Expanded Access Clinical Trial Research Articles

A Qualitative Interview Study on Expanded Access Clinical Trials for Compassionate Use in Japan.

An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them. We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional). All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was "requests from physicians and medical institutions" (nine companies, 90.0%), and the most common reason for not implementing an EACT was "the applicability of the system" (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised. An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due.

Using Real-World Remanufacturing and Recollection Data to Optimize Time-to-Treatment in Patients with out-of-Specification Ciltacabtagene Autoleucel

Ciltacabtagene autoleucel (cilta-cel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor-T cell (CAR-T) immunotherapy approved for the treatment of adults with relapsed/refractory multiple myeloma. Manufacturing of cilta-cel can take approximately 4 weeks from receipt of apheresis material until release for cilta-cel infusion. Though manufacturing is a well-controlled biological production process, delays in release can occur when the final product does not meet predetermined release specifications. Such products are referred to as being out-of-specification(s) (OOS). In the United States, OOS CAR-T products may be released for use via an exceptional release process as part of an expanded access clinical trial (NCT05346835). Additional time is needed as the process requires the prescriber's request for release, an internal safety review to assess benefit/risk, and US Food and Drug Administration (FDA) notification and/or approval. Further delays to treatment may occur if a prescriber requests to remanufacture and potentially recollect new apheresis material, attempting to obtain an in-specification product. In some instances, this increased time has resulted in clinically significant disease progression. We reviewed and characterized the experience from discussions with prescribers regarding OOS cilta-cel over the past 18 months. Options presented to the prescriber included: (1) remanufacture using the original apheresis product, (2) recollection of new apheresis material, (3) exceptional release of the OOS cilta-cel, and (4) cancellation of the order. The outcomes for cases of remanufacturing or recollection were analyzed. To date, remanufacturing from the initial apheresis material has been requested in 37% of OOS cases. Of these cases, 60% of remanufacturing attempts resulted in the same or worse outcomes (ie, additional OOS outcomes or worse performance on the original OOS outcomes). Recollection of new apheresis material was requested in 15% of OOS cases, either because of insufficient remaining material or concern about the impact of therapy received prior to collection. Upon recollection, 65% of these attempts resulted in the same or worse outcomes. The reason cilta-cel was determined to be OOS varied. Of remanufacturing attempts for OOS due to a low proportion of CAR+ cells, none were successful in obtaining an in-specification product. Cases where OOS was due to low cell viability were unsuccessfully remanufactured or recollected 71% and 75% of the time, respectively, whereas OOS due to low dose was unsuccessfully remanufactured 95% of the time. On occasion, the second attempt at remanufactured OOS cilta-cel due to low dose has been combined with the OOS cilta-cel generated in the first manufacture to achieve a combined dose that meets or comes close to the specified dose range. Remanufacturing or recollection success rates were increased in cases where the root cause of the OOS was due to something inadvertent that occurred during the manufacturing process. Our findings on remanufacturing and recollection outcomes may inform physician decisions and help optimize time-to-treatment in patients receiving cilta-cel. Additional studies (eg, NCT05347485) are underway to evaluate the safety and efficacy of OOS cilta-cel.

Osimertinib and Selpercatinib Efficacy, Safety, and Resistance in a Multicenter, Prospectively Treated Cohort of EGFR-Mutant and RET Fusion-Positive Lung Cancers.

Acquired RET fusions have been reported at resistance to treatment with EGFR inhibitors in EGFR-mutant non-small cell lung cancer (NSCLC); however, a multicenter cohort of patients with EGFR-mutant lung cancers treated with osimertinib and selpercatinib for RET fusion-mediated osimertinib resistance has not previously been published. Patients who received selpercatinib in combination with osimertinib on a prospective expanded access clinical trial (NCT03906331) and single-patient compassionate use programs across five countries were centrally analyzed. All patients had advanced EGFR-mutant NSCLC with a RET fusion detected from tissue or plasma following osimertinib therapy. Clinicopathologic and outcomes data were collected. Fourteen patients with EGFR-mutant and RET fusion-positive lung cancers who experienced prior progression on osimertinib received osimertinib and selpercatinib. EGFR exon 19 deletions (±T790M, 86%) and non-KIF5B fusions (CCDC6-RET 50%, NCOA4-RET 36%) predominated. Osimertinib 80 mg daily and selpercatinib 80 mg twice daily were the most commonly administered dosages. The response rate, disease control rate, and median treatment duration were 50% [95% confidence interval (CI), 25%-75%, n = 12], 83% (95% CI, 55%-95%), and 7.9 months (range, 0.8-25+), respectively. Resistance was complex, involving EGFR on-target (EGFR C797S), RET on-target (RET G810S), and off-target (EML4-ALK/STRN-ALK, KRAS G12S, BRAF V600E) mechanisms; RET fusion loss; or polyclonal mechanisms. For patients with EGFR-mutant NSCLC with an acquired RET fusion as a mechanism of EGFR inhibitor resistance, the addition of selpercatinib to osimertinib was feasible and safe and offered clinical benefit, supporting the prospective evaluation of this combination. See related commentary by Krebs and Popat, p. 2951.

