Efficacy Of Pegylated Liposomal Doxorubicin Research Articles

Long-term cure of soft tissue sarcoma with pegylated-liposomal doxorubicin after doxorubicin and ifosfamide failure

BackgroundDoxorubicin is one of the most active drugs available for the treatment of sarcoma. Pegylated-liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the doxorubicin is encapsulated in liposomes coated with methoxypoly (ethylene glycol); this formulation results in decreased uptake by the reticuloendothelial system, higher concentrations of drug in tumor, and less toxicity, including reduced cardiotoxicity, nausea, alopecia, and myelosuppression. No premedication is necessary. While PLD has a better toxicity profile than free doxorubicin, there is no consensus on the relative efficacy of PLD and free doxorubicin in sarcoma.Case presentationIn this report, we describe a patient with high-grade metastatic soft tissue sarcoma with rapid recurrence after adjuvant treatment with free doxorubicin, cisplatin, ifosfamide, and dacarbazine. Second-line treatment with PLD resulted in long-term disease remission during a 20-year follow-up period. Mucositis and hand-foot syndrome were controlled by adjustment of dose and treatment interval.ConclusionsThis case illustrates the curative potential of PLD after failure of free doxorubicin and the absence of long term cardiotoxicity with PLD. As with all drugs, individual adjustment of dose and treatment interval is important.

Phase I/II Trial of Combined Pegylated Liposomal Doxorubicin and Cyclophosphamide in Metastatic Breast Cancer

IntroductionDoxorubicin in combination with cyclophosphamide is active in breast cancer; however, its use in metastatic cancer is limited owing to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was formulated to decrease the toxicity of conventional doxorubicin. We evaluated the safety and efficacy of PLD with metronomic oral cyclophosphamide. Patients and MethodsWe conducted a single-arm open-label phase I/II study of PLD and oral cyclophosphamide in patients with metastatic breast cancer. In phase I, 3 escalating doses of PLD were planned (30, 35, and 40 mg/m2) with cyclophosphamide (60 mg/m2 orally daily) to determine the maximum tolerated dose (MTD). In phase II, the MTD of PLD in combination of oral cyclophosphamide was used to assess the primary endpoint of overall clinical response rate and secondary endpoints of progression-free survival, overall survival, and adverse events. ResultsThirty patients were enrolled in the study (n = 6 in phase I and n = 24 in phase II). The MTD of PLD from phase I was 30 mg/m2. The median progression-free and overall survival for the entire cohort were 6.4 months (95% confidence interval, 3.9 months to N/A) and 18.7 months (95% confidence interval, 15.1-31.5 months), respectively. A total of 21 (75%) patients had clinical benefit, including 6 (21%) patients with partial response and 15 (54%) patients with stable disease. The majority of toxicities were uncomplicated myelosuppression, and no infection or febrile neutropenia were noted in any patient. ConclusionPLD in combination with daily oral cyclophosphamide is an active and tolerable regimen in metastatic breast cancer.

