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Challenges in Cancer Clinical Trials
Published in Wei Zhang, Fangrong Yan, Feng Chen, Shein-Chung Chow, Advanced Statistics in Regulatory Critical Clinical Initiatives, 2022
Two-stage method (Latimer et al. 2017) was designed according to the switching commonly observed in oncology studies, where switch can happen only after disease progression or other disease-related time points. In two-stage method, specific disease-related time point that trigger treatment switching, e.g. disease progression, was required, which is called second baseline. Survival time beyond this second baseline was compared for patients who switched from control arm and for patients who did not switch from control arm by fitting an Accelerated Failure Time (AFT) model. The acceleration factor estimated from AFT model can be used to derive counterfactual survival time for patients who switched. Two-stage method also depends on the assumption of ‘no unmeasured confounders’ at second baseline. In real practice, a lot of laboratory tests and safety monitor could happen before treatment switching to ensure the patient is tolerable for experimental drug, which will provide as many confounder measurements as possible. When estimating acceleration factor, both baseline factors that could affect post second baseline survival time and were not balanced between switchers and non-switchers are recommended to be included in AFT model.
Current Issues in Phase II Cancer Clinical Trials
Published in Susan Halabi, Stefan Michiels, Textbook of Clinical Trials in Oncology, 2019
Cancer clinical trials investigate the efficacy and toxicity of experimental cancer therapies. If an appropriate dose level of an experimental drug is determined from a phase I trial, the drug’s anticancer activity is assessed through phase II clinical trials. Phase II clinical trials screen out inefficacious experimental therapies before they proceed to further investigation through large-scale phase III trials. In order to expedite this process, phase II trials traditionally use a single-arm design to treat patients with experimental therapies only. The efficacy of an experimental therapy is compared with that of a standard therapy using historical controls. The most popular primary endpoint of phase II cancer clinical trials is tumor response, which is measured by the change in tumor size before and during treatment. If the size of a target tumor, defined as the largest diameter of the tumor, decreases by at least 30% compared to that at the baseline, a partial response is declared. A complete response is defined as complete disappearance of the tumor. Overall response is defined as partial or complete response.
Impact of Evolving Regulatory Pathways on Statistical Considerations in Oncology Clinical Trials
Published in Satrajit Roychoudhury, Soumi Lahiri, Statistical Approaches in Oncology Clinical Development, 2018
There are two regulatory pathways for a product to be approved by the Food and Drug Administration for marketing in the United States. These are regular (i.e., full approval) and accelerated approvals. For regular approval, the product is required by law to demonstrate clinical benefit with respect to how long a patient is alive, feels, or functions. In the case of drugs for treating cancer, generally, clinical benefit is demonstrated in a randomized controlled clinical trial by comparing the experimental drug to a control, where the control may be a placebo, a best supportive care, or an active control treatment. By contrast, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit for products developed for treating life-threatening diseases, and which demonstrate to be better than the available therapy. Accelerated approval is a conditional approval and products approved under the accelerated approval are required to demonstrate clinical benefit in the same or subsequent clinical trial(s). On the basis of the results of the confirmatory trial, a product first approved under accelerated approval is then granted regular approval if clinical benefit is demonstrated, failing which it is withdrawn from the market.
To treat or not to treat: is it acceptable to avoid active therapies in advanced prostate cancer today?
Published in Expert Review of Anticancer Therapy, 2021
Orazio Caffo, Francesca Maines, Stefania Kinspergher, Antonello Veccia, Carlo Messina
A meta-analysis of the individual patient data from 21 RCTs in patients with localized PCa showed that MFS can be considered a strong surrogate of OS (R2:0.83, 95%CI 0.71–0.88) [51], but its conclusions cannot be formally applied to nmCRPCa. However, the recent updates of the outcomes of the three pivotal trials have clearly shown that the addition of these ARTAs to ADT significantly improves median OS [52–54]. Interestingly, this improvement was observed despite the fact that the control patients who were not in progression when the trials were unblinded could receive the experimental drug and that the use of new life-prolonging agents was greater in the control group after progression. This suggests that the addition of ARTAs to ADT should also be adopted to treat nmCRPCa patients in everyday clinical practice.
Novel targeted strategies to overcome resistance in small-cell lung cancer: focus on PARP inhibitors and rovalpituzumab tesirine
Published in Expert Review of Anticancer Therapy, 2019
Robin Van Den Borg, Alessandro Leonetti, Marcello Tiseo, Elisa Giovannetti, Godefridus J. Peters
In the subsequent open-label, single arm, phase II trial (TRINITY), DLL3-positive expression was used as an inclusion criteria, and DLL3-high expression was defined as ≥ 25% tumour cells expressing DLL3 by IHC [104]. In this study, the activity of Rova-T in DLL3-expressing SCLC patients after failure to ≥ 2 previous line of treatment, including at least one treatment with platinum-based chemotherapy, was explored [104]. However, the results of this trial were disappointing, as documented by an ORR of 18% in the overall population, and Abbvie decided not to pursue accelerated approval of the experimental drug in the third-line setting [105]. When evaluating DLL3-high patients, median PFS and OS were 3.8 and 5.6 months, respectively. This subgroup of patients had a higher benefit from Rova-T treatment compared to non-DLL3-high, both in terms of ORR (16% vs 6%), best overall response (24% vs 14%) and clinical benefit rate (72% vs 57%) when the data were analysed by an independent review committee. Regarding DLL3-high group, patients who were treated in third line were the most likely to respond to Rova-T. The toxicity profile of Rova-T was in line with the results of the phase I study, with ≥ grade 3 treatment-related adverse events documented in 40% of patients. Noteworthy, ten treatment-related deaths were documented [104].
CheckMate 141 trial: all that glitters is not gold
Published in Expert Opinion on Biological Therapy, 2019
Raffaele Addeo, Massimo Ghiani, Francesco Merlino, Filippo Ricciardiello, Michele Caraglia
The treatment of patients with recurrent/metastatic locally advanced head and neck squamous cell carcinoma (R/M-HNSCC) is rapidly evolving. For these patients, cetuximab in combination with platinum and 5-fluorouracil (PFE) still remains the standard of care (SOC) as the first-line treatment. Until a few months ago, patients who progress after platinum-based therapy have a dismal prognosis and no well-defined standard treatment. The promising clinical results of the second-line phase III trial CheckMate-141 offer a new standard after several years of failures. The anti-PD-1 monoclonal antibody nivolumab represents the new therapeutic option in patients with R/M-HNSCC progressing after platinum-based therapy. This is dependent on the results of CheckMate 141, which showed a survival benefit over standard of care drugs such as single agent weekly cetuximab, methotrexate, or docetaxel. However, only a small part of patients were responsive to Nivolumab and no predictive markers of response were identified. Treatment-related adverse events occurred at similar rates in the two arms, but grade 3–4 toxicities were less frequent with the experimental drug (13%) than the drug of the investigator’s choice (35%). The non-detrimental impact on quality of life and the achievement of the primary end-point overall survival benefit hides the absence of predictive biomarkers of response.