Palmar-plantar Erythrodysesthesia Syndrome Research Articles

A Phase 1b Study of Cetuximab and BYL719 (Alpelisib) Concurrent with Intensity Modulated Radiation Therapy in Stage III-IVB Head and Neck Squamous Cell Carcinoma

Activation of the PI3K/mTOR signaling pathway is common in head and neck squamous cell carcinoma (HNSCC). BYL719 is an α-specific PI3K inhibitor that is synergistic and efficacious when combined with cetuximab, a Food and Drug Administration-approved radiosensitizing agent in the treatment of HNSCC. The agent independently has been shown to enhance radiosensitivity. This study evaluates the addition of BYL719 to cetuximab and radiation in the treatment of locally advanced HNSCC. This is a single-institution, phase 1 study. Patients with American Joint Committee on Cancer seventh edition stage III to IVB HNSCC received standard cetuximab (400 mg/m2 intravenous loading dose) before intensity modulated radiation therapy (IMRT) followed by 250 mg/m2 weekly infusions during IMRT. BYL719 was given orally during IMRT in 3 dose levels: (1) 200 mg/d, (2) 250 mg/d, or (3) 300 mg/d in a standard 3 + 3 dose-escalation design. Eleven patients were evaluable. Dose level 2 was the maximum tolerated dose for BYL719. Two patients on dose level 3 had dose-limiting toxicities of oral mucositis that required a dose reduction of BYL719. One patient on dose level 2 had a dose-limiting toxicity of nausea that led to withdrawal of on-study treatment. Related grade 3 or higher adverse events consisted of decreased lymphocyte count, oral mucositis, dysphagia, hyperglycemia, maculopapular rash, and palmar-plantar erythrodysesthesia syndrome. All 11 patients had a complete response on posttreatment imaging, and 10 remain disease free. Of the 8 patients with mutational analysis, 1 had an activating PIK3CA mutation associated with a rapid response on serial intratreatment magnetic resonance imaging scans. The recommended phase 2 dose of BYL719 is 250 mg/d in combination with cetuximab and IMRT in patients with locally advanced HNSCC. Further evaluation of the addition of BYL719 to the platinum-sparing regimen of cetuximab and IMRT in the treatment of locally advanced HNSCC is warranted.

Efficacy and safety of lenvatinib in 124 Japanese patients with anaplastic thyroid cancer

Abstract Background Anaplastic thyroid cancer (ATC) is a malignant tumor with very poor prognosis. In the Phase 2 study in Japan, the antitumor effect of lenvatinib against ATC has been demonstrated. However, there are few reports on the efficacy and safety of lenvatinib in ATCs in many practical clinical cases. Method: We analyzed 124 ATC patients enrolled in all cases survey that began in May 2015 when lenvatinib was approved for unresectable thyroid cancer in Japan. The observation period per case was 12 months, and the tumor response was evaluated by image findings at 3 months, 6 months, and 12 months after administration of lenvatinib. For safety, frequency and severity of side effects of lenvatinib were evaluated with CTCAE v 4.0. Results: Of the 124 patients, 61.3% were female. The median age was 73 (41-90) years, performance status 0/1/2/3/4 was seen in 38/50/18/13/5 patients, respectively, stage (IVa/IVb/IVc/unknown) was 0/21.8/68.5/8.1%, respectively, the maximum tumor length (less than 10/10-50/50-100/100mm-) was 4.8/32.3/47.6/3.2%. Tumor infiltration in either the carotid artery, jugular vein, trachea or skin were present in 72.6% patients. The initial dose of lenvatinib was 24 mg/day in 70.2% of patients, and the median dose was 15.8 mg/day. The best overall response for CR/PR/SD/PD was 3/44/33/25 cases in a total of 105 evaluable patients. The response rate was 44.8%, and the disease control rate was 76.2%. The survival rate at 1 year after lenvatinib treatment was 18.5%, and factors influencing prognosis were PS 3 or more, liver metastasis, carotid infiltration of tumor. The main side effects (All grade/Grade 3 or more) after administration of lenvatinib were hypertension (69.4/46.8%), proteinuria (29.8/7.3%), palmar-plantar erythrodysesthesia syndrome (25.8/3.2%), and decreased platelet count (22.6/12.9%). Conclusion: The results suggest that lenvatinib demonstrated activity and was well tolerated in ATC patients in clinical practice.

TIVO-3: A Phase 3, Randomised, Open-Label Study Comparing Tivozanib to Sorafenib in Patients with Advanced Renal Cell Carcinoma

