Nivolumab safety profile in Asian and Western patients with chemotherapy-refractory (CTx-R) advanced gastric/gastroesophageal junction (adv G/GEJ) cancer from the ATTRACTION-2 and CheckMate-032 trials.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 90-90
Author(s):  
Ian Chau ◽  
Li-Tzong Chen ◽  
Yoon-Koo Kang ◽  
Taroh Satoh ◽  
Ken Kato ◽  
...  
Keyword(s):  
Racial Differences ◽  
Median Time ◽  
Safety Profile ◽  
Survival Benefit ◽  
Gastroesophageal Junction ◽  
Study Drug ◽  
Safety Population ◽  
Grade 3 ◽  
Time To Onset ◽  
Clinical Trial Information

90 Background: Nivolumab (NIVO) monotherapy demonstrated a survival benefit and durable responses in pts with CTx-R adv G/GEJ cancer (Boku N et al ESMO 2017; Janjigian Y et al ASCO 2017). Here we describe the safety profile of NIVO in Asian (A) and Western (W) pts with CTx-R adv G/GEJ who had received ≥ 2 prior CTx in the ATTRACTION-2 and CheckMate-032 trials, respectively. Methods: The safety population included pts who received ≥ 1 dose of study drug at the data cutoff of August 2016 for ATTRACTION-2 and March 2016 for CheckMate-032. TRAEs, serious TRAEs, and select TRAEs (sTRAE; with a potential immune-related etiology) were assessed. sTRAEs were managed using protocol-specified algorithms, which included corticosteroids as immune-modulating treatment (tx). Time to onset and resolution of sTRAEs were also assessed. Results: Median duration of NIVO tx was 1.9 mo in A and 2.3 mo in W pts. TRAEs (any grade) were reported in 43% of A and 64% of W pts; grade 3–4 TRAEs (A pts:10%; W pts:14%), serious TRAEs (A pts:10%; W pts:7%) and TRAEs leading to discontinuation (≤ 3% of pts in both groups) were infrequent. Most sTRAEs were grade 1–2 (Table) and occurred within the first 3 mo of NIVO tx. In A and W pts, median time to resolution of sTRAEs ranged from 3–19 wk. For those sTRAEs that required tx with immune-modulating agents, the median time to resolution of most sTRAEs ranged from 3–35 wk. Conclusions: NIVO demonstrated an acceptable safety profile in both A and W pts with CTx-R adv G/GEJ cancers with no clinically meaningful racial differences. Most sTRAEs were grade 1–2 in both cohorts and manageable using the recommended tx algorithms. Clinical trial information: NCT02267343 ATTRACTION-2 and NCT01928394 CheckMate 032. [Table: see text]

Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma

2017 ◽  
Vol 35 (34) ◽  
pp. 3815-3822 ◽  
Author(s):  
Mario Sznol ◽  
Pier Francesco Ferrucci ◽  
David Hogg ◽  
Michael B. Atkins ◽  
Pascal Wolter ◽  
...  
Keyword(s):  
Median Time ◽  
Safety Profile ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Advanced Melanoma ◽  
Cytotoxic T Cell ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Grade 3 ◽  
Time To Onset