Abstract B27: Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location

Abstract Introduction and Aim: Diffuse Intrinsic Pontine Glioma (DIPG) and pediatric High Grade Glioma (pHGG) are primary pediatric brain tumors that have a very high mortality and morbidity. Especially tumors that are not (DIPG) or only partially (midline pHGG) eligible for surgical resection have a very poor prognosis. Systemic chemotherapy regimens have failed to deliver satisfactory results but convection enhanced delivery (CED) is a promising technique that delivers chemotherapeutics directly to the tumor. Determining the best agent to deliver via CED is a challenge. Doxorubicin has shown to be highly effective when delivered via CED in preclinical glioma models, and against pHGG and DIPG cells in vitro. Liposomal doxorubicin is thought to improve distribution, bio-availability and subsequent efficacy of CED in glioma models. This preclinical study aims to determine the feasibility of performing CED with free doxorubicin or pegylated liposomal doxorubicin (PLD) in the brainstem and thalamus, and to study the efficacy of PLD and free doxorubicin when treating preclinical DIPG and pHGG models. Methods: Preclinical CED was performed with 15μl doxorubicin in the brainstem and thalamus of 6-week-old nude mice. Maximal tolerated dose was determined by treating mice with doxorubicin concentrations ranging from 2 mg/ml to 0.02 mg/ml. The efficacy study was performed with the highest possible dose and using the orthotopic diffusely growing E98-FM-DIPG model in the brainstem. Mice (n=12) were treated at day 9 after injection of cells. Follow-up consisted of BLI measurements, and determination of body weight and clinical symptoms. Results: Maximal tolerated dose was 0.02 mg/ml in the brainstem and 0.2 mg/ml in the thalamus for both free doxorubicin and PLD. Clinical toxicity after CED with higher concentrations consisted of weight loss and neurological deficits including paresis and loss of balance. Symptoms occurred after three (free doxorubicin) or six days (PLD). E98FM-DIPG bearing mice treated with 0.02 mg/ml of free doxorubicin, or PL-doxorubicin via CED did not show any survival benefit compared to vehicle treated animals. 0.2 mg/ml has previously shown to be effective in treating preclinical glioma models. Conclusions: Local drug delivery of concentrations that are safe in the thalamus show severe toxicity when delivered to the brainstem. No therapeutic window existed for treating orthotopic brainstem tumors in mice. However, therapeutic concentrations could be reached in the thalamus. This data suggest that anatomical location of the tumor is of vital importance when considering the best drugs to deliver via CED. Citation Format: A. Charlotte P. Sewing, Susanna J.E. Veringa, Tonny Lagerweij, David P. Noske, Dannis G. van Vuurden, Gertjan J.L. Kaspers, Esther Hulleman. Toxicity of convection-enhanced delivery with doxorubicin to treat pediatric brain-tumors depends on anatomical location. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B27.

Abstract 3354: Relationship between tumor-associated macrophages (TAMs), tumor delivery, and efficacy of PEGylated liposomal doxorubicin (PLD) and non-liposomal doxorubicin (NL-doxo) in genetically engineered mouse models (GEMMs) of breast cancer (BC).

Abstract Introduction: Solid tumors consist of both malignant cells and non-malignant stromal cells. Stromal cells typically include vascular, mesenchymal, and pro-inflammatory cells. Macrophages are the most abundant pro-inflammatory cell type in solid tumors and are termed TAMs. TAMs are derived from monocytes (mononuclear phagocyte system, MPS) and are associated with tumor progression, angiogenesis, and metastasis. The MPS are responsible for the clearance and distribution of nanoparticle (NP) anticaner agents such as PLD. However, the role of MPS in the tumor delivery of NP have not been evaluated. In this study, we evaluated the relationship between TAM-related tumor microenvironment factors, tumor delivery, and efficacy of PLD and NL-doxo in GEMMs of BC. Methods: Basal-like (C3(1)T-antigen) and claudin-low (T11/TP53-/-) GEMMs of human BC subtypes were evaluated. PLD or NL-doxo was administered at 6 mg/kg IV x 1 via a tail vein. For each GEMM, mice (n=3) were sacrificed prior to dose, and from 5 min to 96 h post dose. Plasma encapsulated and released doxo and sum total doxo conc in tumor was measured by HPLC. Area under the plasma and tumor conc versus time curves (AUC) were calculated. TAM infiltration was visualized and measured via immunohistochemistry (IHC) for F4/80. Endothelial cells in tumors were detected by CD31 IHC. Density of TAMs and endothelial cells in tumors were measured by the Aperio analysis algorithms. In efficacy study, PLD or NL-doxo at 6 mg/kg was administered every week for 6 weeks (n=20 per model). Tumor growth and overall survival were monitored. Results: Mean ± SD of plasma AUC of PLD encapsulated doxo in T11 and C3tag were1,449 ± 57 and 1,610 ± 111 (μg·h/ml), respectively. Mean ± SD of tumor sum total AUC of PLD in T11 and C3tag were 210 ± 26 and 480 ± 71 (μg·h/ml), respectively. Mean ± SD of tumor AUC of NL-doxo in T11 and C3tag were 61 ± 12 and 57 ± 10 (μg·h/ml), respectively. Mean ± SD baseline % positive cells of TAM in T11 and C3tag were 113 ± 45 and 110 ± 50, respectively. Mean ± SD baseline microvessel density in T11 and C3tag were 8.8 ± 2.5 and 6.1 ± 1.8 (number of vessels x10ˆ5 per unit area), respectively. C3tag demonstrated greater antitumor response to PLD compared to T11. Conclusions: There was a substantial difference in tumor exposure of PLD, but not NL-doxo, in the two GEMMs. These findings suggest that TM factors in BC may affect the delivery of NP agents, but not small molecules (SM). However, the similar TAM and microvessel baseline density in GEMMs suggest alternative tumor factors specifically affecting the delivery of NP agents. Further studies are warranted to elucidate the mechanisms underlying the delivery of NP agents in these and other tumors which may explain different tumor phenotypes and therapeutic outcomes related to treatment with NP and SM agents. Citation Format: Gina Song, David B. Darr, Charlene M. Santos, Taylor F. White, Jamie L. Jordan, Mimi Kim, Bentley R. Midkiff, Nana N. Feinberg, Ryan Miller, Arlin B. Rogers, Andrew C. Dudley, Charles M. Perou, William C. Zamboni. Relationship between tumor-associated macrophages (TAMs), tumor delivery, and efficacy of PEGylated liposomal doxorubicin (PLD) and non-liposomal doxorubicin (NL-doxo) in genetically engineered mouse models (GEMMs) of breast cancer (BC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3354. doi:10.1158/1538-7445.AM2013-3354

Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012

Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF. Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m2 on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). Nine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response [CCR] or partial response [PR] as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively. PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.

Use of pegylated liposomal doxorubicin in the management of platinum-sensitive recurrent ovarian cancer: current concepts

Pegylated liposomal doxorubicin (PLD) was first approved for platinum-refractory ovarian cancer in 1999 and then received full approval for platinum-sensitive recurrent disease in 2005 by the US FDA. PLD remains an important therapeutic tool in the management of recurrent ovarian cancer in 2012. Phase-II and III clinical trials of single-agent PLD in patients with platinum-sensitive recurrent ovarian cancer have reported overall mean survival times up to 29 months. Recent interest in PLD/carboplatin combination therapy for patients with platinum-sensitive recurrent ovarian cancer has been stirred from Phase-III trials reporting response rates, progressive-free survival and overall survival similar to other platinum-based combinations, but with a more favorable toxicity profile and convenient dosing schedule. Clinical trials combining PLD with poly (ADP-ribose) polymerase inhibitors, triple angiokinase inhibitors and folate receptor inhibitors are enrolling or under development and may further augment the therapeutic efficacy of PLD.

Phase II, Open-Label, Randomized, Multicenter Study Comparing the Efficacy and Safety of Olaparib, a Poly (ADP-Ribose) Polymerase Inhibitor, and Pegylated Liposomal Doxorubicin in Patients With BRCA1 or BRCA2 Mutations and Recurrent Ovarian Cancer