CTNI-24. SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS

Abstract OBJECTIVE To report single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131]. BACKGROUND ONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. Design/ METHODS Our site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI]. RESULTS Three subjects were registered at our site onto ONC018 with age range 18–44yrs, 2/3 female, residing in Norway, India, and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: Glioblastoma (3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20 % decrease; MDASI:2/3 experienced decrease from baseline [median 6%], consistent with improved quality of life. No clinically significant laboratory abnormalities. All adverse events were grade I–II. CONCLUSIONS We found that the study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of the larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy.

CLRM-02 SINGLE CENTER EXPERIENCE OF DOPAMINE ANTAGONIST ONC-201 FOR RECURRENT H3K27M-MUTANT GLIOBLASTOMA IN ADULTS

OBJECTIVETo report the single center experience of three adult subjects receiving ONC-201 as part of the ONC018 expanded access clinical trial [NCT03134131]. BACKGROUNDONC-201 is an oral investigational antagonist against the D2 dopamine receptor that has shown encouraging results for malignant gliomas harboring the H3K27M mutation in the H3 histone complex. Responses have been reported in pediatric subjects with such tumors. H3K27M tumors are generally located in the midline of the central nervous system which co-localize, for unknown reasons, with key dopaminergic pathways. An expanded access clinical trial (ONC018) was available to eligible patients allowing them access to this agent pending FDA review. DESIGN/METHODSOur site enrolled three subjects on the ONC018 trial. We present the demographic, clinical, and molecular characteristics for our enrolled subjects. We report the tolerability, adverse events, and outcome measures including survival, time-to-progression, response, Karnofsky Performance Status [KPS] and quality-of-life measured by the MD Anderson symptom inventory instrument [MDASI]. RESULTSThree subjects were registered at our site onto ONC018 with age range 18-44yrs, 2/3 female, residing in Norway, India and United states. Tumor locations: brainstem, corpus callosum and thalamus. Pathology: glioblastoma(3/3), MGMT methylated (2/3), IDH1 mutant (0/3), EGFR amplification (0/3) and ATRX (3/3). Median change from baseline KPS: ≤20% decrease; MDASI:2/3 experienced decrease from baseline [median 6%],consistent with improved quality of life. No clinically significant laboratory abnormalities. No serious adverse events observed in any cases. All adverse events grade I-II. CONCLUSIONSIn three subjects with H3K27M-mutant malignant glioma that received ONC201 as part of this expanded access clinical trial, we found that study drug was quite tolerable. No serious adverse events nor radiographic responses were seen. Analyses of larger study cohort and additional randomized controlled trials are necessary to provide insight into the safety and efficacy of this agent for this patient population.

Characteristics of the Compassionate Use Program in Japan: An Analysis of Expanded Access Clinical Trials from 2016 to 2021.

