Pegylated liposomal doxorubicin plus paclitaxel as an individualized chemosensitivity-directed treatment in advanced metastatic melanoma

8551 Background: Melanoma is a cutaneous neoplasm known for its high agressiveness and its poor prognosis once metastasized. Dacarbacine chemotherapy is actually considered standard first-line treatment of metastatic melanoma, with reported response rates of 6–7%. Due to this unsatisfactory situation, a number of non-standard anti-cancer drugs have been tested for improved efficacy. The present study was aimed to test doxorubicin plus paclitaxel in metastatic melanoma patients based on in-vitro chemosensitivity of this drug combination in fresh tumor samples. Methods: The primary study endpoint was objective response, secondary endpoints were safety and overall survival. Patients with histologically confirmed metastatic melanoma (AJCC stage IV), measurable tumor parameters, and an in-vitro chemosensitivity to doxorubicin plus paclitaxel which is superior to other test drugs determined by an ATP-based luminescence viability assay, were eligible. Patients received paclitaxel 175 mg/m2 i.v. followed by pegylated liposomal doxorubicin 30 mg/m2 i.v. at d1 every 28 days. Tumor assessment was performed every 8 weeks and evaluated according to RECIST. Treatment was continued at a tumor response of stable disease (SD) or better, and stopped in case of disease progression (PD) or intolerable side effects. Results: Out of 14 patients enrolled into this study, 12 received study treatment as first-line, and two as second-line therapy. Objective response was 14.3% (1 CR, 1 PR); progression arrest was 28.6% (1 CR, 1 PR, 2 SD). Median overall survival was 9.7 months. Common slight to moderate side effects were myelosuppression and neurotoxicity. Severe toxicities (CTC grade 3/4) were experienced by three patients (21.4%), with two of them presenting severe myelosuppression, and one experiencing myocardial infarction. Conclusions: Pegylated liposomal doxorubicin combined with paclitaxel shows significant efficacy in advanced metastatic melanoma if applied in an individualized, sensitivity- directed regimen. The observed side effects were comparable to other combination chemotherapies. This treatment regimen needs further evaluation in larger clinical trials containing standard therapy control groups. No significant financial relationships to disclose.

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Using CHFR expression to predict response and survival after first line treatment with carboplatin-paclitaxel in NSCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.10625 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 10625-10625

Author(s):

Rathi Narayana Pillai ◽

Seth Aaron Brodie ◽

Ge Li ◽

James Gordon Herman ◽

Malcolm Brock ◽

...

Keyword(s):

Overall Survival ◽

Median Overall Survival ◽

Medical Center ◽

Objective Response ◽

Subsequent Development ◽

Predictive Marker ◽

Staining Intensity ◽

Adverse Outcomes ◽

First Line

10625 Background: The identification of resistance mechanisms for conventional chemotherapy in lung cancer is of fundamental importance not only for personalization of chemotherapy but also for the subsequent development of novel targeted approaches to overcome this resistance. Currently, there is no clinically validated test for the prediction of response to tubulin-targeted agents in NSCLC. Our previous preclinical work identified Checkpoint with Forkhead and Ringfinger domain” (CHFR) as a predictor of taxane cytotoxicity in in vitro models. The current work assessed the translational significance of this finding in a cohort of US veterans treated at a single-institution. Methods: We studied a cohort of patients with advanced NSCLC treated with taxane-containing frontline regimens at the Atlanta VA Medical Center between 2000 and 2009. Archived paraffin-embedded tissue was retrieved and stained for CHFR expression using standard immunohistochemical techniques. Level of protein expression was assessed by light microscopy and scored for intensity of CHFR staining. Intensity of staining was correlated with clinical outcome including objective response and median overall survival using Chi-Square test and Cox proportional models. Results: We analyzed tumor samples from 45 eligible patients with median age 62.6 years, M/F (44/1). In this cohort, high expression of CHFR is strongly associated with adverse outcomes: the risk for progressive disease (PD) after first-line chemotherapy with carboplatin-paclitaxel was 54% in patients with CHFR-high vs. only 18% in those with CHFR-low tumors (HR 3.1; 95% CI 1.09-9.04; p=0.02). Median overall survival was strongly correlated with response to first-line therapy (clinical benefit: 9.24 months; PD: 4.7 months; p<0.001) and with CHFR expression status (CHFR low: 10 months; CHFR high: 5.6 months; p =0.01). Conclusions: CHFR expression is a novel predictive marker of response and overall survival in NSCLC patients treated with taxane-containing chemotherapy.

