Liposomal Doxorubicin In Patients Research Articles

Trabectedin plus pegylated liposomal doxorubicin in patients with disease progression after PARP inhibitor maintenance: a real-life case–control study

ObjectivePoly (ADP-ribose) polymerase (PARP) inhibitor resistance is problematic in epithelial ovarian cancer management and sequencing strategies may be performed to overcome this issue. In this context, our study evaluated the...

A Multicenter Phase I Dose-Finding and Preliminary Efficacy Study of the Histone Deacetylase Inhibitor Romidepsin in Combination with Pegylated Liposomal Doxorubicin for the Treatment of Adults with Relapsed or Refractory Cutaneous and Peripheral T-Cell Lymphomas

IntroductionLiposomal doxorubicin and romidepsin have single agent activity in PTCL and CTCL. In pre-clinical studies, we demonstrated that romidepsin had synergistic effects in combination with doxorubicin. The aim of this study is to determine the safety and feasibility of the combination of romidepsin and liposomal doxorubicin in patients with relapsed/refractory CTCL and PTCL.Materials and Methods:This is a multi-center, single arm, open-label phase I dose-escalation study. Patients with relapsed/refractory CTCL (stage IIA-IV), or PTCL of any stage or subtype who received at least one systemic therapy are eligible. The primary endpoint is to identify the maximum tolerated dose (MTD) of romidepsin in combination with liposomal doxorubicin and the secondary endpoint is to determine the overall response rate (ORR) of this combination. Patients were treated with liposomal doxorubicin 20 mg/m2 on day 1 and romidepsin at four dose levels on days 1, 8 and 15, every 28 days, until 2 cycles beyond the best response, 8 cycles, disease progression (PD), or intolerability; whichever comes first. Dose levels of romidepsin include 8, 10, 12 and 14 mg/m2. Dose limiting toxicity (DLT) is defined as any adverse event during therapy including: grade 5 toxicity, any grade 4 hematologic toxicity lasting >7 days (except neutropenia), or any grade 4 non-hematologic toxicity according to CTCAE version 4.0. The MTD was defined as the highest tested dose level where two or more participants experienced a DLT utilizing a standard 3+3 design. Response was evaluated using the Cheson criteria in PTCL and patients with nodal disease and the mSWAT was utilized in CTCL. Pre-specified in the protocol, after determination of the MTD of romidepsin, up to 12 patients will be treated in a dose-expansion cohort if efficacy is noted.Results:Fourteen patients (5 PTCL, 9 CTCL) were treated at four dose-levels with a median 4 cycles (range 1-8) of therapy. Clinical data regarding these patients is included in Figure 1. Grade 3/4 non-hematologic adverse events occurred in 4 patients including 3 infection, 1 fatigue and 1 atrial fibrillation. Four patients experienced grade 3/4 hematologic toxicities: 1 neutropenia, 2 thrombocytopenia and 3 anemia. The MTD of romidepsin was determined to be 12 mg/m2 and the dose limiting toxicity was prolonged (>7 days) grade 4 thrombocytopenia. The ORR was 57%, including 2 complete responses and 6 partial responses.Given these results, three additional patients have been treated in a pre-specified dose-expansion cohort. For the 17 total patients (including 3 additional patients treated at the MTD), the ORR was 52%. In CTCL the ORR was 78% (1 CR, 6 PR, 2 PD) and among PTCL patients the ORR was 25% (1 CR, 1 PR, 1 PD).Conclusion:Here we report the results of the dose-escalation study of the combination of romidepsin and liposomal doxorubicin with preliminary data on the ORR. This combination has an acceptable toxicity profile at an MTD of 12 mg/m2 for romidepsin and has promising efficacy in both relapsed/refractory PTCL and CTCL. An additional eight patients will be included in a dose-expansion cohort. [Display omitted] DisclosuresAi:Celgene: Research Funding. Porcu:Kiowa: Research Funding; Miragen: Research Funding; Tetralogic: Research Funding; Celgene: Research Funding; Innate Pharma: Research Funding; Cell Medica: Research Funding; Galderma: Research Funding; Kura: Research Funding. Wieduwilt:Sigma-Tau: Research Funding; Reata Pharmaceuticals: Equity Ownership. Brammer:Celgene: Research Funding.

Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer.

5522 Background: There is a medical unmet need for effective treatments in platinum resistant ovarian cancer patients. We assessed the safety and efficacy of a combination of pembrolizumab with bevacizumab and pegylated liposomal doxorubicin (PLD). Methods: This is an open-label phase 1b trial in patients ECOG 0 or 1 with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer. The safety of the dual combinations of pembrolizumab with bevacizumab or with PLD were previously evaluated in 6 patients respectively. In the absence of dose limiting toxicities (DLT) the triple combination was evaluated at a maximum tolerated dose (MTD)-1 for PLD in 3 patients and in the absence of DLT at MTD. The sample size was calculated according to the modified toxicity probability interval design. The primary evaluation criteria was the safety, the secondary endpoint was the outcome. Pharmacokinetics of the flat dose of bevacizumab will be evaluated. Results: 22 patients were enrolled from September 2019 until June 2020 in six French centers. 3 initial patients have been treated at 20mg/m2 of PLD (MTD-1) and 19 patients were treated at the dose of 30mg/m2 of PLD (MTD) combined with 200mg of pembrolizumab until progression, unacceptable toxicity, or withdrawal of consent and 400mg of bevacizumab for a total of six cycles. The patients’ characteristics are reported in the table. No DLT occurred. Grade 3 palmar-plantar erythrodysesthesia were reported in 4 patients. The recommended phase II dose of PLD was 30mg/m2 in combination with pembrolizumab and bevacizumab. For patients treated at MTD, the overall response rate was 32% (6 partial responses) with 74% of clinical benefit with a durable response in 10 patients (53%). Median number of cycles was 7.5 (2 to not reached). Two patients are still on treatment. Correlative studies are ongoing. Conclusions: The combination was well tolerated and demonstrated clinical benefit in 74% platinum resistant ovarian cancer patients with durable response (>6 months) in 53% of patients. Clinical trial information: NCT03596281. [Table: see text]

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

BackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.

A phase I trial of pomalidomide in combination with liposomal doxorubicin in patients with Kaposi sarcoma with or without other KSHV-associated diseases.

11552 Background: Kaposi sarcoma herpesvirus (KSHV, also known as human herpesvirus 8 [HHV-8]), is the causative agent of Kaposi sarcoma (KS), a multicentric angioproliferative tumor, a form of multicentric Castleman disease (KSHV-MCD), and KSHV inflammatory cytokine syndrome (KICS). KS can be difficult to treat when it occurs with KSHV-MCD or KICS; resulting in high mortality rates. Liposomal doxorubicin (LD) is an FDA-approved treatment for KS. Pomalidomide, an oral immunomodulatory drug, is safe and has demonstrated activity in KS, but the activity of the combination (pomalidomide+LD) in KS alone or with KSHV-associated diseases is unknown. Methods: The primary objective was to evaluate safety and tolerability of pomalidomide+LD in two groups of patients with KS requiring systemic therapy: Group I (GI)- KS alone; Group II (GII)- KS with concurrent KSHV-MCD or KICS. Patients received LD at 20 mg/m2 intravenously on day 1 of a 28-day cycle combined with pomalidomide once daily on days 1 to 21 at escalating dose levels (DL) (I - 2mg, II - 3mg, or III- 4mg) in a 3+3 design until plateau of response or other pre-specified criteria. Patients received 81mg of aspirin daily as thromboprophylaxis. KS responses were evaluated using the modified AIDS Clinical Trial Group criteria. Results: Thirty-four cisgender men, all with T1-stage KS [21 patients (62%) in GI and 13 patients (38%) in GII] were treated; 32 (94%) were HIV-infected and 22 (65%) had prior chemotherapy for KS (15/21 GI and 7/13 GII). There were no dose-limiting toxicities (DLTs) at DLIII for GI, and additional patients were treated at DLIII. In GII, grade 3 rash and pharyngeal edema were DLTs observed at 3mg of pomalidomide. Overall a median of 6 cycles were administered; the most common grade 3/4 toxicity was neutropenia. Among evaluable patients receiving &gt;2 cycles,17/21 patients in GI had a response (all partial) (81% [95% confidence interval (CI) 58-95%]) and 5/10 patients in GII had a response (4 partial and 1 complete) (50% [95% CI 19-81%]). Conclusions: Pomalidomide+LD was well-tolerated and active in heavily pretreated patients with KS alone. In patients with KS and other KSHV-associated diseases, activity was noted but less well-tolerated. Clinical trial information: NCT02659930 .

