A Sequential Phase I/Randomized Phase II Trial of Vorinostat and Risk- Adapted Chemotherapy with Rituximab in HIV-Related B-Cell Non-Hodgkin’s Lymphoma
Johns Hopkins Kimmel Cancer Center in Baltimore
Primary Objectives Phase I: Determine the recommended Phase II dose (RPTD) of vorinostat that may be used in combination with R-CHOP (in low-risk disease) or R-DA-EPOCH (in high-risk disease) in subjects with HIV-associated diffuse large B-cell lymphoma (DLBCL). Randomized Phase II: Determine the overall toxicity rates of R-CHOP (in low-risk disease) or R-DA-EPOCH (in high-risk disease) with and without vorinostat; and 2) Determine the efficacy of the combinations of R-CHOP (in low-risk disease) or R-DA-EPOCH (in high-risk disease) with and without vorinostat in HIV-associated DLBCL using complete response (CR) rates as study endpoints. Secondary Objectives (Phase I and Phase II) 1. Determine 1-year event free survival (EFS) and 1 year overall survival (OS). 2. Assess the effect of vorinostat and chemotherapy on residual HIV latently-infected T-cell clones on banked specimens. 3. Assess the effect of vorinostat and/or chemotherapy on HIV, EBV, and HHV-8 viral loads on banked specimens. 4. Assess the effect of vorinostat and/or chemotherapy on T-cell subsets (CD4 and CD8) and plasma immunoglobulin levels. 5. Assess the effect of concurrent vorinostat and rituximab on plasma steady-state concentrations of etoposide, doxorubicin, and vincristine (on Phase I only, and for subjects receiving EPOCH). 6. Perform wide human gene expression profiling in tumors banked at baseline. 7. Evaluate EBV gene expression patterns in positive tumors banked at baseline. Phase I: The Phase I portion of the study will determine the MTD of vorinostat in combination with rituximab plus CHOP or rituximab plus dose-adjusted (DA)-EPOCH chemotherapy. Phase II: The Phase II portion of the study will begin after at least six subjects have been treated at the MTD dose on both R-CHOP and R-DA-EPOCH arms. The objective is to determine toxicity, response, time to disease progression and failure-free survival between low-risk subjects receiving either vorinostat (V)R-CHOP vs. R-CHOP alone or high-risk subjects receiving either vorinostat (V)R-DA-EPOCH vs. R-DA-EPOCH alone. In Phase II, low-risk subjects will be randomized to VR-CHOP or R-CHOP, and high risk subjects randomized to VR-DA-EPOCH or DA-R-EPOCH by the AMC ODMC upon subject registration, as indicated on the enrollment confirmation page in Advantage EDC.
Inclusion Criteria 1. Previously untreated, histologically, or cytologically documented CD20+ DLBCL, as defined by the 2008 WHO classification. 2. Lymphoma must be CD20+. Please note: If only a subset of tumor cells are CD20+, the subject will still be eligible for study entry. If possible, all tumors should be tested for EBV expression by either immunohistochemistry or in situ hybridization. 3. Documentation of HIV infection at any time prior to study entry. Documentation may be serologic (positive ELISA and positive Western blot), or other federally approved licensed HIV test. Prior documentation of HIV seropositivity is acceptable. 4. All stages of disease (See Appendix III, Ann Arbor Staging Criteria). 5. Measurable or non-measurable tumor parameter(s). Non-measurable tumor parameters are defined as not having bidimensional measurements (e.g., gastric or marrow involvement), but can be followed for response by other diagnostic tests such as gallium, PET imaging and/or bone marrow biopsy. 6. Age ï¿½ 18 years. 7. Performance Status (PS) 0, 1, or 2 per the Eastern Cooperative Oncology Group [(ECOG)] Performance Status Scale (Karnofsky Performance Score greater than 50%). See Appendix IV, Performance Status Scale. 8. Able to provide informed consent. 9. Adequate hepatic function: ï¿½Total bilirubin ï¿½ 1.5 institutional upper limit of normal (ULN), unless elevated secondary to lymphomatous involvement of liver or biliary system, or due to other HIV medications (e.g., indinavir, tenofovir, or atazanavir). For direct bilirubin greater than 1.2 due to hepatic involvement by tumor see Section 7.2.4 for the initial dose of CHOP or EPOCH drug adjustment. ï¿½AST/ALT ï¿½ 2.5 institutional ULN (unless elevated secondary to lymphomatous involvement of the liver). 10. Adequate renal function: creatinine less than 2.0 mg/dL, or creatinine clearance ï¿½ 60 mL/min, unless secondary to renal involvement by lymphoma. For creatinine clearance less than 50 mL/min due to kidney involvement by tumor see Section 7.2.3 for chemotherapy adjustment. 11. Adequate hematologic function: granulocytes/ANC greater than 1000/mm3, platelets greater than 75,000/mm3 (unless these parameters are abnormal secondary to lymphomatous involvement of bone marrow). All subjects must cease colony-stimulating factor therapy at least 24 hours prior to institution of Cycle 1 chemotherapy. 