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NIVOLUMAB EXPERIENCE IN THE TREATMENT OF PRE-TREATED PATIENTS WITH METASTATIC SKIN MELANOMA

Malignant tumours ◽

10.18027/2224-5057-2018-8-3-78-85 ◽

2018 ◽

Vol 8 (3) ◽

pp. 78-85

Author(s):

I. V. Samoylenko ◽

Ya. I. Zhulikov ◽

G. Yu. Kharkevich ◽

N. N. Petenko ◽

L. V. Demidov

Keyword(s):

Overall Survival ◽

Metastatic Melanoma ◽

Median Overall Survival ◽

Objective Response ◽

Progression Free Survival ◽

Subsequent Treatment ◽

Skin Melanoma ◽

First Line ◽

Free Survival ◽

Line Of Therapy

The appearance of anti-PD-1 drugs significantly improved prognosis of patients with metastatic skin melanoma. However, little data on the effectiveness of these drugs in the second and subsequent lines of therapy has been accumulated in the international literature. We have analyzed our experience in the use of nivolumab in the treatment of metastatic melanoma. This non-randomized, uncontrolled, continuous study included 53 patients with metastatic or unresectable melanoma, of whom 86.8 % (46) received two or more lines of systemic therapy for metastatic melanoma. The rate of objective response was 22.6 % (95 % Confidence Interval (CI) 53.3–64.4 %). The median progression-free survival was 4.37 months (95 % CI 2.27–6.47). The median overall survival was 17.9 months (95 % CI 8.89–26.99). One-, two-, three-year overall survival contained 66, 35 and 35 %, respectively. The efficacy of nivolumab in the second and subsequent treatment lines is significantly lower than showed in the results of randomized trials of the use of anti-PD-1 drugs in the first line of therapy.

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Vemurafenib (PLX4032): An Orally Available Inhibitor of Mutated BRAF for the Treatment of Metastatic Melanoma

Annals of Pharmacotherapy ◽

10.1345/aph.1q363 ◽

2011 ◽

Vol 45 (11) ◽

pp. 1399-1405 ◽

Cited By ~ 33

Author(s):

Yasser Heakal ◽

Mark Kester ◽

Scott Savage

Keyword(s):

