scholarly journals Rheumatological Adverse Events Following Immunotherapy for Cancer

Medicina ◽  
2022 ◽  
Vol 58 (1) ◽  
pp. 94
Author(s):  
Ioana Cretu ◽  
Bogdan Cretu ◽  
Catalin Cirstoiu ◽  
Adrian Cursaru ◽  
Mihaela Milicescu ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Adverse Reactions ◽  
Cancer Treatments ◽  
Treatment Conditions ◽  
Clinical Presentations ◽  
Rheumatic Manifestations ◽  
Grade 3 ◽  
Dose Dependent ◽  
Rheumatological Manifestations

Background and Objectives: The occurrence of rheumatological side effects in a patient after receiving immunotherapy for cancer is becoming increasingly common. Oncologists often fail to diagnose and refer affected patients to rheumatologists. This paper presents the various rheumatological adverse events that occur after immunotherapy in patients as well as their treatment and evolution. Materials and Methods: A total of 36 patients were monitored between November 2018 and March 2020. The oncologist monitoring the immunotherapy-treated patients identified the occurrence of musculoskeletal side effects. The grading of toxicities was performed by both the oncologist and the rheumatologist using common terminology criteria for adverse events (CTCAE). Rheumatological treatment was administered, and for some patients, immunotherapy was discontinued. Results: The clinical presentations of the patients varied. Mild side effects (grade 1–2) were reported in a higher proportion than severe side effects (grade 3–5). Therefore, thirty-one patients had mild-to-moderate side effects, and five patients had severe side effects. Adverse reactions occurred, on average, 10 weeks after the initiation of immunotherapy; this indicated that the severity of the toxicity was dose dependent. Patients were treated with NSAIDs or prednisone, depending on the severity of the side effects, and for patients with severe manifestations, immunotherapy was discontinued. The remission of rheumatic manifestations varied depending on the grade of the manifestations. Conclusions: The clinical, biological, and ultrasound presentations of the patients with adverse events followed by cancer treatments differed from classic rheumatological manifestations. Thorough examinations of these patients by both oncologists and rheumatologists are needed in order to correctly diagnose and treat rheumatological adverse events. Multiple studies that include a larger number of participants are needed in order to better understand the pathogenesis and clinical evolution of these patients under different treatment conditions.

scholarly journals Mini-Review Discussing the Reliability and Efficiency of COVID-19 Vaccines

Diagnostics ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 579
Author(s):  
Bogdan Doroftei ◽  
Alin Ciobica ◽  
Ovidiu-Dumitru Ilie ◽  
Radu Maftei ◽  
Ciprian Ilea
Keyword(s):  
Side Effects ◽  
Severe Acute Respiratory Syndrome ◽  
Adverse Events ◽  
Adverse Reactions ◽  
Age Group ◽  
Efficacy And Safety ◽  
Short Time ◽  
Dose Dependent ◽  
Severe Adverse Reactions ◽  
Age And Sex

Severe Acute Respiratory Syndrome Coronavirus 2 is a novel strain of human beta-coronavirus that has produced over two million deaths and affected one hundred million individuals worldwide. As all the proposed drugs proved to be unstable, inducing side effects, the need to develop a vaccine crystallized in a short time. As a result, we searched the databases for articles in which the authors reported the efficacy and safety of the use of several vaccines vaccines by sex, age group, and frequency of adverse reactions. We identified a total of 19 relevant articles that were discussed throughout this manuscript. We concluded that from all eleven vaccines, three had an efficacy >90% (Pfizer–BioNTech (~95%), Moderna (~94%), and Sputnik V (~92%)) except for Oxford–AstraZeneca (~81%). However, Moderna, Sputnik V, and Oxford–AstraZeneca also alleviate severe adverse reactions, whereas in Pfizer–BioNTech this was not revealed. The remaining five (Convidicea (AD5-nCOV); Johnson & Johnson (Ad26.COV2.S); Sinopharm (BBIBP-CorV); Covaxin (BBV152), and Sinovac (CoronaVac)) were discussed based on their immunogenicity, and safety reported by the recipients since only phases 1 and 2 were conducted without clear evidence published regarding their efficacy. CoviVac and EpiVacCorona have just been approved, which is why no published article could be found. All adverse events reported following the administration of one of the four vaccines ranged from mild to moderate; limited exceptions in which the patients either developed severe forms or died, because most effects were dose-dependent. It can be concluded that aforementioned vaccines are efficient and safe, regardless of age and sex, being well-tolerated by the recipients.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3025-3025 ◽  
Author(s):  
Gregory Lawrence Beatty ◽  
Peter J. O'Dwyer ◽  
Jason Clark ◽  
Jack G Shi ◽  
Robert Charles Newton ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Adverse Events ◽  
Immune Responses ◽  
Dose Escalation Study ◽  
Advanced Malignancies ◽  
Common Grade ◽  
Ido1 Expression ◽  
Grade 3 ◽  
Tumor Types ◽  
Dose Dependent

