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Introduction: Vorinostat (VOR), a histone deacetylase inhibitor, enhances the anti-tumor effects of rituximab (R) and cytotoxic chemotherapy, induces viral lytic expression and cell killing in Epstein-Barr virus-positive (EBV + ) or human herpesvirus-8-positive (HHV-8 + ) tumors, and reactivates latent human immunodeficiency virus (HIV) for possible eradication by combination antiretroviral therapy (cART)., Patients and Methods: We performed a phase I trial of VOR given with R-based infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride) (n = 12) and cART in aggressive HIV-associated B-cell non-Hodgkin lymphoma (NHL) in order to identify safe dosing and schedule. VOR (300 or 400 mg) was given orally on days 1 to 5 with each cycle of R-EPOCH for 10 high-risk patients with diffuse large B-cell lymphoma (1 EBV + ), 1 EBV + /HHV-8 + primary effusion lymphoma, and 1 unclassifiable NHL. VOR was escalated from 300 to 400 mg using a standard 3 + 3 design based on dose-limiting toxicity observed in cycle 1 of R-EPOCH., Results: The recommended phase II dose of VOR was 300 mg, with dose-limiting toxicity in 2 of 6 patients at 400 mg (grade 4 thrombocytopenia, grade 4 neutropenia), and 1 of 6 treated at 300 mg (grade 4 sepsis from tooth abscess). Neither VOR, nor cART regimen, significantly altered chemotherapy steady-state concentrations. VOR chemotherapy did not negatively impact CD4+ cell counts or HIV viral loads, which decreased or remained undetectable in most patients during treatment. The response rate in high-risk patients with NHL treated with VOR(R)-EPOCH was 100% (complete 83% and partial 17%) with a 1-year event-free survival of 83% (95% confidence interval, 51.6%-97.9%)., Conclusion: VOR combined with R-EPOCH was tolerable and seemingly efficacious in patients with aggressive HIV-NHL., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To conduct an exploratory analysis of the relationship between gene expression and recurrence in patients with operable triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin-containing chemotherapy., Experimental Design: RNA was extracted from archived tumor samples derived from 246 patients with stage I-III TNBC treated with adjuvant doxorubicin-containing chemotherapy, and was analyzed by quantitative reverse transcriptase PCR for a panel of 374 genes. The relationship between gene expression and recurrence was evaluated using weighted Cox proportional hazards model score tests., Results: Growth factor receptor bound protein 7 (GRB7) was the only gene for which higher expression was significantly associated with increased recurrence in TNBC (Korn's adjusted P value = 0.04). In a Cox proportional hazards model adjusted for clinicopathologic features, higher GRB7 expression was associated with an increased recurrence risk (HR = 2.31; P = 0.04 using the median as the split). The 5-year recurrence rates were 10.5% [95% confidence intervals (CI), 7.8-14.1] in the low and 20.4% (95% CI, 16.5-25.0) in the high GRB7 groups. External validation in other datasets indicated that GRB7 expression was not prognostic in two adjuvant trials including variable systemic therapy, but in two other trials showed that high GBR7 expression was associated with resistance to neoadjuvant doxorubicin and taxane therapy., Conclusions: GRB7 was associated with an increased risk of recurrence in TNBC, suggesting that GRB7 or GRB7-dependent pathways may serve as potential biomarkers for therapeutic targets. Therapeutic targeting of one or more factors identified which function as interaction nodes or effectors should also be considered.