Purpose The addition of nivolumab (anti–programmed death-1 antibody) to ipilimumab (anti–cytotoxic T-cell lymphocyte–associated 4 antibody) in patients with advanced melanoma improves antitumor response and progression-free survival but with a higher frequency of adverse events (AEs). This cross-melanoma study describes the safety profile of the approved nivolumab plus ipilimumab regimen. Methods This retrospective safety review on data from three trials (phase I, II, and III) included patients with advanced melanoma who received at least one dose of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks × 4 and then nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity while following established guidelines for AE management. Analyses were of all treatment-related AEs, select (immune-related) AEs, time to onset and resolution, and use of immune-modulating agents and their effects on outcome. Results Among 448 patients, median duration of follow-up was 13.2 months. Treatment-related grade 3/4 AEs occurred in 55.5% of patients; 35.7% had treatment-related AEs that led to discontinuation. The most frequent treatment-related select AEs of any grade were skin (64.3%) and GI (46.7%) and of grade 3/4, hepatic (17.0%) and GI (16.3%); 30.1% developed a grade 2 to 4 select AE in more than one organ category. Median time to onset of grade 3/4 treatment-related select AEs ranged from 3.1 (skin) to 16.3 (renal) weeks, and with the exclusion of endocrine AEs, median time to resolution from onset ranged from 1.9 (renal) to 4.5 (pulmonary) weeks, with resolution rates between 79% and 100% while using immune-modulating agents. Four (< 1%) on-study deaths were attributed to therapy. Conclusion Frequency of grade 3/4 treatment-related AEs was higher with nivolumab plus ipilimumab and occurred earlier than historical experience with either agent alone, but resolution rates were similar.

Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 145-145
Author(s):  
Ben George ◽  
Eric Van Cutsem ◽  
Howard S. Hochster ◽  
Robert J. Mayer ◽  
Atsushi Ohtsu ◽  
...  
Keyword(s):  
Median Time ◽  
Total Bilirubin ◽  
Gastroesophageal Junction ◽  
Hepatic Function ◽  
Pooled Analysis ◽  
Phase 3 ◽  
Gastroesophageal Junction Cancer ◽  
Normal Hepatic Function ◽  
Time To Onset ◽  
Clinical Trial Information

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin <1.5 X ULN, or AST >ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]

