Official Title: “Two-arm Clinical Trial for Patients With Hematologic Malignancies and Mismatched Donors - Haploidentical and 1 Antigen Mismatch Related or Unrelated - Using a T-cell Replete Allograft and High-dose Post-transplant Cyclophosphamide”

The goal of this clinical research study is to learn about the safety of giving a stem cell transplant from a tissue-mismatched donor, followed by cyclophosphamide, to patients with certain types of blood disorders or blood cancers. Melphalan, thiotepa, and fludarabine will also be given before the transplant.

Researchers will study the heath status of these patients at 3 months after the transplant.

Study Type: Interventional

Study Design: Treatment, Non-Randomized, Open Label, Single Group Assignment, Safety/Efficacy Study

Study Primary Completion Date: November 2012

The Study Treatment:

Cyclophosphamide is designed to interfere with the multiplication of cancer cells, which may slow or stop their growth and spread throughout the body. This may cause the cancer cells to die.

In this study, researchers want to learn if cyclophosphamide can help to prevent graft-versus-host disease (GVHD -- when transplanted immune tissue, such as white blood cells, attacks the tissues of the recipient's body).

Melphalan, thiotepa, and fludarabine are commonly used in combination with a stem cell transplant.

Screening Tests:

Signing this consent form does not mean that you will be able to take part in this study.

You will have "screening tests" to help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed: - Blood (about 4 tablespoons) and urine will be collected for routine tests. - You will have a physical exam. - You will have a lung function test. - You will have a chest x-ray to check for a lung infection. - You will have a computed tomography (CT) scan of the sinuses to check for infection. - You will have an electrocardiogram (ECG--a test to measure the electrical activity of the heart). - You will have a multi-gated acquisition (MUGA) scan or an echocardiogram (ECHO) to test your heart function. - You will have a bone marrow biopsy to check the status of the disease. To collect a bone marrow biopsy, an area of the hip is numbed with anesthetic, and a small amount of bone marrow and bone is withdrawn through a large needle. - Women who are able to have children must have a negative blood pregnancy test. This blood will be drawn as part of the routine sample described above.

The study doctor will discuss the screening test results with you. If the screening tests show that you are not eligible to take part in the study, you will not be enrolled. Other treatment options will be discussed with you.

Study Treatment Administration:

If you are found to be eligible to take part in this study, you will receive chemotherapy for 6 days: - You will receive melphalan by vein over 30 minutes on Day -8 (8 days before the transplant). - You will receive thiotepa by vein over 4 hours on Day -7. - You will receive fludarabine by vein over 1 hour on Days -6, -5, -4, and -3.

On Day 0, you will receive the donor's stem cells by vein. This may last anywhere from 15 minutes to several hours.

On Days 3 and 4, you will receive cyclophosphamide by vein over 3 hours. You will also receive mesna by vein over 30 minutes every 4 hours for a total of 10 mesna doses on Days 3 and 4. Mesna is given to lower the risk of side effects to the bladder.

Starting on Day 5, you will receive tacrolimus and mycophenolate mofetil (MMF) to help lower the risk of GVHD. Tacrolimus will be given by vein as a continuous infusion for about 2 weeks. After the 2 weeks of taking tacrolimus by vein, you will take tacrolimus by mouth as a pill for at least 3 months. MMF will be given by mouth, 3 times a day, usually until Day 35.

Starting on Day 7, you will receive filgrastim (G-CSF) once a day as an injection under the skin, until your blood cell counts reach a high enough level.

Depending on the type of disease that you have, your doctor may decide to give you rituximab by vein over several hours on Days -13, -6, 1, and 8. Rituximab is given to help the body get rid of abnormal white blood cells.

Length of Study Participation:

You will be in the hospital for about 4 weeks after the transplant. You will be taken off study if the disease gets worse. The study drugs will be stopped if intolerable side effects occur.

Follow-Up Visits:

You will be asked to stay close enough to Houston to be able to come back for any visits for at least 100 days after the transplant.

On the day of the transplant (Day 0), blood (about 4 tablespoons) will be drawn to measure tumor cells and to predict graft failure and/or relapse.

At 1, 3, 6, and 12 months after the transplant, the following tests and procedures will be performed: - You will have a physical exam. - Blood (about 4 tablespoons) will be drawn for routine tests. - You will have a bone marrow biopsy to check the status of the disease. - Blood (about 4 tablespoons) will be drawn to measure tumor cells and to predict graft failure and/or relapse. - You may have urine collected and/or scans performed such as x-rays, CT scans, and/or a positron emission tomography (PET) scan. These scans and urine tests would only be done if the study doctor thinks they are needed to check the status of the disease.

If you have MM, you will have a bone survey once a year.

If the study doctor thinks it is needed based on side effects you may be having, additional follow-up tests will be performed.

You may be contacted by phone 1-2 times a year to ask about the status of the disease. These calls will take about 10 minutes to complete.

This is an investigational study. All of the drugs used in this study are commercially available and FDA approved. However, it is investigational to give high-dose cyclophosphamide for preventing GVHD that may occur after a stem cell transplant from a tissue-mismatched donor.

Up to 72 patients will take part in this study. All will be enrolled at M. D. Anderson.

