Linking kinases to adverse events through kinase inhibitors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
Afsheen Iqbal ◽  
Shan Zhao ◽  
Sonia Evelyn Reichert ◽  
Robert G. Maki
Keyword(s):  
Adverse Events ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Attributable Risk ◽  
Unequal Variance ◽  
Prevalence Data ◽  
Hand Foot Syndrome ◽  
Average Probability ◽  
The Difference ◽  
Grade 3

e13524 Background: Small molecule oral kinase inhibitors (SMOKIs) are anticancer agents with unique activity and toxicity. We sought to determine if specific kinases blocked by SMOKIs could be linked to specific adverse events (AEs). Methods: We identified studies in which cancer indications for SMOKIs were compared to placebo or other therapy, and collected prevalence data of grade 3, 4, and 5 AEs for each study arm. Targets of each SMOKI were screened from existing data on kinase specificity, selecting Kd<500nM. Each SMOKI was mapped to its respective kinases. We compared the frequency of AEs from all studies when the kinase of interest was involved to AE frequency when the kinase was not involved, and computed the probabilities for attributed risk for each kinase and the significance of association between AE and drug of interest via t-test. We evaluated the significance in a pair-wise manner, computing the difference in probability for a single AE for each study independently, and then evaluating the significance of the average probability, assuming unequal variance across studies. Results: 67 trials fit our criteria, and led to the identification of AEs associated with varying number of kinases, e.g. diarrhea (45 kinases), asthenia (43), hypertension (30), rash (30), thrombocytopenia (plts, 29), and neutropenia (21). Most associations, while statistically significant, had low attributable risk (≤5%), except diarrhea (24 kinases), hand-foot syndrome (19), and plts (13). BRAF (5.4% attributable risk) and VEGFR1 (4.9%) inhibition were most strongly associated with hypertension; AXL (5.3%), FGFR3 (5.3%), MAP4K5 (5%), and YES1 (5%) were associated with neutropenia; and TNIK (5.4%), PLK4 (5.3%), STK16 (5.3%), RPS6KA1 (5.1%), and FGFR3 (5%) were associated with asthenia. Conclusions: Certain AEs are common to many SMOKIs and thus many kinases. Other AEs such as neutropenia and asthenia were more tightly linked to specific kinases. By developing SMOKIs that block the target of interest but not kinases identified from these data, it may be possible to decrease the toxicity burden of future generations of SMOKIs.

The efficacy and safety of anlotinib in refractory/recurrent/advanced pediatric solid tumors: A retrospective study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11556-11556
Author(s):  
Suying Lu ◽  
Ye Hong ◽  
Huimou Chen ◽  
Liuhong Wu ◽  
Jia Zhu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Effective Treatment ◽  
Solid Tumors ◽  
Objective Response ◽  
Cancer Center ◽  
Treatment Schedule ◽  
Efficacy And Safety ◽  
Pediatric Solid Tumors ◽  
Hand Foot Syndrome ◽  
Grade 3

11556 Background: Refractory and recurrent advanced pediatric solid tumors are short of effective treatment and with a dismal outcome, thus an urgent need for novel and effective treatment. The aim of the study is to evaluate the efficacy and safety of anlotinib, a novel and oral multi-target receptor tyrosine kinase inhibitor, in refractory or recurrent advanced pediatric solid tumors. Methods: The retrospective, single-institutional, observed study was conducted in Sun Yat-sen University cancer center in China. Refractory, recurrent, or advanced pediatric solid tumors patients treated with anlotinib between 2018 to 2020 were evaluated. Results: Forty-one patients and thirty patients were enrolled in the study to evaluated efficacy and safety, respectively. The objective response ratio (ORR) was 12.2% (95%CI 1.7-22.7): complete response (n = 0) and partial response (n = 5) (Table). The disease control rate (DCR) was 65.9% (95%CI 50.7-81). The median progression-free survival (PFS) was 2.87 months (95%CI 0.86-4.88). According to anlotinib treatment schedule, all patients were divided into three groups: anlotinib monotherapy (A, n = 16), anlotinib combined with immune checkpoint inhibitor treatment (A + ICI, n = 6), anlotinib combined with salvage chemotherapy (A + SC, n = 19). The ORR, DCR and median PFS for three groups were 6.3% (95%CI 7.1-19.6), 56.3% (95%CI 28.9-83.6), 2.43months, 16.7% (95%CI 26.2-59.5), 66.7% (95%CI 12.5-120.9), 1.13months, 15.8% (95%CI 2.3-33.8), 73.7% (95%CI 51.9-95.5), 2.87months, respectively. There was no significantly difference between three groups in aforementioned response index. The incidence rates of any grade and grade 3-4 adverse events were 80% and 20%, respectively. Bleeding (20%), hand-foot syndrome (13.3%), and diarrhea (13.3%) were the most common adverse events. Grade 3-4 adverse events include hypertension, hand-foot syndrome, diarrhea, anemia, and thrombocytopenia. There was no adverse events-related death. Conclusions: For heavily pretreated pediatric solid tumors, anlotinib may be an effective treatment with tolerable adverse events. Further prospective randomized controlled clinical study is warranted.[Table: see text]