The Bruton's Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Is Active and Tolerated in Relapsed Follicular Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 156-156 ◽  
Author(s):  
Nathan H Fowler ◽  
Ranjana H Advani ◽  
Jeff Sharman ◽  
Sonali M. Smith ◽  
Jesse McGreivy ◽  
...  
Keyword(s):  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Median Time ◽  
Phase I Study ◽  
Study Drug ◽  
Employment Equity ◽  
Phase Ii Studies ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 156 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling and is essential for normal B-cell development. Subtypes of non-Hodgkins lymphoma (NHL) may be dependent on chronic activation of the BCR pathway and primary follicular lymphoma (FL) cells have been found to maintain enhanced signaling when compared to normal B-cells (Irish JM, et al. Blood 2006; 108: 3135). Ibrutinib is an orally administered, covalently-bound inhibitor of BTK which induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. Based on promising preclinical data in B-cell malignancies, a phase I study was conducted to test the safety, tolerability, pharmacokinetics, and pharmacodynamics of ibrutinib in relapsed NHL. We report the long-term tolerability and sustained activity of ibrutinib in FL patients in this study with extended follow-up. Methods Adult patients with relapsed or refractory B-cell lymphoma were eligible for trial entry and 16 patients with FL were enrolled in this Phase I study. Ibrutinib was administered orally with dose escalation according to protocol-defined dose-limiting toxicities (DLT) to define a maximum tolerated dose (MTD) or until 3 dose levels above attainment of full BTK occupancy. A 28-day on/7-day off (intermittent) schedule was evaluated in 5 cohorts (1.25–12.5 mg/kg PO qd) and a once daily oral dose (without a drug holiday) in 2 cohorts (8.3 mg/kg and 560-mg fixed dose). Patients were evaluable for safety if they received study drug. Efficacy was evaluated in all patients who received 2.5 mg/kg or higher (which achieves full BTK occupancy) and had one on-study imaging assessment. Efficacy was also analyzed at higher doses to determine if there was improved efficacy. Responses were assessed every 2 months using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results Median age 60 (41–71), equal numbers of males and females, median time from diagnosis 54 months (19–186), median number of prior therapies 3 (1–5) including: stem cell transplantation (6%), alkylators (88%), anthracyclines (56%), nucleoside analogs (19%), and rituximab (100%). FLIPI scores at baseline: low risk = 19%, intermediate risk = 37%, high risk = 44%. Treatment-emergent AEs occurring in ≥ 25% included: diarrhea (50%), fatigue (44%), nausea (38%), cough (31%) and myalgia (25%). Observed grade 3 AEs included: anemia, anxiety, hypersensitivity, hypokalemia, hypophosphatemia, decreased neutrophil count, non-cardiac chest pain, pancytopenia, pneumonia and vomiting (one event each). A Grade 4 hypokalemia occurred and was considered to be related to study drug by the investigator. One case of myelodysplastic syndrome occurred 29 days after the last dose of ibrutinib in a patient with pre-existing anemia and multiple lines of prior treatment and was considered to be unrelated by the investigator. One patient in the 2.5 mg/kg/day intermittent cohort experienced DLTs of grade 2 neutropenia resulting in the ibrutinib dose being held > 7 days and a grade 4 hypokalemia. One patient in the 8.3 mg/kg/day intermittent cohort experienced a Grade 3 hypersensitivity reaction. No DLTs were observed in the 12.5 mg/kg/day cohort and the MTD was not reached. In the 16 patients with FL, 11 patients received ibrutinib at 2.5 mg/kg or higher and were evaluable for efficacy (2 patients at 2.5 mg/kg, 1 at 5 mg/kg, 3 at 8.3 mg/kg intermittent, 3 at 12.5 mg/kg, 2 at 8.3 mg/kg continuous dosing). Median time on ibrutinib was 7 months (0–29). Overall response rate (ORR) 54.5% (3 CRs, 3 PRs), duration of response (DOR) 12.3 months, median PFS 13.4 months. In the 9 patients who received ibrutinib at 5 mg/kg or higher, the median time on ibrutinib, ORR and DOR were similar to the efficacy in the 11 patients. However, there was a slight trend toward improved PFS of 19.6 months; 2 patients are still responding to ibrutinib at 25 and 29 months. Conclusions The BTK inhibitor ibrutinib (PCI-32765) is well tolerated and active in patients with relapsed FL. Based upon drug occupancy and clinical responses, a dose of 5 mg/kg/day or above is recommended for phase II studies. Extended dosing did not appear to increase toxicity and response rates improved with continued treatment in some patients. Phase II studies with ibrutinib in FL are planned. Disclosures: Advani: Pharmacyclics, Inc: Research Funding. Sharman:Celgene: Consultancy; Pharmacyclics: Honoraria; Calistoga: Honoraria; Portola pharmaceuticals: Consultancy. McGreivy:pharmacyclics: Employment. Kunkel:Pharmacyclics: Employment, Equity Ownership. Troung:Pharmacyclics, Inc: Employment, Equity Ownership. Zhou:Pharmacyclics, Inc.: Employment, Equity Ownership.

Ramucirumab (R) plus pembrolizumab (P) in treatment naive and previously treated advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: A multi-disease phase I study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4046-4046 ◽  
Author(s):  
Ian Chau ◽  
Johanna C. Bendell ◽  
Emiliano Calvo ◽  
Rafael Santana-Davila ◽  
Hendrik-Tobias Arkenau ◽  
...  
Keyword(s):  
Median Duration ◽  
Gastroesophageal Junction ◽  
Survival Rates ◽  
Kidney Injury ◽  
Primary Objective ◽  
Treatment Naïve ◽  
Previously Treated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

