Introduction to Ii Trials

In phase III trials, ixabepilone has extended progression-free survival and increased overall response rates, with a manageable toxicity profile.

Two small randomized phase II trials on synchronous disease showed an improvement in progression free survival, with the addition of LAT, and one also demonstrated an overall survival benefit.

Results from placebo-controlled phase III trials showed that IV amisulpride is efficacious both in the prevention of PONV (used either alone or in combination with an antiemetic of a different class) and in the treatment of PONV (irrespective of prior antiemetic prophylaxis status).

Messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccines have been shown to be effective in preventing symptomatic COVID-19 in randomized placebo-controlled Phase III trials (1,2); however, the benefits of these vaccines for preventing asymptomatic and symptomatic SARS-CoV-2 (the virus that causes COVID-19) infection, particularly when administered in real-world conditions, is less well understood.

For patients with NSCLC, two randomized phase II trials also suggested that the addition of a radical local treatment results in encouraging survival data, with a good safety profile.

A total of 486 mCRC patients treated with FOLFIRI/bevacizumab from two randomized phase III trials, TRIBE and FIRE-3, were included in the current study.

Methods: In two 52-week, randomized, double-blind, placebo-controlled, phase III trials, ECZTRA 1 and ECZTRA 2, adults with moderate-to-severe AD were randomized (3 : 1) to subcutaneous tralokinumab 300 mg every 2 weeks (Q2W) or placebo.

The efficacy and safety of guselkumab were demonstrated in four randomized, double-blind, Phase III trials (VOYAGE 1 and 2, NAVIGATE, and ECLIPSE), which demonstrated high levels of clinical response over three years of continuous treatment, regardless of sex, age, body weight, and race, maintaining a favourable safety profile and long-term tolerability.

Methods: We conducted a meta-analysis of randomized controlled, phase II or III trials by searching of electronic databases from inception to September 1, 2020.

All randomized controlled Phase III trials (RCTs) evaluating the administration of third-generation aromatase inhibitors (AIs) and CDK4/6 inhibitors in postmenopausal women in the metastatic setting were considered eligible for this review.

Two such inhibitors, sotorasib (AMG 510) and adagrasib (MRTX849), were recently evaluated in phase I-III trials for the treatment of non-small cell lung cancer with KRAS-G12C mutations, heralding a new era of precision oncology.

Results from phase II trials of two HER2-targeting agents, the antibody-drug conjugate trastuzumab deruxtecan and the HER2-targeting tyrosine kinase inhibitor poziotinib, indicate promising efficacy that could lead to new standards of care for HER2-mutant non-small cell lung cancer.

Phase II trials suggest that SBRT added to palliative therapy may improve overall survival and may delay the initiation of systemic therapy in OMD patients.

RESULTS The 113 EORTC TOSs examined in this analysis were mainly standard-sized, international, multicentre phase III trials using a relatively simple, randomised, open-label design and comparing pharmacological combination regimens against standard-of-care treatments in terms of their potential to improve overall survival of patients with cancer.

INTRODUCTION AND OBJECTIVE:Recently, bacillus Calmette Guerin (BCG) unresponsive criteria was established based on expert opinion to facilitate single arm Phase II/III trials for patients with NMIB.

Moreover, the proposed Bayesian designs using the exact posterior distributions accommodate the single-arm phase II trials with small sample sizes.

Based on the data from two pivotal phase III trials the drug was recently approved for marketing in the US as a topical treatment for actinic keratosis.

Approval was based on two pivotal phase II trials in which romidepsin demonstrated an overall response rate (ORR) of 34% and a complete response (CR) rate of 6% with a duration of response of 13.

Its combination with the anti‐PD1 (programmed cell death protein 1) immune checkpoint inhibitor, pembrolizumab, has generated encouraging results in phase Ib and is currently being tested in phase III trials.

Programmed cell death protein 1 (PD-1) inhibitors have demonstrated promising activity among patients with advanced soft tissue sarcomas (STS) in phase II trials.

Introduction Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with anemia of chronic kidney disease (CKD) who were not on dialysis (NDD).

Addition of the nonsteroidal MRA finerenone to optimal RAS blockade recently reduced CV and kidney outcomes in two large phase III trials in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D).

Preliminary early-phase human trial data support the proposition that NAICI in NSCLC may provide an feasible and potentially efficacious future treatment strategy and large, randomized phase III trials are currently recruiting to assess this approach.

Numerous attempts to combine R-CHOP with targeted agents failed in large randomized phase III trials.

