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.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15064-e15064
Author(s):  
Sun Young Rha ◽  
Se-Hoon Lee ◽  
Yen-Chuan Ou ◽  
Jin-Hee Ahn ◽  
Yen-Hwa Chang ◽  
...  
Keyword(s):  
Total Population ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Asian Population ◽  
Primary Objective ◽  
Open Label ◽  
Total Study Population ◽  
Expanded Access ◽  
Asian Patients ◽  
Grade 3

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.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e15047-e15047
Author(s):  
Se-Hoon Lee ◽  
Suleyman Buyukberber ◽  
Yen-Chuan Ou ◽  
Jeremy David Shapiro ◽  
Ashok Panneerselvam ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
Safety Issues ◽  
Expanded Access ◽  
Expanded Access Program ◽  
Access Program

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 < .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.

Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated in Patients with AP and BP CML and Ph+ ALL.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1101-1101 ◽  
Author(s):  
Carlo Gambacorti- Passerini ◽  
Enrico Maria Pogliani ◽  
Michele Baccarani ◽  
Giovanni Martinelli ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Growth Factor Receptor ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Open Label ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally available, Src/Abl kinase inhibitor with minimal activity against platelet derived growth factor receptor (PDGFR) and c-kit. An open-label study of patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase (BP) CML and Ph+ ALL who failed prior imatinib therapy is ongoing. Patients receive 500 mg/day of bosutinib. Preliminary data for 101 subjects, median age 51.5 yrs (range 18 – 84 yrs) and 56% male are reported. 44 pts were in AP, 35 in BP, 21 had Ph+ ALL, and 1 was unclassified. Prior therapy in addition to imatinib included interferon (35 pts), dasatinib (40 pts), nilotinib (15 pts) and stem cell transplant (11 pts). 49 pts failed imatinib (and received no other tyrosine kinase inhibitor [TKI]) and 52 pts failed both imatinib and other TKIs, with median duration of bosutinib treatment to date 4.4 mos (range 0.3 – 21.3 mos) and 2.0 mos (range 0.3 – 18.8), respectively. Among pts with no TKI exposure other than imatinib, complete hematological response (CHR) was obtained in 12/25 evaluable pts (48%), including 7/11 pts (64%) with AP-CML, 4/11 pts (36%) with BP-CML and 1 pt with Ph+ ALL. Major cytogenetic response (MCyR) was achieved in 16/22 evaluable pts (73%) with no TKI exposure other than imatinib, including 9/13 pts (69%) with AP-CML and 6/8 pts (75%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Major molecular response (MMR) was achieved in 9/25 evaluable pts (36%) with no TKI exposure other than imatinib, including 1/7 pts (14%) with AP-CML, 4/10 pts (40%) with BP-CML and 4/8 pts (50%) with Ph+ ALL. Among pts with other TKI exposure in addition to imatinib, CHR was obtained in 3/15 evaluable pts (20%), all with AP-CML; MCyR was achieved in 6/20 evaluable pts (30%), including 3/12 pts (25%) with AP-CML and 2/7 pts (29%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Of the 20 pts with other TKI exposure in addition to imatinib who were evaluable for MMR, 1 pt with Ph+ ALL (5%) achieved this response. Of 60 pts with baseline samples tested for mutations, 15 different mutations were found in 32 pts (53%), including 8 instances of T315I. CHR occurred in 2/8 evaluable pts (25%) with non-P-loop mutations; the 1 evaluable pt with a P-loop mutation did not achieve CHR. MCyR occurred in 4/11 evaluable pts (36%) with non-P-loop mutations and in 1/2 evaluable pts (50%) with P-loop mutations. Treatment was generally well tolerated. The most common adverse events among treated pts (n=101) were gastrointestinal (diarrhea [66%], nausea [46%] and vomiting [42%]) but these were usually grade 1 – 2, manageable and transient, reducing in frequency and severity after the first 3 – 4 weeks of therapy. Grade 3 – 4 non-hematologic toxicities occurring in ≥ 5% of pts were diarrhea (7%), vomiting (6%), pneumonia (6%) and increased ALT (5%). Fluid retention was reported as grade 1 – 2 in 18 pts and grade 3 – 4 in only 3 pts (including 2 pleural effusions, neither related to bosutinib). Grade 3 – 4 hematologic laboratory abnormalities reported include thrombocytopenia (68%), neutropenia (48%) and anemia (37%). 38 pts had at least 1 temporary treatment interruption and 22 pts had at least 1 dose reduction due to toxicity. 11 pts have permanently discontinued treatment due to adverse event. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations.