Olaparib (AZD2281), an orally active poly (ADP-ribose) polymerase inhibitor that induces synthetic lethality in BRCA1- or BRCA2-deficient cells, has shown promising clinical efficacy in nonrandomized phase II trials in patients with ovarian cancer with BRCA1 or BRCA2 deficiency. We assessed the comparative efficacy and safety of olaparib and pegylated liposomal doxorubicin (PLD) in this patient population. In this multicenter, open-label, randomized, phase II study, patients with ovarian cancer that recurred within 12 months of prior platinum therapy and with confirmed germline BRCA1 or BRCA2 mutations were enrolled. Patients were assigned in a 1:1:1 ratio to olaparib 200 mg twice per day or 400 mg twice per day continuously or PLD 50 mg/m(2) intravenously every 28 days. The primary efficacy end point was Response Evaluation Criteria in Solid Tumors (RECIST) -assessed progression-free survival (PFS). Secondary end points included objective response rate (ORR) and safety. Ninety-seven patients were randomly assigned. Median PFS was 6.5 months (95% CI, 5.5 to 10.1 months), 8.8 months (95% CI, 5.4 to 9.2 months), and 7.1 months (95% CI, 3.7 to 10.7 months) for the olaparib 200 mg, olaparib 400 mg, and PLD groups, respectively. There was no statistically significant difference in PFS (hazard ratio, 0.88; 95% CI, 0.51 to 1.56; P = .66) for combined olaparib doses versus PLD. RECIST-assessed ORRs were 25%, 31%, and 18% for olaparib 200 mg, olaparib 400 mg, and PLD, respectively; differences were not statistically significant. Tolerability of both treatments was as expected based on previous trials. The efficacy of olaparib was consistent with previous studies. However, the efficacy of PLD was greater than expected. Olaparib 400 mg twice per day is a suitable dose to explore in further studies in this patient population.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06)

Background: Pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients.Methods: Bevacizumab (10 mg/kg) and PLD (20 mg/m2) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination.Results: Thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%.Conclusions: In this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Pegylated Liposomal Doxorubicin, Bleomycin, Vinblastine and Dacarbazine (CBVD) in the Treatment of Advanced Primary Cutaneous Lymphomas.

Abstract 3717Poster Board III-653 IntroductionPrimary cutaneous lymphomas (PCL) present in the majority of histologic variants an indolent behaviour and a good prognosis with a prolonged survival. In a very small number of patients (pts), PCL is aggressive at the onset while in pts who are resistant or have relapsed after repeated topic or systemic therapies an advanced disease is more frequently observed. In these patients no therapy is capable of inducing a stable remission of the disease. The efficacy and low toxicity of Pegylated Liposomal Doxorubicin (PLD) as a single agent in second-line therapy of PCL was recently demonstrated. In our study we tested the safety and efficacy of PLD (Caelyx®) (C) in association with three drugs of proven effectiveness in nodal lymphoprolipherative and other primary cutaneous neoplastic disorders: Bleomycin (B), Vinblastine (B) and Dacarbazine (D) (CBVD). Patients and MethodsFrom February 2003 to December 2008 we observed 37 consecutive pts with advanced PCL: 19 Cutaneous T-Cell Lymphomas (CTCL) and 18 cutaneous B-Cell Lymphomas (CBCL). The CTCL pts were: 15 males and 4 females, with median age 59 (27-86) years, of which 7 pts with Anaplastic Large Cell Lymphoma (ALCL) CD30 positive, 7 pts with transformed Mycosis Fungoides (tMF), 3 pts with CD30 negative ALCL, 1pt with Panniculitis-like (Pl) Lymphoma and 1 pt with transformed Sezary Syndrome (tSS), according to the WHO-EORTC consensus classification. Nine pts presented with a nodal involvement and 10 pts were resistant or relapsed after 1 or more systemic treatments. Among the CBCL pts there were: 8 males and 10 females, with median age 61 (42-84) years, 12 pts had a Follicular Centre Lymphoma (FCL), 3 a Marginal Zone Lymphoma (MZL) and 3 a Diffuse Large B-Cell Lymphoma Leg Type (LT). Five pts presented a nodal involvement and 11 pts had received 1 or more previous systemic therapy. All 37 pts received CBVD therapy at following dosage: C: 20 mg/m2, B: 10 mg/m2, V: 6 mg/m2, D: 325 mg/m2 at days 1 and 15, administered intravenously every 4 weeks for a maximum of 6 cycles. Rituximab (R) at dosage of 375 mg/m2 was administered to CBCL pts at 1st day of each cycle. Before the treatment, pts were submitted to a complete staging of disease including TC-scan, bone marrow biopsy, and immunophenotyping of peripheral blood cells. ResultsIn the CTCL group 4 pts received 4 CBVD cycles, 14 pts received 6 CBVD cycles and 1 pt presented a progressive disease after the 1st cycle. Overall Response Rate (ORR) was 94.7% (18/19 pts). Sixteen out of 18 pts (88.8%) had a Complete Remission (CR) with disappearance of nodal involvement and cutaneous lesions, 2/18 pts obtained a Partial Remission (PR) with disappearance of nodal involvement and 75% of cutaneous lesions. In the CBCL group 3 pts received 2 R-CBVD cycles, 3 pts 4 cycles and 11 pts 6 cycles: ORR was 100% and all pts obtained a CR. The occurrence of palmoplantar erytrodisesthesia in 5 pts and grade 2-3 granulocytopenia in 12 pts did not modify the therapy program. Two CTCL pts (1 tSS, 1Pl) and 1 CBCL (LT) pt in CR after therapy received an allogeneic Hemopoietic Stem Cells (HCS) transplant and 1 CBCL(FCL) pt a syngeneic HCS transplant. In CTCL group 11 (61%) pts maintained their response after a median follow up of 15.5 (9-71) months. Among CBCL pts 14 (77.7%) pts are still in CR after a median follow up of 15 (4-36) months. ConclusionsOur experience demonstrates that the CBVD association is an effective and safe therapy for advanced PCL in inducing an important tumour burden reduction with a high CR rate. The assessment of response duration requires a longer observation. A larger number of patients in a multicentric trial are needed to confirm our promising results. Disclosures:Off Label Use: liposomial doxorubicin has a peculiar cutaneous tropism and low cardiac toxicity compared with other anthracyclines.