Background: Treatment for renal cell carcinoma (RCC) has been revolutionised by vascular endothelial growth factor receptor (VEGFR) inhibitors. TIVO-3 was designed to compare the efficacy and safety of tivozanib (a potent and selective VEGFR inhibitor) versus sorafenib as third- or fourth-line therapy for metastatic RCC. Methods: Patients with metastatic RCC with at least two prior systemic treatments, including at least one prior VEGFR inhibitor, were stratified by IMDC risk category and type of prior therapy, then randomised 1:1 to either tivozanib 1·5 mg orally once daily in 4-week cycles (21 days on treatment followed by 7 days off treatment) or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival; key secondary endpoints were objective response rate, overall survival, and safety. Findings: 350 patients were randomly assigned to tivozanib or sorafenib. Median progression-free survival was significantly longer for tivozanib (5·6 months) than sorafenib (3·9 months; hazard ratio [HR] 0·73 [95% CI 0·56-0·94], p=0·0165). Objective response rate was higher for tivozanib than sorafenib (18% vs 8%; p=0·0168). At the time of this analysis, preliminary overall survival was not significantly different (HR 1·12 [95% CI 0·84-1·51], p=0·437). The most common treatment-related adverse events were hypertension (36%), diarrhoea (33%), and fatigue (29%) for tivozanib and diarrhoea (50%), palmar-plantar erythrodysesthesia syndrome (38%), and hypertension (25%) for sorafenib. Adverse events led to fewer dose interruptions (48% vs 63%, p=0·007) and reductions (24% vs 38%, p=0·005) for tivozanib versus sorafenib. No treatment-related deaths were reported. Interpretation: Tivozanib demonstrated improved progression-free survival versus sorafenib as third- or fourth-line therapy for metastatic RCC. Tivozanib was better tolerated than sorafenib, with fewer dose reductions and interruptions, and is the first to demonstrate clinical benefit in a third-line or later setting in RCC. Trial Registration: This trial is registered with ClinicalTrials.gov, NCT02627963. Funding Statement: This study was sponsored by AVEO Oncology. Declaration of Interests: BIR has received research funding from Peloton, and research funding and and honoraria from AVEO, Pfizer, Bristol-Myers Squibb, and Merck. SKP has received honoraria from and served as a consultant to Pfizer, Novartis, AVEO, Genentech, Exelixis, Bristol-Myers Squibb, Astellas, Eisai, Roche, and Ipsen. BJE has received research funding from AVEO, Bristol-Myers Squibb and Novartis, and honoraria from Bristol-Myers Squibb, Roche, Pfizer, Oncorena, AVEO, and Ipsen. MBA has served as an advisor to and received honoraria from AVEO, Merck, Bristol-Myers Squibb, Eisai, Pfizer, Exelixis, Roche, Novartis, and Arrowhead. TEH has served as an advisor to Pfizer, Exelexis, Bristol-Myers Squibb, AVEO, and Janssen. CP has served as a consultant to and on the speakers’ bureaus of EUSA, Bristol-Myers Squibb, MSD, Pfizer, Ipsen, Eisai, AstraZeneca, Janssen, Novartis, and General Electrics, and honoraria from Roche. EV has served as an advisor to and on the speakers’ bureaus of Eusa Pharma, Pfizer, Novartis, Bristol-Myers Squibb, Merck, and Ipsen. MNN is an employee of AVEO. DFM has served as an consultant to Array BioPharm, Genentech, Alkermes, Inc., Jounce Therapeutics, Peloton, EMD Serono and Eli Lilly, received research funding from X4 Pharma, Prometheus, Genentech and Alkermes, and has served as a consultant to and received research funding from Bristol-Myers Squibb, Pfizer, Merck, Novartis, and Exelius. Ethics Approval Statement: This trial was approved by the institutional review board or ethics committee at every centre and complied with Good Clinical Practice guidelines, the Declaration of Helsinki, and local laws. All patients provided written informed consent before any trial procedure.

Efficacy of apatinib on multiple advanced-stage nongastric cancers.

Apatinib has been approved for the treatment of advanced gastric adenocarcinoma and gastric-esophageal junctional adenocarcinoma, but its efficacy is unknown for other advanced solid tumors. We retrospectively reviewed the use of apatinib for multiple advanced-stage non-gastric cancers. Ninety-two patients from 7 hospitals who received additional treatment except apatinib more than once were enrolled. The primary end-point was the overall response rate (ORR), and the secondary end-points included progression-free survival (PFS), disease control rate (DCR), overall survival, and adverse reactions. We categorized all the patients into six groups according to their cancer type. In the lung cancer group, the ORR was 9% (95% confidence interval [CI], 3%-23%), DCR was 88% (95% CI, 74%-96%), and median PFS was 3 months (95% CI, 1.9-5.4 months). In the cervical cancer group, the ORR was 25% (95% CI, 3%-65%), DCR reached 100%, and median PFS was 3.5 months (95% CI, 0.6-9.0 months). There were different ORRs between the other cancer groups. In addition, the most common adverse effect of apatinib was palmar-plantar erythrodysesthesia syndrome (37%), followed by proteinuria (14%) and hypertension (13%). These results suggest that apatinib might be effective for not only gastric cancer but also other carcinomas including lung cancer, colorectal cancer, cervical cancer, liver cancer, breast cancer, and nasopharyngeal cancer. Thus, apatinib is a promising targeted drug for multiple types of cancer.

Treatment with Combination of Dabrafenib and Trametinib in Patients with Recurrent/Refractory BRAF V600E-Mutated Hairy Cell Leukemia (HCL)

