Allogeneic Hematopoietic Stem Cell Transplantation Recipient, Chronic Lymphocytic Leukemia, Prolymphocytic Leukemia, Richter Syndrome
Conditions
Brief summary
This phase I/II trial studies the best dose and side effects of gemcitabine and how well it works with clofarabine and busulfan and donor stem cell transplant in treating participants with chronic lymphocytic leukemia. Drugs used in chemotherapy, such as gemcitabine, clofarabine, and busulfan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a donor stem cell transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. The donated stem cells may also replace the patient's immune cells and help destroy any remaining cancer cells.
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) of gemcitabine when administered with busulfan and clofarabine. II. To estimate the day 100 treatment-related mortality (TRM) for the preparative regimen busulfan, clofarabine, and gemcitabine followed by allogeneic hematopoietic cell transplantation (HCT) for patients with chronic lymphocytic leukemia (CLL). SECONDARY OBJECTIVES: I. To determine the rate of progression-free survival (PFS), graft versus host disease (GVHD), engraftment, and overall survival (OS) for this treatment regimen at one year post treatment completion. OUTLINE: This is a dose-escalation study of gemcitabine. Participants receive gemcitabine intravenously (IV) over 10-25 minutes on days -6 and -4, clofarabine IV over 1 hour and busulfan IV over 3 hours on days -6 to -3. Participants with matched unrelated donors also receive anti-thymocyte globulin IV over 4 hours on days -3 to -1. Starting day -2, participants receive tacrolimus orally (PO) daily for up to 6 months. Participants undergo hematopoietic allogeneic stem cell transplant on day 0, then receive methotrexate IV over 15 minutes on days 1, 3, 6 and 11, and filgrastim subcutaneously (SC) once daily (QD) beginning 1 week after transplant until blood cell levels return to normal. After completion of study treatment, participants are followed up at 3, 6 and 12 months, then every 6 months for 1 year.
Interventions
PROCEDUREAllogeneic Hematopoietic Stem Cell Transplantation
Undergo stem cell transplant
BIOLOGICALAnti-Thymocyte Globulin
Given IV
DRUGBusulfan
Given IV
DRUGClofarabine
Given IV
BIOLOGICALFilgrastim
Given SC
DRUGGemcitabine
Given IV
DRUGMethotrexate
Given IV
DRUGTacrolimus
Given PO
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Patients with chronic lymphocytic leukemia, prolymphocytic leukemia, or Richter's transformation who are eligible for allogeneic transplantation and are not eligible for protocols of higher priority * A 10/10 HLA matched (high resolution typing at A, B, C, DRB1, DQ1) sibling or unrelated donor * Left ventricular ejection fraction (EF) \> 40% * Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and corrected diffusion capacity of the lung for carbon monoxide (DLCO) \> 40% * Serum creatinine \< 1.6 mg/dL * Serum bilirubin \< 2 X upper limit of normal * serum glutamate pyruvate transaminase (SGPT) \< 2X upper limit of normal * Voluntary signed, written Institutional Review Board (IRB)-approved informed consent * Men and women of reproductive potential must agree to follow accepted birth control methods for the duration of the study. Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) for the duration of the study. Male subject agrees to use an acceptable method for contraception for the duration of the study
Exclusion criteria
* Patient with active central nervous system (CNS) disease * Pregnant (positive beta human chorionic gonadotropin \[HCG\] test in a woman with child bearing potential defined as not post-menopausal for 12 months or no previous surgical sterilization) or currently breast-feeding. Pregnancy testing is not required for post-menopausal or surgically sterilized women * Known infection with human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV)-I, hepatitis B, or hepatitis C * Active uncontrolled bacterial, viral or fungal infections * Patient has received other investigational drugs within 1 week before enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 100 Day Treatment Related Mortality (TRM) | 100 days post transplant | Number of deaths related to treatment by day 100 post allogeneic transplant |
| Maximum Tolerated Dose (MTD) | Enrollment up to day 30 post transplant | To find the maximum tolerated dose (MTD) of Gemcitabine when administered with Busulfan & Clofarabine |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 1 year post transplant | Will be estimated by the method of Kaplan and Meier. Time-to-event distributions as function of patient baseline covariates will be evaluated using Bayesian time-to-event regression modeling. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to 1 year post transplant | Number of patients without any relapse post treatment completion |
| Time-to-engraftment | 30 days post transplant | The number of days until participants by dose level reach engraftment. |
| Acute and Chronic Graft Verse Host Disease (GvHD) | Up to 1 year post transplant | GvHD (Graft versus Host Disease) occurs when immune cells transplanted from a non-identical donor (graft) recognizes the transplant recipient (the host) as foreign, thereby initiating an immune reaction in the transplant recipient. Acute GvHD typically occurs around the time of engraftment and manifests in skin, GI system, and liver abnormalities. Chronic GvHD is defined by manifestations such as ocular, oral, lung, sclerosis skin, failure to thrive, fascia, cholestasis in liver, esophagus strictures. |
Countries
United States
Participant flow
Recruitment details
Participants enrolled at MD Anderson clinic starting on November 21, 2012 on Phase I of the study. No participants were enrolled on Phase II.