3025 Background: INCB024360 is a potent, selective inhibitor of IDO1. As the catabolism of tryptophan (Trp) to kynurenine (Kyn) by IDO1 inhibits immune responses and IDO1 expression is elevated in many human cancers, IDO1 inhibition may potentiate effective antitumor immune responses. Methods: This dose-escalation study in adult pts with advanced malignancies used a 3+3 design to determine MTD, toxicity, PK, PD, and tumor response rate. Daily doses of INCB024360 were evaluated in 28-day cycles in 8 cohorts (50 mg once daily; 50 mg, 100 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg BID). Treatment continued until disease progression or unacceptable toxicity. PK and PD samples were drawn on days 1 and 15. Results: 52 pts have been treated. Tumor types included colorectal (56%), melanoma (12%), and other (33%). The most common adverse events (≥20%) were fatigue, nausea, decreased appetite, vomiting, constipation, abdominal pain, diarrhea, dyspnea, back pain, and cough. The most common grade 3 or 4 adverse events were abdominal pain, hypokalemia, and fatigue (9.6% each). One DLT each was observed at 300 mg BID (grade 3 radiation pneumonitis) and 400 mg BID (grade 3 fatigue); no DLTs were observed in the 18 pts treated with 600 mg or 700 mg BID. There were no objective responses. At 56 days, stable disease was seen in 15 patients and lasted ≥112 days in 7 patients. Significant dose-dependent reductions in plasma Kyn/Trp ratios and Kyn levels were detected at all doses and in all pts. Maximal effects were observed at doses ≥300 mg BID. With repeat dosing, 700 mg BID provided an average plasma concentration ~5-fold the projected IC90. Overall, doses ≥300 mg BID achieved greater than 90% inhibition of IDO1 throughout the dosing period. Conclusions: INCB024360 was generally well tolerated at doses of up to 700 mg BID and there appears to be no correlation of dose with toxicity. Doses ≥300 mg BID were capable of >90% inhibition of IDO1 activity and found to effectively normalize plasma Kyn levels. The recommended dose as monotherapy is 600 mg BID. Clinical trial information: NCT01195311.

Clinical considerations of sleep related amnestic behaviours associated with zolpidem

2020 ◽  
Vol 36 (1) ◽  
pp. 23-31
Author(s):  
Agata M. Grzegorzewska ◽  
Jerzy J. Landowski ◽  
Wiesław J. Cubała
Keyword(s):  
Side Effects ◽  
Adverse Reactions ◽  
Case Reports ◽  
Anterograde Amnesia ◽  
Gaba A ◽  
Concurrent Use ◽  
Comprehensive Search ◽  
Insomnia Treatment ◽  
Dose Dependent ◽  
Neuropsychiatric Side Effects

Objective. Zolpidem is a non-benzodiazepine agonist of GABA-A receptor indicated for the short-term insomnia treatment. Over the years, there have been reports in literature on zolpidem abuse complications and neuropsychiatric side effects involving headache, dizziness, nightmares, confusion, depression, sleepiness, memory deficits as well as hallucinations, sensory distortions, delirium and sleep-related complex behaviours with anterograde amnesia. The aim of this work is to review and highlight the most serious adverse reactions to zolpidem with emphasis on sleep-related amnestic behaviours. We also focus our attention on common traits, patterns and predisposing factors. This paper refers to zolpidem side effects or complex amnestic behaviours, or sleep related amnestic behaviours presented in literature. Literature review. A comprehensive search of PubMed and Google Scholar was conducted to find relevant studies, case reports and literature reviews addressing the zolpidem use in insomniac patients. Conclusions. Zolpidem may pose a risk for serious adverse reactions most common dose-dependent and associated with age, gender, concurrent use of medications and concomitant comorbidities. If severe adverse reactions occur, the drug should be immediately discontinued or switched to another hypnotic. This review indicates an association between psychotic reactions and complex sleep related behavioural abnormalities in patients using zolpidem alone or in combination with other psychotropic medications. Clinicians should adopt a cautious approach prescribing zolpidem and be alert to possible unusual adverse effects of the drug.