Compassionate use is a system that provides patients with exceptional access to investigational new drugs to treat life‐threatening diseases that have no effective conventional treatments. The purpose of this study was to characterize and assess the current status of the compassionate use program’s application in Japan by evaluating expanded access clinical trials (EACTs) conducted between 2016 and 2021. In this study, a data set containing all EACTs, and pivotal clinical trials (PCTs) conducted in Japan between February 2016 and April 2021 was obtained from the Pharmaceutical and Medical Devices Agency, systemically reviewed, and analyzed. During the 5 years since EACTs began in Japan, out of 2,031 PCTs, 31 EACTs were conducted in Japan. Twenty‐four trials (77.4%) of the 31 EACTs used anticancer drugs and 5 of those trials (16.1%) were conducted in children. Furthermore, we conducted an EACT survey for drugs with a high degree of social and patient demands as recommended in the EACT notification. Among the 2,031 PCTs, we found 152 trials with high degree of social and patient demands. Of these, EACT was implemented in 17 trials (11.2%). Days from the start of the EACT to the submission of new drug applications and the approval were 9.0 (67.0–56.5) and 208.0 (172.8–308.8) days, respectively. Of the 31 EACTs conducted, 24 (77.4%) drugs have been approved as of August 2021. This first comprehensive study on EACTs clarified the current status and issues of Japan’s compassionate use system and the 5 years since the program initiated.

An anti-CD6 monoclonal antibody (itolizumab) reduces circulating IL-6 in severe COVID-19 elderly patients

BackgroundSince the COVID-19 outbreak an unprecedented challenge for healthcare systems around the world has been placed. In Cuba, the first case of COVID-19 was reported on March 11. Elderly with multiple comorbidities have been the most risky population. Although most patients present a mild to moderate disease, some have developed severe symptoms. One of the possible mechanisms underlying rapid disease progression is a cytokine storm, in which interleukin (IL) -6 seems to be a major mediator. Itolizumab is a humanized recombinant anti-CD6 monoclonal antibody (MAb), with the ability of reducing serum interferon gamma (INF-γ), tumour necrosis factor alpha (TNFα) and IL-6. Based on these previous results in patients with psoriasis and rheumatoid arthritis, an expanded access clinical trial was approved by the Cuban regulatory agency for COVID-19 critically, severely and moderately ill patients.ResultsWe show here a short kinetic of IL-6 serum concentration in the first 24 COVID-19 patients treated with itolizumab. Most of patients were elderly with multiple comorbidities. We found that with one itolizumab dose, the circulating IL-6 decreased in critically and severely ill patients, whereas in moderately ill patients the values didn’t rise as compared to their low baseline levels.ConclusionThese findings suggest that itolizumab could be an attractive therapeutic option to decrease the negative outcome of the cytokine storm in COVID-19 patients.Trial registrationCECMED IIC RD-EC 179, RPCEC00000311. Registered 4 May 2020 - Retrospectively registered, http://rpcec.sld.cu/ensayos/RPCEC00000311-Sp or http://rpcec.sld.cu/trials/RPCEC00000311-En

Use of a Humanized Anti-CD6 Monoclonal Antibody (Itolizumab) in Elderly Patients with Moderate COVID-19

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a recent outbreak of coronavirus disease (COVID-19). In Cuba, the first case of COVID-19 was reported on March 11, 2020. Elderly individuals with multiple comorbidities are particularly susceptible to adverse clinical outcomes in the course of SARS-CoV-2 infection. During the outbreak, a local transmission event took place in a nursing home in Villa Clara province, Cuba, in which 19 elderly residents tested positive for SARS-CoV-2. Methods: Based on the increased susceptibility to cytokine release syndrome, inducing respiratory and systemic complications in this population, 19 patients were included in an expanded access clinical trial to receive itolizumab, an anti-CD6 monoclonal antibody. Results: All patients had underlying medical conditions. The product was well tolerated. After the first dose, the course of the disease was favorable, and 18 of the 19 patients (94.7%) were discharged clinically recovered with negative real-time reverse transcription polymerase chain reaction test results at 13 days. After one dose of itolizumab, circulating IL-6 decreased within the first 24–48 h in patients with high baseline values, whereas in patients with low levels, this concentration remained over low values. To preliminarily assess the effect of itolizumab, a control group was selected among the Cuban COVID-19 patients that did not receive immunomodulatory therapy. The control subjects were well matched regarding age, comorbidities, and severity of the disease. The percentage of itolizumab-treated, moderately ill patients who needed to be admitted to the intensive care unit was only one-third of that of the control group not treated with itolizumab. Additionally, treatment with itolizumab reduced the risk of death 10 times as compared with the control group. Conclusion: This study corroborates that the timely use of itolizumab in combination with other antivirals reduces COVID-19 disease worsening and mortality. The humanized antibody itolizumab emerges as a therapeutic alternative for patients with COVID-19. Our results suggest the possible use of itolizumab in patients with cytokine release syndrome from other pathologies.

