Safety and Efficacy Pilot Trial of the Anti-Viral and Anti-Tumor Activity of Velcade Combined with (R)ICE in Subjects with Relapsed/Refractory AIDS-Associated Lymphoma
Evaluate the safety and overall lymphoma response rate of Velcade combined with ICE (ifosfamide, carboplatin, etoposide) +/- rituximab in subjects with EBV and/or HHV-8 positive relapsed/refractory HIV-associated NHL.
Inclusion Criteria Patient must be: - Age greater than or equal to 18 years - Histologically or cytologically confirmed relapsed or refractory HIV-associated NHL; patients with clinical relapsed/refractory disease where biopsy is not feasible need to have had histologic or cytologic documentation of AIDS-associated NHL previously (i.e., at time of diagnosis). Subjects must have documented HIV seropositivity. - Subjects who are on antiretroviral therapy at the time of entry must be on a stable regimen for at least 12 weeks prior to study entry. - Demonstration of EBV and or HHV-8 infection within the lymphoma (i.e. LMP-1 or LANA expression, positive Epstein-Barrâ??encoded RNAs (EBERs)). - ECOG performance status 0, 1 or 2 (Karnofsky Performance Status â?¥ 50%) - Life expectancy greater than 2 months - Subjects must have adequate organ and marrow function as defined below: oANC greater than equal to 1,000/mm3* oHemoglobin greater than equal to 8.0 gm/dL* oPlatelets greater than equal to 100,000/mm3 oTotal bilirubin less than equal to 1.5 mg/dL oAST(SGOT) and ALT(SGPT) less than equal to 2.5 X institutional upper limit of normal (ULN) oSerum creatinine less than equal to institutional ULN oCreatinine clearance greater than equal to 50 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal. *Subjects may be receiving growth factor support to meet these criteria *Subjects with lymphomatous involvement of the bone are eligible even if they do not meet the hematologic criteria listed above. - Female subjects must have a negative pregnancy test within 2 weeks of entering into the study and all subjects agree to use adequate birth control if conception is possible during the study. It is recommended that women avoid pregnancy and men avoid fathering children while in the study. Should a woman subject or partner of a male subject become pregnant or suspect she is pregnant while the subject is participating in this study, she should inform her treating physician immediately. - Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria - Subjects who have had chemotherapy within 3 weeks prior to entering the study, radiation therapy within 2 weeks or those who have not recovered from AEs due to agents administered more than 3 weeks earlier. Glucocorticoid therapy within the last 3 weeks is allowed. - Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Subjects with opportunistic infections that are controlled by antimicrobial or suppressive therapy are eligible for participation unless the Investigator judges the infection likely to become life-threatening in the setting of multi-agent chemotherapy. - Subjects must not require concurrent therapy with moderate to strong CYP3A4 inducers or inhibitors other than protease inhibitors due to interactions with bortezomib and ifosfamide metabolism. See Section 7.5 for a list of prohibited concurrent medications - Pregnant women are excluded from this study because Velcade, ifosfamide, carboplatin and etoposide are agents with the potential for teratogenic or abortifacient effects. All of these drugs are known to be excreted in breast milk. Because there is an unknown but potential risk for AEs in nursing infants secondary to treatment of the mother with Velcade, ifosfamide, carboplatin or etoposide, breastfeeding should be discontinued if the mother is treated with Velcade, ifosfamide, carboplatin or etoposide. These potential risks may also apply to other agents used in this study. - Female subject is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening. Pregnancy testing is not required for post-menopausal or surgically sterilized women - Subject has greater than or equal to Grade 2 peripheral neuropathy within 14 days prior to enrollment. - Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure (see Appendix V), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any electrocardiogram (ECG) abnormality at Screening has to be documented by the Investigator as not medically relevant. - Subject has hypersensitivity to compounds of similar chemical or biologic composition to Velcade, boron, mannitol, ifosfamide, carboplatin, or etoposide. - Subject has received other investigational drugs within 14 days prior to enrollment. - Acute active HIV-associated opportunistic infection requiring antibiotic treatment. Subjects with Mycobacterium avium or candidiasis are not excluded except when concurrent therapy with moderate to strong CYP3A4 inducers or inhibitors is required because of this infection. Chronic therapy with potentially myelosuppressive agents is allowed provided that entry hematologic criteria are met. - Concurrent malignancy excluding in situ cervical cancer, in situ anal cancer, or non-metastatic non-melanomatous skin cancer, or Kaposi?s sarcoma not requiring systemic chemotherapy. - Serious medical or psychiatric illness likely to interfere with participation in this clinical study. - Patients found to have an active hepatitis B infection (hepatitis B surface not eligible unless they meet ONE of the following criteria: oPatient is able to start dual anti-Hep B therapy prior to enrollment with adefovir and telbivudine. oPatient is already on dual anti-hepatitis B therapy; if either of the agents has activity against HIV (i.e., entecavir, tenofovir, lamivudine or emtricitabine) they must have been on this regimen for at least 12 weeks prior to study enrollment Consultation and co-management with a hepatitis expert regarding hepatitis B treatment is strongly encouraged before and during the trial.