BACKGROUNDHairy cell leukemia is a rare, indolent, B-cell lymphoproliferative disease characterized by the BRAF V600E mutation in 90% to 100% of patients. Few treatment options are available for patients who progress on first-line therapy with a purine analogue and/or rituximab. The efficacy of combined BRAF and MEK inhibition is well established in BRAF V600-mutated melanoma, non-small cell lung cancer, and anaplastic thyroid cancer. Here we report interim results of treatment with the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) in patients with recurrent/refractory BRAF V600E-mutated HCL. METHODSIn this phase 2, open-label trial (ROAR; NCT02034110), patients with BRAF V600E mutations in 9 rare tumor types, including HCL, received continuous dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) until unacceptable toxicity, disease progression, or death. For the HCL cohort, eligible patients had histologically confirmed HCL (according to WHO classification) that was refractory to first-line treatment with a purine analogue or relapsed after ≥ 2 prior lines of treatment. The presence of a BRAF V600E mutation was assessed locally and confirmed by a central laboratory. The primary endpoint was investigator-assessed overall response rate (ORR) based on criteria adapted from NCCN guidelines. Secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Minimal residual disease (MRD) status was assessed by flow cytometry in both peripheral blood and bone marrow aspirates. For complete response (CR) without MRD, both peripheral blood and bone marrow aspirate samples had to be negative. RESULTSAt the data cutoff (January 3, 2018), 43 patients with HCL had enrolled. Median age was 67 years (range, 40-81) and 38 (88%) were male. Twenty-one patients (49%) had received ≥ 4 prior treatments. At the time of data cutoff, 35 patients (81%) remained on study treatment, 5 (12%) in follow-up; 2 (5%) had withdrawn from study (loss to follow-up and consent withdrawal [n = 1 each]), and 1 (2%) had died. Eight patients had discontinued therapy due to adverse events (AEs; 5 [12%]), study withdrawal (2 [5%]), or disease progression (1 [2%]). Median time on study treatment was 17 months (range, 1-39). Among 41 patients evaluable for response, the investigator-assessed confirmed ORR was 78% (32/41; 95% CI, 62%-89%) with 20 (49%) having CR, (6 [15%] CR without MRD and 14 [34%] CR with MRD), and 12 (29%) partial response. All responses were ongoing at the data cutoff; 16 (50%) responses were lasting ≥ 18 months. PFS and OS rates at 12 months were both 97.6% (95% CI, 83.9%-99.7%). The most common AEs in patients with HCL were pyrexia (67%), chills (51%), hyperglycemia (44%), nausea (44%), peripheral edema (42%), cough (40%), and fatigue (40%). Grade 3/4 AEs were reported in 49% of patients, with the most common (> 5%) being hyperglycemia (9%), anemia (7%), and neutropenia (7%). AEs led to dose reduction and treatment interruption in 42% and 56% of patients, respectively. AEs led to permanent discontinuation in 5 patients (12%; headache and malaise [n = 1]; pyrexia, chills and palmar-plantar erythrodysesthesia syndrome [n = 1]; fat necrosis [n = 1]; hyperglycemia and pancreatic adenocarcinoma [n = 1]; Hodgkin lymphoma [n = 1]). CONCLUSIONSDabrafenib + trametinib was well tolerated and demonstrated a high rate of durable responses in patients with heavily pretreated recurrent/refractory BRAF V600E-mutated HCL. DisclosuresKreitman:NIH: Patents & Royalties: Co-inventor on the NIH patent for Moxetumomab Pasudotox. Moreau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blay:Roche: Honoraria, Other: Non-financial support, Research Funding; Novartis: Honoraria, Other: Non-financial support, Research Funding. Wainberg:Merck: Consultancy; EMD Serono: Consultancy; Lilly: Consultancy; Five Prime: Consultancy; Novartis: Consultancy. Stein:Novartis: Other: Patient documentation fees; GSK: Other: Patient documentation fees. Willenbacher:Merck: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Amgen: Honoraria, Other: Steering board, Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Abbvie: Research Funding; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau. Burgess:Novartis: Employment. Mookerjee:Novartis: Employment. Subbiah:Roche/Genentech: Research Funding; LOXO: Research Funding; Blueprint Medicine: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Bayer: Research Funding.

Real-world use of sunitinib in Japanese patients with pancreatic neuroendocrine tumors: results from a post-marketing surveillance study

BackgroundSunitinib is approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients.MethodsSunitinib 37.5 mg once daily was orally administered in Japanese patients aged ≥ 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR).ResultsSunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7–26.3) and clinical benefit rate was 70.6%.ConclusionsThere were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population.

A phase 1b study of transforming growth factor-beta receptor I inhibitor galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma

SummaryBackground Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Population exposure\u2013response analysis of cabozantinib efficacy and safety endpoints in patients with renal cell carcinoma

BackgroundIn the phase III METEOR trial, tyrosine kinase inhibitor cabozantinib significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival compared to everolimus in patients with advanced renal cell carcinoma (RCC) who had received prior VEGFR inhibitor therapy. In METEOR, RCC patients started at a daily 60-mg cabozantinib tablet (Cabometyx™) dose but could reduce to 40- or 20-mg to achieve a tolerated exposure.Objectives and methodsExposure–response (ER) models were developed to characterize the relationship between cabozantinib at clinically relevant exposures in RCC patients enrolled in METEOR and efficacy (PFS and tumor response) and safety endpoints.ResultsCompared to the average steady-state cabozantinib concentration for a 60-mg dose, exposures at simulated 40- and 20-mg starting doses were predicted to result in higher risk of disease progression or death [hazard ratios (HRs) of 1.10 and 1.39, respectively], lower maximal median reduction in tumor size (− 11.9 vs − 9.1 and − 4.5%, respectively), and lower ORR (19.1 vs 15.6 and 8.7%, respectively). The 60-mg exposure was also associated with higher risk for selected adverse events (AEs) palmar-plantar erythrodysesthesia syndrome (grade ≥ 1), fatigue/asthenia (grade ≥ 3), diarrhea (grade ≥ 3), and hypertension (predicted HRs of 2.21, 2.01, 1.78, and 1.85, respectively) relative to the predicted average steady-state cabozantinib concentration for a 20-mg starting dose.ConclusionER modeling predicted that cabozantinib exposures in RCC patients at the 60-mg starting dose would provide greater anti-tumor activity relative to exposures at simulated 40- and 20-mg starting doses that were associated with decreased rates of clinically relevant AEs.

Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)–An ACCRU Network study.

