Clinical Trial: NCT01203722 - My Cancer Genome

NCT01203722

Description:

If transplantation using mismatched unrelated donors or non-first-degree relatives could be performed with an acceptable toxicity profile, an important unmet need would be served. Towards this goal, the current study extends our platform of nonmyeloablative, partially HLA-mismatched bone marrow transplant (BMT) and Peripheral Blood Stem Cell Transplant (PBSCT) to the use of such donors, investigating up to several postgrafting immunosuppression regimens that incorporate high-dose Cy. Of central interest is the incorporation of sirolimus into this postgrafting immunosuppression regimen. The primary goal for phase 1 is to identify a transplant regimen associated with acceptable rates of severe acute GVHD and NRM by Day 100 and for phase 2 estimate the 6-month probability of survival without having had acute grade III- IV GVHD or graft failure.

Related Conditions:

Acute Biphenotypic Leukemia
Acute Leukemia
Acute Lymphoblastic Leukemia
Acute Myeloid Leukemia
Anaplastic Large Cell Lymphoma
Burkitt Lymphoma
Chronic Lymphocytic Leukemia
Chronic Myeloid Leukemia
Chronic Myelomonocytic Leukemia
Hodgkin Lymphoma
Juvenile Myelomonocytic Leukemia
Lymphoblastic Lymphoma
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasm
Myeloproliferative Neoplasm
Non-Hodgkin Lymphoma
Prolymphocytic Leukemia
Small Lymphocytic Lymphoma
Therapy-Related Myelodysplastic Syndrome

Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

URL:

https://clinicaltrials.gov/show/NCT01203722

Trial Eligibility

Document

Title

Brief Title: Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies
Official Title: Reduced Intensity, Partially HLA Mismatched Allogeneic BMT for Hematologic Malignancies Using Donors Other Than First-degree Relatives

Clinical Trial IDs

ORG STUDY ID: J1055
SECONDARY ID: NA_00039823
SECONDARY ID: P01CA015396
NCT ID: NCT01203722

Conditions

Hematologic Malignancies

Interventions

Drug	Synonyms	Arms
Fludarabine		REGIMEN B
Cytoxan	High-dose Cytoxan	REGIMEN B
Mycophenolate Mofetil	MMF	REGIMEN B
Sirolimus		REGIMEN B
Tacrolimus		REGIMEN C

Purpose

Trial Arms

Name	Type	Description	Interventions
REGIMEN B	Active Comparator	Pre-BMT : Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV Day -1: 400 cGy total body irradiation (TBI) administered in a single fraction Day 0: Allogeneic blood or marrow transplantation (BMT) Post-Transplantation Immunosuppression Consisting of: Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV Day 5: Sirolimus loading dose 6 mg PO once Day 5 thru Day 35: Mycophenolate Mofetil (MMF) 15 mg/kg PO TID (maximum daily dose 3 g/day) Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL	Fludarabine Cytoxan Mycophenolate Mofetil Sirolimus
REGIMEN C	Active Comparator	Pre-BMT: Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV Day -1: 400 cGy TBI administered in a single fraction Day 0: BMT Post-Transplantation Immunosuppression Consisting of: Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) Day 5 thru Day 180: Tacrolimus 1 mg administered IV QD	Fludarabine Cytoxan Mycophenolate Mofetil Tacrolimus
REGIMEN B2	Active Comparator	Pre-PBSCT: Day -6 through -2: Fludarabine 30 mg/m2/day (adjusted for renal function; maximum cumulative dose, 150 mg/m2) administered IV Day -6 and -5: Cytoxan 14.5 mg/kg/day administered IV Day -1: 400 cGy TBI administered in a single fraction Day 0: Peripheral Blood Stem Cell Transplant (PBSCT) Post-Transplantation Immunosuppression Consisting of: Day 3 and 4: High-dose Cytoxan 50mg/kg/day (adjusted according to IBW) administered IV Day 5: Sirolimus loading dose 6 mg PO once Day 5 thru Day 35: MMF 15 mg/kg PO TID (maximum daily dose 3 g/day) Day 6 thru Day 180: Sirolimus maintenance dose 2 mg PO QD with dose adjustments to maintain trough of 3 - 12 ng/mL	Fludarabine Cytoxan Mycophenolate Mofetil Sirolimus

Eligibility Criteria

        Patient Inclusion Criteria:

          -  Patient age 0.5-75 years

          -  Absence of a suitable related or unrelated bone marrow donor who is molecularly
             matched at HLA-A, B, Cw, DRB1, and DQB1.

