Efficacy and safety of the antibody-drug conjugate (ADC) SAR408701 in patients (pts) with non-squamous non-small cell lung cancer (NSQ NSCLC) expressing carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9505-9505
Author(s):  
Anas Gazzah ◽  
Charles Ricordel ◽  
Sophie Cousin ◽  
Byoung Chul Cho ◽  
Emiliano Calvo ◽  
...  
Keyword(s):  
Overall Response Rate ◽  
Human Study ◽  
Dose Intensity ◽  
Hematological Toxicity ◽  
Antibody Drug Conjugate ◽  
Dose Modification ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

9505 Background: We report updated safety and efficacy of DM4-conjugated anti-CEACAM5 ADC from the expansion part of the first-in-human study (NCT02187848; Gazzah A et al. J Clin Oncol. 2019;37:15, 9072) in 92 NSQ NSCLC pts. Methods: CEACAM5 expression was assessed by immunohistochemistry on archived tumor samples. Two cohorts of pts have been analyzed: moderate and high expressors, with CEACAM5 expression at ≥2+ intensity between ≥1% to < 50% and ≥50% of the tumor cell population, respectively. SAR408701 was administered at 100 mg/m2 IV every 2 weeks. Tumor assessments were done every 4 cycles (8 weeks). Primary endpoint was overall response rate (ORR). Results: As of January 2020, 92 pts were treated: 28 moderate and 64 high expressors, with median age 62.5 years (31–91; 42.4% of pts ≥65), 51.1% male, 71.7% ECOG PS ≥1; median of 3 prior treatments (1–10 lines) for advanced disease, including anti-tubulin agents (60.9%) and anti-PD1/PD-L1 (75%). In the moderate expressor cohort, 2 confirmed partial responses (PR) were observed (ORR 7.1%). In the high expressor cohort, 13 pts had confirmed PRs (ORR 20.3% [95% confidence interval 12.27%–31.71%]); 27 (42.2%) had stable disease; ORR of 17.8% was observed in 45 pts who had prior anti-PD1/PD-L1. Pts had a median of 7 (1–49) cycles; median relative dose intensity was 0.98. Six pts discontinued due to treatment-emergent adverse events (TEAEs). Most frequent TEAEs (all grades) were asthenia (38.0%), keratopathy/keratitis (38.0%), peripheral neuropathy (26.1%), dyspnea (23.9%), and diarrhea (22.8%). 31 pts had dose modification due to a TEAE, including dose reduction for keratopathy/keratitis in 10 pts. Hematological toxicity included leukopenia (14.4%), neutropenia (4.4%), and thrombocytopenia (13.3%). Grade ≥3 TEAEs occurred in 47.8% of pts and were assessed as drug-related in 15.2%. Conclusions: SAR408701 shows promising antitumor activity in heavily pretreated advanced NSQ NSCLC pts with high CEACAM5 expression. SAR408701 was well tolerated, with minimal hematological toxicity compared to conventional chemotherapy; keratopathy was reversible and manageable with dose modification. These data support the activity of SAR408701 in NSQ NSCLC CEACAM5 high expressors. A phase 3 trial evaluating the activity of CEACAM5-DM4 ADC monotherapy in comparison with docetaxel in NSQ NSCLC CEACAM5 high expressors after failure of standard first line chemotherapy and anti-PD1/PD-L1 is underway. Clinical trial information: NCT02187848 .