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials

BackgroundHyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and MethodsAdults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. ResultsIn RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. ConclusionHyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies.

CPC-089 Multidisciplinary Collaboration in the Treatment of Paediatric Hematopoietic Transplant Rejection with Allogeneic Mesenchymal Cells. A Case Report

BackgroundAdvanced treatments represent a source of hope for rare diseases. However, they are complex as they require the participation of several professionals and experience is necessary for optimal use.Purpose To...

Efficacy of sorafenib in advanced renal cell carcinoma (RCC) independent of prior treatment, histology, or prognostic group.

465^ Background: Multiple targeted therapies have become available for RCC over the past decade. Sorafenib is an orally active multikinase inhibitor which has been shown to improve progression free survival in low-risk and intermediate-risk status advanced clear-cell RCC after previous systemic therapy. Methods: Between May 2006 and December 2010, patients with advanced RCC with either clear cell or non-clear cell histopathology who had progressed on prior systemic chemotherapy or were treatment naïve, ECOG performance status 0-2, commenced treatment with sorafenib (400-mg twice daily continuously) through an expanded access clinical trial in two tertiary centres in Sydney and Melbourne. We report the pooled outcomes of these two studies. Results: Total 47 patients with metastatic RCC were treated with sorafenib. The median overall survival of advanced RCC was 11.9 months. After median follow up of 51.3 months, the median PFS was 6.5 months. 38 patients died by the time of analysis. Overall 1 patient showed complete response (CR), 6 patients (13%) had partial response (PR), and 29 patients (62%) had stable disease (SD) as the best response. 8 (17%) had non-clear cell histopathology and 5 (10%) had sarcomatoid features. In non-clear cell cohort, 5 patients (62.5%) showed SD. 23 (49%) patients were treatment naïve; 1/23 showed CR, 5/23 had PR and 13/23 had SD (clinical benefit: 83%). Overall 14 (30%) and 22 (47%) patients had high risk status according to MSKCC and Heng prognostic scores, respectively. Median PFS for poor prognostic patients was 5.1 and 4.2 months based on MSKCC and Heng scores, respectively. In MSKCC poor prognostic group, 1 patient had CR, 2/14 showed PR and 8/14 had SD (clinical benefit: 79%). In Heng poor prognostic group, one patient had CR, 2/22 showed PR and 13/22 had SD (clinical benefit: 73%). Sorafenib-related serious adverse events were seen in 10 patients. The most common adverse events were hand-foot syndrome (53%), rash (47%), fatigue (42%), nausea (40%), and diarrhoea (32%). Conclusions: This study confirms the efficacy and tolerability of sorafenib in a different spectrum of advanced RCC patients including non-clear cell histology, poor prognostic status and as first-line treatment. Clinical trial information: ACTRN12606000140550.

Safety of Everolimus by Treatment Duration in Patients With Advanced Renal Cell Cancer in an Expanded Access Program

To retrospectively analyze the effects of treatment duration on outcomes of everolimus treatment of patients in the RAD001 Expanded-Access Clinical Trial in RCC (REACT) program. Patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor received everolimus (10 mg once daily), with dosing interruption or modifications allowed for toxicity. All serious and grade 3/4 adverse events and grade 1/2 adverse events leading to a change in drug administration were reported. Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors. The study stratified 1367 evaluable patients into treatment duration groups of <3 months, ≥3 and <6 months, ≥6 months and <1 year, and ≥1 year. Pneumonia, noninfectious pneumonitis, and hyperglycemia occurred more frequently in patients receiving everolimus for ≥1 year but did not result in treatment discontinuations. First occurrence of adverse events presented early in the treatment course for most patients. Treatment duration of ≥6 months was associated with improved disease control rates. Everolimus is well tolerated in patients with metastatic renal cell carcinoma for treatment durations≥1 year and not associated with cumulative toxicity.