          -  Absence of a suitable partially HLA-mismatched (haploidentical), first-degree related
             donor.

          -  Eligible diagnoses:

               -  Relapsed or refractory acute leukemia in second or subsequent remission, with
                  remission defined as <5% bone marrow blasts morphologically

               -  Poor-risk acute leukemia in first remission, with remission defined as <5% bone
                  marrow blasts morphologically:

               -  AML with at least one of the following:

                    -  AML arising from MDS or a myeloproliferative disorder, or secondary AML

                    -  Presence of Flt3 internal tandem duplications

                    -  Poor-risk cytogenetics: Complex karyotype [> 3 abnormalities], inv(3),
                       t(3;3), t(6;9), MLL rearrangement with the exception of t(9;11), or
                       abnormalities of chromosome 5 or 7

                    -  Primary refractory disease

               -  ALL (leukemia and/or lymphoma) with at least one of the following:

                    -  Adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or MLL rearrangement

                    -  Clear evidence of hypodiploidy

                    -  Primary refractory disease

                    -  Biphenotypic leukemia

               -  MDS with at least one of the following poor-risk features:

                    -  Poor-risk cytogenetics (7/7q minus or complex cytogenetics)

                    -  IPSS score of INT-2 or greater

                    -  Treatment-related MDS

                    -  MDS diagnosed before age 21 years

                    -  Progression on or lack of response to standard DNA-methyltransferase
                       inhibitor therapy

                    -  Life-threatening cytopenias, including those generally requiring greater
                       than weekly transfusions

               -  Interferon- or imatinib-refractory CML in first chronic phase, or non-blast
                  crisis CML beyond first chronic phase.

               -  Philadelphia chromosome negative myeloproliferative disease.

               -  Chronic myelomonocytic leukemia.

               -  Juvenile myelomonocytic leukemia.

               -  Low-grade non-Hodgkin lymphoma (including SLL and CLL) or plasma cell neoplasm
                  that has progressed after at least two prior therapies (excluding single agent
                  rituximab and single agent steroids), or in the case of lymphoma undergone
                  histologic conversion

               -  Poor-risk CLL or SLL

               -  Aggressive non-Hodgkin lymphoma as follows, provided there is stable disease or
                  better to last therapy:

                    -  NK or NK-T cell lymphoma, hepatosplenic T-cell lymphoma, or subcutaneous
                       panniculitic T-cell lymphoma, blastic/ blastoid variant of mantle cell
                       lymphoma

                    -  Hodgkin or aggressive non Hodgkin lymphoma that has failed at least one
                       multiagent regimen, and the patient is either ineligible for autologous BMT
                       or autologous BMT is not recommended. Eligible subtypes of aggressive
                       non-Hodgkin lymphoma include:

                         -  mantle cell lymphoma

                         -  follicular grade 3 lymphoma

                         -  diffuse large B-cell lymphoma or its subtypes, excluding primary CNS
                            lymphoma

                         -  primary mediastinal large B-cell lymphoma

                         -  large B-cell lymphoma, unspecified

                         -  anaplastic large cell lymphoma, excluding skin-only disease

                         -  peripheral T-cell lymphoma, including angioimmunoblastic T-cell
                            lymphoma

                         -  Burkitt's lymphoma or atypical Burkitt's lymphoma (high-grade B-cell
                            lymphoma, unclassifiable, with features intermediate between diffuse
                            large B-cell lymphoma and Burkitt's), in complete remission

          -  Patients with CLL, SLL, or prolymphocytic leukemia must have < 20% bone marrow
             involvement by malignancy (to lower risk of graft rejection).

          -  One of the following, in order to lower risk of graft rejection:

               -  Cytotoxic chemotherapy, an adequate course of 5-azacitidine or decitabine, or
                  alemtuzumab within 3 months prior to start of conditioning; or

               -  Previous BMT within 6 months prior to start of conditioning. NOTE:Patients who
                  have received treatment outside of these windows may be eligible if it is deemed
                  sufficient to reduce graft rejection risk; this will be decided on a case-by-case
                  basis by the PI or co-PI.

          -  Any previous BMT must have occurred at least 3 months prior to start of conditioning.

          -  Adequate end-organ function.

