Phase I/II Trial of Dose-Adjusted EPOCH Chemotherapy with Bortezomib Combined with Integrase Inhibitor Therapy for HTLV-1 Associated T-Cell Leukemia Lymphoma
This research is being done to determine if an antiretroviral agent, called Raltegravir, a drug that blocks HTLV-1, if given in combination with chemotherapy, is effective and well tolerated. Raltegravir, is U.S. Food and Drug Administration (FDA) approved for this use, however because it is given in combination with other drugs, Raltegravir is considered investigation in this study. The study will also evaluate the effect of chemotherapy and antiretrovirals on the response rates of your leukemia/lymphoma, and viral load (the level of HTLV-1 in the bloodstream). The chemotherapy used in this study is a combination of etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin, known as (EPOCH). These combinations of drugs (EPOCH) are FDA approved for this use. In addition, you will also receive the drug bortezomib (RR). Bortezomib is an FDA approved drug for multiple myeloma and previously treated mantle cell lymphoma, however it is not FDA approved for this use and is considered investigational in this study.
3.1 Inclusion Criteria 3.1.1 Histologically or cytologically documented ATLL. Patients with previously untreated or treated ATLL are eligible. 3.1.2 Tumors must be CD3 positive ( greater than 50% cells express CD3). 3.1.3 Documented HTLV-1 infection: documentation may be serologic assay (ELISA, Western blot) and confirmed to be HTLV-1 rather than HTLV-2 by differential Western blot (e.g. Genelabs Diagnostics HTLV Blot 2.4) or PCR. 3.1.4 Measurable disease must be present. 3.1.5. All stages are eligible. 3.1.6Adequate hematologic function within 14 days before enrollment: ANC greater than 1000 cells/mm3, platelet count greater than 75,000 cells/mm3 unless cytopenias are secondary to ATLL. All patients must be off hematologic growth factors for at least 24 hrs. 3.1.7 Adequate hepatic function, transaminase less than 3 times the upper limit of normal unless due to hepatic involvement by tumor; bilirubin less than 2.0 unless secondary to hepatic infiltration with lymphoma or isolated indirect hyperbilirubinemia. For bilirubin greater than 3.0 due to hepatic involvement, vincristine and doxorubicin will not be given in cycle 1. 3.1.8 Creatinine less than 2.0 unless due to lymphoma. 3.1.9 KPS at least 50 (Appendix I). 3.1.10 Age at least 18. 3.1.11 Voluntary written informed consent before performance of any study- related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. 3.1.12Female patients of child bearing potential must have a negative pregnancy test within 72 hrs of initiation of therapy. Female patients are either post-menopausal or surgically sterilized or willing to use two acceptable methods of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, condom with spermicide, or abstinence) during the study. Male patients must agree to use two acceptable methods for contraception for the duration of the study. Women must avoid pregnancy and men avoid fathering children while in the study. 3.1.13 HIV positive patients are eligible if they are receiving at least two other active anti-HIV therapies other than zidovudine or atazanavir. 3.1.14Patients with active HBV infection are eligible if they are receiving effective anti-HBV therapy. 3.1.15Inclusion of Women and Minorities: Both men and women and members of all races and ethnic groups are eligible for this trial. 3.2 Exclusion Criteria Patients meeting any of the following exclusion criteria are not to be enrolled in the study. 3.2.1 Acute active infection requiring acute therapy. Chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met. 3.2.2 Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy. 3.2.3Women who are pregnant or breastfeeding. Confirmation that the subject is not pregnant must be established by a negative serum ï¿½-human chorionic gonadotropin (ï¿½-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women. 3.2.4.Patient has ï¿½Grade 2 peripheral neuropathy within 14 days before enrollment. 3.2.5.Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix VI), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant. 3.2.6.Patient has hypersensitivity to bortezomib, boron or mannitol. 3.2.7.Patient has received other investigational drugs with 14 days before enrollment 3.2.8.Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 3.2.9.Total bilirubin greater than 2.0 if not due to hepatic involvement by lymphoma
Bortezomib1.0 mg/m2 is infused on days 1 and 4 Etoposide 50 mg/m2/d given as a continuous 96 hr IV infusion on days 1-4 Vincristine 0.4 mg/m2/d given as a continuous 96 hrs IV infusion on day 1-4 Doxorubicin 10 mg/m2/d given as a continuous 96 hrs IV infusion on days 1-4 Prednisone 60 mg/m2/d given orally on days 1-5 Cyclophosphamide (day 5) 375 mg/m2 given IV on day 5 over 30 min Cycles 2-6: If ANC nadir greater than 500/mm3 and platelet nadir greater than 25,000/mm3 in the previous cycle, then increase doses of etoposide, doxorubicin, and cyclophosphamide doses by 20%. If ANC nadir less than 500/mm3 on at least 3 measurements OR nadir platelet count less than 25,000/mm3 on at least 1 measurement during the previous cycle, then decrease etoposide, doxorubicin, and cyclophosphamide doses by 20% Note: The cyclophosphamide, etoposide, and doxorubicin doses should be escalated only if there is no previous episode of grade 3-4 febrile neutropenia or any other toxicity that required a dose reduction of cyclophosphamide Raltegravir is given orally 400 mg bid every day starting with cycle 2 therapy Note: See section 7.0 for dose modifications for hematololgic and non-hematologic toxicity. Cycles will be repeated every 21-28 days for two cycles beyond best response, or a maximum of 6 cycles. Best response is the response achieved when 1 or more additional cycles of chemotherapy are given and no additional tumor shrinkage is noted. That may include stable or progressive disease after 2 cycles of chemotherapy. Plus: Neulasta 6 mg SQ on days 6, 7, or 8 or G-CSF 5 ug/kg SQ daily for 10 days starting on day 6 or until the absolute neutrophil account has recovered to greater than 4000 cells/mm3
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