A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1).

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. CRA8007-CRA8007 ◽  
Author(s):  
Suresh S. Ramalingam ◽  
Glenwood D. Goss ◽  
Zoran Gojko Andric ◽  
Igor Bondarenko ◽  
Bojan Zaric ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Lung Adenocarcinoma ◽  
Biological Effects ◽  
Single Agent ◽  
Heat Shock Protein 90 ◽  
Phase Iii ◽  
Second Line ◽  
Second Line Therapy ◽  
Line Therapy

CRA8007 Background: Heat shock protein 90 chaperone function is critical for the biological effects of several oncoproteins. Ganetespib (G) is a highly potent 2nd-generation Hsp90 inhibitor with a favorable safety profile and single-agent clinical activity. Methods: Based on synergistic preclinical interactions between docetaxel (D) and G, we conducted a randomized (1:1), international open-label study of D with or without G. Patients with advanced lung adenocarcinoma, one prior systemic therapy, and ECOG PS 0/1 were included. D was given at 75 mg/m2 on day 1 of a three-week cycle. In the experimental arm, D was given on day 1 and G at 150 mg/m2 on days 1 and 15. The co-primary endpoints were PFS in patients with elevated LDH (eLDH) levels, or tumors harboring KRAS mutations. Key secondary endpoints were OS and PFS in all adenocarcinoma patients. Target enrollment was 240 adenocarcinoma, 120 eLDH, and 80 mKRAS patients. Statistical tests are 1-sided. Results: Enrollment of 255 adenocarcinoma patients completed in November 2012; results are reported for this population. Patient characteristics were balanced (median age 60 years, males ~60%, PS 0 ~40% and never-smoker ~25%). For D+G vs. D the median number of cycles delivered was 5 vs. 4; the grade 3/4 adverse events were neutropenia 38% vs. 37%; fatigue 4% vs. 3%; anemia 7% vs. 6%; diarrhea 3% vs. 0; fever with neutropenia 8% vs. 2%. At the time of abstract submission OS HR was 0.69 (90% CI 0.48 to 0.99, p=0.093), the PFS HR was 0.70 (90% CI 0.53 to 0.94, p=0.012), and the ORR was 15% vs 11%, favoring D+G. For patients that were enrolled >6 months after diagnosis of advanced NSCLC (N=175; 69%), a prespecified stratification factor, the OS HR was 0.41 (90% CI 0.25 to 0.67, p=0.0009), the PFS HR was 0.47 (90% CI 0.32 to 0.69, p=0.0005), and the ORR was 16% vs 12%. Updated results for both populations above, as well as for the eLDH and mKRAS subsets, will be presented. Conclusions: D+G demonstrated improvement in OS, PFS, and ORR over D alone for second-line therapy of lung adenocarcinoma. A phase III study in second-line advanced adenocarcinoma patients (> 6 months from diagnosis) is ongoing (GALAXY-2). Clinical trial information: NCT01348126.

A randomized study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel versus docetaxel alone for second-line therapy of lung adenocarcinoma (GALAXY-1).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. CRA8007-CRA8007 ◽  
Author(s):  
Suresh S. Ramalingam ◽  
Glenwood D. Goss ◽  
Zoran Gojko Andric ◽  
Igor Bondarenko ◽  
Bojan Zaric ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Randomized Study ◽  
Heat Shock Protein 90 ◽  
Second Line ◽  
Second Line Therapy ◽  
Daily News ◽  
Online Supplement ◽  
Line Therapy ◽  
Final Text

CRA8007 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.

scholarly journals Heat Shock Protein Inhibitor 17-Allyamino-17-Demethoxygeldanamycin, a Potent Inductor of Apoptosis in Human Glioma Tumor Cell Lines, Is a Weak Substrate for ABCB1 and ABCG2 Transporters

2021 ◽  
Vol 14 (2) ◽  
pp. 107
Author(s):  
Nikola Pastvova ◽  
Petr Dolezel ◽  
Petr Mlejnek
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
Tumor Cell ◽  
Cell Lines ◽  
Single Agent ◽  
Heat Shock Protein 90 ◽  
Genetic Alterations ◽  
Tumor Cell Lines ◽  
Cytotoxic Effects ◽  
Glioma Tumor

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults and has a poor prognosis. Complex genetic alterations and the protective effect of the blood–brain barrier (BBB) have so far hampered effective treatment. Here, we investigated the cytotoxic effects of heat shock protein 90 (HSP90) inhibitors, geldanamycin (GDN) and 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin), in a panel of glioma tumor cell lines with various genetic alterations. We also assessed the ability of the main drug transporters, ABCB1 and ABCG2, to efflux GDN and 17-AAG. We found that GDN and 17-AAG induced extensive cell death with the morphological and biochemical hallmarks of apoptosis in all studied glioma cell lines at sub-micro-molar and nanomolar concentrations. Moderate efflux efficacy of GDN and 17-AAG mediated by ABCB1 was observed. There was an insignificant and low efflux efficacy of GDN and 17-AAG mediated by ABCG2. Conclusion: GDN and 17-AAG, in particular, exhibited strong proapoptotic effects in glioma tumor cell lines irrespective of genetic alterations. GDN and 17-AAG appeared to be weak substrates of ABCB1 and ABCG2. Therefore, the BBB would compromise their cytotoxic effects only partially. We hypothesize that GBM patients may benefit from 17-AAG either as a single agent or in combination with other drugs.