Dermatologic adverse events of brentuximab vedotin: Characteristics, management, and their relationship with dose regimen.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3049-3049
Author(s):  
Yuna Oh ◽  
Alexander Bang ◽  
Nicholas Kurtansky ◽  
Niloufer Khan ◽  
Melissa Pulitzer ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Regimen ◽  
Management Strategies ◽  
Brentuximab Vedotin ◽  
Single Cycle ◽  
Treatment Interruptions ◽  
Grade 3 ◽  
Dermatologic Adverse Events ◽  
Dose Dependent

3049 Background: Owing to its high efficacy and tolerability, brentuximab vedotin (BV) is increasingly being favored over other aggressive systemic therapies for the treatment of various CD30+ Hodgkin and non-Hodgkin lymphomas, including peripheral T-cell lymphoma and cutaneous T-cell lymphomas. Dermatologic adverse events (dAE) are one of the most common toxicities associated with BV but data regarding their characteristics including correlation to dose, time to occurrence, and management is scarce. We aim to describe the clinical and pathologic characteristics of dAEs associated with BV, their relationship with administered dose regimen, and available management strategies. Methods: An IRB-approved retrospective analysis was conducted for all patients who had received at least one cycle of BV from Memorial Sloan Kettering Cancer Center in 2009-2020. Logistic regression, χ2, student’s t-test were performed for univariate analyses. Kaplan-Meier survival and multivariate Cox proportional hazard model evaluated dAE occurrence stratified by 5 major dose regimens (single cycle, 1.2mg q1w, 1.2mg q2w, 1.2mg q3w, 1.8mg q3w). Results: Of 611 patients, 201 experienced dAE with median time-to-event of 24 days and 29% experiencing > 1 dAEs. Rash was the most common (62%; 142/230), followed by alopecia (20%) and xerosis (13%). For rash, 50% reported involvement of only the extremities and/or acral sites compared to 25% who had generalized rash. Of those reported (111), 68 patients had grade 1 dAE (61%), 38 grade 2 (34%), and 5 grade 3 (5%)-all grade 3 were rash (maculopapular/morbilliform). 14 cases (7%) resulted in treatment interruptions and 6 in discontinuations due to dAEs (3%). Pathology were often nonspecific consistent with a hypersensitivity reaction: spongiotic/psoriasiform dermatitis with perivascular lymphocytic infiltrates . Patients undergoing weekly regimen were at a statistically and clinically significantly higher risk of dAE during the first 100 days of BV treatment (p = 0.001). Between the two most frequently administered dose regimens (1.8mg vs. 1.2mg, q3w), the higher dose carried 105% higher risk for dAE (HR: 2.047, p = 0.053). Those who had received a single cycle of BV had the lowest risk compared to all other regimen (1/42, p = 0.001). Topical and/or systemic steroids were most frequently prescribed (43%) with 12% of patients requiring systemic steroids. Other treatments varied ranging from antihistamines to moisturizers. Conclusions: Understanding of the detailed characteristics, management strategies, dose-dependent effects associated with BV is critical to provide clinical guidance for primary providers and minimize treatment interruptions or discontinuations. The results overall suggest that the risk for dAEs is dose-dependent with those undergoing frequent dosing regimens having a greater risk, although most dAEs remain mild or low-grade.

scholarly journals Costs of Grade 3 and 4 Adverse Events Associated with Current Cancer Treatments - Cost Estimations For Sweden, Norway, Finland And Denmark

2017 ◽  
Vol 20 (9) ◽  
pp. A446
Author(s):  
R Lauppe ◽  
P Carlqvist ◽  
B Chavez ◽  
I Lundqvist ◽  
A Ohna ◽  
...  
Keyword(s):  
Adverse Events ◽  
Cancer Treatments ◽  
Grade 3

scholarly journals Safety of adjuvant gemcitabine plus cisplatin chemotherapy in a patient with bilateral ureteral cancer undergoing hemodialysis