Medical Costs of Adverse Events in Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors: Canadian Perspective.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5178-5178
Author(s):  
Nick Newton ◽  
Khalid El Ouagari ◽  
Mireille M. Goetghebeur
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Febrile Neutropenia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Medical Costs ◽  
Icd 10 ◽  
Grade 3

Abstract Background: Imatinib (Gleevec) is recommended first-line therapy for treatment of chronic myeloid leukemia (CML). A relatively small group of patients treated with imatinib develop resistance or are intolerant to the treatment. Dose escalation of imatinib may be used in some cases. Recently, two treatment options, nilotinib (Tasigna) and dasatinib (Sprycel), have become possible alternatives for patients resistant or intolerant to imatinib. Current data indicates that nilotinib and dasatinib have a different side effect profile. Objectives: This study investigated the costs of adverse events (AEs) in patients receiving nilotinib or dasatinib for chronic and accelerated CML. Methods: Incidence rates of grade 3/4 AEs treated with nilotinib or dasatinib were obtained from nilotinib Phase II Summary of Clinical Safety: 120-Day Safety Update Report and dasatinib product information, respectively. Costs for non-hematological AEs were obtained from the Ontario Case Costing Initiative (OCCI) acute inpatient databases, using ICD-10 codes cross-referenced with AEs described in product monographs. For ICD 10 codes identified for this study, there were not enough cases in CML patients (a minimum of five cases is required to access data) and therefore OCCI costs used in this study were those of AEs in oncology patients. These costs were considered a good approximation of costs of AEs in CML patients by the clinical expert. Costs for grade 3 anemia and thrombocytopenia, and non-febrile neutropenia, were assumed to be outpatient costs and were based on literature, expert validation of treatment pathways and resource utilization in the Canadian context. Costs for grade 4 anemia and thrombocytopenia, and febrile neutropenia, were obtained from the OCCI. Multivariate sensitivity analyses were conducted on costs of AEs. The analysis was developed from a payer perspective considering direct medical costs only. Costs are reported in 2006 Canadian dollars. Results: Cost of treatment-related AEs for CML patients was higher for dasatinib than nilotinib. For both treatments, total costs for AEs associated with the accelerated phase were higher than those associated with the chronic phase: $19,902 versus $7,653 for dasatinib; $8,645 versus $3,790 for nilotinib; respectively. Cost attributable to hematological AEs represented between 45% and 71% of total cost of AEs. Ranking observed among treatments for base case costs of AEs was maintained for both high and low cost estimates, indicating that the model was robust to variation in cost of AEs. Conclusions: For patients resistant or intolerant to imatinib, costs of dasatinib-related AEs were approximately twice the costs of nilotinib-related AEs in both chronic and accelerated phases, highlighting the importance of considering the cost of AEs in economic evaluation of new tyrosine kinase inhibitors. Further research is needed to comprehensively evaluate the impact of AEs on healthcare expenditures.

scholarly journals Analysis of cardiovascular and arteriothrombotic adverse events in chronic-phase CML patients after frontline TKIs