Clinical Trial ◽

Overall Survival ◽

Metastatic Melanoma ◽

Immune Modulation ◽

English Language ◽

Objective Response ◽

Chemotherapeutic Agents ◽

First Line ◽

Clinical Safety ◽

Clinical Trial Registries

Objective: To summarize the preclinical and clinical data on vemurafenib, approved by the Food and Drug Administration (FDA) on August 17, 2011, and discuss the drug's clinical advantages and limitations. Data Sources: An English-language literature search of MEDLINE/PubMed (1966-August 2011), using the terms PLX4032, RG7204, R05185426, vemurafenib, and metastatic melanoma, was conducted. In addition, information and data were obtained from meeting abstracts, clinical trial registries, and news releases from the FDA. Study Selection and Data Extraction: All relevant published articles and abstracts on vemurafenib were included. Clinical trial registries and meeting abstracts were used to obtain information regarding ongoing trials. All peer-reviewed articles containing information regarding the clinical safety and efficacy of vemurafenib were evaluated for inclusion. Data Synthesis: Before the recent approval (March 2011) of ipilimumab, there was no first-line standard-of-care therapy, with proven overall survival benefit, for the treatment of malignant metastatic melanoma. Unlike ipilimumab, which acts through immune-modulation, vemurafenib is a novel, molecularly targeted therapeutic with preferential efficacy toward a specific mutated oncogenic BRAF-signaling mediator. In recently published results of a Phase 3 clinical trial comparing dacarbazine with vemurafenib, vemurafenib prolonged progression-free and overall survival, with confirmed objective response rate of 48% (95% CI 42 to 55) versus 5% (95% CI 3 to 9) for patients who received dacarbazine (p < 0,001) Conclusions: Vemurafenib offers a novel, first-line, personalized therapy for patients who have mutated BRAF, Clinical trials of vemurafenib in combination with ipilimumab or other targeted or cytotoxic chemotherapeutic agents may provide more effective regimens with long-term clinical benefit.

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Gemcitabine-Containing Chemotherapy for the Treatment of Metastatic Myxofibrosarcoma Refractory to Doxorubicin: A Case Series

Current Oncology ◽

10.3390/curroncol28010078 ◽

2021 ◽

Vol 28 (1) ◽

pp. 813-817

Author(s):

Arielle Elkrief ◽

Suzanne Kazandjian ◽

Thierry Alcindor

Keyword(s):

Overall Survival ◽

Soft Tissue ◽

Soft Tissue Sarcoma ◽

Objective Response ◽

Case Series ◽

Progression Free Survival ◽

Distant Metastases ◽

First Line ◽

Pleomorphic Sarcoma ◽

Line Setting

Background: Myxofibrosarcoma is a type of soft-tissue sarcoma that is associated with high rates of local recurrence and distant metastases. The first-line treatment for metastatic soft-tissue sarcoma has conventionally been doxorubicin-based. Recent evidence suggests that myxofibrosarcoma may be molecularly similar to undifferentiated pleomorphic sarcoma (UPS), which is particularly sensitive to gemcitabine-based therapy. The goal of this study was to evaluate the activity of gemcitabine-containing regimens for the treatment of metastatic myxofibrosarcoma refractory to doxorubicin. Material and Methods: We retrospectively evaluated seven consecutive cases of metastatic myxofibrosarcoma at our institution treated with gemcitabine-based therapy in the second-line setting, after progression on doxorubicin. Baseline clinical and baseline characteristics were collected. Primary endpoints were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). Results: After progression on first-line doxorubicin, a partial, or complete radiological response was observed in four of seven patients who received gemcitabine-based chemotherapy. With a median follow-up of 14 months, median progression-free and overall survival were 8.5 months and 11.4 months, respectively. Conclusions: Gemcitabine-based chemotherapy was associated with encouraging response rates in this cohort, similar to those seen in UPS. Both entities could be studied together for novel gemcitabine-based regimens.

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Pegylated liposomal doxorubicin re-challenge in patients with ovarian cancer relapse: a multicenter retrospective study

International Journal of Gynecological Cancer ◽

10.1136/ijgc-2018-000034 ◽

2019 ◽

Vol 29 (1) ◽

pp. 153-157 ◽

Cited By ~ 1

Author(s):

Elisa Tripodi ◽

Gennaro Cormio ◽

Ugo De Giorgi ◽

Giorgio Valabrega ◽

Daniela Rubino ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Liposomal Doxorubicin ◽