2021 ◽  
Author(s):  
Yumiko Goto ◽  
Kent Kanao ◽  
Kazuhiro Matsumoto ◽  
Ikuo Kobayashi ◽  
Keishi Kajikawa ◽  
...  
Keyword(s):  
Side Effects ◽  
Adverse Events ◽  
Standard Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Old Japanese ◽  
Left And Right ◽  
The Common ◽  
Grade 3 ◽  
Stimulating Factor

AbstractAn 80 year old Japanese man with bilateral ureteral cancer underwent laparoscopic bilateral nephroureterectomy and lymph-node dissection. The pathological stage of the left and right ureteral tumors was pT3pN0M0. He received two courses of adjuvant gemcitabine and cisplatin chemotherapy while undergoing hemodialysis. The standard dose of gemcitabine and 50% of the standard dose of cisplatin were administered on the same day. Hemodialysis was started 6 h after gemcitabine administration and 1 h after cisplatin administration. The side effects were evaluated according to the Common Terminology Criteria for Adverse Events v4.0. In the first course, Grade 4 side effects including leukopenia, neutropenia, and thrombocytopenia were observed. He was treated with granulocyte colony-stimulating factor and platelet transfusion. Because the second course was administered without reducing the doses, granulocyte colony-stimulating factor was administered prophylactically, and Grade 4 side effects were reduced to Grade 3. Gemcitabine plus cisplatin chemotherapy can be administered safely in a patient with advanced ureteral cancer undergoing hemodialysis by adequately managing adverse events.

scholarly journals Safety review of 42 cases of COVID-19 treated with low-dose chloroquine

2020 ◽  
Author(s):  
Bo Zhou ◽  
Jing Zhang ◽  
Yanqing Liu ◽  
Wenxin Hong ◽  
Fengbi Jian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Adverse Reactions ◽  
Low Dose ◽  
Information Management System ◽  
Controlled Clinical Trial ◽  
Global Pandemic ◽  
High Incidence ◽  
The Mean ◽  
Grade 3

Abstract BackgroundCoronavirus Disease 2019 (COVID-19) has become a global pandemic and caused over one hundred thousand death. Chloroquine (CQ) and hydroxychloroquine (HCQ) were recommended for off-label use in the treatment of COVID-19 in some countries despite their unclear benefit. However, the toxicity of these agents has been ignored, so the investigation of their safety in the treatment of COVID-19 is crucial for providing a reference for the rational use. MethodsThe medical records obtained from the information management system of Guangzhou Eighth People’s Hospital were reviewed to extract data about patients who received chloroquine phosphate tablets for COVID-19 treatment from January 20th to March 5th, 2020. The data were assessed to determine the correlation of adverse reaction with chloroquine phosphate based on Chinese CFDA standards as well as the severity of adverse events based on American CTCAE5.0 standard, and evaluate the safety of this medication.ResultsA total of 42 patients (23 males and 19 females, average 42.19±14.29 years old) with COVID-19 were treated with low-dose chloroquine phosphate (oral, 500 mg, once per day). Totally 18 patients（42.86%）experienced 20 adverse events. The mean duration of CQ administration was 6.57 days (SD, 3.16 days; range: 1 day to 16 days) and 52.4% received CQ for 7 to 9 days. The adverse events occurred within 6–8 days of treatment. For the 20 adverse events, 19 were not higher than grade 2 and only one was grade 3 because of the severely limited self-care ability in one patient. The most common adverse events were related to the digestive, circulatory, hepatic, and nervous systems.ConclusionOral chloroquine phosphate tablets resulted in a high incidence of adverse reactions. In the clinical trial of chloroquine phosphate for COVID-19 treatment, it should be used under pharmaceutical care; timely evaluation of the drug safety during the treatment process is necessary and a randomized controlled clinical trial should be conducted.