2019 ◽  
Vol 3 (6) ◽  
pp. 851-861 ◽  
Author(s):  
Preetesh Jain ◽  
Hagop Kantarjian ◽  
Prajwal C. Boddu ◽  
Graciela M. Nogueras-González ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Adverse Events ◽  
Myeloid Leukemia ◽  
Regression Models ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Increased Risk ◽  
Prospective Trials ◽  
Grade 3 ◽  
New Onset

Abstract Cardiovascular or arteriothrombotic adverse events (CV- or AT-AEs) are reported in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). The incidence and characteristics across different TKI have not been systematically analyzed. We analyzed 531 patients treated with frontline TKIs in different prospective trials: imatinib 400 mg (n = 71) and 800 mg (n = 203), nilotinib (n = 108), dasatinib (n = 106), and ponatinib (n = 43). Characteristics and incidence of new-onset CV-AEs and AT-AEs were analyzed. Poisson regression models assessed factors associated with AE incidence. Median follow-up was 94 months (range, 2-195). Overall, 237 patients (45%) developed CV-AEs and 46 (9%) developed AT-AEs. Hypertension was the most common AE seen in 175 patients (33%; grade 3/4 in 17%). CV-AE and AT-AE incidence ratios (IRs) with 95% confidence intervals (CIs) were 8.6 (7.6-9.8) and 1.7 (1.2-2.2) per 100 person-years. Among the TKIs, ponatinib showed the highest IR (95% CI) for CV-AEs and AT-AEs at 40.7 (27.9-59.4) and 9.0 (4.1-20.1). In multivariate analysis, ponatinib therapy was associated with increased incidence rate ratio (IRR) for CV-AEs (4.62; 95% CI, 2.7-7.7; P &lt; .0001) and AT-AEs (6.38; 95% CI, 1.8-21.8; P &lt; .0001) compared with imatinib 400. In summary, there is an increased risk of CV-AEs (except hypertension) and AT-AEs in CML patients treated with newer TKIs, particularly with ponatinib. Patients on TKIs must be informed and closely monitored for vascular AEs. These studies were registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, #NCT00050531, #NCT00254423, #NCT00129740, and #NCT01570868.

Difference in adverse-event profiles between mTOR inhibitors, temsirolimus, and everolimus for advanced renal cell carcinoma.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 461-461 ◽  
Author(s):  
Masahiro Nozawa ◽  
Takashi Kikuchi ◽  
Mitsutoshi Nishimoto ◽  
Yasuyuki Kobayashi ◽  
Hirotsugu Uemura
Keyword(s):  
Renal Cell Carcinoma ◽  
Adverse Event ◽  
Adverse Events ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors ◽  
Two Agents ◽  
Significant Difference ◽  
The Difference ◽  
Grade 3

461 Background: Everolimus and temsirolimus have proven their efficacy and are used for patients with metastatic renal cell carcinoma (mRCC). They both are rapamycin derivatives and are categorized as mTOR inhibitors. There have been few reports that examined the difference between these two agents regarding adverse events. Our objective was to investigate the difference in the safety of both agents on the basis of our clinical experience. Methods: We identified patients with mRCC who had been treated with everolimus or temsirolimus at our hospital. Treatment duration, relative dose intensity, laboratory data, and adverse events during treatment with each agent were evaluated. Results: A total of 55 patients were evaluable. 43 of those had been treated with everolimus, 22 with temsirolimus, and 10 with both agents. There was no significant difference in age and gender between the two treatment groups. Median treatment durations of the everolimus and temsirolimus groups were 2.4 months and 1.8 months, respectively. Relative dose intensities of the everolimus and temsirolimus groups were 71.6 % and 75.4 %, respectively. Anemia, hyperglycemia, stomatitis, and interstitial lung disease (ILD) were detected with higher frequency in the everolimus group. In the everolimus group, 31 % of patients developed any grade of ILD including 15 % of grade 3, whereas ILD was reported in only one patient treated with temsirolimus with no grade 3 or higher. Frequencies of adverse events of grade 3 or higher were 49 % in the everolimus group and 26 % in the temsirolimus group. Conclusions: Adverse-event profiles of everolimus and temsirolimus may differ from each other. Respiratory disorders may occur more frequently and severely in patients treated with everolimus than temsirolimus. These findings suggest the difference in the pharmacodynamics, pharmacokinetics, and treatment regimen of these two agents may result in different adverse events even though they target the same molecule.

The clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15081-e15081
Author(s):  
Min Yuan ◽  
Juemin Fang ◽  
Zhongzheng Zhu ◽  
Wei Mao ◽  
Hui Wang ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Hand Foot Syndrome ◽  
Prior Systemic Therapy ◽  
Grade 3

e15081 Background: Anlotinib (AL3818) is a novel multi-target tyrosine kinase inhibitor (TKI) for tumor angiogenesis and tumor cell proliferation. Modulation of vascular endothelial growth factor-mediated immune suppression via angiogenesis inhibition may augment the activity of immune checkpoint inhibitors. We reported results from the clinical activity and safety of anlotinib combined with anti-PD-1 antibodies in patients with advanced solid tumors. Methods: 21 patients with advanced lung, gallbladder, endometrial, gastric, pancreatic, penile cancers and melanoma were treated since January 2019. Patients received a combination of anlotinib (12mg) once daily on day 1 to day 14 (21 days as a course) plus anti-PD-1 antibodies every 3 weeks until progression or unacceptable toxicity. Radiologic imaging was performed every 6 weeks for the first year of therapy. Results: Among 21 enrolled patients, 11 tumor types were represented, with lung, gallbladder, endometrial cancers and sarcoma being the most common.Most patients had received prior systemic therapy for metastatic disease (76.2%). The objective response rate (ORR) was 19.1%, including one complete responses (CR) (4.8%) and three partial responses (PR) (14.3%) and a disease control rate (DCR = CR+PR+SD) of 81.0% (17 of 21). One CR and three PRs have lasted 4, 4, 5 and 8 months, respectively. Thirteen patients (61.9%) had stable disease (SD) that lasted 1.5 to 13 months. Treatment-related adverse events occurred in 12 patients (57.1%). Three patients (14.3%) had grade 3 treatment-related adverse events. There were no grade 4 and 5 treatment-related adverse events. Grades 3 toxicities included hand-foot syndrome (n = 1) and hypertension (n = 2). Conclusions: anlotinib can be administered combined with anti-PD-1 antibodies with acceptable toxicity and promising durable antitumor efficacy that warrant further testing in a randomized trial.

Comparative Toxicities of Neoadjuvant Chemotherapy With or Without Bevacizumab in HER2-Negative Breast Cancer Patients: A Meta-analysis

2019 ◽  
Vol 54 (6) ◽  
pp. 517-525 ◽  
Author(s):  
Bi-Cheng Wang ◽  
Chen Fu ◽  
Lin-Ka Xie ◽  
Bo-Hua Kuang ◽  
Yan-Xia Zhao
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Adverse Events ◽  
Cancer Patients ◽  
Ventricular Dysfunction ◽  
Meta Analysis ◽  
Left Ventricular ◽  
Breast Cancer Patients ◽  
Hand Foot Syndrome ◽  
Grade 3

Background: The addition of bevacizumab to neoadjuvant chemotherapy improves the pathological complete response rate of human epidermal growth factor 2 (HER2)-negative breast cancer patients. However, the characteristics of adverse events associated with the use of bevacizumab should receive more attention from clinicians. Objective: This meta-analysis aimed to detect the adverse events of adding bevacizumab to neoadjuvant chemotherapy compared with neoadjuvant chemotherapy alone in HER2-negative breast cancer patients. Methods: PubMed, Cochrane Library, Web of Science, and EMBASE databases were systematically accessed to find eligible studies from January 1, 2000, to October 20, 2019. Reference lists were searched for additional studies. Pooled risk ratios for adverse events of bevacizumab were meta-analyzed. Results: Overall, 6 of 829 initially identified studies met the inclusion criteria, with 4681 patients randomized (2321 in the bevacizumab plus neoadjuvant chemotherapy group and 2360 in the neoadjuvant chemotherapy group). The incidence of grade ≥3 hypertension, left-ventricular dysfunction, mucositis, febrile neutropenia, infection, pain, hand-foot syndrome, hemorrhage, and neutropenia significantly increased in patients treated with bevacizumab plus neoadjuvant chemotherapy. However, adding bevacizumab to neoadjuvant chemotherapy was not associated with increasing the incidences of grade ≥3 proteinuria, dyspnea, heart failure, peripheral neurotoxicity, thrombosis, thrombocytopenia, fatigue, leucopenia, vomiting, nausea, and diarrhea. Conclusion and Relevance: Adding bevacizumab to neoadjuvant chemotherapy to treat HER2-negative breast cancer patients increased adverse events. However, most adverse events are clinically manageable. Patients, therefore, need to be monitored carefully for hypertension, left-ventricular dysfunction, mucositis, febrile neutropenia, infection, pain, hand-foot syndrome, hemorrhage, and neutropenia when treated with bevacizumab and neoadjuvant chemotherapy simultaneously.