Background: Paclitaxel and pegylated liposomal doxorubicin (PLD) are active cytotoxic agents for the treatment of human immunodeficiency virus (HIV)-associated Kaposi sarcoma (KS). A randomized trial comparing the efficacy and toxicity of paclitaxel and PLD was performed, and the effects of therapy on symptom palliation and quality of life were determined., Methods: Patients with advanced HIV-associated KS were randomly assigned to receive paclitaxel at a dose of 100 mg/m2 intravenously (iv) every 2 weeks or PLD at a dose of 20 mg/m2 iv every 3 weeks. The KS Functional Assessment of HIV (FAHI) quality of life instrument was used before and after every other treatment cycle., Results: The study included 73 analyzable patients enrolled between 1998 and 2002, including 36 in the paclitaxel arm and 37 in the PLD arm; 73% of patients received highly active antiretroviral therapy (HAART) and 32% had an undetectable viral load (<400 copies/mL). Treatment was associated with significant improvements in pain (P=.024) and swelling (P<.001). Of the 36 patients who reported that pain interfered with their normal work or activities at baseline, 25 (69%) improved. Of the 41 patients who reported swelling at baseline, 38 (93%) improved. Comparing the paclitaxel and PLD arms revealed comparable response rates (56% vs 46%; P=.49), median progression-free survival (17.5 months vs 12.2 months; P=.66), and 2-year survival rates (79% vs 78%; P=.75), but somewhat more grade 3 to 5 toxicity for paclitaxel (84% vs 66%; P=.077)., Conclusions: Treatment with either paclitaxel or PLD appears to produce significant improvements in pain and swelling in patients with advanced, symptomatic, HIV-associated KS treated in the HAART era., (Copyright (c) 2010 American Cancer Society.)

The purpose of this trial was to determine cardiac toxicity and overall efficacy of the pegylated liposome doxorubicin (PLD)-docetaxel couplet alone if HER2-negative metastatic breast cancer (internal control) or with trastuzumab if HER2-positive disease. Upon central HER2 confirmation, 84 eligible patients received induction with PLD (30 mg/m(2)) and docetaxel (60 mg/m(2)) every 3 weeks (maximum eight cycles), alone if HER2-negative (arm A; N = 38) or plus trastuzumab (4 mg/kg once, then 2 mg/kg weekly) if HER2-positive disease (arm B; N = 46) as first-line therapy. Maintenance therapy (without PLD) allowed. Primary objectives were to determine whether congestive heart failure (CHF) rate >3% and the efficacy/toxicity of each arm. CHF rate was <3% in each arm. Response rate, median progression-free-, and overall survival in arms A and B were 47.4 and 45.7%, 11 and 10.6 months, and 24.6 and 31.8 months, respectively. Trastuzumab arm was associated with higher rates of hand foot syndrome (grade 3: 22 vs. 38%; P = 0.16; overall 51 vs. 75%, P = 0.03) and treatment discontinuation due to toxicity/patient withdrawal (13 vs. 28%; P = 0.11). Febrile neutropenia occurred in approximately 10% of patients. In conclusion, concurrent administration of trastuzumab with PLD-docetaxel was not associated with higher risk of cardiac toxicity compared with PLD-docetaxel alone, but led to excessive hand-foot syndrome.

Purpose: To determine whether the combination of pegylated liposomal doxorubicin (PLD) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy., Patients and Methods: This international, phase III study randomly assigned 751 patients to receive either docetaxel 75 mg/m(2) (n = 373) or PLD 30 mg/m(2) followed by docetaxel 60 mg/m(2) every 21 days (n = 378) and continued until disease progression or prohibitive toxicity. The primary end point was time to progression (TTP). Secondary end points were overall survival (OS), objective response rate (ORR), cardiac toxicity, and safety., Results: Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months (hazard ratio [HR] = 0.65; 95% CI, 0.55 to 0.77; P = .000001) and the ORR from 26% to 35% (P = .0085). OS was similar between the two groups (HR = 1.02; 95% CI, 0.86 to 1.22). The incidence of grade 3 or 4 adverse events were similar (78% v 72%), although a higher incidence of hand-foot syndrome (24% v 0%) and mucositis/stomatitis (12% v 1%) were observed in the PLD-docetaxel combination. Protocol-defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5% and 1% in both treatment arms, respectively., Conclusion: The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity, although mucocutaneous toxicity was more common.

