL, Raetz E, Gardner S, Gastier-Foster JM, Howrie D, Goyal RK, Douglas JG, Borowitz M, Barnes Y, Teachey DT, Taylor C, Grupp SA. The addition of sirolimus to tacrolimus/methotrexate GVHD prophylaxis in children with ALL: a phase 3 Children's Oncology Group/Pediatric Blood and Marrow Transplant Consortium trial. Blood. 2014 Mar 27;123(13):2017-25. doi: 10.1182/blood-2013-10-534297. Epub 2014 Feb 4.