NCT00520130

Chemotherapy and Unrelated Donor Stem Cell Transplantation for Patients With Cancers of the Blood and Immune System

Completed Phase 1, PHASE2 Results posted Last updated 5 March 2019

What this trial tests

Phase 1, PHASE2 trial testing Rituximab in Myelodysplastic Syndrome in 92 participants. Completed in 31 December 2018.

Timeline

30 October 2007

Primary endpoint
14 October 2015

31 December 2018

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 1, PHASE2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	92
Start date	30 October 2007
Primary completion	14 October 2015
Estimated completion	31 December 2018
Sites	1 location across United States

Drugs / interventions tested

• Rituximab — full drug profile →
• Cyclosporine (cyclosporine) — full drug profile →
• Allogenic stem cell transplant (ASCT)
• Conditioning Chemotherapy
• TMS
• FLAG
• EPOCH-F
• Alemtuzumab (ALEMTUZUMAB) — full drug profile →

Conditions studied

• Myelodysplastic Syndrome — all drugs for Myelodysplastic Syndrome →
• Hodgkin's Lymphoma — all drugs for Hodgkin's Lymphoma →
• Non-Hodgkin's Disease — all drugs for Non-Hodgkin's Disease →
• Acute Leukemia — all drugs for Acute Leukemia →

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 18 to 74, any sex, with Myelodysplastic Syndrome or Hodgkin's Lymphoma. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Percentage of Participants With Grade II-IV Acute Graft Versus Host Disease (GVHD) Primary · 6 months

Acute GVHD is assessed by the 1994 Consensus Conference on Acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	42	26 – 57
B - Cyclosporine (AC) Arm	38	23 – 53

Percentage of Participants With Chronic Graft Versus Host Disease (cGVHD) Primary · 2 years post transplant

Chronic GVHD is assessed by the 2005 Chronic GVHD Consensus Project. First the individual organ scoring is done, and then based on that the Global score is determined (mild-moderate-severe). See Citation: Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant. 2005; 11:945-56., for grading criteria.

Moderate or Severe cGVHD

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	50	32 – 65
B - Cyclosporine (AC) Arm	12	4 – 25

Severe cGVHD

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	28	14 – 43
B - Cyclosporine (AC) Arm	5	1 – 15

Recovery of Naïve Cluster of Differentiation 4 (CD4) T Cells Primary · Recipient recovery at 6, 12 and 24 months post transplant

The percentage of C-C motif chemokine receptor 7 (CCR7)+CD45RA+ naïve T cells within the CD4 T cell populations was determined by flow cytometry.

6 mo (TMS=28; AC= 28)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	24	2 – 65
B - Cyclosporine (AC) Arm	1	0 – 22

12 mo (TMS=25; AC= 21)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	22	5 – 48
B - Cyclosporine (AC) Arm	7	0 – 42

24 mo (TMS=18; AC= 13)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	20	4 – 60
B - Cyclosporine (AC) Arm	25	1 – 60

Recovery of Naïve Cluster of Differentiation 8 (CD8) T Cells Primary · Recipient recovery at 6, 12 and 24 months post transplant

The percentage of CCR7+CD45RA+ naïve T cells within the CD4 and CD8 T cell populations was determined by flow cytometry.

6 mo (TMS=28; AC= 28)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	20	0 – 75
B - Cyclosporine (AC) Arm	3	0 – 78

12 mo (TMS=25; AC= 21)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	17	7 – 79
B - Cyclosporine (AC) Arm	6	0 – 79

24 mo (TMS=18; AC= 13)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	16	1 – 60
B - Cyclosporine (AC) Arm	6	0 – 65

Changes in Cluster of Differentiation 4 (CD4) T Cell Receptor Vbeta Repertoire Primary · Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant

Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lowe

1 month

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	48	26 – 69
B - Cyclosporine (AC) Arm	90	63 – 111

3 months

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	31	23 – 60
B - Cyclosporine (AC) Arm	66	47 – 93

6 mo (TMS=7; AC= 9)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	35	21 – 57
B - Cyclosporine (AC) Arm	75	32 – 93

12 mo (TMS=7; AC=9)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	30	23 – 81
B - Cyclosporine (AC) Arm	67	25 – 92

