A Feasibility Study of Co-administering Combination Antiretroviral Therapy (cART) and R-EPOCH Chemotherapy for the Management of ARL
A Feasibility Study of Co-administering Combination Antiretroviral Therapy (cART) and R-EPOCH Chemotherapy for the Management of ARL
No standard regimen currently exists for the treatment of AIDS-related lymphoma. Based on the
 encouraging NCI results with DA-EPOCH, the US AIDS Malignancy Consortium is currently
 administering a phase II randomized protocol comparing EPOCH with sequential versus
 concurrent rituximab (AMC protocol 034). In this AMC trial, the decision to co-administer
 cART is left to the discretion of the treating physician and the patient. While the AMC phase
 II study may establish an acceptable chemotherapy regimen suitable for further study in a
 phase III randomized trial, the results will not address adherence, pharmacokinetic
 interactions or the role of cART in AIDS-related lymphoma. The contribution of cART to the
 anti-lymphoma efficacy of any regimen needs to be formally studied. Our proposed trial to
 demonstrate the feasibility of co-administering cART with chemotherapy would justify the use
 of combined therapy in future AMC/International phase III protocols.
Study Design & Duration This is a prospective, single-arm, multi-centre, phase II trial of
 immuno-chemotherapy (rituximab and EPOCH) with mandatory combination antiretroviral therapy
 for initial treatment of AIDS-related lymphoma. Patients diagnosed with previously-untreated
 AIDS-related diffuse large B-cell lymphoma will be eligible for this trial. Patients are
 eligible regardless of whether they have previously been treated with or are naïve to
 antiretroviral therapy. The total sample size of 18 patients is required to determine the
 feasibility of co-administering cART and chemotherapy as measured by adequate adherence to
 the antiretroviral regimen.

 Patients will receive EPOCH and rituximab chemotherapy for 6 cycles each given every 21 days.
 Day 1 of each cycle will consist of an infusion of rituximab followed by the initiation of a
 96-hour continuous infusion of etoposide, doxorubicin, and vincristine and oral prednisone.
 Cyclophosphamide will be administered on Day 5 with initial dose based on initial CD4+ cell
 count to minimize hematologic toxicity.

 Combination antiretroviral therapy will be administered to all patients enrolled in the
 trial. Patients already responding to their current cART regimen will continue with the same
 therapy. Otherwise, patients can be initiated on a preferred regimen of tenofovir (TDF),
 emtricitabine (FTC), and efavirenz (EFV) according to the US Department of Health and Human
 Services (DHHS) guidelines. Patients initiated on the preferred regimen of TDF/FTC/EFV will
 start the antiretroviral treatments on Day 7 of the trial, after the first cycle of R-EPOCH
 is administered. Treatment will subsequently be continued for the duration of the trial and
 thereafter, according to the discretion of the treating physician.

 The primary endpoint for this feasibility study will be medication adherence to cART
 treatment. "Acceptable adherence" will be defined as the proportion of patients able to
 complete >90% of all prescribed cART doses during the course of chemotherapy as measured by
 pill counts. As previously reported, study participants will be asked to bring their pill
 bottles to clinic prior to each chemotherapy cycle (every three weeks) so that remaining
 pills can be counted by the participating study nurse/pharmacist. The number of missed doses
 will be computed from the difference between the actual and expected number of pills
 remaining in the bottle. Secondary outcomes include the toxicity of the combination therapy,
 as measured by adverse events graded according to the Common Terminology Criteria for Adverse
 Events (CTCAE) Version 3.0. CD4+ cell counts and HIV-1 mRNA viral loads will be obtained on
 all patients at baseline, following recovery from cycles 3 and 6, and every three months
 thereafter for two years. Secondary outcomes will also include complete and partial lymphoma
 response rate, progression-free survival, and overall survival, all defined by International
 Working Group criteria. The pharmacokinetics of etoposide, vincristine and doxorubicin will
 be studied in the patients initiating the preferred antiretrovirals TDF/3TC/EFV on Day 7 of
 the protocol (after completion of the first cycle of R-EPOCH). Thus the analysis of PK
 interactions will be on this subgroup of patients receiving a uniform treatment strategy.
 Pharmacokinetics will be assessed with the first cycle (when chemotherapy is given alone) and
 subsequent cycle of R-EPOCH (when chemotherapy is given with cART).

 Study administration and data collection will occur under the auspices of the Ontario
 Clinical Oncology Group (OCOG). OCOG operates from within the Clinical Trials Methodology
 Group at the Henderson Research Centre in Hamilton and is co-directed by oncologists at the
 Juravinski Cancer Centre and Toronto Sunnybrook Cancer Centres. OCOG has a well-established
 research environment to guide the administration of this trial across four unique clinical
 sites across Canada. The clinical sites for the study include Toronto Sunnybrook Regional
 Cancer Centre (TSRCC), Princess Margaret Hospital (PMH), St. Michael's Hospital (SMH), and at
 the St. Paul's Hospital (SPH) in Vancouver. Each clinical site is expected to enroll 1-4
 patients per year. An overall accrual rate of 8-10 patients per year is expected. Therefore,
 it will be possible to register 18 patients within 2 years of study initiation. For the
 individual patient, the chemotherapy treatment duration is 18 weeks. Following this phase of
 therapy (18 weeks), individual patients will be followed every 3 months for an additional 2
 years.
Inclusion Criteria:

 1. HIV seropositivity

 2. Biopsy diagnosis of a CD20+ diffuse large B-cell lymphoma or variants (including
 mediastinal (thymic) large B-cell lymphoma and plasmablastic lymphoma), atypical
 Burkit/Burkitt-like lymphoma, or Burkitt lymphoma diagnosed according to the World
 Health Organization (WHO) classification

 3. Age 18 years or older

 Exclusion Criteria

 1. Performance status ≥3 according to ECOG (Zubrod) scale (see Appendix I)

 2. Known primary central nervous system lymphoma or parenchymal brain involvement with
 lymphoma

 3. Non-measurable disease by physical examination or radiographic evaluation

 4. Absolute CD4+ cell count <50 cells/mm3 within 3 months prior to trial initiation

 5. Inadequate hepatic function (total bilirubin ≥35 µmol/L, alkaline phosphatase ≥2 xUL
 normal, AST/ALT ≥2 xUL normal) unless directly attributable to lymphoma or known
 Hepatitis B or C co-infection.

 6. Inadequate renal function (serum creatinine ≥125µmol/L) unless directly attributable
 to lymphoma

 7. Inadequate haematological function (haemoglobin ≤85 g/L, absolute neutrophil count
 ≤1000 cells/mm3, platelet count ≤75,000 cells/mm3) unless directly attributable to
 lymphoma or autoimmune thrombocytopenia.

 8. Evidence of left ventricular (LV) dysfunction (ejection fraction ≤ 50%) in patients
 over the age of 60 or in patients with a prior history of hypertension, congestive
 heart failure, peripheral vascular disease, cerebrovascular disease, coronary artery
 disease, or cardiac arrhythmia

 9. Pregnant or lactating women who intend to breast-feed during the trial period

 10. Men of reproductive potential and women of childbearing potential who are not using or
 not willing to use effective contraception

 11. Known intolerance to the prescribed chemotherapy or antiretroviral drugs

 12. Life-expectancy ≤ 3 months

 13. Geographically inaccessible for follow-up