4046 Background: Angiogenesis and immunosuppression are hallmarks of tumor growth. This is the first study to combine R (anti-VEGFR2) with P (anti-PD-1) to simultaneously target both processes in the tumor microenvironment. Methods: Ongoing, multi-cohort, phase 1a/b trial enrolled pts with G/GEJ adenocarcinoma, measurable disease, ECOG PS 0-1, previously treated (Cohorts A and B) or untreated (Cohort A2) for advanced disease. PD-L1 was positive (tumor proportion score [TPS] ≥1%) or negative (TPS < 1%) using the DAKO PD-L1 22C3 IHC pharmDx assay. R was administered at 8 mg/kg on Days 1&8 (Cohorts A and A2) or 10 mg/kg on Day 1 (Cohort B) with P 200 mg on Day 1 q3W. Primary objective- assess safety and tolerability of R+P; preliminary efficacy will be examined. Results: As of 21-Nov-2016, 41 previously treated G/GEJ pts were enrolled. Median age was 58 y, 76% male, 66% had ECOG PS of 1, 46% were PD-L1+, and 59% received study treatment as third or subsequent line. Median duration on therapy was 2.8 mo and 4.1 mo for A and B, respectively. Overall, 33 (80%) pts experienced a treatment-related AE (TRAE) and similar between cohorts A and B. Ten (24%) pts experienced grade 3-4 TRAEs, most commonly colitis (7%) and hypertension (7%). One treatment-related death occurred (pneumonitis and pulmonary sepsis). Responses occurred in 3 (7%) pts with 46% disease control rate (DCR). Progression-free and overall survival rates at 6 mo were 22.4 % (95% CI, 9.8-38.0) and 51.2% (95% CI, 33.9-66.1) respectively. Nine (22%) pts remain on treatment. Eighteen of 25 planned treatment naïve G/GEJ pts were enrolled. Median age was 70 yr, 83% male, 56% had ECOG PS of 0, and PD-L1 status is pending. Median duration on therapy was 2.1 mo. Twelve (67%) pts experienced a TRAE. Grade 3 TRAEs occurred in 5 (28%) pts (hypertension [n = 3], diarrhea, and acute kidney injury). No grade 4-5 events occurred. Preliminary efficacy data showed 3 (17%) pts responded with 50% DCR. Median PFS is immature and 89% of pts remain on treatment. Conclusions: R+P generated no new safety signals and demonstrated encouraging antitumor activity in treatment naïve and previously treatedadvanced G/GEJ adenocarcinoma. Clinical trial information: NCT02443324.

First-line (1L) avelumab treatment in patients (pts) with metastatic Merkel cell carcinoma (mMCC): Preliminary data from an ongoing study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9530-9530 ◽  
Author(s):  
Sandra P. D'Angelo ◽  
Jeffrey Russell ◽  
Jessica Cecile Hassel ◽  
Celeste Lebbe ◽  
Bartosz Chmielowski ◽  
...  
Keyword(s):  
Safety Profile ◽  
Response Rate ◽  
Objective Response ◽  
Durable Response ◽  
Phase 2 Study ◽  
Grade 3 ◽  
Related Reaction ◽  
Unacceptable Toxicity ◽  
Clinical Trial Information

9530 Background: MCC is a rare, aggressive skin cancer. Avelumab is a fully human anti–PD-L1 antibody. In a phase 2 study in pts with distant mMCC who progressed after prior chemotherapy (JAVELIN Merkel 200; NCT02155647), avelumab showed a manageable safety profile and durable responses, including an objective response rate (ORR) of 31.8%, estimated 6-month durable response rate of 29%, and 6-month overall survival rate of 69%. Here, we report preliminary results from a separate cohort of pts with chemotherapy-naïve mMCC enrolled in the same study. Methods: Eligible pts with mMCC and no prior systemic treatment for metastatic disease received avelumab 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or withdrawal. Tumors were assessed every 6 weeks (RECIST v1.1). Adverse events (AEs) were assessed by NCI CTCAE v4.0. Results: As of Dec 30, 2016, 29/112 planned pts had been enrolled. Median age was 75.0 years (range 47–87). Median treatment duration was 8.1 weeks (range 2.0–37.9). Of 16 pts with ≥3 months of follow-up, unconfirmed ORR was 68.8% (95% CI 41.3–89.0) with CR in 18.8%; confirmed ORR was 56.3% (95% CI 29.9–80.2; 1 unconfirmed PR with discontinuation). Of 25 pts with ≥6 weeks of follow-up, unconfirmed ORR was 64.0% (95% CI 42.5–82.0). All responses were ongoing at last follow-up, including in 5/5 pts with ≥6 months of follow-up (potential to confirm responses). 20/29 pts (69.0%) had a treatment-related AE (TRAE), including grade 3–4 TRAE in 5 pts (17.2%). TRAEs led to discontinuation in 5 pts (17.2%): 2 pts with infusion-related reaction, and 1 pt each with elevated AST and ALT, cholangitis, and paraneoplastic syndrome. There were no treatment-related deaths. 21/29 pts (72.4%) remain on treatment. Conclusions: In initial results from a cohort of chemotherapy-naïve pts with mMCC, avelumab was associated with early responses and a manageable safety profile, consistent with findings for second-line or later avelumab treatment in a previous cohort. These results suggest that responses mature to become durable and the use of 1L avelumab may increase the probability of response vs later-line treatment. Enrollment and follow-up in this 1L cohort are ongoing. Clinical trial information: NCT02155647.