611 Background: Regorafenib is an oral multikinase inhibitor with survival benefit in refractory mCRC patients (pts). Toxicities such as Palmar-plantar erythrodysesthesia syndrome (PPES), fatigue and hypertension (HTN) have limited its use. Despite absence of supportive data, various dosing or interval scheduling have been implemented into clinical practice. Methods: A randomized phase II study of regorafenib dose-escalation (Arm A: 80 mg/day, weekly dose escalation if no significant drug-related toxicities, up to 160 mg/day) vs. standard dose (Arm B: 160 mg/day) in pts with mCRC for 21 days of a 28-day cycle. Pts were randomized 1:1:1:1 to arms A1 and B1 (Pre-emptive Clobetasol for PPES); A2 and B2 (Reactive Clobetasol). The primary endpoint was the proportion of patients who completed 2 cycles of treatment and initiated the 3rd in Arm A (Pooled A1 + A2) vs. Arm B (Pooled B1 + B2). Superiority for Arm A was to be declared if the one-sided p-value calculated using Fisher’s exact method was less than 0.2. Results: From June 2015 to June 2017, 123 pts were randomized with 116 (A = 54, B = 62) evaluable for the primary endpoint. Demographic data were well balanced with overall median age of 61yrs (range: 29-81), M/F (61/39%) and ECOG PS 0/1 (37/63%) and KRAS MT/WT/UNK (47/44/9%).The study met its primary endpoint with 43% of pts on Arm A initiating the 3rd vs. only 25% of pts Arm B [one-sided p-value 0.028]. Median Overall Survival (OS) was improved in Arm A vs. Arm B (9.0 mos vs. 5.9 mos; p = 0.094). Median Progression Free Survival (PFS) was 2.5 mos for Arm A vs. 2.0 mos for Arm B (p=0.553). Overall rates of grade 3/4 toxicity were more favorable for Arm A vs. Arm B (% PPES 15 vs. 16, HTN 7 vs. 15 and fatigue 13 vs. 18, respectively). Multiple QOL parameters were improved in A vs. B primarily at week 2 of the first cycle. Conclusion: A strategy with weekly dose escalation of regorafenib from 80 mg to 160 mg/day was found to be superior to a starting dose of 160 mg/day. These results establish a new standard for optimizing regorafenib dosing. Further data on outcomes of preemptive vs. reactive clobetasol strategies are undergoing analysis and will be presented later. Clinical trial information: NCT02368886.

A Phase I/Randomized Phase II Study to Evaluate the Safety, Pharmacokinetics, and Efficacy of Nintedanib versus Sorafenib in Asian Patients with Advanced Hepatocellular Carcinoma

Background: Nintedanib is an oral, triple angiokinase inhibitor of vascular endothelial growth factor/platelet-derived growth factor/fibroblast growth factor receptors. This randomized, multicenter, open-label, phase I/II study evaluated the safety, pharmacokinetics, maximum tolerated dose (MTD) in terms of dose-limiting toxicities (DLTs), and efficacy of nintedanib versus sorafenib in Asian patients with unresectable advanced hepatocellular carcinoma (HCC). Patients and Methods: For the phase I portion, patients were stratified into two groups according to their alanine aminotransferase/aspartate aminotransferase (ALT/AST) and Child-Pugh score at baseline. For phase I, the primary endpoint was determination of the MTD in terms of DLTs. For phase II, patients with a Child-Pugh score of 5–6, an Eastern Cooperative Oncology Group performance score ≤2, and an ALT/AST ≤2× the upper limit of normal were enrolled and randomized 2: 1 to nintedanib 200 mg twice daily (b.i.d.) (the MTD determined in phase I) or sorafenib 400 mg b.i.d. continuously in 28-day cycles until intolerable adverse events (AEs) or disease progression (PD); treatment beyond PD was allowed if clinical benefit was perceived. The primary endpoint for phase II was time to progression (TTP) by central independent review (CIR; by Response Evaluation Criteria in Solid Tumors v1.0); the secondary endpoints included overall survival (OS). All analyses were exploratory. Results: The MTD was 200 mg in both groups. For phase II, 95 patients were randomized to nintedanib (n = 63) or sorafenib (n = 32). For nintedanib and sorafenib, respectively, the median CIR TTP was 2.8 vs. 3.7 months (hazard ratio [HR] = 1.21, 95% confidence interval [CI] 0.73–2.01) and the median OS 10.2 vs. 10.7 months (HR = 0.94, 95% CI 0.59–1.49). Nintedanib-treated patients had fewer grade 3 or higher AEs (56 vs. 84%), serious AEs (46 vs. 56%), and AEs leading to dose reduction (19 vs. 59%) and drug discontinuation (24 vs. 34%). AEs associated more frequently with nintedanib were vomiting and nausea, whereas those associated more frequently with sorafenib were ALT/AST increases, diarrhea, rash, and palmar-plantar erythrodysesthesia syndrome. Conclusions: Nintedanib showed numerically similar efficacy to sorafenib for CIR TTP and OS in Asian patients with advanced HCC and adequate liver function. AEs were generally manageable.