A phase I study determining the safety and tolerability of combination therapy with pazopanib, a VEGFR/PDGFR/raf inhibitor, and GSK1120212, a MEK inhibitor, in advanced solid tumors enriched with patients with advanced differentiated thyroid cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3117-TPS3117 ◽  
Author(s):  
Shabina Roohi Ahmed ◽  
Nilofer Saba Azad ◽  
Douglas Wilmot Ball ◽  
Michelle A. Rudek ◽  
Barry Nelkin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Phase I ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Critical Role ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
Open Label ◽  
Expansion Cohort

TPS3117 Background: Mutations of the RAS/RAF/MEK/ERK signaling pathway, especially RAS, BRAF and IGF-I/II receptor genes play a critical role in the development of many different types of cancers, including breast, colorectal, melanoma, NSCLC, and thyroid. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy, but there is currently no approved therapy for advanced radioiodine-resistant disease. In DTC xenograft models, vertical inhibition of this pathway, achieved by targeting the vascular endothelial growth factor receptor (VEGFR) and MEK, has shown greater clinical efficacy than with either agent alone. Pazopanib (P) is a small molecule tyrosine kinase inhibitor that selectively inhibits VEGFR1-3, PDGFR-α, PDGFR-b, c-kit, and FGFR 1-3. Phase II data in advanced DTC from Bible, et al, indicate a 49% response rate with a PFS of 11.7 months in a patients with PD within 6 months. GSK1120212 (G) is a potent, highly selective, allosteric inhibitor of MEK1/2. In a phase I/II study, Infante et al. reported an ORR of 81% in BRAF mutant melanoma patients when G was combined with a RAF inhibitor. Methods: A phase I, open label, dose escalation trial with P+G is currently accruing pts with advanced malignancies. The study is a standard 3+3 design with an expansion cohort of 25 pts with advanced DTC for correlative endpoints and PK studies. Pts will be treated with P at 400 mg QD, 600 mg QD and 800 mg QD, with G held constant at 1 mg QD; G will then be escalated to 1.5 mg QD and 2 mg QD. Eligibility includes advanced solid tumor, good end organ function and performance status, and PD within 6 months in the expansion cohort. The primary objective is to determine the safety and tolerability of the combination and determine the MTD. Secondary objectives include assessing preliminary efficacy as defined by RECIST criteria and PFS, and exploration of PK/PD endpoints. Serial tumor biopsies will be evaluated for changes in signaling through p-ERK. RAS and RAF mutation sites will be sequenced in order to correlate with PD endpoints and disease response. Currently, DL1 has accrued with no DLTs.

Safety results of the Canadian Expanded Access Program (EAP) of palbociclib (PAL) plus letrozole (L) in postmenopausal patients (pts) with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) deemed appropriate candidates for first-line (1L) endocrine therapy (ET) with L.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e12534-e12534
Author(s):  
Anil A. Joy ◽  
Shailendra Verma ◽  
Louise Provencher ◽  
Kathy Puyana Theall ◽  
Dongrui (Ray) Lu ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Study Drug ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
Hormone Receptor Positive ◽  
Patient Reported ◽  
Scale Scores ◽  
Grade 3 ◽  
Metastatic Sites

