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Collection of bone marrow and/or PBSC (Up to 40 donors)

PTCy at de-escalating doses (25 mg/kg/day on days +3 and +4, and PTCy 25 mg/kg on day +4) to assess for safety and determine Phase II dose (up to 12 evaluable patients)

MMF at de-escalating duration (days +5 to +18 only, no MMF))

Standard PTCy 50 mg/kg/day on days +3 and +4, in a small pilot (up to 5 evaluable patients) for comparative data

PTCy at shortest duration, safe dose (from Phase I) to assess efficacy at providing adequate protection from grade 3-4 acute GVHD (up to 14 additional patients)

MMF at duration identified from de-escalation evaluation.

Busulfan should be administered intravenously via a central venous catheter as a three-hour infusion every 24 hours.

Fludarabine will be infused by IV over 60 minutes.

IV cyclophosphamide will be administered over 2 hours. Slower rates of infusion may be used to decrease side effects. A fluid intake of greater than 2 L/day is recommended during and for 1 to 2 days after cyclophosphamide administration.

Any oral formulation should be taken on an empty stomach, 1 hour before or at least 2 hours after meals. Oral formulations should not be administered simultaneously with antacids. Avoid inhalation or direct contact with skin or mucous membranes of dry powder contained in capsules or suspension. IV solutions should be administered over at least two hours through either a peripheral or central vein and should not be administered by rapid or bolus injection.

Mycophenolate Mofetil

Oral tablets should be administered approximately 4 hours after cyclosporine administration. Sirolimus is administered orally, once daily, without food. Patients unable to tolerate tablets may take the oral solution formulation.

Ashley N DeVries, R.N.

Christopher G Kanakry, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

Background:

Stem cell or bone marrow transplants can cure or control blood cancers. Sometimes the donor cells see the recipient's body as foreign. This can cause complications. A high dose of the drug cyclophosphamide (PTCy) can help reduce these risks. Researchers want to see if a lower dose of PTCy can have the same benefits. Based on encouraging results from the first part of the study, researchers now are investigating whether a lower dose of PTCy can allow other immunosuppression to be decreased.

Objective:

To see if a lower dose of PTCy and now also shorter duration of another immunosuppressant called mycophenolate mofetil will help people with blood cancers have a more successful transplant and fewer side effects.

Eligibility:

People ages 15-65 with leukemia, lymphoma, or multiple myeloma that is not curable with standard therapy and is at high risk of returning without transplant, and their healthy adult relatives

Design:

Transplant participants will be screened with:

Blood, urine, breathing, and heart tests

Scans

Chest x-ray

Bone marrow samples: A needle inserted into the participant s pelvis will remove marrow and a bone fragment.

Transplant recipients will stay at the hospital and be prepped with chemotherapy over 6 days for the transplant. They will get stem cells through a catheter in the chest or neck. They will get the cyclophosphamide chemotherapy. They will stay in the hospital about 4 more weeks. They will have blood transfusions. They will have frequent blood tests and 2 bone marrow samples within 1 year after the transplant.

Donor participants will be screened with:

Blood, urine, and heart tests

Chest x-ray

Scans

Donor participants will have bone marrow taken from their pelvis or stem cells taken from their blood. For the blood donation, blood will be taken from a vein in one arm, move through a machine to remove white blood cells, and be returned through a vein in the other arm.

Participation will last up to 5 years....

Background:

Post-transplantation cyclophosphamide (PTCy) reduces rates of severe acute and chronic graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) and safely facilitates human leukocyte antigen (HLA)-haploidentical HCT

When clinically translated, the dose (50 mg/kg) and timing (days +3 and +4) of PTCy used were partly extrapolated from murine major histocompatibility complex (MHC)-matched skin allografting models and were partly empirical

In both MHC-haploidentical and MHC-disparate murine HCT models, a dose of 25 mg/kg/day was superior to 50 mg/kg/day on days +3 and +4 in terms of GVHD severity and mortality

In the MHC-haploidentical HCT model, a dose of 25 mg/kg on day +4 was equivalent to 25 mg/kg/day on days +3 and +4

In addition to better GVHD prevention, lower dosing of PTCy is associated with less broad reduction of T-cell numbers after PTCy

Mycophenolate mofetil (MMF), used as adjunct immunosuppression with standard dose PTCy, can have substantial gastrointestinal toxicity and can impede immune reconstitution and pathogen-specific immunity.