Perifosine (P), active as a single agent for renal cell carcinoma (RCC), now in phase I trials combined with tyrosine kinase inhibitors (TKI)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15622-15622 ◽  
Author(s):  
J. Stephenson ◽  
M. Schreeder ◽  
J. Waples ◽  
J. Hargis ◽  
L. Campos ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Two Phase ◽  
Phase 1 Trials ◽  
Phase 2 Trial ◽  
Hand Foot Syndrome ◽  
Grade 3

15622 Background: P is an oral alkylphosphocholine with effects on multiple pathways including Akt, MAPK and JNK. Akt/S6 is often activated in RCC and associated with resistance. In a phase I study of P, 3/6 RCC patients (pts) had stable disease (SD) lasting for 4, 6 and 14 months (m). RCC was further assessed in a broad phase 2 trial, and subsequently, two phase 1 trials combining P with TKIs have been initiated. This is an update of the phase II and first report of the phase I combination trials. Methods: From 3/05 to 5/06 241 pts, including 13 with RCC, were randomized to P, 50 mg daily or 1200 mg weekly. Subsequently the protocol was amended to P, 100 mg daily or 900 mg weekly, and enrollment continues. Pts with measurable disease who received at least 2 courses of P and at least one tumor measurement after initiation of P were considered evaluable for response using RECIST criteria. After demonstrating P activity in RCC, two phase 1 studies of P combined with either sorafenib (SOR) or sunitinib (SUT) were initiated. In each study, the dose of P is escalated from 50 mg qd to 50 mg tid. SOR is escalated from 400 mg qd to 400 mg bid and SUT from 25 to 50 mg qd for 4 weeks out of 6. Results: In the broad phase II study, 6 pts (66%) achieved clinical benefit. (See table ) including 3 pts (33%) with partial responses [duration 4, 6.5 and 9 m] and 3 pts (33%) with SD [9+, 9+ and 10 m]. Three pts progressed. The main toxicities were grade 1 nausea, vomiting, diarrhea, and fatigue. Daily P was significantly better tolerated than weekly and data are presented in detail in another abstract. Enrollment in cohorts 1 and 2 of the P/SOR study is complete. No grade 3 or 4 toxicities and increase in hand foot syndrome has been seen. Accrual to cohort 1 of the P/SUT study is also complete. Enrollment will be complete by May 2007. Conclusions: P is active in RCC. Phase 1 trials of P with TKIs have demonstrated no increased toxicity with less than maximal doses of P and TKI [Table: see text] No significant financial relationships to disclose.

scholarly journals A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs

Blood ◽  
2021 ◽  
Author(s):  
Delphine Rea ◽  
Michael J Mauro ◽  
Carla Boquimpani ◽  
Yosuke Minami ◽  
Elza Lomaia ◽  
...  
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitors ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Molecular Response ◽  
Open Label ◽  
Phase 3 ◽  
The Difference