Donor CD4 cells (TMS=8; AC=8)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	23	17 – 29
B - Cyclosporine (AC) Arm	22	18 – 35

Changes in CD8 T Cell Receptor Vbeta Repertoire Primary · Donor at time of collection and recipient at 1, 3, 6 and 12 months post transplant

Ribonucleic acid (RNA) was extracted from sorted CD4 and cluster of differentiation 8 (CD8) T cells and analyzed for Vbeta repertoire by nested polymerase chain reaction (PCR) analysis using Vbeta family specific primers and a labeled constant region primer (spectratyping). The receptor repertoire diversity was calculated from spectratyping data by creating a normal standard for repertoire diversity from healthy normal controls and assessing the divergence of individual patient's T cell receptor repertoire from these standard normal donor values. In this Vbeta repertoire divergence index, lowe

1 month

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	62	42 – 91
B - Cyclosporine (AC) Arm	78	53 – 111

3 months

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	54	35 – 64
B - Cyclosporine (AC) Arm	81	52 – 88

6 mo (TMS=7; AC= 9)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	62	53 – 81
B - Cyclosporine (AC) Arm	84	71 – 118

12 mo (TMS=7; AC= 9)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	55	39 – 108
B - Cyclosporine (AC) Arm	89	58 – 110

Donor CD8 cells (TMS=8; AC= 8)

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	47	27 – 53
B - Cyclosporine (AC) Arm	43	31 – 62

Percentage of Participants With Grade III-IV Acute Graft Versus Host Disease (GVHD) Secondary · 6 months

Acute GVHD is assessed by the 1994 Consensus Conference on acute GVHD Grading criteria. See Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995; 15:825-8., for grading criteria.

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	13	5 – 26
B - Cyclosporine (AC) Arm	21	11 – 35

Toxicities Secondary · 103 months and 22 days

Here are the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	43
B - Cyclosporine (AC) Arm	42

Days to Engraftment of Neutrophils Secondary · 2 years

Days to engraftment is defined as neutrophil recovery: designated by the first of 3 consecutive days with an absolute neutrophil count (ANC) above 500/mm(3).

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	11	3 – 19
B - Cyclosporine (AC Arm)	9	7 – 36

Days to Engraftment of Platelets Secondary · 2 years

Platelet recovery: designated by the first of 7 days where the platelet count remains above 20,000/mm(3) without transfusion support

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	19	1 – 99
B - Cyclosporine (AC Arm)	14	1 – 431

Days to Engraftment of Lymphocytes Secondary · 2 years

Lymphocyte recovery: designated by the first of 3 consecutive days with absolute lymphocyte count (ALC) above 500/mm(3).

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	16	1 – 194
B - Cyclosporine (AC Arm)	76	16 – 264

Overall Survival Secondary · Patients were followed for an average of up to 5 years.

Time between the first day of transplant to the day of death.

Group	Value	95% CI
A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm	41.7	26.7 – NA
B - Cyclosporine (AC) Arm	18.8	10.4 – NA

Adverse events — posted to ClinicalTrials.gov

Time frame: 103 months and 22 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

A - Tacrolimus, Methotrexate, Sirolimus (TMS) Arm

Serious: 36/44 (82%)

Deaths: 8/44

B - Cyclosporine (AC) Arm

Serious: 41/45 (91%)

Deaths: 19/45

Serious adverse events (143 terms)

Reaction	System	A - Tacrolimus, Methotrexa…	B - Cyclosporine (AC) Arm
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Catheter-related	Infections and infestations	—	—
Death not associated with CTCAE term::Disease progression NOS	General disorders	—	—
Renal failure	Renal and urinary disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Infection ::Blood	Infections and infestations	—	—
Colitis, infectious (e.g., Clostridium difficile)	Gastrointestinal disorders	—	—
Death not associated with CTCAE term::Death NOS	General disorders	—	—
Rash/desquamation	Skin and subcutaneous tissue disorders	—	—
Febrile neutropenia	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Sinus	Infections and infestations	—	—
Adult Respiratory Distress Syndrome (ARDS)	Respiratory, thoracic and mediastinal disorders	—	—
Hypertension	Cardiac disorders	—	—
Hypotension	Cardiac disorders	—	—
Pneumonitis/pulmonary infiltrates	Respiratory, thoracic and mediastinal disorders	—	—
ALT, SGPT (serum glutamic pyruvic transaminase)	Metabolism and nutrition disorders	—	—
AST, SGOT(serum glutamic oxaloacetic transaminase)	Metabolism and nutrition disorders	—	—
Dyspnea (shortness of breath)	Respiratory, thoracic and mediastinal disorders	—	—
Infection::Catheter-related	Infections and infestations	—	—
Infection ::Lung (pneumonia)	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Skin (cellulitis)	Infections and infestations	—	—
Left ventricular systolic dysfunction	Cardiac disorders	—	—
Secondary Malignancy - possibly related to cancer treatment (AML);	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	—	—