Phase II randomised discontinuation trial of cabozantinib in patients with advanced solid tumours

BackgroundCabozantinib is an inhibitor of tyrosine kinases, including MET, vascular endothelial growth factor receptor, AXL and RET. This multi-cohort phase II randomised discontinuation trial explored anticancer activity of cabozantinib in nine tumour types. Patients and methodsCabozantinib was administered (100 mg, once daily) to patients with advanced, recurrent or metastatic cancers. Those with stable disease at week 12 were randomised 1:1 to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) in the randomised phase. ResultsA total of 526 patients were enrolled. The highest ORR was observed in ovarian cancer (OC) (21.7%); the largest PFS benefit was observed in castration-resistant prostate cancer (CRPC) (median 5.5 versus 1.4 months for placebo; hazard ratio 0.14, 95% confidence interval: 0.04, 0.52). Disease control rates were >40% for CRPC, OC, melanoma, metastatic breast cancer (MBC), hepatocellular carcinoma (HCC) and non–small cell lung cancer. Median duration of response ranged from 3.3 (MBC) to 11.2 months (OC). Encouraging efficacy results and symptomatic improvements prompted early suspension of the randomised stage and conversion to open-label non-randomised expansion cohorts. Dose reductions to manage adverse events (AEs) occurred in 48.7% of patients. The most frequent grade III–IV AEs were fatigue (12.4%), diarrhoea (10.5%), hypertension (10.5%) and palmar-plantar erythrodysesthesia syndrome (8.7%). ConclusionsClinical antitumour activity of cabozantinib was observed in a subset of tumour types: CRPC and OC were evaluated further in expansion cohorts. Phase III programs were initiated in CRPC and HCC. Interpretation of efficacy outcomes was limited by early termination of the randomised portion of the trial. Trial registration numberNCT00940225.

A phase 2 randomised discontinuation trial of cabozantinib in patients with ovarian carcinoma

BackgroundCabozantinib (XL184), an orally bioavailable inhibitor of vascular endothelial growth factor receptor 2 and MET, was assessed in a cohort of ovarian carcinoma patients as part of a phase 2 randomised discontinuation trial (RDT) with cohorts from nine different tumour types. Patients and methodsPatients received 100-mg cabozantinib daily. Those with stable disease (SD) per Response Evaluation Criteria in Solid Tumors at week 12 were randomised to cabozantinib or placebo. Primary end-points were objective response rate (ORR) at week 12 and progression-free survival (PFS) after random assignment. ResultsSeventy patients with ovarian carcinoma, 50% of whom were platinum refractory/resistant, were enrolled in this RDT. Median PFS from day 1 was 5.5 months for all patients. The ORR at week 12 was 21%; one patient achieved a complete response (CR), and 14 patients (20%) achieved a confirmed partial response (PR). The overall disease control rate (CR + PR + SD) at week 12 was 50%. Throughout the study, 70% of the patients with ≥1 postbaseline scan had tumour regression, and randomisation was discontinued early. For patients with SD randomised to cabozantinib, PFS was 5.9 months after randomisation. The most common grade 3/4 adverse events were diarrhoea (14%), palmar-plantar erythrodysesthesia syndrome (6%), asthenia (6%), hypertension (6%) and neutropenia (6%). Dose reductions were required in 37% of the patients during the first 12 weeks. ConclusionCabozantinib demonstrates clinical activity, with acceptable toxicities, in patients with ovarian carcinoma based on ORR and regression of tumour target lesions. RegistrationThis trial is registered at ClinicalTrial.gov (NCT00940225).

Abstract CT002: A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors

Abstract Background: BGB-283 is a novel inhibitor of the RAF dimer with potent and reversible inhibitory activities against RAF family kinases including wild type A-RAF, B-RAF, C-RAF and B-RAF V600E, as well as EGFR. BGB-283 demonstrated acceptable safety and early clinical activity in its Phase 1A study. In this Phase IB dose expansion study, we further evaluated safety and tolerability of BGB-283 and investigated efficacy in pre-selected patients (pts) with B-RAF or K-RAS/N-RAS-mutated solid tumors. Methods: This Phase 1B study was a multicenter, open-label, multiple-arm, dose expansion study. Pts were treated at the RP2D of BGB-283 at 30 mg/day. There were 10 different expansion arms for: B-RAF V600-mutated melanoma (not previously treated with a B-RAF or MEK inhibitor, and B-RAF and/or MEK inhibitor-resistant pts), colorectal cancer (CRC), non-small cell lung cancer (NSCLC), papillary thyroid cancer (PTC) and other solid tumors with B-RAF mutations; K-RAS/N-RAS-mutated endometrial cancer, NSCLC, CRC, and other solid tumors with K-RAS/N-RAS or NF-1 mutations. The primary end point was the response rate based on RECIST Version 1.1. Adverse events (AEs) are reported per CTCAE V4.03. Results: As of 19th Sep 2016, 96 pts were enrolled: median age was 63 years (range: 20 to 82 years) with all pts having baseline ECOG PS of 0 or 1. Forty-seven (49.0%) subjects had received ≥3 prior lines of treatment, 22 (22.9%) had received 2 prior lines of treatment, and 18 (18.8%) had received 1 prior line of treatment. BGB-283 was generally well-tolerated. Drug-related AEs were mostly Grade 1/2 in severity; the most common were fatigue in 37 (38.5%) subjects, nausea in 16 (16.7%), decreased appetite in 21 (21.9%), and diarrhea in 17 (17.7%). A total of 34 (35.4%) subjects experienced study drug-related Grade 3/4 AEs, notably drug-related thrombocytopenia (6.3%), palmar-plantar erythrodysesthesia syndrome (1.0%) and hypertension (8.3%). In the cohorts with previously-untreated B-RAF V600-mutated melanoma (n=7), PTC with B-RAF mutation (n=3) and NSCLC with K-RAS mutation (n=6), the response rates were 42.9% (95% confidence interval [CI], 9.9, 81.6), 33.3% (95% CI, 0.8, 90.6) and 16.7% (95% [0.4, 64.1]), respectively. Confirmed PR was seen in the single case of ovarian cancer with B-RAF mutation enrolled and also in one of 4 melanoma subjects with a confirmed B-RAF V600 mutation, who had not responded to B-RAF and/or MEK inhibitor(s). One unconfirmed PR was found in two NSCLC subjects with a B-RAF mutation. Conclusions: BGB-283 was generally well-tolerated during the Phase 1B stage of the study. Antitumor activity was not only observed in subjects with B-RAF V600-mutated solid tumors including melanoma, PTC, and ovarian cancer, but also in subjects with K-RAS-mutated NSCLC. When added to the efficacy data in the Phase IA portion of this study, with objective responses noted in these tumor subtypes as well as in K-RAS-mutated endometrial carcinoma, BGB-283 demonstrated a desirable risk-benefit profile for further efficacy and safety investigation. Citation Format: Jayesh Desai, Hui Gan, Catherine Barrow, Michael B. Jameson, Ben Solomon, Victoria Atkinson, Andrew Haydon, Michael Millward, Stephen Begbie, Michael Brown, Benjamin Markman, William Patterson, Andrew Hill, Lisa Horvath, Adnan Nagrial, Gary Richardson, Christopher Jackson, Michael Friedlander, David Gibbs, Phillip Parente, Jason Yang, Lai Wang, Yunxin Chen, Lusong Luo. A Phase IB study of RAF dimer inhibitor BGB-283 in patients with B-RAF or K-RAS/N-RAS mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT002. doi:10.1158/1538-7445.AM2017-CT002

