Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer

Lhommé, C.; Joly, Florence; Walker, Joan L.; Lissoni, Andrea Alberto; Nicoletto, Maria Ornella; Manikhas, Gregory M.; Baekelandt, M.; Gordon, Alan N.; Fracasso, Paula M.; Mietlowski, William; Jones, Gary J.; Dugan, Margaret

doi:10.1200/jco.2007.14.9807

Cited by 131 publications

(109 citation statements)

References 27 publications

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“…The phase III study was conducted in the ovarian cancer patients, in whom the paclitaxel dose was reduced from 175 mg/m 2 in control patients to 80 mg/m 2 with valspodar (5 mg/kg every 6 h for 12 doses) for patients undergoing the combination therpay (42). The addition of valspodar to standard chemotherapy regimens did not significantly improve progression-free survival (PFS) or OS, but increased the frequency of adverse events experienced.…”

Section: Clinical Datamentioning

confidence: 99%

Repurposing itraconazole as an anticancer agent

et al. 2017

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Abstract. Itraconazole, a common anti-fungal agent, has demonstrated potential anticancer activity, including reversing chemoresistance mediated by P-glycoprotein, modulating the signal transduction pathways of Hedgehog, mechanistic target of rapamycin and Wnt/β-catenin in cancer cells, inhibiting angiogenesis and lymphangiogenesis, and possibly interfering with cancer-stromal cell interactions. Clinical trials have suggested the clinical benefits of itraconazole monotherapy for prostate cancer and basal cell carcinoma, as well as the survival advantage of combination chemotherapy for relapsed non-small cell lung, ovarian, triple negative breast, pancreatic and biliary tract cancer. As drug repurposing is cost-effective and timesaving, a review was conducted of preclinical and clinical data focusing on the anticancer activity of itraconazole, and discusses the future directions for repurposing itraconazole as an anticancer agent.

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Section: Clinical Datamentioning

confidence: 99%

Repurposing itraconazole as an anticancer agent

et al. 2017

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“…Four trials underestimated the actual outcome (A/E ratio of >1.25), Eleven trials were accurate (A/E ratio of 0.75‐1.25), and 5 trials overestimated the outcome (A/E ratio of 0.75) (Table 2). 12, 14, 17, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 The A/E ratios ranged from 0.5 to 1.6, with a mean and median ratio of 1.0 and 1.0, respectively (Fig. 3).…”

Section: Resultsmentioning

confidence: 98%

Estimation of expectedness: Predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer

Castonguay

Wilson

Díaz-Padilla

et al. 2014

Cancer

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BACKGROUNDThe anticipated clinical outcome of the standard/control arm is an important parameter in the design of randomized phase 3 (RP3) trials to properly calculate sample size, power, and study duration. Changing patterns of care or variation in the study population enrolled may lead to a deviation from the initially anticipated outcome. The authors hypothesized that recent changes in patterns of care in epithelial ovarian cancer (EOC) have led to challenges in correctly estimating the outcome of control groups.METHODSA systematic review of the literature was conducted for RP3 trials of EOC published between January 2000 and December 2010. The expected outcome of the control arm as well as the actual outcome achieved by this cohort was collected and a ratio (actual‐over‐expected ratio) was calculated. The estimation of outcome was deemed accurate if the outcome of the control arm was between 0.75 to 1.25 times the anticipated outcome.RESULTSA total of 35 trials were eligible for analysis. Fifteen trials had survival as the primary endpoint whereas 20 had a progression‐based primary endpoint. In total, 12 of 15 trials with a survival‐based endpoint significantly underestimated the outcome of the control arm, whereas only 4 of 20 trials with a progression‐based endpoint did. Studies with a survival endpoint underestimated outcome more frequently than those with a progression endpoint (P<.001).CONCLUSIONSSurvival of the control arm has frequently been underestimated in recent EOC RP3 trials. This underestimation means that the initial statistical assumptions of these trials may have been inaccurate. Underestimating the outcome of the control arm may result in trials being underpowered to demonstrate the absolute benefit they were designed to show. Cancer 2015;121:413–422. © 2014 American Cancer Society.

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“…More patients had partial responses in the valspodar group, but the difference was not statistically significant and was counteracted by increased toxicity that led to inferior survival, which the investigators attributed to higher bioactive levels of doxorubicinol in the patients receiving valspodar. In the second study 18 , women with stage IV or suboptimally debulked stage III epithelial ovarian or primary peritoneal cancer were randomly assigned to receive paclitaxel and carboplatin with or without valspodar as first line-chemotherapy. Valspodar was dosed orally at 5 mg/kg every 6 hours for three days with chemotherapy starting one day after valspodar; a reduced dose of paclitaxel was used in the valspodar group to provide equivalent exposure and toxicity between groups.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

“…One targeted patients with relapsed/refractory multiple myeloma 17 , another was done in women with stage IV or suboptimally debulked stage III ovarian or primary peritoneal cancer 18 , and the third enrolled newly diagnosed patients under 60 years old with acute myeloid leukemia 19 . The addition of valspodar did not improve objective results in any of these studies, and it generally enhanced toxicity associated with chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

et al. 2017

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We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

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Phase III Study of Valspodar (PSC 833) Combined With Paclitaxel and Carboplatin Compared With Paclitaxel and Carboplatin Alone in Patients With Stage IV or Suboptimally Debulked Stage III Epithelial Ovarian Cancer or Primary Peritoneal Cancer

Abstract: The addition of valspodar to PC did not improve TTP or OS and was more toxic compared with PC in untreated patients with advanced ovarian or primary peritoneal cancer.

Cited by 131 publications

References 27 publications

Repurposing itraconazole as an anticancer agent

Repurposing itraconazole as an anticancer agent

Estimation of expectedness: Predictive accuracy of standard therapy outcomes in randomized phase 3 studies in epithelial ovarian cancer

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

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