Other adverse events (212 terms — click to expand)

Reaction	System	A - Tacrolimus, Methotrexa…	B - Cyclosporine (AC) Arm
ALT, SGPT (serum glutamic pyruvic transaminase)	Metabolism and nutrition disorders	—	—
Leukocytes (total WBC)	Blood and lymphatic system disorders	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—
Neutrophils/granulocytes (ANC/AGC)	Blood and lymphatic system disorders	—	—
AST, SGOT(serum glutamic oxaloacetic transaminase)	Metabolism and nutrition disorders	—	—
Hemoglobin	Blood and lymphatic system disorders	—	—
Rash/desquamation	Skin and subcutaneous tissue disorders	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood	Infections and infestations	—	—
Platelets	Blood and lymphatic system disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Phosphate, serum-low (hypophosphatemia)	Metabolism and nutrition disorders	—	—
Potassium, serum-low (hypokalemia)	Metabolism and nutrition disorders	—	—
Bilirubin (hyperbilirubinemia)	Metabolism and nutrition disorders	—	—
Magnesium, serum-high (hypermagnesemia)	Metabolism and nutrition disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Albumin, serum-low (hypoalbuminemia)	Metabolism and nutrition disorders	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia)	Infections and infestations	—	—
Infection::Blood	Infections and infestations	—	—
Creatinine	Metabolism and nutrition disorders	—	—
Mucositis/stomatitis (clinical exam)::Oral cavity	Gastrointestinal disorders	—	—
Potassium, serum-high (hyperkalemia)	Metabolism and nutrition disorders	—	—
Febrile neutropenia	Infections and infestations	—	—
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Sinus	Infections and infestations	—	—
Infection with normal ANC or Grade 1 or 2 neutrophils::Upper airway NOS	Infections and infestations	—	—
Magnesium, serum-low (hypomagnesemia)	Metabolism and nutrition disorders	—	—
Sodium, serum-low (hyponatremia)	Metabolism and nutrition disorders	—	—
Dry eye syndrome	Eye disorders	—	—
Mucositis/stomatitis (functional/symptomatic)::Oral cavity	Gastrointestinal disorders	—	—
PTT (Partial Thromboplastin Time)	Blood and lymphatic system disorders	—	—
Alkaline phosphatase	Metabolism and nutrition disorders	—	—
Hypertension	Cardiac disorders	—	—
Uric acid, serum-high (hyperuricemia)	Metabolism and nutrition disorders	—	—
Infection ::Bladder (urinary)	Infections and infestations	—	—
Infection ::Lung (pneumonia)	Infections and infestations	—	—
Infection with unknown ANC::Upper airway NOS	Infections and infestations	—	—
Renal/Genitourinary - Other (failure; hematuria; insufficiency; dysuria)	Renal and urinary disorders	—	—
Thrombosis/thrombus/embolism	Vascular disorders	—	—
Carbon monoxide diffusion capacity (DL(co))	Respiratory, thoracic and mediastinal disorders	—	—
Fatigue (asthenia, lethargy, malaise)	General disorders	—	—

Most-reported serious reactions: Infection with normal ANC or Grade 1 or 2 neutrophils::Blood, Infection with normal ANC or Grade 1 or 2 neutrophils::Lung (pneumonia), Infection with normal ANC or Grade 1 or 2 neutrophils::Catheter-related, Death not associated with CTCAE term::Disease progression NOS, Renal failure, Diarrhea, Hypoxia, Infection ::Blood.

Data from ClinicalTrials.gov NCT00520130 adverse events section.

