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B-cell Childhood Acute Lymphoblastic LeukemiaPhase 3NCT00382109

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

A Phase 3 study testing thiotepa, cyclophosphamide and tacrolimus in people with B-cell Childhood Acute Lymphoblastic Leukemia and Childhood Acute Lymphoblastic Leukemia in Remission, run by Children's Oncology Group at 50 sites in 3 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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… Read more about this study

Who is it for?
Ages 1 year to 21 years
What is being tested?
thiotepa, cyclophosphamide and tacrolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
146 participants
Where
50 sitesin 3 countries
Study dates
Mar 2007to 30 Jun 2017
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 1 year to 21 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • 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)
Show all 39Show fewer
  • 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

Who cannot join

None listed.

Trial locations and contacts

50 sites in 3 countries.

50 sites in 3 countries

United States44 sites

  • C S Mott Children's Hospital

    Ann Arbor, Michigan, 48109

  • Children's Healthcare of Atlanta - Egleston

    Atlanta, Georgia, 30322

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

  • Johns Hopkins University

    Baltimore, Maryland, 21287-8936

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • Childrens Memorial Hospital

    Chicago, Illinois, 60614

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

  • Rainbow Babies and Childrens Hospital

    Cleveland, Ohio, 44106

  • Cleveland Clinic Foundation

    Cleveland, Ohio, 44195

  • Nationwide Children's Hospital

    Columbus, Ohio, 43205

  • University of Texas Southwestern Medical Center

    Dallas, Texas, 75390

  • Wayne State University

    Detroit, Michigan, 48202

  • City of Hope Medical Center

    Duarte, California, 91010

  • Cook Children's Medical Center

    Fort Worth, Texas, 76104

  • Hackensack University Medical Center

    Hackensack, New Jersey, 07601

  • Penn State Hershey Children's Hospital

    Hershey, Pennsylvania, 17033

  • Indiana University Medical Center

    Indianapolis, Indiana, 46202

  • University of Iowa Hospitals and Clinics

    Iowa City, Iowa, 52242

  • The Childrens Mercy Hospital

    Kansas City, Missouri, 64108

  • Kosair Children's Hospital

    Louisville, Kentucky, 40202

  • University of Wisconsin Hospital and Clinics

    Madison, Wisconsin, 53792

  • Midwest Children's Cancer Center

    Milwaukee, Wisconsin, 53226

  • Vanderbilt-Ingram Cancer Center

    Nashville, Tennessee, 37232

  • Children's Hospital-Main Campus

    New Orleans, Louisiana, 70118

  • Columbia University Medical Center

    New York, New York, 10032

  • Children's Hospital and Research Center at Oakland

    Oakland, California, 94609-1809

  • Childrens Hospital of Orange County

    Orange, California, 92868-3874

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

  • Phoenix Childrens Hospital

    Phoenix, Arizona, 85016

  • Children's Hospital of Pittsburgh of UPMC

    Pittsburgh, Pennsylvania, 15224

  • Oregon Health and Science University

    Portland, Oregon, 97239

  • Virginia Commonwealth University

    Richmond, Virginia, 23298

  • University of Rochester

    Rochester, New York, 14642

  • Primary Children's Medical Center

    Salt Lake City, Utah, 84113

  • Methodist Children's Hospital of South Texas

    San Antonio, Texas, 78229

  • Rady Children's Hospital - San Diego

    San Diego, California, 92123

  • University of California San Francisco Medical Center-Parnassus

    San Francisco, California, 94143

  • Seattle Children's Hospital

    Seattle, Washington, 98105

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • All Children's Hospital

    St. Petersburg, Florida, 33701

  • New York Medical College

    Valhalla, New York, 10595

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

Other trials in United States

Canada4 sites

  • The Montreal Children's Hospital of the MUHC

    Montreal, Quebec, H3H 1P3

  • Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

  • British Columbia Children's Hospital

    Vancouver, British Columbia, V6H 3V4

  • CancerCare Manitoba

    Winnipeg, Manitoba, R3E 0V9

Other trials in Canada

Australia2 sites

  • Royal Brisbane and Women's Hospital

    Herston, Queensland, 4029

  • Princess Margaret Hospital for Children

    Perth, Western Australia, 6008

Other trials in Australia

About this study

Official title: A Randomized Trial of Sirolimus-Based Graft Versus Host Disease Prophylaxis After Hematopoietic Stem Cell Transplantation in Relapsed Acute Lymphoblastic Leukemia

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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.