Purpose: Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified., Experimental Design: Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (alpha = 0.05, beta = 0.10)., Results: Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01)., Conclusion: Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

Purpose: The combination of doxorubicin and cyclophosphamide (AC) is a standard adjuvant regimen. Doxorubicin and docetaxel (AT) is one of the most active cytotoxic regimens for metastatic breast cancer. The purpose of this trial was to determine whether adjuvant AT improved disease-free survival compared with AC in operable breast cancer., Patients and Methods: Women with invasive breast cancer were eligible if there were one to three positive lymph nodes or if the node-negative tumor was greater than 1 cm. Patients were randomly assigned after surgery to receive doxorubicin (60 mg/m(2)) plus either cyclophosphamide (600 mg/m(2); AC) or docetaxel (60 mg/m(2); AT) given every 3 weeks for four cycles, followed by hormone therapy for patients with estrogen receptor (ER) and/or progesterone receptor (PR)-positive tumors., Results: There were 2,882 eligible patients enrolled. After a median follow-up of 79.5 months, there was no significant difference in disease-free survival (DFS; 85% in both arms) or overall survival (91% v 92%) at 5 years. The hazard ratio for AC versus AT was 1.02 (95% CI for DFS, 0.86 to 1.22; P = .78). In an exploratory analysis of prespecified stratification factors by ER and PR expression there were trends toward improved DFS for AT in ER/PR-negative disease. Grade 3 neutropenia associated with fever or infection occurred more often with AT (26% v 10%; P < .05)., Conclusion: AT did not improve DFS or overall survival in this population, and was associated with more toxicity.

Preclinical studies have established the pharmacologic advantages of liposomal anthracyclines, including pharmacokinetic profiles after bolus dosing that resemble continuous infusion of conventional anthracyclines, increased drug concentrations in tumor cells compared with the surrounding tissues, and reduced toxicity relative to conventional anthracycline treatment. Based on these studies, many phase I and phase II clinical trials were conducted to assess the safety and potential activity of liposomal anthracyclines in the management of both solid and hematologic tumors. These studies provided valuable insight into the safety of pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]), nonpegylated liposomal doxorubicin (Myocet [NPLD]), and liposomal daunorubicin (DaunoXome [DNX]) over a range of doses, either as single-agent therapy or in combination with other cytotoxic agents. Other liposomal anthracyclines in development may be well tolerated but their activity remains to be elucidated by clinical trials. The available data also suggest that liposomal anthracyclines have activity not only against tumor types with known sensitivity to conventional anthracyclines, but also potentially for tumors that are typically anthracycline-resistant. Despite the availability of clinical data from a wide variety of tumor types and patient populations, further studies of liposomal anthracycline therapy are needed to fully establish their safety, efficacy, and dosing in the treatment of these patients.

For patients whose breast cancers are not responsive to endocrine therapy, there are a large number of cytotoxic drugs that will induce a response. In spite of the introduction of new, very active drugs such as the taxanes, vinorelbine, capecitabine, gemcitabine, and trastuzumab, the anthracyclines are still as active as any--and more active than most--drugs used to treat breast cancer. Their inclusion in combinations to treat early and advanced disease prolongs survival. However, they cause nausea, vomiting, alopecia, myelosuppression, mucositis, and cardiomyopathies. There is no evidence that increasing the dose of conventional anthracyclines or any other of the cytotoxics beyond standard doses will improve outcomes. Schedule may be more important than dose in determining the benefit of cytotoxics used to treat breast cancer. Weekly schedules and continuous infusions of 5-fluorouracil and doxorubicin may have some advantages over more intermittent schedules. Liposomal formations of doxorubicin reduce toxicity, including cardiotoxicity; theoretically they should also be more effective because of better targeting of tumor over normal tissues. Both pegylated liposomal doxorubicin (Doxil/Caelyx [PLD]) and liposomal doxorubicin (Myocet [NPLD]) appeared to be as effective as conventional doxorubicin and much less toxic in multiple phase II and phase III studies. PLD has been evaluated in combinations with cyclophosphamide, the taxanes, vinorelbine, gemcitabine, and trastuzumab, and NPLD has been evaluated in combination with cyclophosphamide and trastuzumab. Both liposomal anthracyclines are less cardiotoxic than conventional doxorubicin. The optimal dose of PLD is lower than that of conventional doxorubicin or NPLD. Patients treated with PLD have almost no alopecia, nausea, or vomiting, but its use is associated with stomatitis and hand-foot syndrome, which can be avoided or minimized with the use of proper dose-schedules. In contrast, the optimal dose-schedule of NPLD is nearly identical to that of conventional doxorubicin. The toxicity profile of NPLD is similar to that of conventional doxorubicin, but toxicities are less severe and NPLD is better tolerated than conventional doxorubicin at higher doses.