Sponsor's own description

Background:

Major problems with stem cell transplantation (SCT) for cancer treatment are a lack of suitable donors for patients without a human leukocyte-antigen (HLA) tissue-matched sibling and graft-versus-host disease (GVHD), a serious side effects of immune-suppressing chemotherapy that is given to bring the cancer under control before SCT. In GVHD, the patients immune system attacks the transplanted donor cells.

This study will try to improve the results of SCT from unrelated HLA-matched donors using targeted immune-depleting chemotherapy to bring the cancer under control before transplantation and to lower the chance of graft rejection, followed by reduced-intensity transplant chemotherapy to make the procedure less toxic.

Objectives:

To evaluate the safety and effectiveness of targeted immune-depleting chemotherapy followed by reduced-intensity transplant chemotherapy in patients with advanced cancers of the blood and immune system.

To evaluate the safety and effectiveness of two different drug combinations to prevent GVHD. Both regimens have been successful in preventing GVHD, but they work by different mechanisms and affect the rebuilding of the immune system after the transplant.

Eligibility:

People 18 to 74 years of age with advanced or high-risk cancers of the blood and immune system who do not have a suitable HLA-matched sibling.

Design:

All patients receive chemotherapy before transplant to treat the cancer and suppress immune function.

All patients receive a conditioning regimen of cyclophosphamide for 4 days and fludarabine for 4 days before SCT to prepare for the transplant.

Patients are randomly assigned to one of two combination drug treatments to prevent GHVD as follows:

* Group 1: Tacrolimus starting 3 days before SCT and continuing for 6 months, plus methotrexate on days 1, 3, 6, and 11 post-SCT, plus sirolimus starting 3 days before the SCT and continues for 6 months following SCT.
* Group 2: Alemtuzumab for 4 days starting 8 days before SCT, plus cyclosporine starting 1 day before SCT and continuing for 6 months.

Patients receive the donors stem cells and immune cells 2 days after completing the conditioning regimen.

Patients are followed at the clinic regularly for the first 6 months after SCT, and then less often for at least 5 years. Some visits may include bone marrow aspirates and biopsies, blood draws, and other tests to monitor disease status.

A skin biopsy, oral mucosa biopsy, and saliva collection are done to study chronic GVHD.

...

Publications & conference data

7 peer-reviewed publications reference this trial (live from Europe PMC):

1. Upregulation of IFN-Inducible and Damage-Response Pathways in Chronic Graft-versus-Host Disease.
   Hakim FT, Memon S, Jin P, Imanguli MM, et al · · 2016 · cited 53× · PMID 27694491 · DOI 10.4049/jimmunol.1601054
2. Quantitative salivary proteomic differences in oral chronic graft-versus-host disease.
   Bassim CW, Ambatipudi KS, Mays JW, Edwards DA, et al · · 2012 · cited 33× · PMID 22806177 · DOI 10.1007/s10875-012-9738-4
3. Glycolytic metabolism of pathogenic T cells enables early detection of GVHD by 13C-MRI.
   Assmann JC, Farthing DE, Saito K, Maglakelidze N, et al · · 2021 · cited 32× · PMID 32785680 · DOI 10.1182/blood.2020005770
4. Salivary ZG16B expression loss follows exocrine gland dysfunction related to oral chronic graft-versus-host disease.
   Costa-da-Silva AC, Aure MH, Dodge J, Martin D, et al · · 2022 · cited 30× · PMID 35005541 · DOI 10.1016/j.isci.2021.103592
5. Disseminated microsporidiosis in an immunosuppressed patient.
   Meissner EG, Bennett JE, Qvarnstrom Y, da Silva A, et al · · 2012 · cited 27× · PMID 22709509 · DOI 10.3201/eid1807.120047
6. High-dose alemtuzumab and cyclosporine vs tacrolimus, methotrexate, and sirolimus for chronic graft-versus-host disease prevention.
   Holtzman NG, Curtis LM, Salit RB, Shaffer BC, et al · · 2024 · cited 8× · PMID 38669315 · DOI 10.1182/bloodadvances.2023010973
7. Chronic graft-versus-host disease is characterized by high levels and distinctive tissue-of-origin patterns of cell-free DNA.
   Pang Y, Andargie TE, Jang MK, Kong H, et al · · 2023 · cited 8× · PMID 38026221 · DOI 10.1016/j.isci.2023.108160