Cardiac safety of trabectedin monotherapy and in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer.

11547 Background: Trabectedin (T) is an established option as monotherapy for advanced soft tissue sarcomas (STS; Leiomyosarcomas and Liposarcomas in the USA) and in combination with pegylated liposomal doxorubicin (PLD) for recurrent ovarian cancer (ROC). This retrospective analysis evaluated the cardiac safety profile in over 1500 patients (pts) from clinical trials administering T monotherapy for STS or in combination with PLD (T+PLD) for ROC. Methods: Integrated cardiac safety data was analyzed from ten Phase 2 trials and one Phase 3 trial in STS (T) and two Phase 3 ROC trials (T+PLD). Cardiac-related treatment-emergent adverse events (TEAEs) were summarized using MedDRA terminology and by Kaplan-Meier analysis for time-to-event variables. Subgroup analyses were performed for cardiac-related TEAEs, including any significant decrease in LVEF. Results: Integrated data on T monotherapy included 982 pts (Table). Of these, 110 (11.2%) pts who received ≥1 dose of T experienced a cardiac-related TEAE, including tachycardia (3.1%), palpitations (1.5%), LVEF decrease (1.3%), sinus tachycardia (1.0%), and/or congestive cardiac failure (1.0%). A multivariate analysis revealed factors associated with increased risk to be cardiovascular medical history (risk ratio [RR]: 1.90; 95% CI: 1.24-2.91; p = 0.003) and age &gt; 65 years (RR: 1.78; 95% CI: 1.12,2.83; p = 0.014). Cardiac-related TEAEs were reported in 78 (12.6%) of 619 pts receiving T+PLD (Table). Incidence of cardiac-related TEAEs was greater with T+PLD compared with PLD monotherapy (12.6% vs 5.6%). A multivariate analysis showed that pts were at increased risk for experiencing cardiac-related TEAEs when treated with T+PLD compared to PLD monotherapy (RR: 2.70; 95% CI: 1.75,4.17; p &lt; 0.0001) and when there was a history of prior cardiac medication (RR: 1.88; 95% CI: 1.16,3.05; p = 0.010). Conclusions: Although infrequent, patients receiving T after prior anthracyclines or in combination with PLD are at risk for cardiac dysfunction, and appropriate clinical awareness and monitoring is encouraged to optimize patient outcomes. [Table: see text]

A retrospective study of carboplatin and liposomal doxorubicin in patients with locally advanced or recurrent squamous cell carcinoma of the cervix.

e18021 Background: The efficacy and safety of the combination of carboplatin and liposomal doxorubicin was tested in in patients with locally advanced or recurrent cervical cancer. Methods: The combination of carboplatin (area under the concentration curve AUC = 5) and liposomal doxorubicin (starting dose, 40 mg/m2) was administered intravenously every 28 days to 75 patients with locally advanced or recurrent cervical cancer to determine the drug efficacy and safety. Results: During the observation, all patients were received surgery or radiation before combination chemotherapy. 58 patients were assessable for response, and 12 patients were assessable for toxicity. During therapy, none patients required discontinuation of chemotherapy while only 2 patients needed dose reduction, because of side effect. The overall response rate was 77.3%, the median time to response was 8 weeks, the median duration of response was 24 weeks, and the median survival was 37 weeks. The most common adverse events with these patients included myelosuppression (69.0%), neutropenia (31.0%), anemia (23.0%), thrombocytopenia (21.0%) and neutropenic fever (11.0%). Conclusions: The combination of carboplatin and liposomal doxorubicin shows clinical efficacy and acceptable safety in patients with locally advanced or recurrent cervical carcinoma. It might provide a noval treatment for late stage cervical cancer.