Objective Response ◽

Pegylated Liposomal Doxorubicin ◽

Complete Response ◽

Recurrent Ovarian Cancer ◽

Hematological Toxicity ◽

Cancer Relapse ◽

Platinum Agent

BackgroundPegylated liposomal doxorubicin (PLD) is an active and well-tolerable treatment in ovarian cancer relapse, either alone or in combination with other drugs. No data are available on the possibility to rechallenge PLD treatment in long survivor patients with recurrent ovarian cancer, as evaluated for platinum agent, paclitaxel and gemcitabine. The aim of the present study was to evaluate the anti-tumor activity and the toxicity profile of re-challenge of PLD in recurrent ovarian cancer patients.MethodsData on 27 patients with epithelial ovarian cancer treated in the last ten years (2007-2017) with palliative PLD rechallenge were included in this multicenter retrospective Italian study.ResultsThe objective response rate to PLD re-treatment were complete response in 19%, partial response in 30% and stable disease in 37%. Only 1 case of G4 hematological toxicity was reported. No patient experienced severe cardiac impairment (G2-4).ConclusionPLD rechallenge represents an active and safe possibility of treatment for long survivor ovarian cancer patients.

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Efficiency of lenalidomide, bortezomib and prednisone (RVP) in patients with newly diagnosed multiple myeloma

Oncohematology ◽

10.17650/1818-8346-2019-14-1-14-19 ◽

2019 ◽

Vol 14 (1) ◽

pp. 14-19 ◽

Cited By ~ 1

Author(s):

K. A. Belousov ◽

T. A. Mitina ◽

Yu. Yu. Chuksina ◽

A. K. Golenkov ◽

E. V. Kataeva ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Renal Replacement Therapy ◽

Replacement Therapy ◽

Objective Response ◽

Hematological Toxicity ◽

Efficacy And Safety ◽

First Line ◽

First Line Therapy ◽

Line Therapy

Objective: to study the efficacy and safety of the antitumor RVP program (lenalidomide, bortezomib, prednisone) as a first-line therapy in patients with multiple myeloma (MM). Materials and methods. A prospective study involved 39 patients with MM (15 women, 24 men), median age 61 years (30–76 years). All patients had Durie–Salmon stage III disease. According to the paraprotein isotype variant, 19 patients (48.7 %) had Gk myeloma, 8 (20.5 %) had Gλ, 4 (10.2 %) – Ak, 1 – Aλ, 1 – Dk, 1 – paraproteinemia Bens-Jones k and 1 – Bens-Jones λ, 2 – Dλ, and 2 patients – nonsecreting MM. The average level of plasma cells in the bone marrow was 31.7 % (0.8–80.0 %). In 14 (35.8 %) patients there were plasmacytomas of various localization (spine, cranial bones, clavicle, pleura). Nine (23.0 %) patients had renal failure, requiring the start of renal replacement therapy. The average Karnovsky index in the study group was 50 %. All patients received RVP therapy (lenalidomide 25 mg in 1–14 days, bortezomib 1.3 mg subcutaneously in 1, 4, 8, 11 days, prednisolone 60 mg/m2; the interval between courses was 42 days) as the first line therapy. Evaluation of therapy efficacy, characterized by overall survival, objective response rates (the number of complete, very good partial and partial remissions) was performed after 6 treatment courses. Results. The median follow-up was 15 months; the median of overall survival was not achieved. Objective antitumor response achieved in 29 (74.3 %) patients, including complete remissions in 3 (7.6 %), very good partial remissions – in 7 (17.9 %), partial remissions – in 19 (48.7 %) patients. In 2 out of 9 patients who received renal replacement therapy, independence from dialysis therapy was achieved. Cases of III–IV stage hematological and non-hematological toxicity in the study were not noted. Conclusion. The antitumor RVP program showed high efficacy and safety as a first-line therapy in a non-selective group of patients, including those with a complicated MM course.