Survival of Patients With Advanced Colorectal Cancer Improves With the Availability of Fluorouracil-Leucovorin, Irinotecan, and Oxaliplatin in the Course of Treatment

2004 ◽  
Vol 22 (7) ◽  
pp. 1209-1214 ◽  
Author(s):  
Axel Grothey ◽  
Daniel Sargent ◽  
Richard M. Goldberg ◽  
Hans-Joachim Schmoll
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Cytotoxic Agents ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
First Line Therapy ◽  
Line Therapy ◽  
Phase Iii Trials

Purpose Fluorouracil (FU)-leucovorin (LV), irinotecan, and oxaliplatin administered alone or in combination have proven effective in the treatment of advanced colorectal cancer (CRC). Combination protocols using FU-LV with either irinotecan or oxaliplatin are currently regarded as standard first-line therapies in this disease. However, the importance of the availability of all three active cytotoxic agents, FU-LV, irinotecan, and oxaliplatin, on overall survival (OS) has not yet been evaluated. Materials and Methods We analyzed data from seven recently published phase III trials in advanced CRC to correlate the percentage of patients receiving second-line therapy and the percentage of patients receiving all three agents with the reported median OS, using a weighted analysis. Results The reported median OS is significantly correlated with the percentage of patients who received all three drugs in the course of their disease (P = .0008) but not with the percentage of patients who received any second-line therapy (P = .19). In addition, the use of combination protocols as first-line therapy was associated with a significant improvement in median survival of 3.5 months (95% CI, 1.27 to 5.73 months; P = .0083). Conclusion Our results support the strategy of making these three active drugs available to all patients with advanced CRC who are candidates for such therapy to maximize OS. In addition, our findings suggest that, with the availability of effective salvage options, OS should no longer be regarded as the most appropriate end point by which to assess the efficacy of a palliative first-line treatment in CRC.

scholarly journals Evaluation of second line and subsequent targeted therapies in metastatic renal cell cancer (mRCC) patients treated with first line cediranib

2014 ◽  
Vol 8 (11-12) ◽  
pp. 398 ◽  
Author(s):  
Suzanne Richter ◽  
Jo-An Seah ◽  
Gregory R Pond ◽  
Hui K Gan ◽  
Mary J. Mackenzie ◽  
...  
Keyword(s):  
Renal Cell ◽  
Kinase Inhibitor ◽  
Cell Cancer ◽  
Phase Iii ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Pivotal Phase ◽  
Line Therapy ◽  
To Receive

Introduction: Pivotal phase III trials have positioned angiogenesis inhibitors as first-line therapy for the management of most advanced or metastatic renal cell carcinomas (mRCC). Approaches to second-line therapy, however, remain more controversial with respect to drug selection and drug sequencing.Methods: In this study we evaluated mRCC patients who were initially treated on the first-line National Cancer Institute (NCI) trial with the highly potent vascular endothelial growth factor receptor tyrosine kinase inhibitor (TKI), cediranib, to determine the efficacy and tolerability of subsequent therapies.Results: Twenty-eight (65.1%) of the 43 patients enrolled on the first-line cediranib trial were known to receive second-line therapy, most commonly sunitinib (n = 21), with 4 (14%), 2 (7%) and 1 (3%) patients receiving temsirolimus, sorafenib, and interleukin, respectively. Of these, 14 (50%) went on to have 3 or more lines of therapy. The progression-free survival (PFS) proportion (PFS) at 1 year from starting second line was 30% (14.5%–47.9%). Longer duration of first-line cediranib treatment was modestly associated with longer duration of second-line treatment (Spearman rho 0.26). Patients who discontinued cediranib for toxicity were less likely to receive second-line sunitinib.Conclusion: In this real world evaluation, sequential use of TKIs for the management of mRCC was common. PFS with sequential TKIs was similar to observed and published results for any second-line therapy. Prior toxicity affected treatment patterns and the frequent use of at least 3 lines of therapy underscores the need for prospective sequencing trials in this disease.

Intravenous vinorelbine as first-line and second-line therapy in advanced breast cancer.