Apatinib for metastatic breast cancer in non-clinical trial setting: Satisfying efficacy regardless of previous anti-angiogenic treatment.

Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2. This study aimed to evaluate the efficacy and safety of apatinib in metastatic breast cancer (MBC) under non-clinical trial setting, and to study the impact of previous antiangiogenic treatment to the efficacy of apatinib. 52 MBC patients treated with apatinib under non-clinical trial setting in Fudan University Shanghai Cancer Center between January 1st 2015 and October 1st 2016 were included. All patients were included in time-to-treatment failure (TTF) analysis, while 45 patients were enrolled for progression-free survival (PFS) and overall survival (OS) analysis because 7 of the patients with treatment discontinuation due to intolerable toxicities had too short time for efficacy assessment. Impact of previous exposure to antiangiogenic treatment and other factors to patients' survival were analyzed by Log-rank analysis and Cox multivariate analysis. The median PFS, median OS, and median TTF were 4.90 (95% confidence interval [CI] 3.44 - 6.36), 10.3 (unable to calculate 95% CI), and 3.93 (95% CI 1.96 - 5.90) months, respectively. Previous treatment of bevacizumab did not affect the efficacy of apatinib. Previous exposure to anthracycline, age of 60 years or older and palmar-plantar erythrodysesthesia syndrome were independent predictors for prolonged PFS. Discontinuation of treatment was more common in age group of 60 years or older than that in younger group, although the difference was not significant. Although toxicities were generally managable, a previously unrecorded grade 3~4 adverse event of dyspnea has been observed. This study confirmed the encouraging efficacy and manageable safety of apatinib on pretreated MBC patients in non-clinical trial setting. For the first time to our knowledge, this study found that previous treatment of bevacizumab did not affect the efficacy of apatinib, and reported an undocumented severe adverse effect of dyspnea.

RESILIENCE: Phase III Randomized, Double-Blind Trial Comparing Sorafenib With Capecitabine Versus Placebo With Capecitabine in Locally Advanced or Metastatic HER2-Negative Breast Cancer

IntroductionSorafenib is a multikinase inhibitor with antiangiogenic/antiproliferative activity. In this randomized, double-blind, placebo-controlled phase III trial, we assessed first- or second-line capecitabine with sorafenib or placebo in patients with locally advanced/metastatic HER2-negative breast cancer resistant to a taxane and anthracycline and with known estrogen/progesterone receptor status. Patients and MethodsA total of 537 patients were randomized to capecitabine 1000 mg/m2 orally twice per day for days 1 to 14 every 21 days with oral sorafenib 600 mg/d or placebo. The primary end point was progression-free survival (PFS). Patients were stratified according to hormone receptor status, previous chemotherapies for metastatic breast cancer, and geographic region. ResultsTreatment with sorafenib with capecitabine, compared with capecitabine with placebo, did not prolong median PFS (5.5 vs. 5.4 months; hazard ratio [HR], 0.973; 95% confidence interval [CI], 0.779-1.217; P = .811) or overall survival (OS; 18.9 vs. 20.3 months; HR, 1.195; 95% CI, 0.943-1.513; P = .140); or enhance overall response rate (ORR; 13.5% vs. 15.5%; P = .515). Any grade toxicities (sorafenib vs. placebo) included palmar-plantar erythrodysesthesia syndrome (PPES; 79.2% vs. 59.6%), diarrhea (47.3% vs. 37.8%), mucosal inflammation (15.4% vs. 6.7%), and hypertension (26.2% vs. 5.6%). Grade 3/4 toxicities included PPES (15.4% vs. 7.1%), diarrhea (4.2% vs. 6.4%), and vomiting (3.5% vs. 0.7%). ConclusionThe combination of sorafenib with capecitabine did not improve PFS, OS, or ORR in patients with HER2-negative advanced breast cancer. Rates of Grade 3 toxicities were higher in the sorafenib arm.

Palmar-plantar erythrodysesthesia syndrome following treatment with high-dose methotrexate or high-dose cytarabine.