Two phase III trials in adult patients with non–small-cell lung cancers evaluating a platinum-based doublet with or without the programmed death 1 (PD-1) inhibitor pembrolizumab recommended that all patients receive dexamethasone as a component of the prophylactic antiemetic regimen.

In October 2015, based on the results of Phase II trials demonstrating the safety and efficacy of anti-PD-1 antibodies, the US Food and Drug Administration (FDA) expanded its approval of nivolumab to include the treatment of advanced, refractory metastatic nonsmall cell lung cancer (NSCLC) [2].

The TRINITI-1 trial investigated ribociclib, a CDK4/6i that has recently demonstrated significant overall survival benefit in two phase III trials, in combination with everolimus and exemestane in patients with HR+, HER2− advanced breast cancer (ABC) after progression on a CDK4/6i.

A patient-reported outcome (PRO) is a measurement of the patient’s condition, reported directly by the patient, without the interpretation by a clinician or anyone else [1] Recently, there has been a growing interest in the integration of PROs as part of data collection about toxicity and symptoms experienced by patients with cancer This integration could have relevant implications not only for a more accurate reporting of adverse events and definition of quality of life (QoL) within clinical trials [2], but also for a better patients’ management in routine clinical practice [3] Many tools and questionnaires have been validated to properly measure QoL and symptoms in patients with lung cancer The inclusion of these measures in clinical trials has several important advantages It allows providing a patient-focused assessment of the burden and the impact of disease Moreover, it allows completely assessing the clinical benefit of a therapy, by complementing the information provided by commonly used efficacy endpoints, including overall survival, and the traditional description of safety based on physicians’ assessment Furthermore, the availability of QoL data from trials could allow a more accurate patient-physician communication about the treatment strategies offered in clinical practice However, a systematic review that we performed in order to evaluate the adoption of QoL among endpoints in randomized phase III trials conducted in lung cancer, published between 2012 and 2018 in 11 major journals, showed quite disappointing findings [4] Beyond the importance in clinical trials, PROs can play an important role in clinical practice Several studies have demonstrated a clear benefit in terms of patients’ QoL [5,6] Our experience, focused on the adoption of PROs in patients receiving active anticancer treatment at Mauriziano Hospital in Turin, showed that the introduction of PROs, thanks to an active role of nurses, was feasible, produced high patients’ satisfaction and a significant QoL improvement compared to the traditional modality of visit [6] In details, we compared 2 groups: patients in the control group underwent “usual” visits, while patients in the “PRO” group received a paper questionnaire by a dedicated nurse before each visit, in order to provide information about symptoms and toxicities After 1 month, mean change from baseline of global QoL was significantly better in the PRO group, and significantly higher proportion of patients obtained a clinically significant improvement in global QoL score In addition to QoL benefit, several studies have shown a significant improvement in overall survival with the adoption of electronic PROs in patients with lung cancer [7-9] In a pivotal randomized trial involving US patients with different solid tumors (including lung cancer) undergoing chemotherapy, patients assigned to the control arm received usual care, while subjects assigned to experimental arm could report their symptoms remotely from home, using tablet computers or computer kiosks [5,7] Doctors received a report of symptoms referred by patients during visits, and nurses received email alerts when patients reported severe or worsening symptoms Beyond the QoL improvement (the primary endpoint of the trial), a significantly longer life expectancy in the experimental arm (median 31 2 months) compared to the usual care arm (26 0 months) was reported [7] A French randomized trial, conducted in lung cancer patients without evidence of disease progression after or during initial treatment, compared a web-mediated follow-up algorithm (experimental arm), based on weekly self-scored patient symptoms, with routine follow-up with CT scans scheduled every 3-6 months according to the disease stage (control arm) [8] In the experimental arm, the oncologist received automatically an alert email when self-scored symptoms matched predefined criteria Notably, a significant improvement in overall survival was found in patients assigned to experimental arm [9] The adoption of electronic PROs in clinical practice could have many advantages [10] Regular discussion of PROs questionnaires, filled out electronically by patients and received by nurses or doctors, could allow a systematic check of the clinical trend of symptoms and side-effects The early, proactive identification of worsening symptoms and toxicities could help prevent the occurrence of severe adverse events needing ER access and hospitalization Adoption and discussion of PROs would reasonably have a positive psychological impact on patients, increasing their satisfaction with healthcare services While the adoption of electronic PROs could initially appear as a challenging organizational effort, we believe that their benefits will definitely be evident in the long-term The use of PROs may allow a significant benefit in terms of patients’ QoL, and this should be more than enough to consider its adoption in clinical practice, which - overall survival benefit or not – is worth the trouble References: 1 Di Maio M, et al Patient-reported outcomes in the evaluation of toxicity of anticancer treatments Nat Rev Clin Oncol 2016;13(5):319-25 2 Marandino L, et al Deficiencies in health-related quality-of-life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016 Ann Oncol 2018;29:2288-2295 3 Sperti E, Di Maio M Outcomes research: Integrating PROs into the clinic - overall survival benefit or not, it's worth the trouble Nat Rev Clin Oncol 2017;14(9):529-530 4 Reale ML, et al Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018 Lung Cancer 2020 Jan;139:47-54 5 Basch E, et al Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial J Clin Oncol 2016;34(6):557-65 6 Baratelli C, et al The role of patient-reported outcomes in outpatients receiving active anti-cancer treatment: impact on patients' quality of life Support Care Cancer 2019;27(12):4697-4704 7 Basch E, et al Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment JAMA 2017;318(2):197-198 8 Denis F, et al Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients J Natl Cancer Inst 2017 Sep 1;109(9) 9 Denis F, et al Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer JAMA 2019;321(3):306-307 10 Marandino L, et al COVID-19 Emergency and the Need to Speed Up the Adoption of Electronic Patient-Reported Outcomes in Cancer Clinical Practice JCO Oncol Pract 2020;16(6):295-298 Keywords: patient-reported outcomes, health-related quality of life, ePROs.