          -  ECOG performance status < 2 or Karnofsky or Lansky score > 60

        Patient Exclusion Criteria:

          -  Not pregnant or breast-feeding.

          -  No uncontrolled bacterial, viral, or fungal infection.

               -  Note: HIV-infected patients are potentially eligible. Eligibility of HIV-infected
                  patients will be determined on a case-by-case basis.

          -  No previous allogeneic BMT (syngeneic BMT permissible).

          -  Active extramedullary leukemia or known active CNS involvement by malignancy. Such
             disease treated into remission is permitted.

        Donor Inclusion Criteria:

          -  Potential donors consist of:

               -  Unrelated donors

               -  Second-degree relatives

               -  First cousins

          -  The donor and recipient must be identical at at least 5 HLA alleles based on high
             resolution typing of HLA-A, -B, -Cw, -DRB1, and -DQB1, with at least one allele
             matched for a HLA class I gene (HLA-A, -B, or -Cw) and at least one allele matched for
             a class II gene (HLA-DRB1 or -DQB1).

          -  Meets institutional selection criteria and medically fit to donate.

          -  Lack of recipient anti-donor HLA antibody. Note: In some instances, low level,
             non-cytotoxic HLA specific antibodies may be permissible if they are found to be at a
             level well below that detectable by flow cytometry. This will be decided on a
             case-by-case basis by the PI and one of the immunogenetics directors. Pheresis to
             reduce anti-HLA antibodies is permissible; however eligibility to proceed with the
             transplant regimen would be contingent upon the result.

        Donor Exclusion Criteria:

          -  Donor must not be HLA identical to the recipient.

          -  Has not donated blood products to recipient.

Maximum Eligible Age:	75 Years
Minimum Eligible Age:	6 Months
Eligible Gender:	All
Healthy Volunteers:	Accepts Healthy Volunteers

Primary Outcome Measures

Measure:	Transplant regimen as determined by rates of severe acute graft-versus-host-disease (GVHD)
Time Frame:	Study Day 100
Safety Issue:
Description:	Two immunosuppressive regimens with Fludarabine-Cytoxan-TBI conditioning will be studied in reduced-intensity, partially HLA mismatched allogeneic BMT from unrelated or non-first-degree related donors. Transplant regimen will be determined by acceptable rates of severe acute GVHD (< 25%).

Secondary Outcome Measures

Measure:	Progression-free survival
Time Frame:	7 years
Safety Issue:
Description:	All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.

Measure:	Event-free survival
Time Frame:	7 years
Safety Issue:
Description:	All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.

Measure:	Overall survival
Time Frame:	7 years
Safety Issue:
Description:	All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.

Measure:	Cumulative incidence of progression or relapse
Time Frame:	7 years
Safety Issue:
Description:	All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.

Measure:	Cumulative incidence of NRM.
Time Frame:	7 years
Safety Issue:
Description:	All patients will be tracked from Day 0 to date of first objective disease progression, death from any cause, or last patient evaluation. Patients who have not progressed or died will be censored at the last date they were assessed and deemed free of relapse or progression.

Measure:	Cumulative incidence of acute grade II-IV GVHD.
Time Frame:	1 year
Safety Issue:
Description:	All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded.

Measure:	Cumulative incidence of acute grade III-IV GVHD
Time Frame:	1 year
Safety Issue:
Description:	All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded.

Measure:	Cumulative incidence of chronic GVHD
Time Frame:	1 year
Safety Issue:
Description:	All suspected cases of acute GVHD must be confirmed histologically by biopsy of an affected organ (skin, liver, or gastrointestinal tract). Date of symptom onset, date of biopsy confirmation of GVHD, maximum clinical grade, and dates and types of treatment will be recorded. Dates of symptom onset of grade II or higher GVHD and grade III-IV GVHD will be recorded.

Details

Phase:	Phase 1/Phase 2
Primary Purpose:	Interventional
Overall Status:	Recruiting
Lead Sponsor:	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Trial Keywords

Reduced intensity
partially HLA mismatched allogeneic BMT
Acute leukemias
Chronic leukemias
Myelodysplasia
Lymphomas
Unrelated or non-first-degree related donors
Peripheral blood stem cell transplant

Last Updated

January 14, 2021

Clinical Trials /

Reduced Intensity, Partially HLA Mismatched BMT to Treat Hematologic Malignancies