12. Left ventricular ejection fraction (LVEF) that is at or above the lower institutional limits of normal, as assessed by Multiple Gated Acquisition (MUGA) scan or echocardiogram within the 6 weeks prior to registration. 13. Concurrent radiation, with or without steroids, for emergency conditions secondary to lymphoma (i.e. cord compression, etc.) will be permitted. 14. Female subjects must have a negative pregnancy test within 7 days of entering into the study. Both men and women of child bearing potential must agree to use adequate methods of contraception for the duration of the treatment. Women must avoid pregnancy, and men must avoid fathering children while in the study and for 6 months following the last study drug treatment. 15. Subjects on an antiretroviral regimen should be receiving treatment that is in accordance with the current International AIDS Society guidelines. The specific agents are at the discretion of the Investigator and use of agents currently available on an expanded access basis is allowed but use of experimental antiretroviral agents or those containing zidovudine (including CombivirÂ® and TrizivirÂ®) are prohibited. Changes to HAART therapy may be made if medically necessary (toxicity, failure of regimen, etc.). Antiretroviral naÃ¯ve subjects: Subjects who are not on HAART at study entry MUST begin therapy (utilizing the above guidelines) AFTER Cycle 1 of chemotherapy has been completed. Changes to HAART therapy may be made if medically necessary (toxicity, failure of regimen, etc.). Concurrent therapy with zidovudine or a zidovudine-containing regimen (including CombivirÂ® and TrizivirÂ®) will be prohibited until 2 months following the subjectï¿½s completion of chemotherapy as part of this protocol. 16. Subjects already receiving erythropoietin or colony-stimulating factor therapy are eligible for participation, although the latter must be discontinued at least 24 hours prior to receiving chemotherapy. 17. Subjects must be able to swallow oral medications. Exclusion Criteria 1. Absolute CD4 count of less than 50 cells/ mm3. 2. Presence of second active tumor, other than non-melanoma skin cancer, carcinoma in situ of the cervix, or Kaposiï¿½s sarcoma (KS) that does not require systemic therapy. 3. CNS involvement by lymphoma including parenchymal brain or spinal cord lymphoma or known presence of leptomeningeal disease prior to registration (See Section 3.5.3. 4. Subjects who are Hepatitis B core antibody positive are eligible only if they start or are on prophylactic therapy. Subjects with active Hepatitis B (surface antigen or core antigen positive) are ineligible. 5. Subjects with known chronic active Hepatitis C are ineligible. If Hepatitis C is discovered after enrollment the patient must be evaluated by a specialist in order to determine the need for treatment. 6. Pregnant women or nursing mothers. 7. ECOG Performance Score greater than 3 (KPS less than 50%) (Appendix IV). 8. Expected survival less than 2 months. 9. Unable to comply with the requirements of the protocol, or unable to provide adequate informed consent in the opinion of the Principal Investigator. 10. Serious, ongoing, non-malignant disease or infection, which in the opinion of the Investigator and/or the sponsor would compromise other protocol objectives. Subjects with active opportunistic infections are ineligible. 11. Major surgery, other than diagnostic surgery, occurring 4 weeks prior to study entry. 12. Rituximab therapy within the 12 months prior to study entry. Patients treated with rituximab within 12 months prior to study registration are eligible only if it was given for indications other than the treatment of aggressive lymphoma. 13. Prior cytotoxic chemotherapy or radiotherapy for this lymphoma, except as outlined in Section 4.1.13. 14. History of cutaneous or mucocutaneous reactions, or diseases in the past, due to any cause, severe enough to cause hospitalization or an inability to eat or drink for greater than 2 days. This exclusion relates to the long-term possibility of severe cutaneous or mucocutaneous reactions to rituximab that might occur at increased frequency in patients who have had severe skin disease or reactions in the past. 15. Use of zidovudine as part of the HAART regimen (a drug substitution for zidovudine at the time of study entry is allowed). 16. Any acute, inter-current infection that may interfere with planned protocol treatment. Patients with mycobacterium avium will not be excluded from study entry. Chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met. 17. Myocardial infarction (MI) within 6 months prior to study entry, New York Heart Association (NYHA) Class II or greater heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, clinically significant pericardial disease, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities (See Appendix XIV). 18. Subjects should not have taken valproic acid or another histone deacetylase inhibitor for at least 2 weeks prior to study enrollment.