Phase Ia, first-in-human study of AbGn-107, a novel antibody-drug conjugate (ADC), in patients with gastric, colorectal, pancreatic, or biliary cancers.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 713-713 ◽  
Author(s):  
Andrew H. Ko ◽  
Andrew L. Coveler ◽  
Benjamin L. Schlechter ◽  
Tanios S. Bekaii-Saab ◽  
Brian M. Wolpin ◽  
...  
Keyword(s):  
Human Study ◽  
Duration Of Treatment ◽  
Antibody Drug Conjugate ◽  
Eligibility Criteria ◽  
Best Response ◽  
Grade 3 ◽  
Ecog Ps ◽  
Dose Levels

713 Background: AbGn-107 is an ADC directed against AG-7 antigen, a Lewis A-like glycol-epitope expressed in 24-61% of gastric (G), colorectal (CRC), pancreatic (PDA), and biliary (BIL) cancers. Based on promising antitumor activity of AbGn-107 in both in vitro and in vivo preclinical studies, we performed a Phase Ia trial in pts with the aforementioned GI malignancies. Methods: Standard 3+3 dose escalation was used. Key eligibility criteria: locally adv or metastatic G, CRC, PDA, or BIL cancer, previously treated, ECOG PS 0-1; positive AG-7 expression was not required. Two dosing intervals were tested: AbGn-107 administered i.v. Q4 weeks (at doses ranging from 0.1-1.2 mg/kg) and Q2 weeks (at doses from 0.8-1.0 mg/kg). DLTs were based on grade 3/4 hematologic and non-heme AEs occurring during the initial 4-week rx window. Pts were treated until dz progression or unacceptable toxicity, with tumor assessments Q8 weeks. 1o objectives: safety and MTD; 2o objectives: PK, immunogenicity, and efficacy defined by ORR (RECIST 1.1). Results: 35 patients were enrolled across 6 dose levels (median age 61.5 yo (range 40 – 81); G (0)/CRC (12)/PDA (20)/BIL (3); median # lines of prior rx = 3 (range 1-7). Safety: 5 pts experienced Grade 3 or 4 neutropenia, all at higher dose levels, with 1 episode of febrile neutropenia. Other frequent drug-related AEs, mostly grade 1/2, inc. fatigue (29%), nausea (20%), and diarrhea (14%). DLTs include grade 4 CK elevation (n = 1) at 0.8 mg/kg Q4W and grade 3 arthralgias (n = 1) at 1.2 mg/kg Q4W. MTD was not reached at either 1.2 mg/kg Q4W or 0.8 mg/kg Q2W; the 1.0 mg/kg Q2W cohort will complete enrollment in Oct 2019. Efficacy: Median duration of treatment = 56 days (range, 8 – 225 days); best response observed to date is stable dz lasting > 6 months at 0.8 mg/kg Q4W and Q2W cohorts (n = 1 each). Conclusions: Overall, AbGn-107 appears well-tolerated with encouraging prelim signs of efficacy (prolonged dz control) in non-biomarker selected pts with advanced GI cancers. Pre-screening for high AG-7 expression is underway for subjects with G, CRC, PDA, and BIL cancers for the cohort expansion phase of this study, which will be open across multiple sites in U.S. and Taiwan. Clinical trial information: NCT02908451.

Clinical Outcomes and Safety of Patients Treated with NAb-Paclitaxel Plus Gemcitabine in Metastatic Pancreatic Cancer: The NAPA Study

2020 ◽  
Vol 20 (11) ◽  
pp. 887-895 ◽  
Author(s):  
Martina Catalano ◽  
Giandomenico Roviello ◽  
Raffaele Conca ◽  
Alberto D’Angelo ◽  
Valeria Emma Palmieri ◽  
...  
Keyword(s):  
Performance Status ◽  
Real Life ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Free Survival ◽  
Grade 3 ◽  
Ecog Ps ◽  
Prognostic And Predictive Markers