For improving the prognosis of PC, intraperitoneal (IP) chemotherapy has been introduced in the clinical setting, and phase III trials proved the superiority of IP chemotherapy to IV chemotherapy, in particular, in advanced ovarian cancer.

OBJECTIVE To evaluate the acceptability of early palliative care (EPC) among patients with advanced ovarian cancer and determine the feasibility of larger-scale phase III trials.

While phase III trials on therapies targeting KRAS, especially KRASG12C, are ongoing, the clinical efficacy of anti-programmed death protein-1 (PD-1) or its ligand (PD-L1) against KRAS-mutant NSCLCs remains a topic of debate.

Of the eight studies analysed, two were randomised controlled trials comparing neoadjuvant chemotherapy followed by oncological resection to upfront surgery and adjuvant chemotherapy, three were prospective single-arm phase II trials analysing neoadjuvant chemotherapy followed by surgery only, one was a retrospective study comparing neoadjuvant chemotherapy followed by surgery versus surgery first followed by adjuvant chemotherapy and the remaining two were single-arm retrospective studies of neoadjuvant chemotherapy followed by surgery.

Several phase I and II trials have shown that PARP inhibitors are effective as monotherapy in patients with metastatic breast cancer and germline BRCA1/2 mutation.

For patients with NSCLC, two randomized phase II trials also suggested that the addition of a radical local treatment results in encouraging survival data, with a good safety profile.

5%) trials were phase II trials, while 12 (37.

OBJECTIVE AND METHODS Post hoc analyses of data from the TRANSFORMS, FREEDOMS, and FREEDOMS II trials and their extensions assessed the effects of fingolimod (0.

METHODS This post-hoc analysis pooled data from the phase 3 FREEDOMS and FREEDOMS II trials (N=1556).

RESULTS Eight phase III trials evaluating novel NSAAs (vs.

Methods We analyzed ORR alone or in combination with DOR (RMTR) in available phase I, II, and III trials evaluating nivolumab monotherapy or in combination with ipilimumab across solid tumor types.

Tosedostat is a selective oral aminopeptidase inhibitor, which in phase I/II trials showed acceptable toxicity and encouraging efficacy.

Results from placebo-controlled phase III trials showed that IV amisulpride is efficacious both in the prevention of PONV (used either alone or in combination with an antiemetic of a different class) and in the treatment of PONV (irrespective of prior antiemetic prophylaxis status).

Overall response rates appear comparable to published phase III trials comparing the combination of Pd with or without an anti-CD38 monoclonal antibody (Table 1).

Two European phase III trials comparing D1 and D2 demonstrated that D2 did not improve the overall survival and was associated with a high mortality related to splenectomy.

Little is known about the risk/benefit ratio for pediatric cancer phase II trials testing targeted therapies.

Our objectives were to describe the incidence of MPEs in recently published phase III trials testing systemic treatments in patients with advanced cancer; the main characteristics of trials adopting MPEs; the presence of mature results for all endpoints in the primary publication; consistency between results of each endpoint and authors' conclusions.