e12534 Background: In the PALOMA-2 study, 1L PAL+L prolonged progression-free survival in women with estrogen receptor-positive/HER2- ABC vs placebo + L (hazard ratio 0.58; P< 0.001). Here we assess a cohort of Canadian pts treated with 1L PAL+L for ABC in an EAP study (NCT02142868). Methods: This was an open-label, single-arm study of US and Canadian postmenopausal women (N = 337) with HR+/HER2- ABC for whom 1L ET with L was deemed appropriate. The primary objective was to allow pt access to PAL in combination with L. PAL (125 mg/d orally [3 wk on, 1 wk off]) was administered with L (2.5 mg orally QD) until PAL was commercially available. Secondary objectives included safety and patient-reported outcomes (PROs). Results: 96/97 (99%) treated/enrolled Canadian pts were assessed for safety and PROs (treated pt characteristics: median age 62.5 y, white/Asian [89%/7%], metastatic sites bone/lung/liver [71%/25%/17%], ECOG PS 0-1/2 [93%/7%], 89% with prior systemic anticancer treatment [tx]). Median exposure was 4 x 28 d cycles of tx, and the median average PAL dose was 125 mg/d. All-causality treatment-emergent adverse events (AEs) were reported in 100% pts; 68% had grade 3/4 events, the most common events were neutropenia (61%), infections (3%), and alanine aminotransferase increase (3%). Grade 4 neutropenia and grade 3 febrile neutropenia were reported in 2% and 1% of pts, respectively. Due to AEs, PAL was temporarily discontinued in 59% and 31% had ≥1 dose reduction. The main reasons pts permanently discontinued from the study were sponsor study termination, 77%; objective progression, 11%; and AE related/unrelated to study drug, 6%/2%. All EQ-5D questions were completed by 96% pts at baseline and 85% by end of tx (EOT). At EOT, the median EQ-5D index and the EQ visual analog scale scores were not significantly changed from baseline. Conclusions: A safe and tolerable profile was observed for PAL+L in 1L treatment of Canadian pts with HR+/HER2− ABC, consistent with other studies. Sponsor Pfizer Clinical trial information: NCT02142868.

SAVOIR: A phase III study of savolitinib versus sunitinib in pts with MET-driven papillary renal cell carcinoma (PRCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Toni K. Choueiri ◽  
Daniel Yick Chin Heng ◽  
Jae-Lyun Lee ◽  
Mathilde Cancel ◽  
Remy B Verheijen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Chromosome 7 ◽  
Phase Iii ◽  
Open Label ◽  
Grade 3 ◽  
Dose Modifications

5002 Background: PRCC is the most common type of non-clear cell RCC, accounting for 10–15% of renal malignancies. As a subset of PRCC cases are MET-driven, MET inhibition may be an appropriate targeted treatment approach. In a single-arm Phase II study, savolitinib (AZD6094, HMPL‐504, volitinib), a highly selective MET-tyrosine kinase inhibitor, demonstrated antitumor activity in pts with MET-driven PRCC (Choueiri et al. JCO 2017). The Phase III SAVOIR study (NCT03091192) further assessed savolitinib vs standard of care sunitinib in pts with MET-driven PRCC. Methods: In this open-label (sponsor blinded), randomized study, pts with centrally confirmed MET-driven ( MET and/or HGF amplification, chromosome 7 gain and/or MET kinase domain mutations), metastatic PRCC were randomized to savolitinib 600 mg once daily (QD), or sunitinib 50 mg QD 4 weeks on / 2 weeks off. Primary objective was progression-free survival (PFS; RECIST 1.1 by blinded independent central review). Secondary objectives included overall survival (OS), objective response rate (ORR), and safety and tolerability. Results: After external data on predicted PFS with sunitinib in pts with MET-driven disease became available, study enrollment was closed. At data cutoff (Aug 2019), only 60 of the planned 180 pts were randomized (savolitinib n = 33; sunitinib n = 27). Most had chromosome 7 gain (savolitinib 91%; sunitinib 96%) and no prior therapy (savolitinib 85%; sunitinib 93%). PFS, OS, and ORR were numerically improved with savolitinib vs sunitinib (Table). CTCAE grade ≥3 adverse events (AEs) were reported in 42% and 81% of pts; dose modifications were related to AEs in 30% and 74% of pts with savolitinib and sunitinib respectively. After discontinuation, 36% of all savolitinib and 19% of all sunitinib pts received subsequent anticancer therapy. Conclusions: Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted. Clinical trial information: NCT03091192 . [Table: see text]