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Venetoclax and Decitabine Show Robust Activity in Advanced Systemic Mastocytosis

Blood ◽

10.1182/blood-2020-138826 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 25-26

Author(s):

Tahani Atieh ◽

Janet Woodroof ◽

Abdulraheem Yacoub

Keyword(s):

Overall Survival ◽

Induction Chemotherapy ◽

Systemic Mastocytosis ◽

Objective Response ◽

Publicly Traded ◽

First Line ◽

Private Company ◽

Allogenic Stem Cell Transplantation ◽

Best Response ◽

Kit D816v

Systemic mastocytosis (SM) is a heterogeneous group of diseases characterized by the proliferation of abnormal mast cells in the bone marrow or other organs. 1 Activating mutations in KIT are found in the majority of patients, with the KIT D816V mutation being the most common .2 While patients with indolent systemic mastocytosis (ISM) have a life-expectancy similar to the general population, approximately 40-53% of patients with SM have an associated hematologic neoplasm (SM-AHN) with a median overall survival of 2 years. 1-3 Treatment of SM-AHN is primarily directed at the AHN as this determines overall survival, with symptomatic treatment for SM if needed.4 Midostaurin is the only approved agent for SM with KIT K816V mutation and overall response rates in SM-AHN are <60%. 5-6 No agents are approved beyond first line. We present the unique case of an 81-year-old male who presented with SM and low risk CMML (46 XY with ASXL1, KIT (p.D816V), SRSF2, TET2, RUNX1, MSH2, CBL). He received first line therapy with midostaurin 100 mg twice a day and achieved an early partial response but progressed after 7 months with increasing mastocytosis burden, rising tryptase and transformation of CMML to AML (image 1). He was subsequently treated with combination standard dose decitabine and venetoclax. The best response for the AML was CRi which was achieved after the first cycle and continues to be ongoing over 12 months since initiation of therapy. We also observed objective response of the SM disease burden on BM exams and steady decline in tryptase levels that continues to be ongoing (figure 1 and 2). Best response by IWG-MRT-ECNM is partial remission achieved after 9 months of therapy. SM-AML is rare and can be diagnosed concomitantly with SM or as a transformation of an SM-AHN. Additional mutations are often present, with the presence of ASXL1 and RUNX1 being associated with a particularly poor prognosis.7-8 Treatment for SM-AML is similar to standard AML treatment with allogenic stem cell transplantation (ASCT) being preferred in those able to tolerate it. While ASCT is the only potential cure for both diseases, SM often persists even with response of the AML.9-11 In a case report of 11 patients with SM-AML, 8 patients received induction chemotherapy with cytarabine and daunorubicin while 3 received induction with cytarabine and idarubicine. Seven patients received ASCT but five relapsed and eventually expired. None of the 3 long-term survivors had a c-KIT D816V mutation and two of them received ASCT. In 7 out of the 10 patients in CR or after ASCT, SM persisted. 9 In 2 case reports of SM-AML with D816V mutation, treatment consisted of induction and consolidation chemotherapy plus dasatinib and chemotherapy with ASCT and dasatinib. Both patients achieved HCR but again had persistent SM.10-11 The activity of hypomethylating agents (HMA) with venetoclax has not previously been reported in patients with SM-AML. Venetoclax plus either HMAs or low-dose cytarabine was approved for the treatment of AML in the elderly and those unable to tolerate induction chemotherapy in 2018. Venetoclax is an oral inhibitor of BCL-2, an antiapoptotic protein important in the pathophysiology of AML. In the initial study, the CR/Cri rate was 68% with a median time to response of 1.2 cycles. Venetoclax has also shown activity in other hematologic malignancies, including chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.12 SM-AML is an aggressive disease with limited treatment options. To our knowledge, this is the first report of sustained response of both SM-AHN and AML using a HMA and venetoclax. Given the difference in response time and dynamics, this treatment combination seems to have activity in both disease clones independently. This case suggests a potential treatment option for this unmet need and demonstrates the importance of research into the utility of venetoclax in mast cell neoplasms. Disclosures Yacoub: Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.