Pegylated liposomal doxorubicin in patients with metastatic triple-negative breast cancer: 8-year experience of a single center

BackgroundThe known efficacy of doxorubicin in metastatic breast cancer is countered by its dose-limiting myelosuppression and cardiotoxicity. Pegylated liposomal doxorubicin (PLD) was discovered to overcome these problems. But the data regarding its use in metastatic TNBC (triple-negative breast cancer) is still insufficient. Our study aimed to assess the factors affecting the outcome of the patients with metastatic TNBC who received PLD.ResultsDuring a period of 8 years (January 2011–December 2018), we analyzed 39 eligible patients. The disease control rate (DCR) was 51.3%. Among all the analyzed factors, two of them significantly affected DCR. The first factor was the chemosensitivity to prior anthracycline. As patients with chemosensitive disease had higher DCR than those with the chemoresistant disease (P = .001). The second factor was the number of prior lines of chemotherapy. As the patients who received two prior lines had a higher DCR than those who received three lines or more (P = .023). Chemosensitivity was the only significant independent factor for DCR (odds ratio = .095, P = .008).For the studied patients, the median progression-free survival (PFS) was 7 months. The anthracycline-chemosensitivity was the only significant independent prognostic factor for PFS (P = .002). The median overall survival (OS) was 12 months. There was a marginally significant effect of anthracycline-chemosensitivity on OS (P = .052).ConclusionThe anthracycline-chemosensitivity is an independent predictive and prognostic factor for the patients with metastatic TNBC receiving PLD. In developing countries, PLD should be reserved for the patients whose tumors are anthracycline-chemosensitive.

Cardiac Safety with High Cumulative Dose of Pegylated Liposomal Doxorubicin in Patients with Metastatic Breast Cancer Previously Treated with Conventional Anthracyclines

Introduction: The treatment of metastatic breast cancer (MBC) is still challenging. Many studies documented the efficacy of pegylated liposomal doxorubicin (PLD) in patients with MBC, but there is a limited data about the cardiac safety with high cumulative dose (HCD) of PLD. Aim of the work: We conducted this trial to outline the cardiac safety of HCD of PLD in patients with MBC who previously received conventional anthracyclines. Methods: During the period of nine years (January 2011 to December 2019). We extracted the data of the patients with MBC receiving PLD at Medical Oncology Department, South Egypt Cancer Institute, Assiut University. These included patients’ demographics and therapeutic data including the full data of PLD, prior conventional anthracyclines, prior trastuzumab, and prior radiotherapy. Also, data about comorbidities as well as cardiac and other toxicities of PLD were obtained. The data was analysed using SPSS v. 21. Results: For all 81 eligible patients, the mean age was 43.9 years (±standard deviation (SD) 13.2). The mean cumulative dose of PLD was 378.4 mg/m2 (± SD of 250.2) and a range of 100 - 1200 mg/m2. About thirty-one (38.3%) patients received high cumulative dose (400 mg/m2 or more), while the remaining 50 patients did not. The decline in left ventricular ejection fraction (LVEF) was relatively rare; and of low grade. Grade 2 decline in LVEF occurred in only two patients who received high cumulative dose of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or without HCD. Regarding other toxicities, there was a significant increase in incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients who received HCD of PLD when compared to those who did not reach the HCD (38.7% versus 16% respectively; p = 0.021). Conclusion: Our study concluded that the use of PLD seems to be a justified agent in the treatment of MBC who previously treated by conventional anthracyclines in the adjuvant, metastatic or both settings, even in patients reaching the cumulative dose of conventional anthracycline.