Carfilzomib weekly-melphalan-prednisone in untreated elderly multiple myeloma: IFM2012-03.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8004-8004 ◽  
Author(s):  
Xavier Leleu ◽  
Guillemette Fouquet ◽  
Lionel Karlin ◽  
Brigitte Kolb ◽  
Mourad Tiab ◽  
...  
Keyword(s):  
Phase I ◽  
Safety Profile ◽  
Overall Response Rate ◽  
Tumor Lysis Syndrome ◽  
Standard Of Care ◽  
Maximum Tolerated Dose ◽  
Cardiac Insufficiency ◽  
Grade 3 ◽  
Hepatic Cytolysis ◽  
Clinical Trial Information

8004 Background: Melphalan-prednisone-bortezomib (MPV) is a standard of care upfront for newly diagnosed elderly myeloma (eNDMM). Despite significant improvements on MPV’s safety profile, toxicity issues remain. Carfilzomib (K) is a novel generation proteasome inhibitor with a different safety profile from Bortezomib. Carmysap phase I/II study (twice a week Carfilzomib+MP) demonstrated K at 36mg/m² safe and active in eNDMM. We thought to study the K weekly-MP combination in eNDMM. Methods: IFM2012-03 is a multicenter phase I/II study in eNDMM (65 and older) aimed to determine the maximum tolerated dose (MTD) of K weekly. 4 cohorts of 6 patients each were recruited at K 36, 45, 56 and 70 mg/m2 on days 1, 8, 15, 22 IV of 35-days cycles, with oral Melphalan and Prednisone from days 1 to 4 at usual doses. Patients received a 9-cycles induction followed by a K monotherapy maintenance at 36 mg/m2 IV every 2 weeks for 1 year. 3 dose-limiting toxicities (DLTs) defined MTD at the lower N-1 dose. Results: 24 patients were included at K 36, 45, 56 and 70 mg/m². One DLT occurred at 36 mg/m² (grade 4 lymphopenia), one at 45 mg/m² (tumor lysis syndrome with grade 4 renal insufficiency), two at 56 mg/m² (grade 3 cardiac insufficiency and grade 3 febrile neutropenia) and two at 70 mg/m² (grade 3 nausea/vomiting and grade 3 hepatic cytolysis). One patient died from cardiac dysfunction considered related to K at 56 mg/m². 3 patients stopped therapy and 3 others required dose reduction of K. Following DSMB’s request a second 6-patients cohort was recruited at 70 mg/m², with increased attention around hyperhydration and monitoring HTA. We observed no DLT and no grade 3/4 adverse event in this cohort. Median age was 75 years, 56% patients were R-ISS 2 or 3. For the whole cohort (N=30), the overall response rate was 87% including 67% very good partial responses and 44% complete responses. Conclusions: The MTD of weekly K in the KMP combination is 70 mg/m² upfront for eNDMM, but it seems reasonable to recommend 56mg/m² after 75 years-old for safety reasons. KMP offers high response rates and possibly greater CR rate. However, since the CLARION study (VMP vs KMP) will not allow KMP’s approval in eNDMM in Europe, IFM decided to stop IFM2012-03 after phase I without performing phase II. Clinical trial information: NCT02302495.