scholarly journals Camrelizumab Plus Apatinib in Patients With Advanced Cervical Cancer (CLAP): A Multicenter, Open-Label, Single-Arm, Phase II Trial

2020 ◽  
Vol 38 (34) ◽  
pp. 4095-4106
Author(s):  
Chunyan Lan ◽  
Jingxian Shen ◽  
Yin Wang ◽  
Jundong Li ◽  
Zhimin Liu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Advanced Cervical Cancer ◽  
Open Label ◽  
Duration Of Response ◽  
Grade 3

PURPOSE Camrelizumab is an antibody against programmed death protein 1. We assessed the activity and safety of camrelizumab plus apatinib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2, in patients with advanced cervical cancer. METHODS This multicenter, open-label, single-arm, phase II study enrolled patients with advanced cervical cancer who progressed after at least one line of systemic therapy. Patients received camrelizumab 200 mg every 2 weeks and apatinib 250 mg once per day. The primary end point was objective response rate (ORR) assessed by investigators per RECIST version 1.1. Key secondary end points were progression-free survival (PFS), overall survival (OS), duration of response, and safety. RESULTS Forty-five patients were enrolled and received treatment. Median age was 51.0 years (range, 33-67 years), and 57.8% of patients had previously received two or more lines of chemotherapy for recurrent or metastatic disease. Ten patients (22.2%) had received bevacizumab. Median follow-up was 11.3 months (range, 1.0-15.5 months). ORR was 55.6% (95% CI, 40.0% to 70.4%), with two complete and 23 partial responses. Median PFS was 8.8 months (95% CI, 5.6 months to not estimable). Median duration of response and median OS were not reached. Treatment-related grade 3 or 4 adverse events (AEs) occurred in 71.1% of patients, and the most common AEs were hypertension (24.4%), anemia (20.0%), and fatigue (15.6%). The most common potential immune-related AEs included grade 1-2 hypothyroidism (22.2%) and reactive cutaneous capillary endothelial proliferation (8.9%). CONCLUSION Camrelizumab plus apatinib had promising antitumor activity and manageable toxicities in patients with advanced cervical cancer. Larger randomized controlled trials are warranted to validate our findings.

scholarly journals Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study

2010 ◽  
Vol 28 (21) ◽  
pp. 3491-3497 ◽  
Author(s):  
Sam J. Lubner ◽  
Michelle R. Mahoney ◽  
Jill L. Kolesar ◽  
Noelle K. LoConte ◽  
George P. Kim ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Primary Objective ◽  
Clinical Activity ◽  
Biliary Cancer ◽  
Vegf Inhibitor ◽  
Grade 3

Purpose Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras. Patients and Methods Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction. Results Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes. Conclusion Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.