Therefore, we provide a complete overview of all phase II and phase III trials investigating targeted therapies in AML and their primary endpoints over the past two decades in perspective of their clinical benefit.

PubMed, Embase, and Cochrane Library were systematically searched for phase I and phase II trials investigating an experimental compound as a single agent or in combination with dexamethasone, published from January 1, 2010 to July 1, 2020.

Both agents were approved based on phase III trials demonstrating that they were associated with improved progression-free survival compared with treatment of physician’s choice in patients receiving second-third line therapy for locally advanced, inoperable, or metastatic breast cancer in patients with germline pathogenic BRCA 1 or BRCA2 variants.

Purpose of review The pivotal phase III trials demonstrating efficacy and safety of direct oral anticoagulants (DOACs) in the treatment of venous thromboembolism (VTE) or nonvalvular atrial fibrillation (NVAF) excluded patients with important and common comorbidities, including obesity, advanced chronic kidney disease, cirrhosis, cancer and antiphospholipid antibody syndrome.

Phase II trials suggest that SBRT added to palliative therapy may improve overall survival and may delay the initiation of systemic therapy in OMD patients.

On the contrary, latest evidence of some phase II trials suggests efficacy of consolidating WBRT is comparable to ASCT.

This review describes preclinical studies of omidenepag, published results of phase I–III clinical trials, and preliminary results of phase III trials currently in progress.

Two phase III trials currently underway—the “Randomized Trial of IMPT versus IMRT for the Treatment of Oropharyngeal Cancer of the Head and Neck” and the “TOxicity Reduction using Proton bEam therapy for Oropharyngeal cancer (TORPEdO)” trial—are expected to provide prospective, level I evidence regarding the effectiveness of IMPT for such patients.

EXPERT OPINION Bortezomib-lenalidomide-dexamethasone (VRd), daratumumab-bortezomib-melphalan-prednisone (DaraVMP) and daratumumab-lenalidomide-dexamethasone (DaraRd) represent new standard of care (SOC) treatments for NDTIMM patients, based on phase III trials showing their superior efficacy as compared with previous SOCs.

This was evident with the Ebola vaccine (Johnson & Johnson) wherein a mixeddose approach was specifically adopted in phase I and phase II trials showing safety and longlasting immunity.

