Adult T-cell Leukemia-Lymphoma, ATLL
Conditions
Brief summary
The investigators propose to use Belinostat in combination with AZT as consolidation therapy for the treatment of ATLL.
Interventions
DRUGBelinostat
Belinostat will be administered as 1,000 mg/m2 IV infusion over 30 minutes on Days 1- 5 every 21 days (Exception as per FDA-approved Package Insert: In patients known to be homozygous for the UGT1A1\*28 allele, the starting belinostat dose must be 750mg/m2) for up to 8 cycles.
DRUGZidovudine
Zidovudine shall be administered in the outpatient setting as 300 mg tablets orally (PO), three times daily (TID) for 21 days on cycles 1 to 8, followed by maintenance therapy (+/- IFN-alfa) up to the end of Month 12.
OPTIONAL: For subjects receiving interferon therapy at baseline, continue Interferon alfa-2b 5 million IU daily or pegylated interferon alfa-2b 1.5 μg/kg once weekly, subcutaneously (SQ) for up to 12 months.
DRUGPegylated Interferon-Alfa-2b
OPTIONAL: For subjects receiving interferon therapy at baseline, continue Interferon alfa-2b 5 million IU daily or pegylated interferon alfa-2b 1.5 μg/kg once weekly, subcutaneously (SQ) for up to 12 months.
DRUGLymphodepleting Therapy
OPTIONAL: For subjects with any increase in lymphocyte count. Cyclophosphamide administered as 375 mg/m2 via intravenous infusion once during Cycle 1 after Day 5 of Belinostat therapy.
Sponsors
University of Miami
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically documented adult T-cell leukemia/lymphoma (ATLL) with the following characteristics: * Any stage of disease, * Aggressive types (for definition of ATLL subtypes see Appendix H), * Documented presence of ATLL cells in peripheral blood by either morphology, histology, flow cytometry or gene rearrangement studies. 2. One of the following: * Initiated AZT/IFNα therapy prior or at the time of enrollment. OR; * Received chemotherapy or other antineoplastic drug therapy ≥ 2 weeks prior to enrollment with the exception of dose-reduced vincristine/and or cyclophosphamide, or high dose steroids, administered for cytoreductive purpose. (Note: Continuation of zidovudine and interferon therapy is allowed.). 3. Presence of ATLL based on morphology, histology, flow cytometry, or T-cell clonality in peripheral blood during screening period prior enrollment. 4. Documented Human T-cell lymphotropic virus type 1 (HTLV-1) infection: Documentation may be serologic assay (ELISA) confirmed by Western blot or polymerase chain reaction (PCR). 5. Measurable or evaluable disease, including presence of ATLL by immunophenotyping from either histology or flow cytometry studies, or molecular disease as evidence by T-cell clonality detected by gene rearrangement studies. 6. 18 years of age or older. 7. Karnofsky performance status (KPS) ≥ 50% or Eastern Cooperative Oncology Group (ECOG) performance status ≤ 3 8. Patients must have adequate end organ and bone marrow function as defined below: * absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 \[Exception: Unless cytopenias are secondary to ATLL\] * platelets (PLT) ≥ 50,000 cells/mm3 \[Exception: Unless cytopenias are secondary to ATLL\] * Adequate hepatic function: * transaminase ≤ 2.5 the institutional upper limit of normal (ULN), * total bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN), \[Exception: Unless secondary to hepatic infiltration with lymphoma. If the elevated bilirubin is felt to be secondary to Indinavir or Atazavinir therapy (or anti-HIV medications), patients will be allowed to enroll.\] * Creatinine clearance (CrCl) ≥ 40 mL/min, \[Exception: Unless secondary to renal involvement by lymphoma is suspected.\] 9. Patients who are human immunodeficiency virus positive (HIV+) are also eligible. 10. Females of childbearing potential (CBP) must have a negative serum pregnancy test within one week of enrollment. Women should avoid pregnancy while receiving study treatment. Males and females must agree to use adequate birth control during participation in this trial and for 3 months after completing therapy. 11. Patients receiving erythropoietin or Granulocyte-colony stimulating factor (G-CSF) from baseline are eligible.