Sunitinib in metastatic renal cell carcinoma (mRCC): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5010-5010 ◽  
Author(s):  
M. E. Gore ◽  
C. Porta ◽  
S. Oudard ◽  
G. Bjarnason ◽  
D. Castellano ◽  
...  
Keyword(s):  
Metastatic Disease ◽  
Kinase Inhibitor ◽  
Open Label ◽  
Eligibility Criteria ◽  
Expanded Access ◽  
Open Label Trial ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
Ecog Ps

5010 Background: Sunitinib is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs and PDGFRs, approved multinationally for advanced RCC. The primary aim of this international, open-label trial was to provide sunitinib to mRCC pts who failed =1 prior systemic therapy and were ineligible for other sunitinib trials or had no access to sunitinib before regulatory approval in their country. Methods: Eligibility criteria were minimized to broaden the enrolment population. Pts who were 18 yrs of age or older with histologically-confirmed mRCC received oral sunitinib 50 mg/day in 6-wk cycles (4 wks on Tx, 2 wks off). Physical exam, safety and concomitant meds were assessed every 4 wks. Results: As of Sept 1, 2006, 4,000 pts were enrolled from 181 sites in 36 countries; 2,158 pts (median age, 59 [19- 85]; male/female, 74%/26%) were included in this analysis. Baseline demographics included 106 pts (5%) with non-clear cell histology; 173 pts (8%) with brain mets; 158 pts (7%) with prior antiangiogenic Tx; and 288 pts (13%) with ECOG PS =2. Median Tx duration was 128 days (range 1- 2444) with interruptions in 17% of pts and dose reductions in 30%; 672 pts (31%) discontinued, of which 80 pts (12%) discontinued due to AEs. The median Tx duration was similar to the overall population regardless of age or site of metastatic disease at baseline (brain, bone, lung, liver, lymph nodes or other), but was longer in pts with ECOG PS 0/1 (154 days, range 1–2,444) than with ECOG PS =2 (83 days, range 1–449). The most common treatment-related AEs were diarrhea (39% any grade, 3% grade 3/4), fatigue (35%, 7%) and nausea (33%, 2%), the incidences of which were similar in pts regardless of age or site of baseline metastatic disease; overall, they occurred more frequently in pts with ECOG PS 0/1 vs. ECOG PS =2 (42% vs. 21%, 38% vs. 23%; and 34% vs. 25%, respectively), but differences in grade 3/4 severity were not observed. Median overall survival has not been reached; 19% of pts have died, the lowest incidence among pts with ECOG PS 0/1 (15%) and highest in pts with ECOG PS =2 (43%) and brain mets (34%). Conclusions: Preliminary observations suggest that sunitinib is associated with acceptable tolerability in an expanded access trial regardless of age or site of baseline metastatic disease. [Table: see text]

Open-label, phase IIIb, multicenter, expanded access study of everolimus in patients with advanced neuroendocrine tumors (NET).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4138-4138
Author(s):  
Oliver Edgar Bechter ◽  
Nicole Unger ◽  
Ivan Borbath ◽  
Sergio Ricci ◽  
Tsann-Long Hwang ◽  
...  
Keyword(s):  
Performance Status ◽  
Safety Data ◽  
Primary Objective ◽  
Phase Iii ◽  
Open Label ◽  
Serious Adverse Events ◽  
Double Blind ◽  
Expanded Access ◽  
Open Label Phase ◽  
Grade 3