A patient-reported outcome (PRO) is a measurement of the patient’s condition, reported directly by the patient, without the interpretation by a clinician or anyone else [1] Recently, there has been a growing interest in the integration of PROs as part of data collection about toxicity and symptoms experienced by patients with cancer This integration could have relevant implications not only for a more accurate reporting of adverse events and definition of quality of life (QoL) within clinical trials [2], but also for a better patients’ management in routine clinical practice [3] Many tools and questionnaires have been validated to properly measure QoL and symptoms in patients with lung cancer The inclusion of these measures in clinical trials has several important advantages It allows providing a patient-focused assessment of the burden and the impact of disease Moreover, it allows completely assessing the clinical benefit of a therapy, by complementing the information provided by commonly used efficacy endpoints, including overall survival, and the traditional description of safety based on physicians’ assessment Furthermore, the availability of QoL data from trials could allow a more accurate patient-physician communication about the treatment strategies offered in clinical practice However, a systematic review that we performed in order to evaluate the adoption of QoL among endpoints in randomized phase III trials conducted in lung cancer, published between 2012 and 2018 in 11 major journals, showed quite disappointing findings [4] Beyond the importance in clinical trials, PROs can play an important role in clinical practice Several studies have demonstrated a clear benefit in terms of patients’ QoL [5,6] Our experience, focused on the adoption of PROs in patients receiving active anticancer treatment at Mauriziano Hospital in Turin, showed that the introduction of PROs, thanks to an active role of nurses, was feasible, produced high patients’ satisfaction and a significant QoL improvement compared to the traditional modality of visit [6] In details, we compared 2 groups: patients in the control group underwent “usual” visits, while patients in the “PRO” group received a paper questionnaire by a dedicated nurse before each visit, in order to provide information about symptoms and toxicities After 1 month, mean change from baseline of global QoL was significantly better in the PRO group, and significantly higher proportion of patients obtained a clinically significant improvement in global QoL score In addition to QoL benefit, several studies have shown a significant improvement in overall survival with the adoption of electronic PROs in patients with lung cancer [7-9] In a pivotal randomized trial involving US patients with different solid tumors (including lung cancer) undergoing chemotherapy, patients assigned to the control arm received usual care, while subjects assigned to experimental arm could report their symptoms remotely from home, using tablet computers or computer kiosks [5,7] Doctors received a report of symptoms referred by patients during visits, and nurses received email alerts when patients reported severe or worsening symptoms Beyond the QoL improvement (the primary endpoint of the trial), a significantly longer life expectancy in the experimental arm (median 31 2 months) compared to the usual care arm (26 0 months) was reported [7] A French randomized trial, conducted in lung cancer patients without evidence of disease progression after or during initial treatment, compared a web-mediated follow-up algorithm (experimental arm), based on weekly self-scored patient symptoms, with routine follow-up with CT scans scheduled every 3-6 months according to the disease stage (control arm) [8] In the experimental arm, the oncologist received automatically an alert email when self-scored symptoms matched predefined criteria Notably, a significant improvement in overall survival was found in patients assigned to experimental arm [9] The adoption of electronic PROs in clinical practice could have many advantages [10] Regular discussion of PROs questionnaires, filled out electronically by patients and received by nurses or doctors, could allow a systematic check of the clinical trend of symptoms and side-effects The early, proactive identification of worsening symptoms and toxicities could help prevent the occurrence of severe adverse events needing ER access and hospitalization Adoption and discussion of PROs would reasonably have a positive psychological impact on patients, increasing their satisfaction with healthcare services While the adoption of electronic PROs could initially appear as a challenging organizational effort, we believe that their benefits will definitely be evident in the long-term The use of PROs may allow a significant benefit in terms of patients’ QoL, and this should be more than enough to consider its adoption in clinical practice, which - overall survival benefit or not – is worth the trouble References: 1 Di Maio M, et al Patient-reported outcomes in the evaluation of toxicity of anticancer treatments Nat Rev Clin Oncol 2016;13(5):319-25 2 Marandino L, et al Deficiencies in health-related quality-of-life assessment and reporting: a systematic review of oncology randomized phase III trials published between 2012 and 2016 Ann Oncol 2018;29:2288-2295 3 Sperti E, Di Maio M Outcomes research: Integrating PROs into the clinic - overall survival benefit or not, it's worth the trouble Nat Rev Clin Oncol 2017;14(9):529-530 4 Reale ML, et al Quality of life analysis in lung cancer: A systematic review of phase III trials published between 2012 and 2018 Lung Cancer 2020 Jan;139:47-54 5 Basch E, et al Symptom Monitoring With Patient-Reported Outcomes During Routine Cancer Treatment: A Randomized Controlled Trial J Clin Oncol 2016;34(6):557-65 6 Baratelli C, et al The role of patient-reported outcomes in outpatients receiving active anti-cancer treatment: impact on patients' quality of life Support Care Cancer 2019;27(12):4697-4704 7 Basch E, et al Overall Survival Results of a Trial Assessing Patient-Reported Outcomes for Symptom Monitoring During Routine Cancer Treatment JAMA 2017;318(2):197-198 8 Denis F, et al Randomized Trial Comparing a Web-Mediated Follow-up With Routine Surveillance in Lung Cancer Patients J Natl Cancer Inst 2017 Sep 1;109(9) 9 Denis F, et al Two-Year Survival Comparing Web-Based Symptom Monitoring vs Routine Surveillance Following Treatment for Lung Cancer JAMA 2019;321(3):306-307 10 Marandino L, et al COVID-19 Emergency and the Need to Speed Up the Adoption of Electronic Patient-Reported Outcomes in Cancer Clinical Practice JCO Oncol Pract 2020;16(6):295-298 Keywords: patient-reported outcomes, health-related quality of life, ePROs.

Accurate estimation of response and early progression rates based on the data from the phase II trials conducted according to the optimal two-stage designs would be very useful for further testing of the agents in phase II trials.

3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers.

82Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy signals and safety of treatment (tx) combinations acr.

Anti‐angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early‐stage (resectable) cancers.

these findings compare favourably with the outcomes of vemurafenib monotherapy in two multicentre phase ii trials involving a total of 54 patients with r/r HCL.

Even fewer phase III and randomized phase II trials tested an RT-specific hypothesis (11.

Six phase III trials tested the hypothesis that 3 months is noninferior in efficacy to 6 months and reduces long-term side effects for patients.

In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX.

Randomized phase III, and for tyrosine kinase inhibitors (TKIs) also randomized phase II trials enrolling advanced/metastatic NSCLC patients were included.