Objectives:

Determine whether a dose of PTCy 25 mg/kg on day +3 and +4 or on day +4 only can maintain adequate protection against grade III-IV acute GVHD.

Determine whether a reduced duration of MMF, in combination with PTCy 25 mg/kg/day on days +3 and +4, can maintain adequate protection against grade III-IV acute GVHD.

Eligibility:

Histologically or cytologically confirmed hematologic malignancy with standard indication for allogeneic hematopoietic cell transplantation including one of the following:

Acute myeloid leukemia (AML) of intermediate or adverse risk disease by the 2017 European LeukemiaNet criteria in first morphologic complete remission

AML of any risk in second or subsequent morphologic complete remission

B-cell acute lymphoblastic leukemia in first or subsequent complete remission

T-cell acute lymphoblastic leukemia with minimal residual disease detected after first line therapy and/or adverse genetics

Myelodysplastic syndrome of intermediate or higher score by the Revised International Prognostic Scoring System (IPSS-R)

Primary myelofibrosis of intermediate-2 or higher risk by the Dynamic International Prognostic Scoring System (DIPSS)

Chronic myelomonocytic leukemia

Chronic myelogenous leukemia resistant to or intolerant of \>=3 tyrosine kinase inhibitors or with prior history of accelerated phase or blast crisis

B-cell lymphoma including Hodgkin lymphoma that has relapsed within 1 year of completion of primary treatment

Chronic lymphocytic leukemia with 17p deletion and/or unmutated IgHV or refractory to or intolerant of both BTK and PI3K inhibitors

Mature T or NK neoplasms as defined in the WHO guidelines of sufficient type and severity for allogeneic HCT based on the Prognostic Index for T-cell lymphoma (PIT) score of low-intermediate risk or higher or on recently published clinical practice guidelines

Hematologic malignancy of dendritic cell or histiocytic cell type

Multiple myeloma, stage III, relapsing after therapy with both a proteasome inhibitor and an immunomodulatory drug (IMiD)

Age 15-65.

At least one potentially suitable HLA-haploidentical donor.

Karnofsky performance score \>=60

Adequate organ function

Design:

Open-label, single-center, non-randomized, phase I/II study

All patients will receive myeloablative conditioning, HLA-haploidentical bone marrow HCT, and GVHD prophylaxis with PTCy, MMF (depending on cohort), and sirolimus.

A small pilot of 5 evaluable patients will receive the standard PTCy 50 mg/kg on days +3/+4 to obtain a limited amount of comparative pharmacokinetic and T-cell immunophenotyping and repertoire data.

Then the study will proceed to a small, two-level \[1) 25 mg/kg/day on days +3 and +4, 2) 25 mg/kg on day +4 only\] phase I dose de-escalation study based on the standard 3+3 approach

Patients will be evaluated for development of grade III-IV acute GVHD (aGVHD) at day +60 as the dose-limiting toxicity and then phase II will proceed with the shorter duration of the days of treatment (+3/+4 or +4) which is associated with 0-1 of 6 patients with grade III-IV aGVHD at day +60 and with the least amount of toxicity

Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with this decreased PTCy exposure, will be used in the phase II portion of the study which will enroll an additional 14 patients to see if this lower PTCy exposure is associated with a similar rate of grade III-IV acute GVHD as is expected with 50 mg/kg on days +3/+4

Following completion of the phase II portion of the trial evaluating PTCy 25 mg/kg/day on days +3/+4, a dose de-escalation will be conducted to determine if the dose of MMF (standardly days +5 to +35) may be reduced without meaningful impact on avoidance of grade III-IV acute GVHD. The tested dose levels will be 1) MMF from days +5 to +18 and 2) no MMF. This will be followed by a second Simon optimal two-stage phase II trial design, to rule out excess grade III-IV acute GVHD with decreased MMF exposure, which will expand on the lowest MMF dose that is associated with acceptable toxicity and enroll an additional 14 patients to see if this lower MMF is associated with a similar rate of grade III-IV acute GVHD as is expected with full 30 day MMF treatment.

Optimizing PTCy Dose and Timing

Phase I/II Study De-intensifying Exposure of Post-transplantation Cyclophosphamide as GVHD Prophylaxis After HLA-haploidentical Hematopoietic Cell Transplantation for Hematologic Malignancies

.All collected IPD will be shared. @@@@@@@@@@@@All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.