Patients with chronic myeloid leukemia in chronic phase (CML-CP) resistant or intolerant to ≥2 tyrosine kinase inhibitors (TKIs) are at high risk of experiencing poor outcomes due to disease biology and inadequate efficacy and/or safety of current therapies. Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with the potential to overcome resistance or intolerance to approved TKIs. In this phase 3, open-label study, patients with CML-CP previously treated with ≥2 TKIs were randomized (2:1) to receive asciminib 40 mg twice daily vs bosutinib 500 mg once daily. Randomization was stratified by major cytogenetic response (MCyR) status at baseline. The primary objective was to compare the major molecular response (MMR) rate at week 24 for asciminib vs bosutinib. Two hundred and thirty-three patients were randomized to asciminib (n=157) or bosutinib (n=76). Median follow-up was 14.9 months. The MMR rate at week 24 was 25.5% with asciminib and 13.2% with bosutinib. The difference in MMR rate between treatment arms, after adjusting for MCyR at baseline, was 12.2% (95% CI, 2.19-22.30; 2-sided P=.029). Fewer grade ≥3 adverse events (50.6% vs 60.5%) and fewer adverse events leading to treatment discontinuation (5.8% vs 21.1%) occurred with asciminib than with bosutinib. The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile. These results support the use of asciminib as a new therapy in patients with CML-CP who are resistant or intolerant to ≥2 prior TKIs. The trial is registered at www.ClinicalTrials.gov as NCT03106779.

A Phase II Study of Pegylated Liposomal Doxorubicin (PLD), Bortezomib, Dexamethasone and Lenalidomide (DVD-R) for Patients with Relapsed/Refractory (R/R) Multiple Myeloma (MM)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3044-3044
Author(s):  
James R. Berenson ◽  
Ori Yellin ◽  
Alan D. Cartmell ◽  
Thomas B. S. Woliver ◽  
Marshall S. Flam ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Study ◽  
Response Rates ◽  
High Response ◽  
Hand Foot Syndrome ◽  
Previously Treated ◽  
Grade 3

Abstract Abstract 3044 Background: Despite the availability of many new therapeutic options showing efficacy for R/R MM patients, many of these treatments produce significant side effects and the disease remains incurable. The combination of PLD and bortezomib has shown significant anti-MM efficacy leading to FDA approval of that combination for patients who have received one prior therapy and are naïve to bortezomib. Moreover, the combination of lenalidomide and dexamethasone has also been approved for patients who have received one prior regimen. However, both regimens are associated with significant toxicity and produce response rates in only 40–60% of patients. Previous studies in our laboratory show the increased efficacy and improved tolerability of PLD given daily compared to weekly administration in severe combined immunodeficient mice bearing human MM. Based on these results and the frequent occurrence of peripheral neuropathy with bortezomib when given at 1.3 mg/m2 dose on days 1, 4, 8, and 11 of a 3-week schedule, we modified the doses and schedules of both drugs and added intravenous (i.v) dexamethasone for MM patients. Using a modified lower dose (1.0 mg/m2) and longer cycle (4 weeks) of bortezomib administered on days 1, 4, 8, and 11 with lower dose PLD and intravenous (i.v.) dexamethasone administered on the same days for MM patients in both the frontline and R/R setting, we have shown the efficacy and marked reduction in AEs including neuropathy, hematologic, and hand-foot syndrome. A recent phase I/II trial investigating the combination of higher doses of lenalidomide, bortezomib, oral dexamethasone, and PLD on a 3-week schedule for newly diagnosed MM patients showed a high response rate but was associated with frequent AEs. Methods: Thus, we conducted a single-arm multi-center phase II study for R/R MM patients to evaluate the combination of i.v. dexamethasone, bortezomib, PLD, and lenalidomide. The treatment consisted of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and then 4.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Lenalidomide was administered orally at a dose of 10 mg daily on days 1–14 of each cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Eighteen (of 40 planned) patients have been enrolled to date with a median age of 72 years (range, 34–82 years). Patients were heavily pretreated with a median of 4 (1-17) prior regimens. Sixteen (89%) patients received prior bortezomib and 11 (61%) were previously treated with either doxorubicin or PLD. Seven (39%) of these patients were exposed to both drugs. Fifteen (83%) had received prior glucocorticoids. Nine (50%) individuals had received immunomodulatory agents with 6 (33%) having been exposed to lenalidomide and all 9 to thalidomide. The majority of patients (72 %) showed International Staging System II or III disease. To date, 16 patients (89%) have shown objective responses to the DVD-R regimen, including 1 complete response (6%), 5 very good partial responses (28%), 4 partial responses (22%) and 6 minimal responses (33%). One of the nonresponding patients showed stable disease and the other progressed after one cycle of therapy. Thus, disease control was achieved in all but one patient (94%). To date, 6 patients have shown progressive disease after a median follow-up time of 6 months (1+ - 9+ months). The DVD-R regimen was well tolerated and only one patient discontinued treatment because of toxicity (peripheral neuropathy). Ten patients experienced grade 3 or 4 adverse events. The most common grade 3 adverse events were reversible neutropenia (n=3), pneumonia (n=3), reversible anemia (n=2), and thrombocytopenia (n=2). There were two patients with grade 4 thrombocytopenia that was reversible. To date, 5 patients (28%) have developed treatment-emergent peripheral neuropathy (four grade 1 and one grade 3). Notably, there have been no cases of stomatitis or hand-foot syndrome. Conclusions: Thus, these results suggest that the DVD-R regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib, PLD and lenalidomide is a well tolerated treatment that produces high response rates for heavily previously treated MM patients with R/R disease. Disclosures: Berenson: Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Centocor OrthoBiotech: Consultancy. Vescio:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Swift:Millennium: Consultancy.