Participants by arm
| Arm | Count |
|---|---|
| Gemcitabine Dose Level 1 Gemcitabine 100 mg/m2 IV preceded by loading dose of 75 mg/m2 for 2 days + Busulfan(adjusted Pharmacokinetic dosing) IV for 4 days + Clofarabine 30 mg/m2 IV for 4 days + Thymoglobulin 4mg/kg(Matched Unrelated Donor patients only) IV for 3 days + Stem Cell Transplant | 4 |
| Gemcitabine Dose Level 2 Gemcitabine 150 mg/m2 IV preceded by loading dose of 75 mg/m2 for 2 days + Busulfan(adjusted Pharmacokinetic dosing) IV for 4 days + Clofarabine 30 mg/m2 IV for 4 days + Thymoglobulin 4mg/kg(Matched Unrelated Donor patients only) IV for 3 days + Stem Cell Transplant | 0 |
| Gemcitabine Dose Level 3 Gemcitabine 200 mg/m2 IV preceded by loading dose of 75 mg/m2 for 2 days + Busulfan(adjusted Pharmacokinetic dosing) IV for 4 days + Clofarabine 30 mg/m2 IV for 4 days + Thymoglobulin 4mg/kg(Matched Unrelated Donor patients only) IV for 3 days + Stem Cell Transplant | 8 |
| Gemcitabine Dose Level 4 Gemcitabine 250 mg/m2 IV preceded by loading dose of 75 mg/m2 for 2 days + Busulfan(adjusted Pharmacokinetic dosing) IV for 4 days + Clofarabine 30 mg/m2 IV for 4 days + Thymoglobulin 4mg/kg(Matched Unrelated Donor patients only) IV for 3 days + Stem Cell Transplant | 3 |
| Total | 15 |
Baseline characteristics
| Characteristic | Gemcitabine Dose Level 1 | Gemcitabine Dose Level 2 | Gemcitabine Dose Level 3 | Gemcitabine Dose Level 4 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 0 Participants | 7 Participants | 3 Participants | 13 Participants |
| Age, Continuous | 56 years | — | 57.5 years | 60 years | 59 years |
| Disease Category Diseases : Chronic Lymphocytic Leukemia (CLL) | 3 Participants | 0 Participants | 5 Participants | 1 Participants | 9 Participants |
| Disease Category Diseases : Prolymphocytic Leukemia (PLL) | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
| Disease Category Diseases: Richter's | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 0 Participants | 2 Participants | 2 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 6 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 0 Participants | 8 Participants | 3 Participants | 15 Participants |
| Region of Enrollment United States | 4 Participants | 0 Participants | 8 Participants | 3 Participants | 15 Participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 2 Participants | 0 Participants | 5 Participants |
| Sex: Female, Male Male | 1 Participants | 0 Participants | 6 Participants | 3 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 4 | 0 / 0 | 1 / 8 | 1 / 3 |
| other Total, other adverse events | 4 / 4 | 0 / 0 | 8 / 8 | 3 / 3 |
| serious Total, serious adverse events | 0 / 4 | 0 / 0 | 0 / 8 | 0 / 3 |
Outcome results
Primary
100 Day Treatment Related Mortality (TRM)
Number of deaths related to treatment by day 100 post allogeneic transplant
Time frame: 100 days post transplant
Population: No participants were treated at dose level 2.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Gemcitabine Dose Level 1 | 100 Day Treatment Related Mortality (TRM) | Graft versus Host Disease (GVHD) | 0 Participants |
| Gemcitabine Dose Level 1 | 100 Day Treatment Related Mortality (TRM) | Infection | 0 Participants |
| Gemcitabine Dose Level 2 | 100 Day Treatment Related Mortality (TRM) | Infection | 0 Participants |
| Gemcitabine Dose Level 2 | 100 Day Treatment Related Mortality (TRM) | Graft versus Host Disease (GVHD) | 0 Participants |
| Gemcitabine Dose Level 3 | 100 Day Treatment Related Mortality (TRM) | Graft versus Host Disease (GVHD) | 1 Participants |
| Gemcitabine Dose Level 3 | 100 Day Treatment Related Mortality (TRM) | Infection | 0 Participants |
| Gemcitabine Dose Level 4 | 100 Day Treatment Related Mortality (TRM) | Infection | 0 Participants |