821P - Everolimus in Patients with Metastatic Renal Cell Carcinoma Who Progress after Initial Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor (VEGFR-TKI) Therapy: UK Results from the react Trial on Behalf of the UK React Investigators

ABSTRACT Background The phase III RECORD-1 trial demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) who had failed initial VEGFr-TKI therapy. REACT (RAD001 Expanded Access Clinical Trial in RCC) was designed to address an unmet medical need by providing everolimus to patients with mRCC prior to regulatory approval. UK results from the REACT trial are reported here. Methods REACT was an open-label, international, expanded-access program. Eligible patients had measurable or nonmeasurable mRCC of any histology, and had progressed on, or were intolerant of, VEGFr-TKI therapy. Patients received a once-daily oral 10 mg dose of everolimus. The primary objective of REACT was to evaluate long-term safety of everolimus. Tumour response was also assessed according to RECIST. Results A total of 120 patients were enrolled in the UK, 9% of worldwide enrolment. Prior sunitinib was received by 76% of patients; only 5.8% of patients received more than one VEGFr-TKI. Everolimus was received for a median duration of 21.8 weeks (range, 2.0–59.0), numerically longer than reported overall for REACT (14.0 weeks; range, 0.1–83.7). Safety findings and tumour responses were consistent with those observed in the global patient population. The most commonly reported grade 3/4 AEs were anaemia (20.8%), hyperglycaemia (10%), and lower respiratory tract infection (7.5%). Stomatitis and pneumonitis occurred in 13.3% and 10% of patients, respectively (all grades); grade 3 events were reported in 6.7% and 3.3% of patients (no grade 4 events). Investigator-assessed best overall responses were stable disease in 67 (55.8%) patients and a partial response in 1 patient (0.8%), comparable with the overall population. No complete responses were documented in this trial. Conclusions The REACT trial provided everolimus in advance of regulatory approval and commercial availability to mRCC patients in the UK who failed initial VEGFr-TKI therapy. Everolimus was well tolerated, and safety findings were consistent with those reported for global REACT. Disclosure S. Chowdhury: Consultant or Advisory: Novartis, Pfizer, GSK, Sanofi-Aventis, Janssen-Cilag, Dendreon. All other authors have declared no conflicts of interest.

Safety and efficacy of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC) who failed previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy: A subanalysis of REACT.

e15064 Background: Some targeted agents have shown variable safety profiles in Asian vs non-Asian patients with mRCC. A retrospective analysis of sunitinib in Korean patients with mRCC found increased incidence and severity of certain adverse events (AEs) compared with previous global trials (Hong et al. Cancer Res Treat. 2009;41:67-72). The open-label, expanded-access program REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) provided everolimus, a mammalian target of rapamycin (mTOR) inhibitor, before its regulatory approval to 1367 patients with VEGFr-TKI refractory mRCC from 34 countries. Final results of REACT were recently published (Grünwald et al. Eur J Cancer. 2012;48:324-332). This analysis compared study end points in Asian patients with those in the total REACT population. Methods: The primary objective of REACT was to assess the safety of everolimus 10 mg/day, as determined by the overall occurrence of grade 3/4 AEs. Best overall tumor response was evaluated based on RECIST 1.0. Results: Baseline characteristics of Asian patients (n = 109; from South Korea, Taiwan, Thailand, and Singapore) were similar to those of the total study population. Median duration of everolimus exposure was longer in Asian patients than in the total population: 24.1 (range, 2.0-72.7) vs 14.0 (0.1-83.7) weeks. Overall incidence of grade 3/4 AEs was slightly higher in Asian patients than in the total population (70.6% vs 61.6%); common grade 3/4 AEs in Asian patients and the total population, respectively, included anemia (26.6% vs 13.4%), hyperglycemia (11.9% vs 5.5%), pneumonia (10.1% vs 4.2%), stomatitis (6.4% vs 5.4%), thrombocytopenia (3.7% vs 1.0%), and pneumonitis (3.7% vs 2.7%). More patients in the Asian population than in the total population had achieved disease control: partial response, 3.7% vs 1.7%; stable disease, 67.0% vs 51.6%. Conclusions: In this subanalysis of REACT, Asian patients treated with everolimus experienced a greater clinical benefit with a slightly higher incidence of AEs. These results are supportive of the use of everolimus in the Asian population.