Treatment Regimen The treatment plan is a two part design. In Part A, subjects are treated with a lead-in period of Velcade alone as follows: Velcade on Day 1 followed by combination Velcade, dexamethasone and the ICE regimen beginning on Day 8; the Part A cycle length is 28 days. Subjects who tolerate Part A will go on to Part B. Part B consists of Velcade, dexamethasone, and ICE +/- rituximab (based on CD20 status) over a 21-day cycle with Velcade, dexamethasone and the ICE regimen beginning on Day 1 +/- rituximab followed by Velcade again on Day 8. Subjects may receive Part B for two cycles beyond attaining complete response (CR). Subjects may go on to hematopoietic stem cell transplant (HSCT) if deemed appropriate after one or more cycles of Part B. Dose escalations for Velcade are based on the standard dose escalations used in earlier trials of Velcade in subjects with MM and NHL. When Velcade is given on Days 1, 4, 8 and 11 of a 21-day cycle, 1.3 mg/m2 is the typical maximum dose. In protocols combining Velcade with other agents and limiting Velcade dosing to Days 1 and 4 or Days 1 and 8 of a 21-day cycle, 1.5-1.6 mg/m2 has been feasibly employed. The initial dosing of the ICE drugs will be at standard doses to ensure adequate clinical efficacy. A dose de-escalation level is included for Part B where the ICE drugs are reduced by 25% of standard ICE dosing in the event that the combination of ICE with even low-dose bortezomib results in excessive toxicity Part A: Each subject?s Velcade dose will be assigned by the AMC Operations and Data Management Center (ODMC) at the time of enrollment from four pre-specified dose levels (0.7 mg/m2, 1.0 mg/m2, 1.3 mg/m2, 1.5 mg/m2), given on Days 1 and 8 of a 28-day cycle. After the lead-in phase of Velcade alone during Week 1, ICE dosing will start on Day 8 as follows: etoposide 100 mg/m2 IV Days 8-10, carboplatin AUC equal to 5 (maximum 800 mg) IV on Day 9 and ifosfamide 5000 mg/m2 mixed with an equal amount of Mesna as a 24 hour continuous IV infusion on Day 9; dexamethasone 20 mg IV on Days 8-10. Part B: (R)ICE+Velcade will be administered as follows: rituximab 375 mg/m2 IV on Day 1 if subject has CD20+ NHL; etoposide 100 mg/m2 IV daily on Days 1 to 3; carboplatin administered on Day 2 and dosed to an AUC equal to 5, calculated using the Calvert formula (5 x [creatinine clearance + 25]; the maximum dose of carboplatin is 800 mg); ifosfamide 5000 mg/m2 mixed with an equal dose of Mesna administered via continuous infusion for 24 hours beginning on Day 2 dexamethasone 20 mg IV will be given on Days 1-3 and on Day 8; Velcade Days 1 and 8 per the dose escalation schedule that follows. Part B Velcade dosing for a given subject will be the same dose of Velcade received in Part A unless the subject experienced a DLT; if a subject experienced a DLT during Part A, please see Section 7.2.2 for Part B eligibility and dosing.
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