Background: The phase III MPACT trial demonstrated the superiority of gemcitabine (Gem) combined with Nab-paclitaxel (Nab-P) versus gemcitabine alone in previously untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to evaluate the effect of Gem/Nab-P in routine clinical practice. Methods: From January 2015 to December 2018, patients with metastatic PDAC receiving firstline treatment with a combination of gemcitabine and Nab-paclitaxel were included in a multicentre retrospective observational study. Exploratory analyses of efficacy, and prognostic and predictive markers, were performed. Results: The cohort comprised 115 patients (median age 65 [range 50-84] years) with good performance status (ECOG PS 0-1). The median overall survival (OS) was 11 months (95% CI; 9-13) and the median progression-free survival (PFS) was 6 months (95% CI 5-7). Partial response and stable disease were achieved in 44 and 30 patients, respectively, yielding an overall disease control rate (DCR) of 64.3%. Grade 3-4 hematological toxicity frequency was 22.61% for neutropenia, 5.22% for anemia, and 3.48% for thrombocytopenia. Grade 3 asthenia was recorded in 2.61% of patients. No grade 4 non-hematological events were reported. Dose reduction was necessary in 51.3% of the patients. Conclusions: Our results confirm the efficacy and safety of a first-line regimen comprising gemcitabine and Nab-paclitaxel in metastatic PDAC in a real-life population.

scholarly journals Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma

2020 ◽  
pp. JCO.20.02259
Author(s):  
Paul G. Richardson ◽  
Albert Oriol ◽  
Alessandra Larocca ◽  
Joan Bladé ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Free Survival ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

Abbreviated Treatment with Short-Course Dose-Adjusted EPOCH and Rituximab (DA-EPOCH-R) Is Highly Effective in AIDS-Related Lymphoma (ARL).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3111-3111 ◽  
Author(s):  
Kieron Dunleavy ◽  
Richard Little ◽  
Juan Gea-Banacloche ◽  
Nicole Grant ◽  
Seth Steinberg ◽  
...  
Keyword(s):  
Stage Iv ◽  
Dose Intensity ◽  
Cell Loss ◽  
Hematological Toxicity ◽  
Hiv Viral Load ◽  
Cd4 Cell Count ◽  
Short Course ◽  
Ecog Ps ◽  
Cd4 Cell

Abstract In ARL, rituximab may slightly improve CHOP response but is associated with greater toxicity (Proc Am Soc Hem102:1488, 2003). We hypothesized that the addition of rituximab to DA-EPOCH may increase fractional tumor cell kill and allow fewer treatment cycles and lower immune suppression. Patients received DA-EPOCH-R (E=etoposide 50 mg/m2/d, O=vincristine 0.4 mg/m2/d and H=doxorubicin 10 mg/m2/d all CIV d 1–4 (96 hours); C=cyclophosphamide 750 mg/m2 IV d5; P=prednisone 60 mg/m2 PO qd d1–5 and R=rituximab 375 mg/m2 IV d1 and 5) with G-CSF. Prophylactic IT MTX x 6 was administered. HAART was discontinued before and recommenced after DA-EPOCH-R. Unlike our previous study of DA-EPOCH in ARL (BLOOD101:4653, 2003) where the dose of C was lower and based on CD4 cell count, all patients on this study received full dose C on cycle 1 with subsequent reduction if the ANC nadir was < 500/mm3 for ≥ 2 days. Patients received 1 cycle beyond CR, based on CT and PET, for a minimum of 3 cycles. Characteristics of 21 patients include median (range) age 39 (9–61) years; IPI 3 (0–4); ECOG PS 2 (1–4); CD4 212 (0–674) cells/mm3 and HIV viral load 53100 (0– 286472) RNA copies/mL. Additionally, male sex 17 (81%); LDH> nl 15 (71); stage IV 15 (71%) and histology with diffuse large B-cell 9 (90%) and Burkitt’s lymphoma 2 (10%). The 18 patients who completed treatment (2 TE; 1 NE) received a median (range) of 3 (3–5) cycles. Responses are CR/CRu 15 (83%); PR 1 (6%) and NR 2 (11%). At 19 mos median follow-up, overall PFS and OS are both 77%, and both 90% in patients with CD4 > 100 cells/mm3. Treatment outcome of DA-EPOCH-R is similar to DA-EPOCH (CR 74% and PFS 73% at 53 months) but with significantly shorter treatment (median cycles 3 vs. 6). Toxicity on 57 cycles include ANC < 500/mm3 on 27 (47%); platelets < 50,000/mm3 on 15 (26%) and; fever/neutropenia on 20 (35%) cycles. DA-EPOCH-R produced a median (range) CD4 cell decrement of 64 (−541 to + 239) cells/mm3 compared to 189 (−973 to +19) with DA-EPOCH. Hematological toxicity is higher with DA-EPOCH-R compared to DA-EPOCH with ANC < 500/mm3 47% vs 30% and fever/neutropenia 35% vs. 13%, respectively, likely due to higher C dose intensity and/or rituximab. Other toxicities are similar. Abbreviated DA-EPOCH-R is equivalent to DA-EPOCH x 6 and appears to produce less CD4 cell loss. Accrual continues. Figure Figure