Medical subject headings
Graft vs Host Disease, Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • thiotepaDrug

    Also called Oncotiotepa, STEPA, TESPA, Tespamin

    Given IV

  • cyclophosphamideDrug

    Also called CPM, CTX, Cytoxan, Endoxan

    Given IV

  • tacrolimusDrug

    Also called FK 506, Prograf

    Given IV or orally

  • methotrexateDrug

    Also called amethopterin, Folex, methylaminopterin, Mexate

    Given IV

  • sirolimusDrug

    Also called AY 22989, Rapamune, rapamycin, SLM

    Given orally

  • total body irradiationRadiation

    Also called TBI

    Part of the transplant preparatory regimen

Study groups in NCT00382109
Study groupRoleWhat they receive
Tacro-MTX/Sirolimus GVHD Prophylaxis RegimenExperimentalPreparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors) and oral sirolimus (dose 2.5mg/m2/day - 4 mg max starting dose) daily starting on day 0 followed by a taper starting on day 180 through day 207.
Receives: Drug: thiotepa; Drug: cyclophosphamide; Drug: tacrolimus; Drug: methotrexate; Drug: sirolimus; Radiation: total body irradiation
Tacro-MTX GVHD ProphylaxisActive comparatorPreparative regimen of total body irradiation (TBI) 200 cGy BID days -8,-7, \& -6, Thiotepa IV (dose 5 mg/kg/day on days -5 \& -4) \& cyclophosphamide IV (dose 60 mg/kg/day on days -3 \& -2). Tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally (when able) daily on day -2 with a taper starting on day 42 - day 98 (patients undergoing matched sibling donor transplantation) OR tacrolimus IV (dose 0.02 mg/kg/day) continuously or orally daily beginning on day -2 followed by a taper on day 100 through day 180 (patients undergoing other related, unrelated, or cord blood donor transplantation) in the absence of GVHD. Patients also receive methotrexate IV (5 mg/m2/dose) on days 1,3, \& 6 (patients with matched sibling and umbilical cord blood donors) OR days 1,3 6, \& 11 (patients with other related/unrelated bone marrow and peripheral blood stem cell donors).
Receives: Drug: thiotepa; Drug: cyclophosphamide; Drug: tacrolimus; Drug: methotrexate; Radiation: total body irradiation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Estimated Percentage of Participants With Event Free Survival

    An event is defined as relapse or transplant-related mortality. Relapse is defined in section 3.3 study protocol.

    Measured: at 2 years

Secondary outcomes (8)

  1. Rate of Relapses

    An event is defined as relapse.

    Measured: At 2 years

  2. Estimated Transplant Related Mortality Percentage

    Death in a patient who had not relapsed after transplant is defined as transplant-related mortality event.

    Measured: 100 days

  3. Estimated Rate of Acute Graft VS Host Disease (GVHD)

    Any grade acute graft vs host disease (defined in APPENDIX II study protocol).

    Measured: At 200 days

  4. Estimated Rate of Overall Chronic Graft VS Host Disease

    Chronic graft vs host disease is defined in APPENDIX III of study protocol.

    Measured: At 2 years

  5. Relative Contribution of Resistance by Acute Lymphoblastic Leukemia (ALL) Blasts to Cytolytic Therapy (e.g., Chemotherapy/Irradiation) as a Cause of Relapse Post-transplantation

    An event is defined as relapse or transplant-related mortality.

    Measured: Up to 1 year

  6. Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Post Transplantation (Correlating Development of aGVHD With Relapse)

    An event is defined as relapse; estimated probability of relapse.

    Measured: At 1 year

  7. Relative Contribution of ALL Blasts to the Donor Immune Response as a Cause of Relapse Pre-Transplantation (MRD)

    An event is defined as relapse; relapse risk is reported. Not able to be performed given the low numbers of blast samples available.

    Measured: At 2 months

  8. Chimerism

    Evaluate the relative contribution of resistance by ALL blasts to the donor immune response as a cause of relapse post transplantation.

    Measured: Up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted28 Sep 2006 (estimated)
  2. Study startMar 2007
  3. Primary completionMay 2011
  4. Study completion30 Jun 2017

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
146 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00382109
Sponsor's protocol ID
ASCT0431
Other IDs
NCI-2009-01068, CDR0000500131, COG-PBMTC-ONCO51, COG-ASCT0431, U10CA098543
Status last verified
Jun 2019
First submitted
26 Sep 2006
Last updated
7 Aug 2019
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 25862561

  • 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.

    PubMed 24497539

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing thiotepa, cyclophosphamide and tacrolimus in people with B-cell Childhood Acute Lymphoblastic Leukemia and Childhood Acute Lymphoblastic Leukemia in Remission, run by Children's Oncology Group at 50 sites in 3 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 39 inclusion and 0 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 7 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 50 sites in United States, Canada, Australia. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 9 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Estimated Percentage of Participants With Event Free Survival (time frame: at 2 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00382109, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Aug 2019.

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