International, expanded access program of everolimus in patients with metastatic renal cell carcinoma (mRCC) who progressed after previous vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy (VEGFr-TKI): Subanalysis from emerging growth market (EGM) countries.

e15047 Background: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor shown to benefit patients with mRCC after failure of initial VEGFr-TKI therapy. In the phase 3 RECORD-1 trial, median progression-free survival was 4.9 months with everolimus and 1.9 months with placebo (hazard ratio, 0.33; P &lt; .001). REACT (RAD001 Expanded Access Clinical Trial in RCC; NCT00655252) was an open-label, expanded access program that provided everolimus before commercial availability to 1367 patients with VEGFr-TKI refractory mRCC in 34 countries. Final results of REACT were recently published (Eur J Cancer. 2012;48:324-332). Methods: The primary objective of REACT was to evaluate the long-term safety of everolimus 10 mg/day as determined by the overall incidence of grades 3 and 4 adverse events (AEs). Best overall tumor response was assessed according to RECIST 1.0. This subanalysis was conducted to assess primary and secondary end points in a subgroup of patients from 11 EGM countries: Turkey, Australia, Russia, Israel, Lebanon, Jordan, Saudi Arabia, South Korea, Singapore, Taiwan, and Thailand. Results: Baseline characteristics of the EGM population (n = 243) were similar to the overall REACT population: median age, 60.0 years; clear cell histology, 95.1%; and progression on/intolerance to previous VEGFr-TKI therapy, 89.7%/16.9%. Median duration (range) of everolimus exposure was 20.4 (0.3-83.7) weeks. Clinical benefit was observed in 60.1%/53.3% of EGM patients/all patients (stable disease, 55.6%/51.6%; partial response, 4.5%/1.7%). Common grade ≥3 AEs in EGM patients/all patients included anemia (19.8%/13.4%), pneumonia (7.4%/4.2%), hyperglycemia (7.0%/5.5%), stomatitis (5.8%/5.4%), and pneumonitis (2.9%/2.7%); 13.2%/16.6% of EGM patients/all patients discontinued because of AEs. Conclusions: In patients from EGM countries, safety findings and tumor responses were consistent with the overall REACT population and with RECORD-1. Everolimus was well tolerated, with no new safety issues identified.

Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy.

391 Background: Efficacy of everolimus (EVE) in metastatic renal cell carcinoma (mRCC) refractory to vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI) therapy is well established. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with VEGFR-TKI-refractory mRCC access to EVE in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy. Long-term safety of EVE 10 mg/day in patients with mRCC, as determined by overall incidence of grade 3/4 and serious adverse events (AEs) was documented. RECIST-defined tumor response was also assessed by local investigator. Subgroup analyses evaluated effect of prior treatment on safety and efficacy of EVE. Results: Of 1367 patients enrolled, most (92.7%) had progressed on prior VEGFR-TKI therapy, and some (24.4%) were VEGFR-TKI intolerant. Across patient subgroups by prior VEGFR-TKI treatment, median EVE treatment duration was similar (Table). Best overall response rates were similar in the VEGFR-TKI-intolerant subgroup and overall populations: respectively, 1.8% and 1.7% had partial response (PR) while 53.5% and 51.6% had stable disease (SD). Incidence of grade 3/4 AEs across all prior treatment subgroups were similar to those of the overall population. (See table.) Conclusions: Patients enrolled in REACT derived benefit from EVE irrespective of prior VEGFR-TKI therapy, including VEGFR-TKI-intolerant patients. EVE is well tolerated and affords disease stabilization in the majority of patients with VEGFR-TKI-refractory mRCC, and is the standard of care in this patient population. [Table: see text]

Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT.

402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. Methods: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. Results: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9–49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1–83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. Conclusions: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients.

Patients with metastatic renal cell carcinoma treated with everolimus in REACT: Hyperglycemia and hypercholesterolemia and associated outcomes.