Intervention(s) in this Clinical Trial

• Drug: Cyclophosphamide
  • 50 mg/kg/day mixed in D5W (maximum concentration 20 mg/ml) IV over 3 hours on Days 3 and 4.
• Drug: Fludarabine
  • 40 mg/m^2 in 100 ml NS IV over 1 hour (Patients <12 Kg will receive 1.3 mg/kg/day) on Days -6, -5, -4, and -3.
• Drug: Melphalan
  • 140 mg/m^2 (plus 15 mg for tubing) in NS at a concentration of 1.5 mg/ml IV over 30 minutes (Patients <12 Kg will receive 4.6 mg/kg) on Day -8.
• Drug: Mesna
  • 10mg/kg IV every 4 hours for a total of 10 doses starting just prior to first dose of Cyclophosphamide on Days 3 and 4.
• Drug: Rituximab
  • CD20+ lymphoid malignancies: 375 mg/m2 on day -13 followed by 1000 mg/m2 on day -6, +1, and +8.
• Procedure: Stem Cell Transplantation
  • Infusion of donor's stem cells by vein on Day 0, may last anywhere from 15 minutes to several hours.
• Drug: Thiotepa
  • 10 mg/kg in 250 ml NS IV over 4 hours

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Haploidentical related
  • Stem Cell Transplantation using melphalan, thiotepa, and fludarabine conditioning followed by high-dose post-transplant cyclophosphamide for patients with hematologic malignancies without a matched donor.
• Experimental: 1 Antigen Mismatch Related or Unrelated
  • Stem Cell Transplantation using melphalan, thiotepa, and fludarabine conditioning followed by high-dose post-transplant cyclophosphamide for patients with hematologic malignancies without a matched donor.

Primary Measures

• Non-relapse Mortality (NRM)
  • Time Frame: At 100 days and at 6 Months
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Patients </= 65 years old lacking a matched related or unrelated volunteer donor for which a related haploidentical donor (</= 7/8 allele match at the A, B, C, DR loci) or a 7/8 allele matched related or unrelated donor is identified.
• 2. Acute lymphocytic leukemia (ALL) in CR1 with high-risk features including adverse cytogenetics such as t(9;22), t(1;19), t(4;11), or mixed lineage leukemia (MLL) gene rearrangements; ALL in second or greater remission or ALL with relapsed disease
• 3. Acute myeloid leukemia (AML) in CR1 with high-risk features defined as: Greater than 1 cycle of induction therapy required to achieve remission; Preceding myelodysplastic syndrome (MDS) or myeloproliferative disease; Presence of FLT3 mutations or internal tandem duplications; FAB M6 or M7 classification; Adverse cytogenetics, -5, del 5q, -7, del7q, abnormalities involving 3q, 9q, 11q, 20q, 21q, 17, +8 [> 3 abnormalities]
• 4. AML in second or greater remission, primary induction failure and patients with relapsed disease;
• 5. Myelodysplastic syndrome (MDS) with International Prognostic Scoring System (IPSS) intermediate-2 or higher;
• 6. Aplastic anemia with Absolute neutrophil count (ANC)<1000 and transfusion dependent after they failed immunosuppression therapy
• 7. Chronic myeloid leukemia (CML) >/=1st chronic phase, after failed >/=2 lines of tyrosine kinase inhibitors; in accelerated or blast phase with > 30% bone marrow blasts;
• 8. Myeloproliferative diseases including chronic myelomonocytic leukemia (CMML), myelofibrosis with a Lille score greater than 1;
• 9. Chemotherapy-sensitive relapsed lymphoma (Complete or partial response), Hodgkin's or non-Hodgkin's lymphoma;
• 10. Patients with chemo-sensitive CLL with persistent or recurrent disease after fludarabine-based regimens.
• 11. Patients with poor prognosis multiple myeloma by cytogenetics (del13, del 17p, t(1;14) or t(14;16) or hypodiploidy, with advanced disease (stage>/=2) and /or relapsed after autologous stem cell transplant.
• 12. Zubrod performance status 0-1 or Lansky PS greater or equal to 70%.
• 13. Available donor able to undergo a bone marrow harvest
• 14. Bilirubin </= 1.5 mg/dl (unless Gilbert's syndrome), ALT or AST </= 200 IU/ml.
• 15. Creatinine </=1.5 mg/dl or serum creatinine clearance >/=50 ml/min (calculated with Cockroft-Gault formula).
• 16. Diffusing capacity for carbon monoxide (DLCO) >/= 45% predicted corrected for hemoglobin. For pediatric patients, if unable to perform pulmonary function, >/= 92% oxygen saturation with pulse oximetry.
• 17. LVEF >/= 40%.
• 18. Patient or patient's legal representative, parent(s) or guardian should provide written informed consent. Assent of a minor if participant's age is at least seven and less than eighteen years.

Exclusion Criteria:

• 1. HIV positive; active hepatitis B or C
• 2. Uncontrolled infections
• 3. Liver cirrhosis with greater than grade 1 stage 1 inflammation/fibrosis
• 4. Uncontrolled CNS involvement by tumor cells
• 5. Positive Beta HCG test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization.
• 6. Inability to comply with medical therapy or follow-up

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: N/A

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: M.D. Anderson Cancer Center

Overall Clinical Trial Officials and Contacts

Stefan Ciurea, MD Study Chair UT MD Anderson Cancer Center  

Overall Contact: Stefan Ciurea, MD 713-794-5780 

Information obtained from ClinicalTrials.gov on February 04, 2010

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01010217

Study ID Number: 2009-0266

ClinicalTrials.gov Identifier: NCT01010217

Health Authority: United States: Institutional Review Board

UT MD Anderson Cancer Center website