Differences in Haematological and Non Haematological Toxicity during Treatment with Imatinib in Early and Late Chronic Phase Chronic Myeloid Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4281-4281
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Laura Cannella ◽  
Ida Carmosino ◽  
Caterina Stefanizzi ◽  
...  
Keyword(s):  
Weight Gain ◽  
Side Effects ◽  
Adverse Events ◽  
Median Duration ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Severe Thrombocytopenia ◽  
Muscle Cramps ◽  
Grade 3

Abstract Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukaemia (CML). Aim of present study was to analyse the frequency and type of hematological and non hematological adverse events in our series of late and early chronic phase CML patients treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological adverse events were seen in 59 out of 150 (39%) late CP patients: 20 patients (34%) experienced toxicity grade 1, 25 (42%) had toxicity grade 2 and 14 (24%) had toxicity grade 3–4. Of 100 early CP patients, 26 (26%) experienced hematological adverse event: 42% had toxicity grade 1, 50% had toxicity grade 2 and 7% had toxicity grade 3–4. Statistical differences were detected between early and late CP patients for grade 1–2 and 3–4 toxicity. Median duration of toxicity in late CP patients was 20 days (range 4–41) for grade 1, 16 days (range 4–27) for grade 2 and 18 days (range 8–40) for grade 3–4. In early CP patients the median duration of toxicity was 10 days (range 4–21) for grade 1, 14 days (range 6–28) for grade 2 and of 10 days (range 7–15) for grade 3–4. We analysed the clinical features associated to a greater risk of myelosuppression and found that a lower haemoglobin level was significant in early CP patients while a history of cytopenia during IFN therapy and a longer time elapsing from diagnosis was significant in late CP patients. The occurrence of hematological toxicity in late CP patients was associated to the persistent lack of complete cytogenetic response, whereas this correlation was not apparent in early CP patients. We compared the incidence of non hematological adverse events occurring in late and in early CP patients and found that in these latter some side effects were more frequent, such as weight gain, periorbital oedema (p=0.02), muscle cramps (p=0.03), skin rashes (p=0.002), diarrhoea (p=0.01), weeping (p=0.001) and infections (p=0.001). In late CP patients compared to early CP patients, we found as significant the occurrence during therapy of bone pain (p=0.001) and of hemorrhagic symptoms (p=0.002) in the absence of severe thrombocytopenia. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of grade 3–4, whereas in early CP patients the most frequent events were nausea, weight gain and cutaneous rash. Cardiac toxicity was observed in 3 out of 250 patients and cardiac events most frequently occurred in elderly patients with pre-existing conditions that predispose to fluid retention, with overall frequency of these events being 1%. In conclusion, we have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response.

Safety and tolerability of lapatinib in combination with taxanes (T) in patients with breast cancer (BC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1027-1027 ◽  
Author(s):  
J. P. Crown ◽  
H. A. Burris ◽  
S. Jones ◽  
K. M. Koch ◽  
A. Fittipaldo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Side Effects ◽  
Adverse Events ◽  
Safety Profile ◽  
Clinical Studies ◽  
Kinase Inhibitor ◽  
Safety Data ◽  
Systemic Exposure ◽  
Clinical Activity ◽  
Grade 3

1027 Background: Lapatinib (L) is an oral, dual ErbB1/B2 tyrosine kinase inhibitor. T are mainstay of BC treatment. The side-effects seen with T in combination with gefitinib and erlotinib include neutropenia, diarrhea and rash. Based on preclinical synergy, early clinical studies with L and paclitaxel (P) or docetaxel (D) were studied. Methods: We summarize pharmacokinetics (PK) and preliminary safety data from 192 patients. Results: PK analysis for EGF10009 (q3w), show systemic exposure was increased for both L (21%) and P (23%) at doses of 1500mg daily and 175mg/m2/q3w, respectively. PK analysis in EGF10021 , (L 1250 mg & D 75 mg/m2 with prophylactic pegfilgrastim) indicated no significant effect on systemic exposure of either agent. Toxicities across all studies include i.e., for all patients = grade 3, neutropenia (7.3%), diarrhea (18.2%), rash (3.6%). The rate of adverse events for neutropenia and rash were similar to each agent alone, however diarrhea was more common. The frequency and severity of diarrhea was increased in studies EGF10009 and EGF102580 where no proactive treatment of diarrhea was introduced, whereas in EGF105764, with proactive treatment, currently no =grade 3 diarrhea has been reported. The data show that the combination of L and P has clinical activity (>70% RR reported in EGF102580). Conclusions: T plus L combinations have a predictable and manageable safety profile and clinical activity of P plus L combination was observed. Proactive diarrhea management is essential for these combinations. Based on the PK data, no dose adjustments are required, and any dose adjustments should be toxicity-based. Ongoing clinical studies investigating the combinations of L with T, and combinations of L with T plus trastuzumab will be reported in the future. [Table: see text] No significant financial relationships to disclose.

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