407 Background: Correlation between specific adverse events (AEs) and clinical efficacy of targeted therapies in the treatment of patients with metastatic renal cell carcinoma (mRCC) has been noted. Subanalyses of REACT (RAD001 Expanded Access Clinical Trial in RCC) evaluated potential association of hyperglycemia and hypercholesterolemia with outcomes in patients with mRCC treated with everolimus (EVE). Methods: The open-label, international, expanded-access clinical trial REACT (Clinicaltrials.gov: NCT00655252 ) evaluated long-term safety and efficacy of EVE 10 mg/day in patients with mRCC who were intolerant of, or progressed while on, VEGFR-TKI therapy. Based on Common Toxicity Criteria AE v3.0 criteria, all grade 3/4 AEs and any grade 1/2 AEs resulting in study drug modification, temporary interruption, or treatment discontinuation were collected. Subgroup analyses of patients who developed hyperglycemia or hypercholesterolemia of any grade were performed. Results: There were 1364 patients enrolled in REACT, of whom 78 developed hyperglycemia and 14 developed hypercholesterolemia. Median EVE treatment duration was longer for patients who developed hyperglycemia or hypercholesterolemia than for the overall population (19.14, 19.71, and 14.0 weeks, respectively). Overall, 30.3% of REACT patients remained on EVE for ≥6 months compared with 42.3% and 35.7% of patients with hyperglycemia and hypercholesterolemia, respectively. Best overall response was stable disease in 51.6% (overall) compared with 65.4% of patients with hyperglycemia and 71.4% of patients with hypercholesterolemia. Conclusions: Most patients with hyperglycemia and hypercholesterolemia remained on EVE longer than the overall REACT population, suggesting these AEs do not lead to permanent EVE treatment discontinuations. Hyperglycemia and especially hypercholesterolemia were observed in low numbers of patients, but may be associated with improved response to EVE treatment and should be further explored as putative biomarkers for mTOR inhibition.

An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy

Background and objectivesThe RECORD-1 trial established the clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) after failure of initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to address an unmet medical need by providing everolimus prior to commercial availability, and also to further assess the safety and efficacy of everolimus in patients with VEGFr-TKI-refractory mRCC. Patients and methodsREACT (Clinicaltrials.gov: NCT00655252) was a global, open-label, expanded-access programme in patients with mRCC who were intolerant of, or who had progressed on or after stopping treatment with, any available VEGFr-TKI therapy. Patients received everolimus 10mg once daily, with dose and schedule modifications allowed for toxicity. Patients were closely monitored for the development of serious and grades 3/4 adverse events (AEs). Response was assessed by RECIST every 3months for the first year and every 6months thereafter. ResultsA total of 1367 patients were enroled. Safety findings and tumour responses were consistent with those observed in RECORD-1, with no new safety issues identified. The most commonly reported serious AEs were dyspnoea (5.0%), pneumonia (4.7%) and anaemia (4.1%), and the most commonly reported grades 3/4 AEs were anaemia (13.4%), fatigue (6.7%) and dyspnoea (6.5%). Best overall response was stable disease in 51.6% and partial response in 1.7% of patients. Median everolimus treatment duration was 14weeks. ConclusionEverolimus is well tolerated in patients with mRCC and demonstrates a favourable risk–benefit ratio.

Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor–tyrosine kinase inhibitor (VEGFr-TKI) therapy.

4601 Background: The phase III RECORD-1 trial established everolimus as the only agent proven to benefit patients with metastatic renal cell carcinoma (mRCC) after failure of initial VEGFr-TKI therapy. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, more than doubled median progression-free survival compared with placebo, from 1.9 months to 4.9 months. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated in order to address an unmet medical need and provide everolimus in advance of regulatory approval and commercial availability to patients with mRCC after failure of initial VEGFr-TKI therapy. Methods: REACT was an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252). Eligible patients had measurable or nonmeasurable mRCC of any histology, were intolerant of, or progressed while on, VEGFr-TKI therapy, had a Karnofsky performance score ≥70%, and had adequate bone marrow, hepatic, and renal function. Patients received everolimus 10 mg/day orally, with dose and schedule modifications allowed for toxicity. The primary objective of REACT was to evaluate the long-term safety of everolimus in patients with mRCC, as determined by the overall incidence of grade 3/4 and serious adverse events (AEs). Tumor response to everolimus was also assessed according to RECIST. Results: A total of 1367 patients from 34 countries were enrolled. Safety findings and tumor responses were consistent with those observed in RECORD-1. The most commonly reported grade 3/4 AEs were anemia (13.4%), fatigue (6.7%), and dyspnea (6.4%), and the most frequent serious AEs were dyspnea (5.0%), pneumonia (4.7%), and anemia (4.1%). Median dose intensity was 10.0 mg/day; relative dose intensity ranged from 0.90 to 1.10 in 68.9% of patients. Conclusions: REACT evaluated the safety and tolerability of everolimus in a broader patient population than the controlled trial RECORD-1. Everolimus was well tolerated, with no new safety issues identified and infrequent dose reductions/interruptions in the majority of patients.