Phase I: The Phase I portion of the study will determine the MTD of vorinostat in combination with rituximab plus CHOP or rituximab plus dose-adjusted (DA)-EPOCH chemotherapy. Stratum 1: Low-risk (aa-IPI 0-1 and Ki-67 less than 80% and GCB type [if known]) -Vorinostat + R-CHOP (VR-CHOP) Cycle 1: Vorinostat PO once daily, Days 1-5 (dose assignment by AMC ODMC upon enrollment) Rituximab 375 mg/m2 IV, Day 1 (See Section 3.4.4 for dose timing for safety concerns) Cyclophosphamide 750 mg/m2 IV, Day 1 Doxorubicin 50 mg/m2 IV, Day 1 Vincristine 1.4 mg/m2 IV, Day 1 (maximum of 2 mg) Prednisone 100 mg PO Days 1-5 Twenty four to 48 hours after completion of chemotherapy, begin Pegfilgrastim 6 mg SC for one dose or conventional filgrastim 300 mcg [if â?¤ 60 kg] or 480 mcg [if greater than 60 kg] SC daily for 10 days or longer until satisfactory neutrophil recovery. (See section 3.5.4) Cycles 2-6: Repeat VR-CHOP every 21 days if the following criteria are met: â?¢Nadir counts: If absolute neutrophil count (ANC) nadir during any cycle less than 500/mm3 on 2 nonconsecutive days at least 3 days apart OR platelets less than 25,000/mm3, see Section 7.1.1 (dose modification and toxicity management for hematologic toxicity). â?¢ANC â?¥ 1000/mm3 and platelets â?¥ 75,000/mm3 on Day 1 of new cycle (day of retreatment). If these criteria are not met, see Section 7.1.3 (chemotherapy modification guidelines for drug delay). If counts do not recover to the above levels within 2 weeks of completion of any cycle, vorinostat must be discontinued and chemotherapy drugs adjusted accordingly. â?¢Adequately recovered from treatment-associated toxicity. Stratum 2. High-risk (aa-IPI 2-3 or Ki-67 â?¥ 80% or ABC subtype [if known]) - Vorinostat + rituximab and DA-EPOCH (VR-DA-EPOCH) Cycle 1: Vorinostat PO once daily, Days 1-5 (dose assignment by AMC ODMC upon enrollment) Rituximab 375 mg/m2 IV, Day 1 (See Section 3.4.4 for dose timing adjustment for safety concerns) Etoposide 50 mg/m2/24 hours x 4 days (96 hour infusion), Days 1-4 Doxorubicin 10 mg/m2/24 hours x 4 days (96 hour infusion), Days 1-4 Vincristine 0.4 mg/m2/24 hours x 4 days (96 hour infusion), Days 1-4 Prednisone 60 mg/m2 PO daily Days 1-5 Cyclophosphamide: Start at 375 mg/m2 if CD4 equal to 50-200/mm3 or 750 mg/m2 if CD4 greater than 200/mm3 at study entry, IV over 1 hour, Day 5 (See Section 22.214.171.124 for dose adjustment in subsequent cycles). Twenty four to 48 hours after completion of chemotherapy, begin Pegfilgrastim 6 mg SC for one dose or conventional filgrastim 300 mcg [if â?¤ 60 kg] or 480 mcg [if greater than 60 kg] SC daily for 10 days or longer until satisfactory neutrophil recovery. (See section 3.5.4) Cycles 2-6: Repeat VR-DA-EPOCH regimen every 21 days if the following criteria are met: â?¢Nadir counts: If ANC nadir during any cycle less than 500/mm3 on 2 nonconsecutive days at least 3 days apart OR platelets less than 25,000/mm3, see Section 7.1.1 (dose modification and toxicity management for hematologic toxicity). â?¢Day 1 (day of retreatment) ANC â?¥1000/mm3 and platelets â?¥75,000/mm3. If these criteria are not met see EPOCH chemotherapy modification guidelines for drug delay, Section 7.1.2. If counts do not recover to above levels within 2 weeks vorinostat must be discontinued and chemotherapy drugs adjusted accordingly (see Section 126.96.36.199). â?¢Adequately recovered from treatment associated toxicity. 188.8.131.52Cyclophosphamide dose-adjustment (DA-EPOCH) Cycles 2-6 CBC and differential will be obtained on or about (+/- 3 days) Days 9, 12, and 15 of cycle 1 and every cycle in which therapy with cyclophosphamide is escalated (e.g., cycle 2, 3, etc.). If by the second CBC, the nadir has been reached and the ANC is recovering, no further CBCs are necessary (i.e., 2 CBCs will suffice). If nadir ANC greater than 500/mm3 and platelet nadir count â?¥ 50,000/mm3 in the previous cycle, then increase the dose by 187 mg/m2 each cycle (to a maximum dose of 750 mg/m2). 