| Gemcitabine Dose Level 4 | 100 Day Treatment Related Mortality (TRM) | Graft versus Host Disease (GVHD) | 0 Participants |
Primary
Maximum Tolerated Dose (MTD)
To find the maximum tolerated dose (MTD) of Gemcitabine when administered with Busulfan & Clofarabine
Time frame: Enrollment up to day 30 post transplant
Population: MTD analysis was for Phase II. Data were not collected.
Secondary
Overall Survival
Will be estimated by the method of Kaplan and Meier. Time-to-event distributions as function of patient baseline covariates will be evaluated using Bayesian time-to-event regression modeling.
Time frame: Up to 1 year post transplant
Population: All participants were registered on Phase I.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Gemcitabine Dose Level 1 | Overall Survival | 3 Participants |
| Gemcitabine Dose Level 2 | Overall Survival | 0 Participants |
| Gemcitabine Dose Level 3 | Overall Survival | 4 Participants |
| Gemcitabine Dose Level 4 | Overall Survival | 2 Participants |
Other Pre-specified
Acute and Chronic Graft Verse Host Disease (GvHD)
GvHD (Graft versus Host Disease) occurs when immune cells transplanted from a non-identical donor (graft) recognizes the transplant recipient (the host) as foreign, thereby initiating an immune reaction in the transplant recipient. Acute GvHD typically occurs around the time of engraftment and manifests in skin, GI system, and liver abnormalities. Chronic GvHD is defined by manifestations such as ocular, oral, lung, sclerosis skin, failure to thrive, fascia, cholestasis in liver, esophagus strictures.
Time frame: Up to 1 year post transplant
Population: Analysis was for Phase II. No analysis was done due to low accrual on Phase I.
| Arm | Measure | Group | Value |
|---|---|---|---|
| Unknown | Acute and Chronic Graft Verse Host Disease (GvHD) | Chronic GvHD (cGvHD) | — |
| Unknown | Acute and Chronic Graft Verse Host Disease (GvHD) | Acute GvHD(aGvHD) | — |
Other Pre-specified
Progression-free Survival (PFS)
Number of patients without any relapse post treatment completion
Time frame: Up to 1 year post transplant
Population: Analysis was for Phase II. No analysis was done due to low accrual on Phase I.
Other Pre-specified
Time-to-engraftment
The number of days until participants by dose level reach engraftment.
Time frame: 30 days post transplant
Population: No participants were treated at dose level 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 11 | 2 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | <10 days - Graft Failure | 0 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 15 | 0 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 12 | 1 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 10 | 1 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 13 | 0 participants |
| Gemcitabine Dose Level 1 | Time-to-engraftment | Day 17 | 0 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 12 | 0 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 13 | 1 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 10 | 2 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 11 | 4 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 15 | 0 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | Day 17 | 0 participants |
| Gemcitabine Dose Level 3 | Time-to-engraftment | <10 days - Graft Failure | 1 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 15 | 1 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 10 | 0 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | <10 days - Graft Failure | 0 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 17 | 1 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 13 | 0 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 11 | 0 participants |
| Gemcitabine Dose Level 4 | Time-to-engraftment | Day 12 | 1 participants |