The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals. The MMF duration level patients may be compared with the PTCy dose level patients which serves as a baseline for standard duration MMF.

The fraction of evaluable patients who experience grade III-IV aGVHD at day +60 will be determined and reported along with 80% and 95% two-sided confidence intervals.

Rate and timing of neutrophil and platelet engraftment also will be evaluated descriptively, including fractions who attain each condition at day 28 and 100, along with 95% confidence intervals. Ranges and medians will be calculated only in engrafting patients. Grade II-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals. Grade III-IV aGVHD also will be evaluated descriptively including fractions who attain each condition at day 100 and 200 days, and 95% confidence intervals

The phase II MMF duration level patients may be compared with the phase II PTCy dose level patients which serves as a baseline for standard duration MMF.

National Institute of Neurological Disorders and Stroke (NINDS)

National Cancer Institute (NCI)

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Wen-Fang Cheng, MD, PhD

Cervical cancer is the most frequent neoplasm of women in Taiwan and in the world. It influences about 2,700 women with about 1,000 women dying of cervical cancer each year and in Taiwan. Human papillomaviruses (HPV) have been consistently implicated in causing cervical cancer especially those high-risk types which have been strongly associated with cervical cancer. In recent years, there has been compelling evidence that infection with human papillomavirus (HPV) is a major etiologic factor in the development of cervical intraepithelial neoplasia (CIN) and cervical carcinoma.

As in most virus-induced diseases, an adequate immune response is likely to play a key role in the clearance of HPV infections and HPV-related lesions. This assumption is born out by both epidemiological studies and animal models. Immune-compromised patients such as HIV-infected women, organ transplant recipients, and patients suffering from other forms of malignancies, are at a higher risk of developing CIN lesions and invasive cervical cancer. Moreover, several studies establish the existence of natural HPV E7-specific cytotoxic T lymphocyte (CTL) immunity in humans. Only a minority of women infected with oncogenic HPV types develop CIN or cervical cancer. Indeed, the majority of CIN lesions do not progress or even regress to normal cytology, indicating that other factors such as an inadequate immune function are necessary for the development of progressive CIN lesions and cervical carcinoma.

Consequently, the HLA class I and II phenotypes may be correlated with an effective immune response against HPV-associated cervical lesions. Differences in the recognition of foreign antigens, such as those contributed by alleles at the HLA class I or II loci, might be proposed to affect the risk of developing cervical cancer.

In the present proposal, the investigators would like to examine the HLA class I and II associations among Taiwanese women with cervical neoplasia. The purposes of this proposal are:

1. to address the relationships between the HLA class I and II haplotype, HPV infection, and cervical cancer; and
2. to elucidate the immunologic responses to HPV type 16 in different HLA class I and II haplotypes. It will help the investigators to identify which population of HLA genotypes is more susceptible to HPV infection and progresses to invasive cervical cancer. The results of this research will be very useful for the prevention and screening of cervical cancer in the future.

1. To survey the incidence of HPV infection in CIN and cervical cancer patients.

   Using epidemiologic data drawn from a wide range of countries and population groups, investigators have found evidence of HPV in 90% to 95% of cervical cancers. The incidence of HPV in cervical cancer was 79% in our own report. Besides, 91% of high-grade CIN cases and 50% of low-grade CIN cases could be attributed to HPV infection in Taiwanese women. Because these reports for Taiwanese women were published around 10 years ago, it is important to survey and update the incidence of HPV in CIN and cervical cancer patients in Taiwanese women. We will survey the incidence of HPV infection in 500 cervical cancer patients, 100 patients of CIN and 100 normal population patients.
2. To survey the human leukocyte antigen haplotype in CIN and cervical cancer patients.

   HLA class I and II alleles have been reported to associate with the nasopharyngeal carcinoma in Taiwan. Besides, human leukocyte antigen class I and II alleles might interplay in the response to interferon-alpha treatment in Taiwanese patients with chronic hepatitis C virus infection. We will detect the HLA class I and II haplotype first and then correlate them with the CIN and cervical cancer patients.
3. To identify the correlation between HLA class I and II haplotype and HPV infection and CIN and cervical cancer.

   We will further survey the correlation between HLA class I and II and the genotypes of HPV in CIN and cervical cancer patients. We will identify which HLA class I and II haplotypes have positive or negative correlation with HPV infection, CIN and cervical cancer. Then we would determine which specific HLA antigens are important in determining the risk of HPV infection, CIN and cervical cancer.
4. To elucidate the immunologic responses to HPV type 16 in HLA2 with different II haplotypes and the role of immunogenetics in the carcinogenesis of cervical cancer.