Docetaxel (T) followed by capecitabine (X) as first-line chemotherapy in patients (pts) with metastatic breast cancer (MBC): Preliminary findings from a phase II study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10692-10692
Author(s):  
J. L. Bayo ◽  
M. Lomas ◽  
J. Salvador ◽  
M. Ruiz ◽  
A. Moreno
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Metastatic Breast ◽  
Dose Intensity ◽  
First Line ◽  
Recent Trial ◽  
Highly Active ◽  
Grade 3 ◽  
Metastatic Sites ◽  
Ecog Ps

10692 Background: X and T are highly active single agents in MBC. The XT combination leads to superior overall survival (OS), time to progression (TTP) and response rate (RR) vs. T alone in anthracycline-pretreated MBC [O’Shaughnessy et al. J Clin Oncol 2002]. The aim of this trial was to evaluate the efficacy and safety of sequentially administered T then X as first-line treatment in MBC. Methods: Pts ≥ 18 years with previously untreated, HER2neu-negative MBC, ECOG PS ≤ 2, were included in this prospective, multicenter, non-randomized, phase II study. Pts received 3 cycles of T (100mg/m2 d1) followed by 3 cycles of X (1250mg/m2 bid d1–14), every 3 weeks. Results: To date, 38 pts are evaluable for safety and 33 pts for efficacy. Baseline characteristics: median age 54.4 years (range 33–76); PS ≥ 1 50%; 36 (95%) pts had previous (neo)adjuvant anthracyclines, 8 (21%) concomitant with paclitaxel. The most frequent metastatic sites were: bone 47%, nodes 39% and liver 36%. 69% of pts had ≥ 2 metastatic sites. To date, 38 pts have received 3 cycles of T and 33 have also received 3 cycles of X. A total of 195 cycles have been administered: T 108 cycles (median 3, range 1–3); X 87 cycles (median 3, range 1–3). Dose reductions and interruptions for T vs. X were 32 vs. 21% and 21 vs. 21%, respectively. Median relative dose intensity: T 0.97 (range 0.62–1.00), X 0.93 (range 0.26–1.00). T grade 3/4 toxicities (37 evaluable pts): asthenia 19%, mucositis 16%, nausea 13%, febrile neutropenia 11%, rash 5%, diarrhea 5%, infection 3%. X grade 3/4 toxicities (33 evaluable pts): hand-foot syndrome 9%, diarrhea 9%, vomiting 9%, asthenia 6%, nausea 3%, anorexia 3%. In the 33 pts evaluable for efficacy, the RR was 61%, including 4 CRs and 16 PRs. At a median follow-up of 6.1 months, median TTP has not yet been reached. Conclusions: These preliminary results show that the sequential regimen of T followed by X is feasible, effective and well tolerated in first-line MBC, although giving X before T should also be investigated. Findings from a recent trial of XT vs. T followed by X [Beslija et al. ECCO 2005] suggest that XT should be standard in fit poor-prognosis pts with aggressive disease. No significant financial relationships to disclose.