4138 Background: Everolimus (EVE) antitumor efficacy in patients (pts) with advanced NET was demonstrated in 2 double-blind, placebo (P)–controlled, phase III trials (RADIANT-2 and RADIANT-3). Median PFS in pancreatic (pNET) pts was 11.0 months (EVE) vs. 4.6 months (P) (HR 0.35, 95% CI 0.27-0.45, P <0.001) in RADIANT-3. Median EVE exposure in RADIANT-3 was 38 wks. EVE was approved for advanced pNET in the US and Europe in 2011. An expanded access protocol was launched to gather additional safety data and provide access to EVE for pts with advanced NET while awaiting regulatory approval. Methods: Pts aged ≥18 years with biopsy-proven NET; WHO performance status 0-2; and adequate bone, hepatic, and renal function were enrolled. Main exclusion criteria were poorly differentiated NET and cytotoxic therapy within 4 wks of enrollment. EVE (10 mg/d) was administered until disease progression, unacceptable toxicity, discontinuation, death, commercial availability of EVE, or until May 30, 2012. Pts were enrolled from April 21, 2011 to April 20, 2012. Primary objective was grade 3/4 and serious adverse events (AEs). Secondary objectives included investigator-assessed best overall response rate and PFS. Results: The full analysis set included 246 pts (pNET, n=126; non-pNET, n=120); the safety set included 240 pts (pNET, n=123; non-pNET, n=117). Median age was 61 and 66 years; 54% and 49% were male. Main primary tumor sites in non-pNET pts included small intestine (40%) and lung (22%). Median duration of EVE exposure was 12.1 wks and 24 wks in pNET and non-pNET. At data cutoff, there were 21 and 32 PFS events; 105 and 88 pts were censored. Grade 3/4 AEs were reported in 42.3% and 69.2% of pNET and non-pNET; those reported in ≥10% of pts in pNET and non-pNET included hyperglycemia (12.2% and 5.1%), diarrhea (10.6% and 31.6%), stomatitis (9.8% and 11.1%), nausea (8.1% and 10.3%), and anemia (5.7% and 11.1%). Median investigator-assessed PFS was 7.6 (95% CI 5.52-7.62) months and 10.8 (8.77-Not Estimable) months in pNET and non-pNET. Conclusions: EVE was well tolerated in pts with advanced NET. AEs were similar to those previously reported. Protocol-specified early termination of pts limits the interpretation of PFS medians. Clinical trial information: EudraCT Number: 2010-023032-17.

A phase II trial of the effect of perindopril on hand foot syndrome (HFSR) incidence and severity in patients receiving regorafenib with refractory metastatic colorectal carcinoma (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 824-824
Author(s):  
Barbara L. Melosky ◽  
Howard John Lim ◽  
Janine Davies ◽  
Sharlene Gill ◽  
Christian K. Kollmannsberger ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Capillary Endothelium ◽  
Open Label ◽  
Grade 3 ◽  
Overall Survival Benefit ◽  
Ecog Ps

824 Background: Regorafenib is an oral multi-kinase inhibitor (MKI), with a demonstrated overall survival benefit in mCRC refractory to standard therapy ( PMID 23177514). The most common grade 3 adverse event (AE) reported in this trial was HFSR, with 47% of patients (pts) experiencing HFSR of all grades, and 17% with grade 3 severity. The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. Perindopril is an Angiotensin Converting Enzyme (ACE) Inhibitor indicated for the treatment of hypertension, and may also play a role in preventing endothelial dysfunction ( PMID 17140552). We hypothesized that perindopril may prevent or reduce the severity of regorafenib-induced HFSR. Methods: In this single center Phase II, open label trial, 34 pts with refractory mCRC were planned to be treated with regorafenib (160 mg/day) and perindopril (4 mg/day) with both agents given 3 weeks on and 1 week off. An interim analysis was planned after 10 evaluable pts. The primary objective was to assess the proportion of pts with any grade HSFR toxicity. Secondary endpoint included time to development of worst (grade 3) HSFR toxicity, proportion of all grades of hypertension and all grade toxicities, and progression free survival. All toxicities were evaluated using CTCAE v4.03. Results: 12 pts were accrued over a 9 month time period, and 10 pts were considered evaluable as they completed one cycle of treatment. Pt characteristics included (6 M/ 6F, mean age 62, ECOG PS 0 (25%)/ 1 (75%). A planned interim analysis was performed after 10 evaluable pts had completed their first cycle of study treatment. 5/10 (50%) experienced Grade 3 HFSR, and based on the statistical plan it was deemed highly unlikely that perindopril would lead to reduced levels of regorafenib induced HSFR compared with regorafenib alone thus enrolment was stopped. The most frequent other grade 3 toxicities included hypertension (16.7%), and increased AST (16.7%). Conclusions: The addition of perindopril to regorafenib did not appear to reduce HSFR incidence and severity in pts with refractory mCRC. Clinical trial information: NCT02651415.

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