A Pilot Study of Liposomal Doxorubicin Combined with Bevacizumab followed by Bevacizumab Monotherapy in Patients with Advanced Kaposi Sarcoma.

VEGF-A is important in the pathogenesis of Kaposi sarcoma, and bevacizumab has a response rate of 31%. We explored the combination of bevacizumab with liposomal doxorubicin in patients with Kaposi sarcoma. Patients with Kaposi sarcoma requiring systemic therapy were enrolled in one of two cohorts. Cohort 1 included patients with human immunodeficiency virus (HIV)-negative Kaposi sarcoma or with HIV-associated Kaposi sarcoma who would not be expected to respond to antiretroviral therapy (ART) alone (i.e., either stable or progressive Kaposi sarcoma on ART). Cohort 2 included all other patients with HIV-associated Kaposi sarcoma. Patients were treated with six cycles of liposomal doxorubicin with bevacizumab every 3 weeks followed by up to 11 cycles of bevacizumab alone. Sixteen patients were enrolled: 10 (two HIV negative) in cohort 1 and six in cohort 2. Fourteen patients had advanced disease (AIDS Clinical Trials Group T1). Overall response rate (complete and partial responses) was 56% [80% confidence interval (CI), 38%-74%] for all patients and were similar in the two cohorts. Median progression-free survival was 6.9 months (95% CI, 4.5 months-not estimable). Grade 3 and 4 adverse events attributed to therapy included hypertension (n = 5), neutropenia (n = 6), gastrointestinal hemorrhage (n = 1), and cerebral ischemia (n = 1). There was a significant decrease in VEGF-A levels from baseline to the end of six cycles of combination therapy. Pegylated liposomal doxorubicin in combination with bevacizumab has activity in advanced Kaposi sarcoma, but it is unclear whether the combination yields better outcomes than liposomal doxorubicin used alone.

A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas

BackgroundRelapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy.MethodsHere we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m2 monthly).ResultsFifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27–799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response.ConclusionsOur study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted.Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx

Trabectedin in combination with pegylated liposomal doxorubicin in patients with ovarian tumors.

The majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity.

Anti-NaPi2b antibody–drug conjugate lifastuzumab vedotin (DNIB0600A) compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer in a randomized, open-label, phase II study

BackgroundLifastuzumab vedotin (LIFA) is a humanized anti-NaPi2b monoclonal antibody conjugated to a potent antimitotic agent, monomethyl auristatin E, which inhibits cell division by blocking the polymerization of tubulin. This study is the first to compare an antibody–drug conjugate (ADC) to standard-of-care in ovarian cancer (OC) patients. Patients and methodsPlatinum-resistant OC patients were randomized to receive LIFA [2.4mg/kg, intravenously, every 3weeks (Q3W)] or pegylated liposomal doxorubicin (PLD) (40mg/m2, intravenously, Q4W). NaPi2b expression and serum CA-125 and HE4 levels were assessed. The primary end point was progression-free survival (PFS) in intent-to-treat (ITT) and NaPi2b-high patients. ResultsNinety-five patients were randomized (47 LIFA; 48 PLD). The stratified PFS hazard ratio was 0.78 [95% confidence interval (95% CI), 0.46–1.31; P=0.34] with a median PFS of 5.3 versus 3.1months (LIFA versus PLD arm, respectively) in the ITT population, and 0.71 (95% CI, 0.40–1.26; P=0.24) with a median PFS of 5.3 months versus 3.4months (LIFA versus PLD arm, respectively) in NaPi2b-high patients. The objective response rate was 34% (95% CI, 22% to 49%, LIFA) versus 15% (95% CI, 7% to 28%, PLD) in the ITT population (P=0.03), and 36% (95% CI, 22% to 52%, LIFA) versus 14% (95% CI, 6% to 27%, PLD) in NaPi2b-high patients (P=0.02). Toxicities included grade ≥3 adverse events (AEs) (46% LIFA; 51% PLD), serious AEs (30% both arms), and AEs leading to discontinuation of drug (9% LIFA; 8% PLD). Five (11%) LIFA versus 2 (4%) PLD patients had grade ≥2 neuropathy. ConclusionLIFA Q3W was well tolerated and improved objective response rate with a modest, nonstatistically significant improvement of PFS compared with PLD in platinum-resistant OC. While the response rate for the monomethyl auristatin E-containing ADC was promising, response durations were relatively short, thereby highlighting the importance of evaluating both response rates and duration of response when evaluating ADCs in OC. Clinical trials.govNCT01991210