Pegylated liposomal doxorubicin and trastuzumab as 1st and 2nd line therapy in her2/neu positive metastatic breast cancer: a multicenter phase II trial

The combination therapy of doxorubicin and trastuzumab has been proven to be highly effective for metastatic breast cancer (MBC) patients with Her2/neu over-expressing tumors. However, this regimen is characterized by frequent cardiac toxicity, occurring in 27% of all treated patients and aggravating when the two substances are given concurrently. Pegylated liposomal doxorubicin (PLD) as a single agent reduces significantly cardiac toxicity and maintains efficacy compared to conventional doxorubicin. This prospective open labeled, multicenter phase II study assessed the potential cardiotoxicity and efficacy of PLD and trastuzumab as first and second line combination therapy in Her2/neu over-expressing MBC patients. Patients with Her2 over-expressing, measurable MBC with a baseline left ventricular ejection fraction (LVEF) > or =50% were treated with PLD 40 mg/m(2) every 4 weeks for 6 up to 9 cycles and weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg). Cardiotoxicity was defined as the appearance of clinical signs or symptoms of congestive heart failure in combination with a decrease in LVEF < or =44% or > or =10 units below the normal value of 50% in the obligatory, subsequently performed transthoracic echocardiography. Due to conflicting interests, the planned accrual goal of 30 patients was not reached. Finally 16 patients were enrolled. Ten patients presented with more than one metastatic site and six of them were in second-line therapy. The median LVEF in the study cohort was 66.1 +/- 8.68% at baseline, 62.7 +/- 5.11% after 6 cycles of therapy, 64.4 +/- 7.61% at the first follow up and did not change significantly (61.0 +/- 5.56% even at the 5th follow-up). Six out of 12 assessable patients (50.0%) demonstrated a clinical benefit and after a median follow-up of 15.4 months a median progression free survival of 9.67 and a median overall survival of 16.23 months. Non-cardiac side effects were mild with only 3 CTC grade 3 events of 247 treatment cycles (1.2%) and no grade 4 toxicities. The combination of PLD and trastuzumab in patients with Her2/neu over-expressing metastatic breast cancer is a safe, feasible and effective therapy. However, cardiac function should be monitored at close intervals. Due to the promising clinical response rates and mild toxicity profile in this prognostically unfavorable group, this combination therapy should be evaluated in larger studies.