1995 ◽  
Vol 13 (11) ◽  
pp. 2722-2730 ◽  
Author(s):  
B L Weber ◽  
C Vogel ◽  
S Jones ◽  
H Harvey ◽  
L Hutchins ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Advanced Breast Cancer ◽  
Single Agent ◽  
Objective Response ◽  
Advanced Breast ◽  
Line Treatment ◽  
Second Line ◽  
First Line ◽  
Second Line Therapy ◽  
Line Therapy

PURPOSE We evaluated single-agent intravenous (IV) vinorelbine as first- and second-line treatment for advanced breast cancer (ABC) in patients who were not resistant to anthracyclines. Objective tumor response (TR) and toxicity were assessed. PATIENTS AND METHODS A total of 107 women were enrolled onto this multicenter, nonrandomized, open-label phase II study. Patients were stratified into first- and second-line treatment groups, based on prior treatment history. Vinorelbine was initially given at 30 mg/m2/wk, with dose modification for toxicity as indicated. Therapy was continued until disease progression or severe toxicity mandated withdrawal or until the patient asked to be removed from the study. RESULTS The objective response rate for all patients was 34% (95% confidence interval [CI], 25% to 44%): 35% (95% CI, 23% to 48%) for first-line patients and 32% (95% CI, 20% to 47%) for second-line patients. Nine first-line and three second-line patients obtained a complete response (CR). The median duration of objective response was 34 weeks in both groups. The overall survival durations of first- and second-line patients were 67 weeks and 62 weeks, respectively. Granulocytopenia was the predominant dose-limiting toxicity. Two patients died on study as a result of granulocytopenic sepsis. CONCLUSION Single-agent vinorelbine is an effective and well-tolerated agent for first- and second-line therapy of ABC. The results of this study confirm the findings of similar international trials and suggest vinorelbine should be considered a valid treatment option for patients with ABC and a potential component in future combination regimens for this disease.

Pemetrexed in second-line therapy in patients with malignant pleural mesothelioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18198-18198 ◽  
Author(s):  
M. Serke ◽  
T. Bauer
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Clinical Benefit ◽  
Single Agent ◽  
Sensory Neuropathy ◽  
Patient Characteristics ◽  
Pleural Mesothelioma ◽  
Second Line ◽  
Second Line Therapy ◽  
Mild Renal Impairment ◽  
Line Therapy

18198 Introduction: Based on the study of Vogelzang (2003) standard treatment in patients with malignant pleural mesothelioma (MPM) is pemetrexed cisplatin with a medium survival of 12 months compared to 9 months with cisplatin therapy. As this treatment prolongs survival, but is not a curative treatment, many patients will relapse during the course of their disease. In sensitive relapses (within more than 3 months) our policy was to reintroduce pemetrexed therapy in unselected consecutive patients. Methods: Retrospective analysis of 17 consecutive patients treated in our hospital. Patient characteristics: 17 patients (pat), 14 males, 3 females, with MPM were included between April 2004 and November 2006 with an age between 45 and 82 years, with a median age of 65 years. Histologic subtypes were: 16 epithelial, 1 biphasic MPM. Pretreatment: 8 pat. had undergone palliative debulcing surgery (pleurectomy) 1 pat. underwent EPP. All patients were pretreated with platinum /pemetrexed, 5 pat. were pretreated with platinum/Gemcitabine before the availability of pemetrexed. 2nd line chemotherapy: 9 pat. were treated with carboplatin AUC5 / pemetrexed 500 mg/m2, 1 patient had cisplatinum 75 mg/m2/Pemetrexed 500 mg/m2 and 7 patients had pemetrexed single agent therapy (500 mg/m2 d1, WH d21), repeated on day 22 respectively. Results: Response: 6% (n=1) PR, MR: 12% (n=2 )., NC: 47% (n=8)., PD: 35% (n= 6), clinical benefit (PR, MR, NC) was seen in 65% of ou pat. Toxicity: Pemetrexed/Carboplatin or pemetrexed therapy were well tolerated, toxicity was mild: one patient developed mild sensory neurotoxicity (peripheral sensory neuropathy) (WHO II) under 6 cycles pemetrexed, 35% developed mild fatigue (Who I and II), one patient had mild renal impairment, no alopecia was seen. Survival: Only 3 patients had still died, median survival from start of second-line pemetrexed-therapy was not reached, time to progression was between 25 and 630 days, 4 pat. had not progressed until now. Conclusion: Second line therapy in MPM is not yet standard of care. Nevertheless patients with progressive disease following pemetrexed/platinum therapy may benefit from second line pemetrexed reintroduction therapy. Clinical benefit was seen in 65% with low toxicity. No significant financial relationships to disclose.

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