HPV type 16 has been identified to be the highest incidence of malignant HPV genotypes in cervical cancer. Our laboratory has set up immunologic assays for evaluating the immune responses to HPV type 16. We will survey the immune response to HPV type 16 in those HLA class I and II haplotypes which have positive or negative correlation with the HPV infection and cervical cancer. We would identify which population of HLA genotype are more susceptible to HPV infection and invasive cervical cancer and elucidate the role of immunogenetics in the HPV infection and carcinogenesis of cervical cancer.

The Correlation Between the Haplotype of Human Leukocyte Antigen (HLA) and Human Papillomavirus

National Taiwan University Hospital

Heart and Blood Diseases

Leukemia

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Lymphosarcoma

Mesna

Antimetabolites

Busulfan starting dose of 32 mg/m\^2 by vein over 3 hours each day. Test dose day -8 (inpatient) or test dose day -30 to day -8 (outpatient) and then, days -6,-5,-4, and -3. Fludarabine dose of 40 mg/m\^2 by vein over 1 hour each day on Day -6 through Day -3 before receiving Busulfan. Cyclophosphamide dose of 50 mg/kg by vein over 3 hours on Days 3 and 4.

Starting dose of 32 mg/m\^2 by vein over 3 hours each day. Test dose day -8 (inpatient) or test dose day -30 to day -8 (outpatient) and then, days -6,-5,-4, and -3.

Dose of 40 mg/m\^2 by vein over 1 hour each day on Day -6 through Day -3 before receiving Busulfan.

Dose of 50 mg/kg by vein over 3 hours on Days 3 and 4.

Amin Alousi, MD

The goal of this clinical research study is to learn if cyclophosphamide given after busulfan and fludarabine can help to prevent graft versus host disease (GVHD - a condition in which transplanted tissue attacks the body into which it is transplanted) in patients receiving a stem cell transplant. The safety of this drug combination will also be studied.

The Study Drugs:

Busulfan is designed to bind to DNA (the genetic material of cells), which may cause cancer cells to die.

Fludarabine is designed to make cancer cells less able to repair damaged DNA. This may increase the likelihood of the cells dying.

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. It is also designed to suppress the immune system and help prevent GVHD.

Study Drug Administration and Transplant:

If you are an inpatient, on Day -8 (8 days before the date of transplant), you will receive a low-level test dose of busulfan through a needle in your vein over 1 hour.

If you are an outpatient, on Day -30 through Day -8, you will receive a low-level test dose of busulfan through a needle in your vein over 1 hour each day.

You will be given an anti-seizure drug to help prevent seizures each time you receive busulfan. Your doctor will explain how the drug will be given and the drug's risks. Seizures are a rare but serious side effect of busulfan.

On Days -8, -6, and -4, blood (about 1 teaspoon each time) will then be drawn a total of 11 times for pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body at different time points. This PK testing will be done to find the dose of busulfan needed for your body size on the other days that you receive busulfan.

On Day -6 through Day -3, you will receive your body-specific dose of busulfan by vein over 3 hours each day. If you cannot have the blood level tests performed for any reason, you will receive the standard busulfan dose. You will receive fludarabine through a needle in your vein over 1 hour on each of these days before you receive busulfan.

On Day 0, you will receive the donor bone marrow or blood stem cells by vein over about 1 hour.

On Day +3 and Day +4, you will receive cyclophosphamide by vein over 3 hours.

On Days +3 thru +5 just before the first dose of cyclophosphamide and then every 4 hours, you will receive mesna by vein over 30 minutes for a total of 10 doses. Mesna is a drug that protects bladder cells from damage by chemotherapy drugs. It is used to decrease the risk of bleeding in the bladder.

Once a day starting on Day +7, you will receive filgrastim (G-CSF -- a drug that helps with the growth of white blood cells) through a needle under your skin until your blood cell levels reach "recovered" levels for 3 days in a row.

Study Visits:

Every day you are in the hospital and at each outpatient visit, you will have a physical exam to check for symptoms of GVHD.

Blood (about 3 teaspoons) will be drawn at least 2 times a week for the first 100 days after the transplant for routine tests.