Palmar-plantar erythrodysesthesia syndrome (PPES) is an uncommon side effect of high-dose cytarabine or methotrexate. Prior case reports of PPES have been limited, and the predisposing factors for the development of PPES remain unknown. A review of databases identified 22 patients (1.3%) who developed 39 episodes of PPES among 1720 patients after treatment with high-dose cytarabine or methotrexate. Symptoms lasted a mean of 6.4 days. Hands and feet were both involved in 68% of the initial episodes. Parenteral opioids were required for pain control by 27% of the patients. In comparison with the 1698 children treated with similar therapy, the children who developed PPES were older (mean age at diagnosis, 14.3 vs 7.7 years; P = 7.5 × 10-7 ). The frequency of PPES was less common in patients receiving methotrexate alone (7 of 946 or 0.7%) versus cytarabine (7 of 205 or 3.4%; P = .005) but was not different for those receiving both high-dose methotrexate and cytarabine (8 of 569 or 1.4%; P = .32). Prolonged infusions of methotrexate were associated with less frequent PPES in comparison with rapid infusions (P = 1.5 × 10-5 ), as was the co-administration of dexamethasone with cytarabine (P = 2.5 × 10-6 ). Self-described race and sex were not associated with PPES. In a multivariate analysis, older age and high-dose cytarabine administration without dexamethasone remained associated with PPES (P = 1.1 × 10-4 and P = .038, respectively). A genome-wide association study did not identify any associations with PPES meeting the genome-wide significance threshold, but top variants were enriched for skin expression quantitative trait loci, including rs11764092 in AUTS2 (P = 6.45 × 10-5 ). These data provide new insight into the incidence of PPES as well as its risk factors. Cancer 2017;123:3602-8. © 2017 American Cancer Society.

Incidence and timing of common adverse events in Lenvatinib-treated patients from the SELECT trial and their association with survival outcomes

PurposeIn the study of (E7080) lenvatinib in differentiated cancer of the thyroid, most patients experienced an adverse event. In this report, we examine common lenvatinib-emergent adverse events in this phase three, randomized, double-blind study.MethodsAdverse events were graded per Common Terminology Criteria for Adverse Events v4.0. 392 patients were enrolled (lenvatinib: 261, placebo: 131) and received lenvatinib 24 mg/day or placebo. The main outcome measures were: associations with progression-free survival and overall survival in exploratory univariate and multivariate analyses along with additional variables.ResultsThe most common any-grade adverse events (any grade; grade 3) in lenvatinib-treated patients included proteinuria (32%; 10%), diarrhea (67%; 9%), fatigue/asthenia/malaise (67%; 10%), rash (23%; 0.4%), and palmar-plantar erythrodysesthesia syndrome (33%; 3%). There were no grade 4 events for these adverse events. They generally occurred early (median time to first onset [weeks]: proteinuria [6.1], diarrhea [12.1], fatigue/asthenia/malaise [3.0], rash [7.3], and palmar-plantar erythrodysesthesia syndrome [5.9]), and were resolved primarily with dose modifications (median time to resolution [weeks]: proteinuria [8.8], diarrhea [18.1], fatigue/asthenia/malaise [16.3], rash [5.9], and palmar-plantar erythrodysesthesia syndrome [20.0]). Discontinuation due to these adverse events occurred in 2 (1%) patients with proteinuria and 4 (2%) with fatigue. Progression-free survival was not associated with any of the adverse events. Eastern Cooperative Oncology Group performance status (P = 0.001), follicular histology (P = 0.002), and diarrhea (P = 0.023) were associated with overall survival in multivariate analyses (median overall survival for patients with diarrhea: not reached; without: 17.1 months).ConclusionsIn the study of (E7080) lenvatinib in differentiated cancer of the thyroid, the most common adverse events typically occurred early and were primarily managed with dose modifications. Overall survival was significantly associated with diarrhea.

Updated analysis: A retrospective cohort study evaluating the safety and efficacy of regorafenib in patients with metastatic colorectal cancer—HGCSG1401.

778 Background: The CORRECT trial revealed the safety and efficacy of regorafenib (REG) for patients (pts) with colorectal cancer including Japanese. REG was approved in Japan in March 2013. However, there are few studies exploring the efficacy and safety of REG in a large number of patients, particularly in daily practice. Methods: We analyzed 173 pts who received REG from May 2013 in the multi-institutional retrospective study (HGCSG1401). This study was analyzed by CTCAE v4.0 for adverse events (AEs), RECIST v1.1 for response rate (RR)/disease control rate (DCR), and Kaplan-Meier method for progression free survival (PFS) and overall survival (OS). Results: Patients’ characteristics were as follows; male/female 98/75, median age 66 (range 29-87), ECOG PS (0/1/2/3) 58/96/18/1, KRAS Exon2 wild/mutant 98/74 (1 patient ; KRAS Exon2 status was not tested). The initial starting dose was 160 mg (n = 145, 83.8%), 120mg (n = 22, 12.7%), and 80mg (n = 6, 3.5%) respectively. Dose reductions were required in 73 pts (42.2%); 38 pts (22.0%) discontinued therapy due to AEs. The common ≥ grade 3 AEs ( ≥ 15%) were palmar-plantar erythrodysesthesia syndrome (n = 48; 27.7%), hypertension (n = 34; 19.7%), proteinuria (n = 24; 19.2%) and AST increased (n = 24; 13.9%). RR and disease control rate (DCR) were 1.3% and 29.6%, respectively. Median PFS and median survival time (MST) were 2.1 and 6.3 months. In an analysis on relationship between ECOG PS (PS 0-1 vs. PS 2-3) and efficacy, median PFS was 2.3 vs. 1.2 months (HR 3.598, p < 0.001), and MST was 7.0 vs. 2.1 months (HR 4.751, p < 0.001). Conclusions: The efficacy of REG in pts with PS 0–1 was similar to the previous report; however, REG was not effective in patients with PS 2–3. In adverse events, hypertension and liver dysfunction were expressed more frequently than previously reported. We will continue the analysis of the factors associated with liver dysfunction and prognostic/predictive factors.