Onset of neutropenia as an indicator of treatment response in the phase 3 RECOURSE trial of trifluridine/tipiracil (TAS-102) versus placebo in patients with metastatic colorectal cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 775-775 ◽  
Author(s):  
Atsushi Ohtsu ◽  
Takayuki Yoshino ◽  
Alfredo Falcone ◽  
Rocio Garcia-Carbonero ◽  
Guillem Argiles ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Survival Benefit ◽  
Progression Free Survival ◽  
Free Survival ◽  
Initial Onset ◽  
Grade 3 ◽  
Post Hoc ◽  
First Time ◽  
Clinical Trial Information

775 Background: TAS-102 is comprised of an antineoplastic thymidine-based nucleoside analog, trifluridine (FTD), and a thymidine phosphorylase inhibitor, tipiracil. Primary results of the RECOURSE trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) with TAS-102 vs placebo (pbo) in patients (pts) with metastatic colorectal cancer refractory/intolerant to standard therapies. Neutropenia is a common TAS-102–associated adverse event and it has been hypothesized to be associated with a relatively high FTD concentration in pts. Methods: RECOURSE data were analyzed post hoc for correlations between onset of neutropenia (Grade 3/4) and survival benefit. Results: Of 533 pts given TAS-102, 75 (14%) developed Grade 3/4 neutropenia in treatment cycle 1, 86 (16%) for the first time in cycle 2, and 39 (7%) for the first time in cycle ≥3. Onset of neutropenia at any cycle was associated with longer median OS and PFS compared with no neutropenia. A consistent survival benefit was observed regardless of the cycle of initial onset of neutropenia, as demonstrated by the hazard ratio (against cycle-matched pbo control groups) and corresponding median OS differences (Table). Conclusions: An association between occurrence of earliest onset of Grade 3/4 neutropenia and survival benefit was observed. The data indicate that such survival benefit occurred regardless of whether the initial onset of neutropenia occurred after cycle 1, cycle 2, or later. Further analyses are required to fully determine whether FTD pharmacokinetics correlate with TAS-102 efficacy and onset of neutropenia, and whether cycle initiation delays affect response. Clinical trial information: NCT01607957. [Table: see text]

Time to grade ≥3 adverse events in pts receiving trifluridine/tipiracil (TAS-102).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 788-788 ◽  
Author(s):  
Eric Van Cutsem ◽  
Atsushi Ohtsu ◽  
Natividad Lopez Busto ◽  
Akira Kanehisa ◽  
Ronan Fougeray ◽  
...  
Keyword(s):  
Adverse Events ◽  
Rest Period ◽  
Outpatient Setting ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Safety Population ◽  
End Of Treatment ◽  
Grade 3 ◽  
Post Hoc ◽  
Clinical Trial Information

788 Background: The phase 3 RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival versus placebo (7.1 versus 5.3 months, respectively; HR for death 0.68, 95% CI 0.58–0.81, p < 0.001), with few serious adverse events. Trifluridine/tipiracil is administered in 4-week cycles comprising 2 weeks with 5 days at 35 mg/m2 bid followed by 2 rest days, and then a 2-week rest period. Exploration of timing for AEs, particularly within the first cycle of treatment, is important for pt monitoring in the outpatient setting. Methods: We performed a post hoc analysis of the RECOURSE safety population (533 trifluridine/tipiracil; 265 placebo) to explore timing of hematological and nonhematological AEs. Results: Grade ≥ 3 adverse events (AEs) were more frequent with trifluridine/tipiracil than placebo for both hematological AEs (38% vs 0% neutropenia; 4% vs 0% febrile neutropenia; 18% vs 3% anemia; and 5% vs < 1% thrombocytopenia) and nonhematological AEs (2% vs 1% nausea; 2% vs < 1% vomiting; and 3% vs < 1% diarrhea). The median time to nadir in cycle 1 for hematological events was 28 days (17–31) for grade ≥ 3 neutropenia, 22 days (9–39) for grade ≥ 3 anemia, and 18 days (9–33) for grade ≥ 3 thrombocytopenia; similar values were obtained in subsequent cycles. The median times to nadir and values at nadir over the whole treatment duration (all cycles) are presented in the table for hematological and nonhematological AEs. Conclusions: Hematological and nonhematological AEs with trifluridine/tipiracil appear to be most intense towards the end of treatment cycles, which is reassuring for its use in the outpatient setting. Clinical trial information: NCT01607957. [Table: see text]