A multicentric observational trial with metastatic breast cancer (MBC) patients on pegylated liposomal doxorubicin (PLD) regimen

1139 Background: PLD is approved for the treatment of MBC. In 2 randomized phase III studies in MBC patients (pts), PLD showed equal efficacy vs doxorubicin or vinorelbine in 1st- or 2nd-line setting, respectively. In this observational study, the toxicity profile and efficacy of PLD was analyzed under routine conditions. Methods: 125 MBC pts were recruited from June 03 until Nov 05 at 34 sites. ECOG status was 0–1 in 78% of pts. Median age was 62 years (37–84), median number of metastatic sites was 2 (1–5). 52% of pts were in 1st- or 2nd-line, 46% in 3rd - 6th-line therapy. 56% (n=70) of pts were pretreated with an anthracycline-containing regimen and 71% had previous endocrine treatment. Median PLD dose was 40 mg/m² (15–50 mg/m²) with the administration every 4 weeks being the most frequently used (range 2–5). 649 treatment courses were analyzed, the median number of cycles was 4 (1–12). Results: Leucopenia was the most prominent hematologic toxicity, with 3 pts developing grade 3 and 1 pt developing grade 4 toxicity. Only 2 pts had grade 3/4 thrombocytopenia. The predominant nonhematologic toxicity was skin toxicity, observed in 44 pts (20/16/5/1 pts with grade 1,2,3,4 toxicities respectively). No clinical signs, nor symptoms of cardiovascular toxicity were seen. No grade 3, 4 alopecia occurred. In 22% of pts dose reductions and in 30% of pts treatment delays were recorded. 53 pts (42%) showed response to therapy with 6 pts (4.8%) achieving complete remission (CR) and 47 pts (37.6%) PR; 37 pts (30%) had stable disease (SD), and 28 pts (22%) progression (PD); in 7 pts response was unknown. In anthracycline pretreated pts, in 24 cases (34%) response to therapy was observed (2 CR, 22 PR); 25 pts (36%) had SD and 17 pts (24%) PD. In the overall population, median progression-free interval and overall survival (OS) was 7.2 (95% CI: 5.4–8.6), and 20.8 months (95% CI: 15.4–22.6), respectively. Conclusions: In this observational study, PLD therapy was effective and well tolerated, even in heavily pretreated pts. This data compares favourably with data from published randomized trials. Supported by ESSEX Pharma Germany Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Essex Pharma

Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy

Recently, the authors reported improved time to disease progression (TTP) with a combination of pegylated liposomal doxorubicin (PLD) and bortezomib compared with bortezomib alone in a phase 3 randomized trial in patients with recurrent/refractory multiple myeloma (MM). In the current analysis, they determined 1) the efficacy of PLD plus bortezomib versus bortezomib alone in patients with MM who had failed on prior thalidomide/lenalidomide (immunomodulatory drug [IMiD]) treatment and 2) the efficacy and safety profile of PLD plus bortezomib in IMiD-exposed and IMiD-naive patients. This prespecified analysis included 646 patients who were randomized to receive either PLD with bortezomib (n=324; 194 IMiD-naive patients and 130 IMiD-exposed patients) or bortezomib alone (n=322; 184 IMiD-naive patients and 138 IMiD-exposed patients). The primary efficacy endpoint was TTP, and secondary endpoints included overall survival, response rate, and safety. The median TTP was significantly longer with PLD plus bortezomib compared with bortezomib alone in IMiD-exposed patients (270 days vs 205 days). No statistical difference was noted with respect to TTP between IMiD-naive (295 days) versus IMiD-exposed (270 days) subgroups who received PLD plus bortezomib. A sustained trend favoring combination therapy was observed in analyses of overall survival. In patients who achieved a response, the response duration was comparable for IMiD-naive patients and IMiD-exposed patients in the combination treatment group and lasted a median of 310 days and 319 days, respectively. The incidence of grade 3/4 adverse events was similar with PLD plus bortezomib regardless of prior IMiD exposure. A significantly prolonged TTP was observed with combined PLD plus bortezomib combination therapy compared with bortezomib alone despite prior IMiD exposure. For the combination treatment arm in the IMiD-naive and IMiD-exposed subgroups, TTP was comparable. Similarly, the safety profile of the PLD plus bortezomib combination was unaltered by prior IMiD exposure.