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Effects of adding necitumumab to first-line chemotherapy in patients with stage IV non-small-cell lung cancer: Meta-analysis

Journal of Oncology Pharmacy Practice ◽

10.1177/1078155219891631 ◽

2019 ◽

Vol 26 (6) ◽

pp. 1331-1342

Author(s):

Irena Ilic ◽

Sandra Sipetic ◽

Jovan Grujicic ◽

Milena Ilic

Keyword(s):

Overall Survival ◽

Objective Response Rate ◽

Advanced Nsclc ◽

Response Rate ◽

Meta Analysis ◽

Objective Response ◽

Stage Iv ◽

Progression Free Survival ◽

First Line ◽

Free Survival

Introduction Almost half of patients with non-small-cell lung cancer (NSCLC) are diagnosed at an advanced stage. Our aim was to assess the effects of adding necitumumab to chemotherapy in patients with stage IV NSCLC. Material and methods A comprehensive literature search was performed according to pre-specified inclusion and exclusion criteria. Data on overall survival, progression-free survival, objective response rate and adverse events were extracted. A meta-analysis was performed to obtain pooled hazard ratios (HR) and corresponding 95% confidence intervals (CI) for time-to-event data and pooled odds ratio (OR) with 95% CI for dichotomous outcomes. Results The meta-analysis included four randomized clinical trials with 2074 patients. The pooled results showed significant improvement for overall survival (HR = 0.87 (95% CI 0.79–0.95), p = 0.004) when necitumumab was added to chemotherapy in patients with advanced NSCLC. No statistically significant improvement was noted for progression-free survival and objective response rate (HR = 0.83 (95% CI 0.69–1.01), p = 0.06 and OR = 1.46 (95% CI 0.90–2.38), p = 0.13, respectively). Subgroup analysis showed that in patients with non-squamous NSCLC, there was no benefit in overall survival and objective response rate. Patients with advanced NSCLC who received necitumumab were at the highest odds of developing a skin rash (OR = 14.50 (95% CI 3.16–66.43), p = 0.0006) and hypomagnesaemia (OR = 2.77 (95% CI 2.23–3.45), p < 0.00001), while the OR for any grade ≥3 adverse event was 1.55 (95% CI 1.28–1.87, p < 0.00001). Conclusions The addition of necitumumab to standard chemotherapy in a first-line setting in patients with stage IV NSCLC results in a statistically significant improvement in overall survival, while the results were not significant for progression-free survival and objective response rate.

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Overall Survival and Response to Systemic Therapy in Metastatic Extrauterine Leiomyosarcoma

Sarcoma ◽

10.1155/2016/3547497 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

A. N. Shoushtari ◽

J. Landa ◽

D. Kuk ◽

A. Sanchez ◽

B. Lala ◽

...

Keyword(s):

Overall Survival ◽

Systemic Therapy ◽

Objective Response ◽

Soft Tissue Sarcomas ◽

Older Age ◽

First Line ◽

Risk Of Death ◽

First Line Therapy ◽

Line Therapy ◽

Male Sex

Background. Leiomyosarcomas (LMS) represent a heterogeneous subset of soft tissue sarcomas. Factors influencing prognosis for patients with metastatic extrauterine LMS (euLMS) are not well described. Limited data are available regarding responses to systemic therapy.Methods. We collected clinical and pathologic information for all patients with metastatic euLMS seen at Memorial Sloan Kettering Cancer Center between 1989 and 2012. Objective responses to first-line therapy were analyzed for a subset of patients with available baseline and on-treatment imaging using RECIST 1.1.Results. 215 patients with metastatic euLMS had a median overall survival (OS) of 2.6 years from the time of metastasis. Older age, male sex, and ≥3 initial sites of metastasis were associated with worse OS on multivariate analysis. Objective response rate (ORR) inN=113was 19% overall and 25%, 26%, and 25% for gemcitabine, gemcitabine plus docetaxel, and anthracycline-alkylator combinations. Patients whose tumors objectively responded to first-line therapy had a lower risk of death versus those who did not (Hazard Ratio 0.46; 95% CI: 0.26–0.79,p=0.005).Conclusions. Anthracycline- and gemcitabine-based regimens have similar activity in this cohort of euLMS. Prognostic factors for OS include older age, male sex, and ≥3 initial sites.

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