The efficacy of trabectedin in treating ovarian cancer

ABSTRACTIntroduction: The majority of women with epithelial ovarian cancer present with advanced stage disease and there is a critical need for novel drugs and treatment strategies to improve outcomes. Trabectedin is a unique cytotoxic agent with a complex mechanism of action. It binds to guanines in the N2 position in the minor groove of DNA and its cytotoxicity involves DNA repair pathways and transcription regulation. Trabectedin’s activity is also related to the drug-induced changes of the tumor microenvironment. It has been shown to improve progression-free survival in combination with pegylated liposomal doxorubicin in patients with platinum-sensitive relapsed ovarian cancer. The most common adverse events experienced with trabectedin are nausea, vomiting, fatigue, neutropenia and transaminitis. Studies of biomarkers that are predictors of trabectedin benefit are underway.Areas covered: This review covers trabectedin’s mechanism of action and pharmacology, the clinical development of the drug in ovarian cancer, ongoing trials, and the use of biomarkers to predict efficacy to trabectedin.Expert opinion: Ongoing phase III trials with biomarker studies will help to elucidate the patient population that will best benefit from trabectedin and pave the way for personalized treatment decisions and potential future approval of trabectedin in the United States.

Liposomal doxorubicin in patients with breast cancer and concomitant cardiovascular diseases - interdisciplinary expert opinion

The use of liposomal doxorubicin in place of conventional form can significantly reduce the risk of clinically important cardiovascular complications of chemotherapy. The use of liposomal doxorubicin-containing regimen seems to be the most justified in treatment of breast cancer patients with coexisting cardiovascular diseases. The document defines the possible clinical scenarios for the use of chemotherapy with liposomal doxorubicin and presents the optimal cardiac monitoring of this therapy.

A phase Ib study of lapatinib plus pegylated liposomal doxorubicin in patients with advanced HER2-positive breast cancer.

600Background: Conventional anthracyclines are particularly active in HER2-positive breast cancer (BC), but their use concomitantly with anti-HER2 agents is limited by cardiotoxicity. Pegylated lip...

Strong synergy with APR-246 and DNA-damaging drugs in primary cancer cells from patients with TP53 mutant High-Grade Serous ovarian cancer

BackgroundMutation in the tumor suppressor gene TP53 is an early event in the development of high-grade serous (HGS) ovarian cancer and is identified in more than 96 % of HGS cancer patients. APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53 protein by refolding it to wild type conformation, thus inducing apoptosis. APR-246 has been tested as monotherapy in a Phase I/IIa clinical study in hematological malignancies and prostate cancer with promising results, and a Phase Ib/II study in combination with platinum-based therapy in ovarian cancer is ongoing. In the present study, we investigated the anticancer effects of APR-246 in combination with conventional chemotherapy in primary cancer cells isolated from ascitic fluid from 10 ovarian, fallopian tube, or peritoneal cancer patients, 8 of which had HGS cancer.MethodsCell viability was assessed with fluorometric microculture cytotoxicity assay (FMCA) and Combination Index was calculated using the Additive model. p53 status was determined by Sanger sequencing and single strand conformation analysis, and p53 protein expression by western blotting.ResultsWe observed strong synergy with APR-246 and cisplatin in all tumor samples carrying a TP53 missense mutation, while synergistic or additive effects were found in cells with wild type or TP53 nonsense mutations. Strong synergy was also observed with carboplatin or doxorubicin. Moreover, APR-246 sensitized TP53 mutant primary ovarian cancer cells, isolated from a clinically platinum-resistant patient, to cisplatin; the IC50 value of cisplatin decreased 3.6 fold from 6.5 to 1.8 μM in the presence of clinically relevant concentration of APR-246.ConclusionThese results suggest that combination treatment with APR-246 and DNA-damaging drugs could significantly improve the treatment of patients with TP53 mutant HGS cancer, and thus provide strong support for the ongoing clinical study with APR-246 in combination with carboplatin and pegylated liposomal doxorubicin in patients with recurrent HGS cancer.