Purpose: To determine the effectiveness of an infusional chemotherapy regimen in patients with HIV-associated lymphoma treated before and after the use of highly active antiretroviral therapy (HAART) in routine clinical practice., Patients and Methods: Ninety-eight assessable patients with HIV-associated intermediate- or high-grade non-Hodgkin's lymphoma received cyclophosphamide 200 mg/m(2)/d, doxorubicin 12.5 mg/m(2)/d, and etoposide 60 mg/m(2)/d (CDE) given by continuous intravenous infusion for 4 days (96 hours) every 4 weeks plus filgrastim. Concurrent antiretroviral treatment consisted of the nucleoside analog didanosine in the first 43 patients enrolled before December 1996 (pre-HAART group), or HAART in the remaining 55 patients enrolled after that time (HAART group)., Results: Complete response occurred in 44 patients (45%; 95% CI, 35% to 55%). Failure-free survival and overall survival (OS) at 2 years was 36% (95% CI, 26% to 46%) and 43% (95% CI, 33% to 53%), respectively. At the time of the analysis, 30% in the pre-HAART group were alive compared with 47% in the HAART group; when adjusted for varying length of follow-up, patients in the HAART group had improved OS (P =.039). Patients in the HAART group experienced less grade 4 nonhematologic toxicity (22% v 42%; P =.037), thrombocytopenia (31% v 52%; P =.033), and anemia (9% v 27%; P =.021), and had fewer treatment-associated deaths (0% v 10%; P =.013)., Conclusion: Infusional CDE is an effective and potentially curative regimen for patients with HIV-associated lymphoma. Patients treated in the HAART era have less chemotherapy-associated toxicity and improved survival.

Preclinical and clinical evidence suggest a potential advantage for infusional therapy in lymphoma. Sixty-two analyzable patients with predominantly intermediate-grade non-Hodgkin lymphoma received cyclophosphamide (200 mg/m(2) per day), doxorubicin (12.5 mg/m(2) per day), and etoposide (60 mg/m(2) per day) (CDE) by continuous intravenous infusion for 4 days (96 hours) every 3 weeks for a maximum of 8 cycles. By the age-adjusted International Prognostic Index (IPI), 42% were at high risk and 58% were at high-intermediate risk. Complete response (CR) occurred in 30 (48%) patients (95% confidence interval [CI], 35%, 64%), and partial response occurred in 16 (26%) patients, yielding an overall response rate of 74% (95% CI, 62%, 84%). Failure-free survival (FFS) rates at 1 and 2 years were 55% (95% CI, 43%, 67%) and 50% (95% CI, 38%, 62%), respectively. When comparing the outcome for 62 patients receiving infusional CDE with historical data derived from 927 IPI-matched lymphoma patients using a Cox proportional hazards model, there was a nonsignificant trend favoring CDE in FFS (P =.12) and overall survival (P =.09). Severe or life-threatening toxicity included neutropenia (68%), anemia (57%), thrombocytopenia (44%), and infection (24%). Two patients (3%) died of treatment-related infectious complications. The primary end point of improving 1-year FFS from 55% to 70% was not achieved with infusional CDE given as initial therapy in patients with poor-risk intermediate-grade lymphoma. It is unlikely that infusional therapy as used in this study produces a 25% or greater relative improvement in FFS compared with standard therapy.