Phase II study of neoadjuvant chemotherapy with a metronomic regimen of paclitaxel + cyclophosphamide + capecitabine followed by 5-fluorouracil + epirubicin + cyclophosphamide in operable triple-negative breast cancer (JBCRG-13 study).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 1048-1048
Author(s):  
Kenji Higaki ◽  
Norikazu Masuda ◽  
Toshimi Takano ◽  
Nobuki Matsunami ◽  
Takashi Morimoto ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adverse Events ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Breast Conservation ◽  
Dose Intensity ◽  
Complete Response ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Clinical Trial Information

1048^ Background: Triple-negative breast cancer (TNBC) is generally associated with a poor prognosis. Combination therapy with anthracyclines and taxanes is widely used as preoperative systemic chemotherapy (PST), but pathological complete response (pCR) rate is ≤50%. We conducted metronomic PST in TNBC patients. Methods: Patients had primary breast cancer (T1C-3N0M0 or T1-3N1M0) with low ER expression (<10%) diagnosed with either a triple-negative or HER2-negative invasive tumor. They received 4 cycles of a metronomic PCX regimen followed by 4 cycles of 5-fluorouracil (500 mg/m2, q3w) + epirubicin (100 mg/m2, q3w) + cyclophosphamide (500 mg/m2, q3w) (FEC regimen). The metronomic PCX regimen includes weekly administration of paclitaxel (80 mg/m2; days 1, 8, 15), cyclophosphamide (50 mg/body; po, days 1-21) and capecitabine (1200 mg/m2; po, daily), with one cycle set to 21 days. Primary endpoint was pCR rate. Results: Between March 2010 and September 2011, 41 patients were enrolled and 40 patients were treated. Characteristics of these 40 pts (ITT population) were: median age 52 years (range, 33-69), median tumor size 23.7 mm (range, 3.5-82), N(+) in 16 pts (40%), and estrogen receptor weakly positive (ER;1-9%) in 7 pts (17.5%). Median dose intensity for paclitaxel, cyclophosphamide and capecitabine was 89.7%, 92.1% and 89.8%, respectively. Five pts requested discontinuation of PST during PCX and 2 during FEC, primarily due to adverse events, leaving a per protocol population of 33 pts. pCR (ypT0/Tis ypN0) rate was 54.5% (18/33). 22 pts achieved CR, and ORR was 93.9% (95% CI, 79.8-99.3) as assessed by MRI or CT. Breast conservation rate was 72.7% (24/33), and 5 of 13 pts changed to partial resection from pre-planned total mastectomy. Grade 3-4 adverse events were neutropenia (35%), febrile neutropenia (25%), leucopenia (25%), and hand-foot syndrome (7.5%). There was no SAE report, and most pts completed treatment as outpatients. Conclusions: Metronomic PCX followed by FEC provided a high pCR rate and was manageable as PST in patients with TNBC. Clinical trial information: UMIN000003570.

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