91 research outputs found
Radiomic and Volumetric Measurements as Clinical Trial Endpoints—A Comprehensive Review
No full textSimple Summary The extraction of quantitative data from standard-of-care imaging modalities offers opportunities to improve the relevance and salience of imaging biomarkers used in drug development. This review aims to identify the challenges and opportunities for discovering new imaging-based biomarkers based on radiomic and volumetric assessment in the single-site solid tumor sites: breast cancer, rectal cancer, lung cancer and glioblastoma. Developing approaches to harmonize three essential areas: segmentation, validation and data sharing may expedite regulatory approval and adoption of novel cancer imaging biomarkers. Clinical trials for oncology drug development have long relied on surrogate outcome biomarkers that assess changes in tumor burden to accelerate drug registration (i.e., Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria). Drug-induced reduction in tumor size represents an imperfect surrogate marker for drug activity and yet a radiologically determined objective response rate is a widely used endpoint for Phase 2 trials. With the addition of therapies targeting complex biological systems such as immune system and DNA damage repair pathways, incorporation of integrative response and outcome biomarkers may add more predictive value. We performed a review of the relevant literature in four representative tumor types (breast cancer, rectal cancer, lung cancer and glioblastoma) to assess the preparedness of volumetric and radiomics metrics as clinical trial endpoints. We identified three key areas-segmentation, validation and data sharing strategies-where concerted efforts are required to enable progress of volumetric- and radiomics-based clinical trial endpoints for wider clinical implementation
Ask the Experts: Learning from failures and successes, and identifying patients that may benefit from antiangiogenesis therapy
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Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer
No full textAbstract
APR-246 (PRIMA-1MET) is the first clinical-stage compound that reactivates mutant p53. This phase Ib part of a proof of concept study aims to determine the recommended phase II dose (RP2D) of APR-246 in combination with carboplatin and pegylated liposomal doxorubicin (PLD) in platinum sensitive High Grade Serous Ovarian Cancer (HGSOC). Despite high response rates from carboplatin in combination with paclitaxel in first-line treatment of ovarian cancer, most patients relapse and develop resistance. Partially platinum sensitive patients relapse between 6 and 24 months and are commonly treated with second -line carboplatin and PLD (Pujade-Lauraine et al. JCO, 2010). The mechanisms of platinum resistance are multifactorial; two of the main causes are mutations in p53 and increased levels of intracellular glutathione. Like the analog PRIMA-1, APR-246 is a pro-drug that is converted to the active form MQ, which restores wild type conformation to mutant p53 (Lambert et al. Cancer Cell, 2009). In addition, APR-246 has been shown in vitro to reduce glutathione levels, resensitize cancer cells to platinum drugs, and induce ROS levels and ER stress (Mohell et al. Abstract #1801, AACR 2014; Lambert et al. Oncogene, 2010). In the first-in-human phase Ia study, APR-246 monotherapy was found to have a satisfactory safety and pharmacokinetic profile allowing it to be combined with full dose chemotherapy (Lehmann et al., JCO, 2012).
The ongoing phase Ib/II study is enrolling patients with recurrent platinum sensitive HGSOC with positive p53 staining on immunohistochemistry. The phase Ib study has a 3+3 dose escalation design with 3 planned dose levels. APR-246 is administered as a 6h i.v. infusion on 4 consecutive days every 4 weeks. On day 4, APR-246 is given concomitantly with carboplatin AUC 5 and PLD 30 mg/m2. In the phase II part, 164 patients will be randomized to standard chemotherapy with or without APR-246. To date patients have been enrolled to all 3 dose cohorts. One DLT of ruptured diverticulum occurred at the 2nd dose level. No new safety concerns have emerged. The pharmacokinetic profile has not indicated any interaction between APR-246 and the chemotherapy. The first 3 patients have completed their therapy and are now in follow up. All 3 had partial response (PR) by RECIST 1.1 and 2/2 evaluable also had PR by GCIC.
In conclusion, early results from the ongoing clinical study are encouraging and support the continued development of APR-246 in the phase II part of the study comparing platinum based standard chemotherapy with or without APR-246 in patients with HGSOC with mutant p53. Preliminary results from all three dose levels and the RP2D will be presented at the meeting.
Citation Format: Mikael von Euler, Klas G. Wiman, Hani Gabra, James D. Brenton, Bristi Basu, Ignace Vergote, Charlie Gourley, Austin Smith, Jessica Alfredsson, Nina Mohell, John A. Green. Preliminary results from PiSARRO, a phase Ib/II study of APR-246, a mutant p53 reactivating small molecule, in combination with standard chemotherapy in platinum-sensitive ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT204. doi:10.1158/1538-7445.AM2015-CT204</jats:p
Drug development and clinical trial design in pancreatico-biliary malignancies
No full textPancreatico-biliary (P-B) tumors arise from the pancreas, bile duct, and ampulla of Vater. Despite their close anatomical location, they have different etiology and biology. However, they uniformly share a poor prognosis, with no major improvements observed in overall survival over decades, even in the face of progress in diagnostic imaging and surgical techniques, and advances in systemic and loco-regional radiation therapies. To date, cytotoxic treatment has been associated with modest benefits in the advanced disease setting, and survival for patients with stage IV disease has not exceeded a year. Therefore, there is a pressing need to identify better treatments which may impact more significantly. Frequently, encouraging signals of potential efficacy for novel agents in early phase clinical trials have been followed by disappointing failures in larger phase III trials, raising the valid question of how drug development can be optimized for patients with pancreatic adenocarcinoma and biliary tract malignancies. In this article we summarize the current therapeutic options for these patients and their limitations. The biological context of these cancers is reviewed, highlighting features that may make them resistant to standard chemotherapeutics and could be potential therapeutic targets. We discuss the role of early phase clinical trials, defined as phase I and non-randomised phase II trials, within the clinical context and current therapeutic landscape of P-B tumors and postulate how translational studies and trial design may enable better realization of emerging targets together with a proposed model for future patient management. A detailed summary of current phase I clinical trials in P-B tumors is provided.</p
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