Antimetastatic activities of pegylated liposomal doxorubicin in a murine metastatic lung cancer model

To determine whether pegylated liposomal doxorubicin (PLD) could control the metastasis beyond primary tumor, the efficacy of PLD was evaluated in terms of metastatic growth inhibition and increasing life span in a murine lung metastasis model. As early as 20 days after C57BL/6 mice were inoculated with 2 × 106 murine Lewis lung carcinoma cells into the right legs, metastases could be observed in the lungs. Comparing the metastatic status of the PLD treatment conducted one day with one week after the tumor implantation, pathological study of the metastasis in the lungs indicated that without the removal of primary tumor, PLD could prevent metastasis by suppressing the growth of primary tumor. To evaluate the direct antimetastasis ability of PLD with clinical relevance, a surgery was performed to resect the tumor-bearing limb. The treatment was started 3 days after the amputation with free doxorubicin or PLD. In this therapeutic model, PLD targeted directly to the metastasis in the lungs, which resulted in substantially longer survival time than free doxorubicin. Despite the superiority of PLD over free doxorubicin in treating pulmonary metastasis, our observation suggested that without the removal of primary tumor, the effect of PLD was only modest, and surgery plus multiple injections of PLD will be the best choice for patients with metastatic disease.

Pegylated liposomal doxorubicin treatment in recurrent gynecologic cancer patients with renal dysfunction

Objectives A paucity of data exists regarding the efficacy and toxicity of pegylated liposomal doxorubicin (PLD) in cancer patients with chronic kidney disease (CKD). We sought to investigate the toxicity and efficacy of PLD in gynecologic cancer patients with CKD. Methods The clinical records of all patients with recurrent gynecological cancer and CKD at the University of Texas M.D. Anderson Cancer Center from 08/1999 to 08/2006 were reviewed retrospectively to identify patients who received PLD. Results Twenty-eight patients were identified, which included 14 with epithelial ovarian cancer, 4 with peritoneal cancer, and 10 with other gynecologic cancers. CKD was defined as a creatinine clearance (CrCl) of < 90 ml/min/1.73 m 2 and classified as mild (5 patients), moderate (16 patients), or severe (7 patients) (CrCl 60–89, 30–59, and < 30 ml/min/1.73 m 2, respectively). The initial doses of PLD were classified into regular initial dose (40 mg/m 2/4 weeks) and lower initial dose (30–35 mg/m 2/4 weeks). The median cycle was 4.5 (range 1–17). The incidence of grade 3–4 palmar–plantar erythrodysesthesia, stomatitis, and hematologic toxicity was 11.1% (2/18), 5.6% (1/18), and 16.7% (3/18) among 18 patients with an initial dose of 40 mg/m 2/4 weeks, which included 5, 10, and 3 patients with mild, moderate, and severe CKD, respectively. Dose reduction due to toxicities occurred in 33.3% (6/18) patients. In 18 patients with ovarian and peritoneal cancer (all platinum-resistant), the rates of complete response, partial response, stable disease, and progression were 0%, 11.1%, 44.4%, and 44.4%, respectively. Conclusions Patients with CKD who received PLD therapy at an initial dose of 40 mg/m 2/4 weeks may require greater subsequent dose reduction mainly secondary to mucocutaneous and hematologic toxicities. Treatment response in this population with ovarian and peritoneal cancer was similar to that of patients with normal renal function.