184.108.40.206Vorinostat dose escalations rules and definition of MTD Dose escalation of vorinostat will occur separately in each stratum with R-CHOP and R-DA-EPOCH at three planned dose levels as shown in the table described below. Dose levels will be assigned by the AMC ODMC upon subject registration, as indicated on the enrollment confirmation page in Advantage EDCSM. Dose escalation will begin at dose level +1 and proceed to +2 and +3 (and de-escalate to -1 if excessive toxicity is seen at dose level +1). Dose limiting toxicity (DLT) is defined as toxicities that occur during Cycle 1 of therapy (See Section 220.127.116.11). There will be no intrasubject dose escalation of vorinostat. Vorinostat Dose/Schedule Each Dose Level and Stratum Dose LevelStratum 1: Low aa-IPI Risk and Ki-67 less than 80% and GCB-subtype (if known) R-CHOPStratum 2: High aa-IPI Risk or Ki-67 â?¥80% or ABC subtype (if known) R-DA-EPOCH - 1200 mg QD days 1-5200 mg QD days 1-5 +1300 mg QD days 1-5300 mg QD days 1-5 +2400 mg QD days 1-5400 mg QD days 1-5 +3500 mg QD days 1-5500 mg QD days 1-5 aa-IPI equal to age-adjusted International Prognostic Index Vorinostat Dose Escalation Schema No. of Subjects at Dose LevelNo. of Subjects with Cycle 1 DLTAction 30Escalate to next dose level 31Treat up to 3 additional subjects at same dose level 61Escalate to next dose level 3-6 greater than / equal to 2RPTD exceeded, previous dose level is RPTD RPTD equal to recommended Phase II dose 18.104.22.168Definition of dose limiting toxicity (DLT) Dose limiting toxicity will be defined as an adverse event (AE) determined by the Investigator to be possibly, probably, or definitely attributed to vorinostat (refer to the Investigatorâ??s Brochure when assigning attribution for adverse events) that occurs in the first cycle (21 days) and meets the criteria as outlined in the table below. Classification of grade will be determined using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0. ToxicityDLT Definition Hematologicâ?¢ANC less than 500/mm3 that does not improve to a level above 750/mm3 within 14 days. â?¢Febrile neutropenia requiring hospitalization or IV antibiotics. â?¢Platelet count less than 25/mm3 of any duration â?¢Grade 4 anemia of any duration. Non-Hematologicâ?¢Any toxicity that causes a dose delay of greater than 2 weeks for the next planned treatment cycle will also be considered a DLT. â?¢Any adverse event â?¥ Grade 3 severity except: â?¦Fatigue â?¦Grade 2 Alopecia â?¦Grade 3 or 4 nausea, vomiting, and/or diarrhea that is responsive to treatment. â?¦Grade 3 or 4 non-hematologic laboratory abnormalities that resolve to Grade 1 or baseline (if the subject entered the study with an existing laboratory abnormality) within 14 days. 3.4.2Phase II: The Phase II portion of the study will begin after at least six subjects have been treated at the MTD dose on both R-CHOP and R-DA-EPOCH arms. The objective is to determine toxicity, response, time to disease progression and failure-free survival between low-risk subjects receiving either vorinostat (V)R-CHOP vs. R-CHOP alone or high-risk subjects receiving either vorinostat (V)R-DA-EPOCH vs. R-DA-EPOCH alone. In Phase II, low-risk subjects will be randomized to VR-CHOP or R-CHOP, and high risk subjects randomized to VR-DA-EPOCH or DA-R-EPOCH by the AMC ODMC upon subject registration, as indicated on the enrollment confirmation page in Advantage EDCSM. Stratum 1: Low-risk (aa-IPI 0-1 and Ki-67 less than 80% and GCB subtype [if known]) Arm C â?? Vorinostat (V)R-CHOP: Cycle 1: Vorinostat RPTD PO once daily, Days 1-5 Rituximab 375 mg/m2 IV, Day 1 (See Section 3.4.4 for dose timing adjustment for safety concerns) Cyclophosphamide 750 mg/m2 IV, Day 1 Doxorubicin 50 mg/m2 IV, Day 1 Vincristine 1.4 mg/m2 IV, Day 1 (maximum of 2 mg) Prednisone 100 mg PO Days 1-5 Twenty four to 48 hours after completion of chemotherapy, begin Pegfilgrastim 6 mg SC for one dos
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