scholarly journals Comparative Safety of Two Bendamustine Hydrochloride Formulations; A Ready-to-Dilute Low-Volume, Rapid Infusion Solution, and a Lyophilized Powder: Results from a Phase 1 Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4861-4861
Author(s):  
Bassam Mattar ◽  
Stephen P Anthony ◽  
W Jeffrey Edenfield ◽  
Mark Smith ◽  
Adrian Hepner
Keyword(s):  
Abdominal Pain ◽  
Study Design ◽  
Group Performance ◽  
Phase 1 ◽  
Study Drug ◽  
Rapid Infusion ◽  
Safety Population ◽  
Low Volume ◽  
Grade 3 ◽  
Treatment Sequences

Abstract Introduction: This phase 1, open-label, randomized, crossover study was performed to test the bioequivalence and safety of an investigational, ready-to-dilute, rapid infusion (low volume) solution of bendamustine hydrochloride (test product [T]), and the approved bendamustine lyophilized powder formulation (reference product [R]). [ClinicalTrials.gov Identifier: NCT02162888] Methods: Patients were eligible to participate if they had a histologically confirmed diagnosis of any malignant disease (excluding chronic lymphocytic leukemia) for which no curative or standard therapy was available. All patients received bendamustine 120 mg/m2 intravenously as T (in 50 mL; 0.9% NaCl) over 10 min and R (in 500 mL; 0.9% NaCl) over 60 min on days 1 and 2 of two consecutive 28-day cycles. Patients were randomly assigned to one of three treatment sequences for the first three doses of study drug: TRR, RTR, RRT; T was given to all patients at cycle 2, day 2 (dose 4) (Figure). Safety was assessed throughout the 56-day treatment period, with events of special interest (expected reactions to bendamustine or underlying disease) recorded during and up to 1 h after administration; up to 24 h after administration; and on cycle 1 days 21 and 28; cycle 2 day 28; and at the end-of-study visit. Safety assessments included reported adverse events (AEs), Eastern Cooperative Oncology Group performance status, vital sign measurements, physical examination, and clinical laboratory assessments. Results: A total of 83 patients were randomized to the 3 treatment sequences; 81 received at least one dose of study drug and comprised the safety population. Fifty-nine (71.1%) patients received four doses of study treatment, with a similar number (67%-77%) of patients in each treatment sequence arm. Reasons for discontinuation were AEs (4 patients), death (3 patients), insufficient therapeutic response (4 patients), lost to follow-up (1 patient), sponsor request (2 patients), investigator request (3 patients), withdrew consent (5 patients), and other (2 patients). The frequency of treatment-emergent AEs (TEAEs) by most recent study treatment are shown in the Table. The most commonly occurring AEs (> 10%) overall were nausea (R 25%, T 19%), fatigue (R 21%, T 22%), dehydration (R 12%, T 15%), decreased appetite (R 11%, T 15%), anemia (R 12%, T 15%), pyrexia (R 6%, T 16%), constipation (R 11%, T 11%), vomiting (R 11%, T 8%), dyspnea (R 5%, T 12%), hypokalemia (R 4%, T 12%), diarrhea (R 6%, T 10%), abdominal pain (R 5%, T 10%), and thrombocytopenia (R 2%, T 11%). The most common AEs occurring during the infusion and within 1 h after infusion were nausea (R 6%, T 8%) and fatigue (R 5%, T 6%); nausea (R 11%, T 9%) and fatigue (R 8%, T 9%) were also most common in the first 24 h. Infusion reactions were experienced by ≤ 2% of patients treated with either T or R. Serious AEs occurring in > 1 patient were abdominal pain (R 1%, T 5%), chest pain (R 2%, T 0), deep vein thrombosis (R 2%, T 0), dehydration (R 1%, T 1%), pericardial effusion (R 1%, T 1%), and vomiting (R 1%, T 3%). Six deaths were reported; the primary cause of death for all six patients was progressive disease. Conclusions: No new safety signals were observed. The fact that all patients who received 4 doses received T as their final dose introduces a source of bias and may explain the increased overall number of TEAEs attributed to T. Sponsor: Eagle Pharmaceuticals, Inc. Table. TEAEs by Most Recent Treatment (Safety Population) Rn = 81 Tn = 73 Events Patients n (%) Events Patients n (%) During or within 1 h after infusion All TEAEs 40 26 (32.1) 38 21 (28.8) Grade 3-4 0 0 1 1 (1.4) Serious AEs 0 0 1 1 (1.4) Within 24 h of infusion All TEAEs 65 34 (42.0) 50 23 (31.5) Grade 3-4 5 4 (4.9) 10 6 (8.2) Serious AEs 2 2 (2.5) 5 2 (2.7) Overall All TEAEs 263 60 (74.1) 348 49 (67.1) Grade 3-4 46 19 (23.5) 66 20 (27.4) Serious AEs 23 12 (14.8) 12 12 (16.4) Figure 1. Study design. Figure 1. Study design. Disclosures Anthony: Eagle Pharmaceuticals, Inc.: Research Funding. Edenfield:Novartis, Astellas/Medivation: Speakers Bureau. Smith:Eagle Pharmaceuticals, Inc.: Employment. Hepner:Eagle Pharmaceuticals, Inc.: Employment, Equity Ownership.