PurposeThe aims of this study were to determine whether pretreatment plasma levels of cytokines and immune activation-associated molecules changed following treatment for AIDS-NHL with rituximab plus infusional EPOCH, and to determine whether pretreatment levels of these molecules were associated with response to treatment and/or survival.Experimental designWe quantified plasma levels of B-cell activation-associated molecules (sCD27, sCD30, and sCD23) and cytokines (IL6, IL10, and CXCL13) before and after the initiation of treatment in persons with AIDS-NHL (n = 69) in the AIDS Malignancies Consortium (AMC) 034 study, which evaluated treatment of AIDS-NHL with EPOCH chemotherapy and rituximab.ResultsTreatment resulted in decreased plasma levels of some of these molecules (CXCL13, sCD27, and sCD30), with decreased levels persisting for one year following the completion of treatment. Lower levels of CXCL13 before treatment were associated with complete responses following lymphoma therapy. Elevated levels of IL6 pretreatment were associated with decreased overall survival, whereas higher IL10 levels were associated with shorter progression-free survival (PFS), in multivariate analyses. Furthermore, patients with CXCL13 or IL6 levels higher than the median levels for the NHL group, as well as those who had detectable IL10, had lower overall survival and PFS, in Kaplan-Meier analyses.ConclusionsThese results indicate that CXCL13, IL6, and IL10 have significant potential as prognostic biomarkers for AIDS-NHL.

Objective: Poly(ADP-ribosyl) polymerases (PARPs) are nuclear enzymes with roles in DNA damage recognition and repair. PARP1 inhibition enhances the effects of DNA-damaging agents like doxorubicin. We sought to determine the recommended phase two dose (RP2D) of veliparib with pegylated liposomal doxorubicin (PLD) in breast and recurrent gynecologic cancer patients.Methods: Veliparib and PLD were administered in a standard phase 1, 3 + 3 dose-escalation design starting at 50 mg veliparib BID on days 1-14 with PLD 40 mg/mg2 on day 1 of a 28-day cycle. Dose escalation proceeded in two strata: A (prior PLD exposure) and B (no prior PLD exposure). Patients underwent limited pharmacokinetic (PK) sampling; an expansion PK cohort was added.Results: 44 patients with recurrent ovarian or triple negative breast cancer were enrolled. Median age 56 years; 23 patients BRCA mutation carriers; median prior regimens four. Patients received a median of four cycles of veliparib/PLD. Grade 3/4 toxicities were observed in 10% of patients. Antitumor activity was observed in both sporadic and BRCA-deficient cancers. Two BRCA mutation carriers had complete responses. Two BRCA patients developed oral squamous cell cancers after completing this regimen. PLD exposure was observed to be higher when veliparib doses were > 200 mg BID.Conclusions: The RP2D is 200 mg veliparib BID on days 1-14 with 40 mg/m2 PLD on day 1 of a 28-day cycle. Anti-tumor activity was seen in both strata. However, given development of long-term squamous cell cancers and the PK interaction observed, efforts should focus on other targeted combinations to improve efficacy. [ABSTRACT FROM AUTHOR]

BACKGROUND: Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)-associated, aggressive B-cell, non-Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity. METHODS: The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV-associated NHL who received either R-CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R-EPOCH (n = 51; AMC034). Age-adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R-CHOP vs R-EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event-free survival (EFS) and overall survival (OS). RESULTS: Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R-EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment-associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01). CONCLUSIONS: The current analysis provided additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse large B-cell lymphoma (National Clinical Trial no. NCT00118209). Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]