Exclusion criteria
1. Patients with progressive disease (after previous chemotherapy or AZT/IFNα) at the time of enrollment. 2. Patients with chronic leukemia with favorable features, or smoldering type ATLL. 3. Patients receiving any other investigational agents within 14 days prior to initiation of study therapy. (Exception: Patients actively receiving IFN-alfa-2b, PEG-IFN-alfa-2b, or similar forms of IFN-alfa are permitted). 4. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that are likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment. 5. Pregnant or breast-feeding women. 6. Known hypersensitivity to histone deacetylases (HDACs), zidovudine, belinostat or any component of the formulation(s). 7. Acute hepatitis or decompensated liver disease unless due to lymphoma. Chronic hepatitis will be required to be on prophylactic treatment during the study if provided liver function test meet criteria listed above without evidence of cirrhosis to be eligible. 8. Concurrent active malignancies, with the exception of in situ carcinoma of the cervix, non-metastatic, non-melanomatous skin cancer, or Kaposi's sarcoma not requiring systemic chemotherapy. 9. Known New York Heart Association (NYHA) Class 3 or 4 heart disease as per Appendix D. 10. Known ejection fraction \< 45% or institutional limit of normal range 11. Psychological, familial, sociological or geographical conditions likely in the judgment of the Investigator(s) to interfere or limit compliance with study requirements/treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing Treatment-Related Serious Adverse Events and Adverse Events | Up to 13 months | Number of participants experiencing treatment-related serious adverse events (SAEs), and adverse events (AEs). SAEs and AEs will be assessed by and assigned severity and treatment attribution using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 4.03. |
| Number of Participants Achieving Complete Molecular Response in Blood Compartment (CMR) | From end of cycle 3 until at least end of month 12 | Number of participants achieving Complete Molecular Response after receiving protocol therapy will be reported. Complete Molecular Response (CMR) is defined as the disappearance of malignant clone(s), as proven by negative T-cell receptor gene rearrangement studies of peripheral blood DNA and bone marrow. CMR will be evaluated based upon T-cell clonality studies to be conducted while subjects are on Belinostat, and while subjects are receiving Zidovudine (AZT)-based maintenance treatment (after Belinostat completion). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Failure-Free Survival (FFS) Rate at 12 Months Using Kaplan-Meier Method | 12 months | The Failure-Free Survival (FFS) rate at 12 months estimated by the Kaplan-Meier method will be reported as a percentage probability of participants alive without documented disease progression, relapse after response or death (by any cause) at 12 months after starting study therapy. FFS is defined as the elapsed time in months from study treatment initiation until documented disease progression, relapse after response or death (by any cause, in the absence of progression). In the failure-free subjects, FFS will be censored at the last documented date of failure-free status. |
| Number of Participants Exhibiting Disruption of HTLV-1 Latency in Vivo | Up to 13 months | The number of participants exhibiting disruption of Human T-lymphotropic virus 1 (HTLV-1) latency in vivo after receiving Belinostat therapy will be reported. HTLV-1 latency will be evaluated from serum blood samples. |
| Number of Participants Exhibiting Cytotoxic T-Cell Response in Vivo | Up to 13 months | The number of participants exhibiting cytotoxic T-Cell response in vivo after receiving Belinostat therapy will be reported. Cytotoxic T-Cell response will be evaluated from serum blood samples. |
| Overall Survival (OS) Rate at 12 Months Using Kaplan-Meier Method | 12 months | The Overall Survival (OS) rate at 12 months estimated by the Kaplan-Meier method will be reported as the percentage probability of survival beyond 12 months. OS is defined as the elapsed time from study treatment initiation to death or date of censoring. Subjects alive or those lost to follow-up will be censored at the last date known to be alive. |
| HTLV-1 Pro-Viral Load Among Participants | Up to 13 months | HTVL-1 pro-viral load among study participants will be reported as a measure of HTLV-1 infected reservoirs in vivo after receiving Belinostat therapy. HTLV-1 viral load will be evaluated from serum blood samples |
| Number of Participants Achieving Clinical Response | Up to 12 months | Number of participants achieving complete response (CR) or partial response (PR) to study therapy will be reported. Response is assessed on the basis of clinical, radiologic, molecular and pathologic (i.e. bone marrow) criteria. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJuan C Ramos, MD
University of Miami
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 6 Participants |
| Age, Categorical Between 18 and 65 years | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 15 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 11 / 15 |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 7 / 15 |
Outcome results
None listed