Melflufen plus dexamethasone (dex) in patients (pts) with relapsed/refractory multiple myeloma (RRMM) exposed/refractory to prior alkylators: A pooled analysis of the O-12-M1 and HORIZON studies.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8048-8048
Author(s):  
Paula Rodríguez-Otero ◽  
Maria-Victoria Mateos ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Blade ◽  
...  
Keyword(s):  
Safety Profile ◽  
Alkylating Agents ◽  
Safety Data ◽  
Progression Free Survival ◽  
Pooled Analysis ◽  
Study Entry ◽  
Free Survival ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Clinical Trial Information

8048 Background: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that leverages aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM (Richardson et al. Lancet Haematol. 2020;7:5; Richardson et al. J Clin Oncol. 2020;Dec 9 [Epub]). This pooled analysis examines pts from these studies exposed to prior alkylators. Methods: Both the O-12-M1 and HORIZON studies included pts with RRMM who received ≥ 2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the 2 studies were pooled and analyzed according to previous exposure and refractoriness to alkylators before study entry. Refractoriness to prior alkylator therapy was defined as disease that failed to achieve a minimal response or progressed while on therapy, or within 60 d of last therapy. Results: Of 202 pts (HORIZON: n = 157, cutoff January 14, 2020; O-12-M1: n = 45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators in ≥ 1 prior LoT (see Table for subgroups). Pts exposed and refractory to alkylators in ≥ 2 LoTs had the highest number of pts refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 mo of study entry. Meaningful response rates were seen in all subgroups, except for pts who were exposed and refractory to alkylators in ≥ 2 prior LoTs (see Table). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited pt numbers. Grade 3/4 adverse events (AEs) were similar between pts exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). The most common AEs were hematologic, but were mostly reversible and clinically manageable. Nonhematologic AEs were infrequent and primarily grade 1/2. Conclusions: Melflufen in combination with dex showed meaningful efficacy and a clinically manageable safety profile in pts with RRMM exposed/refractory to prior alkylators. Clinical trial information: NCT02963493 and NCT01897714. [Table: see text]

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