Real-World Outcomes of Combination Chemotherapy with Trabectedin plus Pegylated Liposomal Doxorubicin in Patients with Recurrent Ovarian Cancer: A Single-Center Experience

Background: Trabectedin plus pegylated liposomal doxorubicin (PLD) proved efficacious as second-line treatment for patients with recurrent ovarian cancer (ROC). Methods: We report a single-center retrospective analysis of the efficacy and tolerance of trabectedin 1.1 mg/m² every 3 weeks in a cohort of real-life ROC patients. Results: From February 2012 to January 2014, 17 patients were treated with trabectedin alone or combined with PLD. Median age was 61 years (range: 48-78). Performance status was 0-1 in 16 patients (94%). Disease response rate was 53% and disease control rate was 76%. At the end of the follow-up, 8 patients (47%) were alive. Median overall survival was 17.6 months (95% CI 13.6 to not reached). Median progression-free survival was 6.7 months (95% CI 5.4-10.0). The most frequent grade 3-4 toxicities were neutropenia (n = 4, 24%) and nausea/vomiting (n = 4, 24%). Conclusion: Trabectedin combined with PLD seems efficient in and well tolerated by real-life ROC patients.

Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer

Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer

Phase 1b safety study of farletuzumab, carboplatin and pegylated liposomal doxorubicin in patients with platinum-sensitive epithelial ovarian cancer

ObjectiveFarletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha, over-expressed in epithelial ovarian cancer (EOC) but largely absent in normal tissue. Previously, carboplatin plus pegylated liposomal doxorubicin showed superior progression-free survival and an improved therapeutic index compared with carboplatin/paclitaxel in relapsed platinum-sensitive EOC. This study assessed safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive recurrent EOC. MethodsThis multicenter, single-arm study enrolled patients with platinum-sensitive EOC in first or second relapse for treatment with weekly farletuzumab 2.5mg/kg plus carboplatin AUC5-6 and pegylated liposomal doxorubicin 30mg/m2 every 4weeks for 6cycles. Subsequently, maintenance with single-agent farletuzumab 2.5mg/kg once weekly or farletuzumab 7.5mg/kg once every three weeks continued until progression. The primary objective was to assess the safety of farletuzumab/carboplatin/pegylated liposomal doxorubicin. ResultsFifteen patients received a median of 12.0cycles (range, 3–26) of farletuzumab as combination therapy or maintenance, for a median of 45.0weeks (range 9–95). Farletuzumab/carboplatin/pegylated liposomal doxorubicin was generally well tolerated, with no farletuzumab-related grades 3–4 adverse events. The most commonly reported adverse events were associated with combination chemotherapy: fatigue (73.3%), nausea (46.7%), and neutropenia (40%). Ten patients had grade ≥3 adverse events, most frequently neutropenia and fatigue. No cardiac toxicity was seen. Best overall responses (RECIST) were a complete response for one patient, partial responses for 10 patients, and stable disease for four patients. ConclusionsFarletuzumab plus carboplatin/pegylated liposomal doxorubicin in women with platinum-sensitive EOC demonstrated a safety profile consistent with that of carboplatin plus pegylated liposomal doxorubicin.