Pegylated liposomal doxorubicin (PLD) plus cyclophosphamide as 1st-line therapy for metastatic breast cancer in patients previously treated with anthracyclines

745 Background: Anthracyclines are among the most active drugs used for the treatment of breast cancer. Utilization in advanced disease however, is limited by their intrinsic dose limiting cardio-toxicity and extensive exposure in the adjuvant setting. Pegylated Liposomal Doxorubicin (Caelyx/Doxil) has been shown to possess similar activity to conventional doxorubicin, with a more favorable toxicity profile and significantly less cardiotoxicity. Cyclophosphamide is commonly used in combination with anthracyclines, thus represents an interesting drug to use with PLD. Methods: We undertook a multi-center single arm phase II trial to assess the safety and efficacy of PLD 35mg/m2 in combination with cyclophosphamide 600 mg/m2 every 3 weeks. Eligibility criteria included: Measurable disease, prior anthracyclines exposure >12 months prior to study entry, adequate organ and bone marrow function. A 2 stage design was implemented with planned accrual of 70 patients if an objective response rate of ≥ 28% was observed in the first 25 patients in the absence of significant cardiac or other severe toxicities. Results: Previous adjuvant therapy included cyclophosphamide, doxorubicin, epirubicin, 5-Fu and taxanes in 90%, 59%, 41%, 30% and 27% of cases, respectively. Patients received a median of 4 cycles (4–10) of PLD and no major toxicity has been reported after the first 30 patients. Four patients experience asymptomatic >10% declines in LVEF that was reversible upon discontinuation of PLD. The incidence of hand foot syndrome (HFS) was relatively low (13%); only one patient stopped therapy due to grade 3 HFS. Other toxicities were uncommon and usually did not lead to discontinuation of therapy. An early efficacy analysis revealed a 32% objective response rate exceeding the predefined stopping rule. The study is now moving forward to the second stage. Conclusions: The combination of PLD with Cyclophosphamide given every 3 weeks is a safe and active combination in advanced breast cancer patients who relapse more then one year after completion of adjuvant therapy with anthracyclines. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Canada, Aventis, Pfizer, Roche Canada AstraZeneca, Aventis, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer, Schering Amgen Canada, AstraZeneca, Aventis, Bristol-Myers Squibb, GlaxoSmithKline, Hoffmann-La Roche, Novartis, Pfizer

Efficacy of pegylated-liposomal doxorubicin in the treatment of AIDS-related Kaposi's sarcoma after failure of standard chemotherapy.

To determine the efficacy and safety of pegylated-liposomal doxorubicin in patients with AIDS and Kaposi's sarcoma (AIDS-KS) who experienced failure of standard chemotherapy. Fifty-three patients with advanced AIDS-KS who experienced disease progression or intolerable toxicities while receiving standard doxorubicin/bleomycin/vincristine (ABV) or bleomycin/vincristine (BV) chemotherapy were identified from a cohort of patients who were then treated with pegylated-liposomal doxorubicin. Patients received 20 mg/m2 pegylated-liposomal doxorubicin (Doxil; Sequus Pharmaceuticals, Inc, Menlo Park, CA) every 3 weeks. Nineteen patients (36%) had a partial response (PR) and one patient had a clinical complete response (CCR). The median duration of response and time (from study entry) to treatment failure were 128 and 134 days, respectively. Of 28 patients who experienced disease progression while receiving combination regimens that contained standard doxorubicin, the PR rate was 32%, which suggests that the pegylated-liposomal encapsulation increases the therapeutic effect of doxorubicin. Patients obtained clinical benefits such as flattening of lesions (48%), improved lesion color (56%), relief of pain (45%), and loss of edema (83%). Forty-nine percent of patients had more than one clinical benefit. The most common adverse effect was leukopenia, which occurred in 40% of patients. Only 15% of patients had nausea and/or vomiting, none of which was severe; 9% experienced alopecia, also generally mild. Pegylated-liposomal doxorubicin offers a new alternative for treatment of patients who have experienced failure of standard chemotherapy for AIDS-KS.