About 1 month after your transplant, then once every 3 months up to a year, the following tests and procedures will be performed:

* Blood (about 5 tablespoons) will be drawn for routine tests and to check for CMV. Blood draws may be repeated more often, if you doctor thinks it is needed.
* Urine will be collected for routine tests.
* You will have a bone marrow aspirate and biopsy to check the status of the disease.

At Months 1, 2, 3, 6, and 12 after your transplant, blood (about 4 tablespoons) will be drawn to check the status of your immune system.

Tests and procedures may be repeated more often during the study, if your doctor thinks it is needed.

Length of Study:

You will be on study in the hospital for about 4 weeks. You will be taken off study if the disease gets worse or if the study doctor thinks it is in your best interest.

Long-Term Follow-Up:

After the first 24 months, you will receive either a phone call or a letter from the study doctor or your regular doctor 1 time each year to check the status of the disease. If you are contacted by mail, you will be given a self-addressed stamped envelope with which you can return your responses to the doctor.

This is an investigational study. Busulfan is FDA approved and commercially available for the treatment of chronic myelogenous leukemia (CML). Fludarabine is FDA approved and commercially available for the treatment of chronic lymphocytic leukemia (CLL). Cyclophosphamide is FDA approved and commercially available for the treatment of lymphoma. The use of these drugs together for the possible prevention of GVHD is investigational.

Up to 40 participants will take part in this study. All will be enrolled at M. D. Anderson.

Busulfan and Fludarabine Followed by Post-transplant Cyclophosphamide

Busulfan (IV) and Fludarabine Followed by Post-allogeneic Transplantation Cyclophosphamide for Graft-versus-Host Disease Prophylaxis in Patients With Hematologic Malignancies.

Graft Versus Host Disease (GVHD) defined as grade 2 to 4 GVHD within first 100 days post transplant. Death or disease progression before diagnosis of GVHD were considered competing risks in the estimation of the incidence of acute GVHD.

Graft Versus Host Disease (GVHD) defined as grade 3 to 4 GVHD within first 100 days post transplant. Death or disease progression before diagnosis of GVHD were considered competing risks in the estimation of the incidence of acute GVHD.

Treatment-Related Mortality (TRM) was estimated from the date of transplant using the cumulative incidence method to account for competing risks. Disease progression or relapse death were considered competing risk for TRM.

Engraftment defined as the evidence of donor derived cells (more than 5%) by bone marrow chimerism studies in the presence of neutrophil recovery by day 28 post stem cell (SC) infusion. Engraftment date is the first day of three (3) consecutive days that the ANC exceeds 0.5 x109/L. Delayed engraftment is defined as the evidence of engraftment beyond day 28 post SC infusion achieved after the administration of therapeutic (high dose) hematopoietic growth factors.

Progression-free survival (PFS) is defined as the interval between day of transplant and day of death or disease progression.

Overall Survival (OS) is defined as the interval between day of transplant and day of death.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Optimizing PTCy Dose and Timing	NCT03983850	Graft Versus Ho... Hematologic Neo...	Busulfan Fludarabine Cyclophosphamid... Mycophenolate M... Sirolimus	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)
The Correlation Between the Haplotype of Human Leukocyte Antigen (HLA) and Human Papillomavirus	NCT00154479	Cancer of Cervi...		18 Years - 80 Years	National Taiwan University Hospital
Busulfan and Fludarabine Followed by Post-transplant Cyclophosphamide	NCT00800839	Hematologic Dis... Leukemia Lymphoma Myeloma	Busulfan Fludarabine Cyclophosphamid...	6 Months - 75 Years	M.D. Anderson Cancer Center
Busulfan and Fludarabine Followed by Post-transplant Cyclophosphamide	NCT00800839	Hematologic Dis... Leukemia Lymphoma Myeloma	Busulfan Fludarabine Cyclophosphamid...	6 Months - 75 Years	M.D. Anderson Cancer Center
Optimizing PTCy Dose and Timing	NCT03983850	Graft Versus Ho... Hematologic Neo...	Busulfan Fludarabine Cyclophosphamid... Mycophenolate M... Sirolimus	12 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Busulfan and Fludarabine Followed by Post-transplant Cyclophosphamide	NCT00800839	Hematologic Dis... Leukemia Lymphoma Myeloma	Busulfan Fludarabine Cyclophosphamid...	6 Months - 75 Years	M.D. Anderson Cancer Center

Spots Global Cancer Trial Database for human leukocyte antigen