Two randomized, placebo-controlled phase 3 studies of ruxolitinib (Rux) + capecitabine (C) in patients (pts) with advanced/metastatic pancreatic cancer (mPC) after failure/intolerance of first-line chemotherapy: JANUS 1 (J1) and JANUS 2 (J2).

343 Background: The JAK-STAT pathway plays a role in the pathogenesis of PC. In a phase 2 study, the JAK1/2 inhibitor Rux + C improved OS vs C alone in mPC pts with evidence of systemic inflammation. Methods: In two phase 3 studies, advanced/mPC pts with only 1 prior chemotherapy regimen and C-reactive protein > 10mg/L were randomized to 21-day cycles of Rux 15 mg BID + C 2000 mg/m2/d (day 1-14) vs placebo (Pb) BID + C 2000 mg/m2/d (day 1-14). The primary endpoint was OS. The studies were terminated early based on efficacy findings of a planned interim analysis for J1, with J2 enrollment incomplete. Results: 321 pts were randomized in J1 and 86 in J2. The median age was similar between groups (Rux + C vs Pb + C): J1, 68 vs 67 yrs; J2, 68 vs 69 yrs. The most common prior chemotherapy regimens were gemcitabine (gem) + nab-paclitaxel (J1: 50% vs 51%, J2: 42% vs 37%), gem alone (J1: 24% vs 21%, J2: 28% vs 33%). Median study treatment durations were 42 d for both Rux and Pb in J1; 40 d for Rux and 43 d for Pb in J2. Discontinuations were mainly due to disease progression (J1: 62% vs 65%, J2: 51% vs 58%), AEs (J1: 4% vs 10%, J2: 12% vs 12%) or death (J1: 8% vs 5%, J2: 7% vs 5%). Rux + C did not show a benefit over C alone in OS or PFS (see Table). Overall response rates were < 5% in each treatment group (NS).The most common grade 3/4 non-hematologic AEs were abdominal pain (J1: 7% vs 14%; J2: 14% vs 5%), palmar-plantar erythrodysesthesia syndrome (J1: 7% vs 4%; J2: 0% vs 12%), pulmonary embolism (J1: 4% vs 3%; J2: 10% vs 5%), dyspnea (J1: 2% vs 2%; J2: 10% vs 2%) and vomiting (J1: 5% vs 5%; J2: 2% vs 12%). The most common new/worsening hematologic labs abnormalities of grade 3/4 included: anemia (J1: 20% vs 6%; J2: 11% vs 8%) and lymphopenia (J1: 17% vs 9%; J2: 16% vs 8%). Conclusions: When added to C, Rux was well tolerated but did not improve clinical outcomes in the second-line treatment of mPC pts. Clinical trial information: NCT02117479 and NCT02119663. [Table: see text]

Efficacy/safety analysis of a phase 2 study of ruxolitinib (Rux) + regorafenib (Re) in patients (pts) with relapsed/refractory (r/r) metastatic colorectal cancer (mCRC).

663 Background: The JAK-STAT pathway plays a role in the systemic inflammatory response in CRC. Rux, a potent JAK1/2 inhibitor, was evaluated in r/r mCRC pts. Methods: After a safety run-in (Rux 20 mg BID + Re 160 mg QD), pts were randomized to Rux 15 mg BID or placebo (Pb) + Re 160 mg QD. Rux could be titrated to 20 mg BID. The randomized phase included Substudy 1 (S1, pts with C-reactive protein [CRP] > 10 mg/L) and Substudy 2 (S2, pts with CRP ≤ 10 mg/L). Primary endpoint: OS. Results: Rux 20 mg BID was well tolerated in the safety run-in (n = 11). 396 pts were randomized (S1: n = 175; S2: n = 221). Median age in Rux vs (v) Pb groups: 62 v 60 yr (S1), 59 v 61 yr (S2). Most pts had ≥ 3 prior chemotherapy regimens: 85% v 84% (S1); 81% v 78% (S2). Median treatment durations: 57 d with Rux v 56 d with Pb (S1), 106 d with Rux v 56 d with Pb (S2). Discontinuations were mainly due to disease progression (S1: 61% v 63%, S2: 62% v 66%) or AEs (S1: 10% v 19%, S2: 9% v 9%). Rux + Re did not improve OS/PFS over Re + Pb in S1/S2 (see Table). S1 was terminated for futility at interim analysis; S2 was terminated per sponsor decision. The number of events required for final efficacy analysis was reached in S1, not in S2. Most common non-hematologic AEs (Rux v Pb): palmar-plantar erythrodysesthesia syndrome (PPES; S1: 42% v 44%; S2: 58% v 47%), diarrhea (S1: 38% v 31%; S2: 39% v 27%), decreased appetite (S1: 37% v 36%; S2: 26% v 33%), fatigue (S1: 34% v 36%; S2: 41% v 44%), hypertension (S1: 21% v 26%; S2: 42% v 40%). Most common grade (G) 3/4 non-hematologic AEs: PPES (S1: 13% v 15%; S2: 17% v 13%) and hypertension (S1: 9% v 7%; S2: 22% v 16%). Most common G 3/4 hematologic AEs (new/worsening lab abnormalities): lymphopenia (S1: 13% v 8%; S2: 14% v 7%) and anemia (S1: 4% v 5%; S2: 9% v 4%). Conclusions: Rux + Re did not improve OS/PFS in mCRC pts over Re alone. There was a nonsignificant trend towards improved OS/PFS in S2. Rux 15-20 mg BID safety profile was consistent with previous studies in other tumors. Clinical trial information: NCT02119676. [Table: see text]