Phase II study of capecitabine (X) as palliative treatment for patients (p) with squamous head and neck cancer (HNC) with locoregional and/or metastatic relapse after previous platinum-based treatment (PBT): An interim analysis

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6074-6074
Author(s):  
J. Martínez-Trufero ◽  
D. Isla ◽  
J. C. Adansa ◽  
R. Hitt ◽  
J. J. Cruz
Keyword(s):  
Palliative Treatment ◽  
Lung Metastases ◽  
Treatment Options ◽  
Objective Response ◽  
Dose Intensity ◽  
Hematological Toxicity ◽  
Line Treatment ◽  
Metastatic Relapse ◽  
Previously Treated ◽  
Ecog Ps

6074 Background: PBT is the standard therapy for HNC and is widely used as first line treatment. Nevertheless the incidence of relapse remains still high. Therefore, new non-platinum drugs need to be asses as second line treatment options. Taking into account the results obtained with X in HNC, we proposed this study to evaluate activity and tolerability of X when used as palliative monotherapy for relapsed HNC p previously treated with PBT. Methods: Patients aged 18–75 years, ECOG PS 0–2, with advanced squamous HNC with locoregional and/or metastatic relapse previously treated with PBT and adequate bone marrow, renal and hepatic functions were included. X (1,250 mg/m2 BID) during 14 days was administered every 21 days, for at least 2 cycles. Objective response rate (ORR) was assessed according RECIST criteria and toxicity following NCI-CTC v2 criteria. Results: Sixteen patients with median age 57 years old, all of them male, ECOG 0/1 (33.3% / 66.7%) and with squamous HNC, were analyzed. Twelve p had local disease, 4 p adenopathies and 6 p lung metastases. Median time since HNC diagnosis was 30.4 months and since disease extension diagnosis, 1.8 months. All p received a total of 58 cycles of X (median 3, range 1–6) and the median relative dose intensity was 92%. Four p were not evaluable for response (1 is still on treatment; 3 died, 2 due to unknown reasons and 1 due to an infection). ORR was 16.7%.The median follow-up time was 3.3 months, median TTP was 4.2 months and median OS was 4.7 months. Hematological toxicity G3/4 was reported in 2 p. The only grade 4 non-hematological toxicity was dysphagia in 1 p; grade III toxicities were: asthenia (2 p), anorexia (1 p), dehydratation (1 p), diarrhea (1 p), mucositis (1 p), weight loss (1 p) and palmar-plantar erythrodysesthesia (1 p). The most common grade II toxicity was asthenia (2 p). Conclusions: Capecitabine seems to be an active, feasible and well tolerated palliative treatment for advanced HNC patients that have previously received platinum-based schedules. No significant financial relationships to disclose.

A phase II multicenter study of CNTO 328, an anti-IL-6 monoclonal antibody, in patients (pts) with relapsed or refractory multiple myeloma (MM)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8527-8527
Author(s):  
P. M. Voorhees ◽  
R. F. Manges ◽  
G. Somlo ◽  
S. Lentzsch ◽  
S. Jagannath ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Response Rate ◽  
Once Daily ◽  
Overall Response ◽  
Corticosteroid Resistance ◽  
Prior Therapy ◽  
Medical Need ◽  
Heavily Pretreated ◽  
Secondary Endpoints ◽  
Grade 3

8527 Background: Relapsed/refractory MM constitutes a specific and unmet medical need with poor overall response and survival. Interleukin-6 (IL-6) plays an important role in MM cell proliferation, survival, and corticosteroid resistance and previous studies have shown clinical benefit from anti-IL-6 therapy. We therefore evaluated the combination of CNTO328, a chimeric monoclonal antibody with high affinity for human IL-6, and dexamethasone (dex) in pts with relapsed/refractory MM. Methods: Pts were treated with 6 mg/kg CNTO328 IV Q2 weeks. Oral dex (40mg) was given once daily, days 1–4, 9–12, and 17–20 for a max of 4 cycles; and on days 1–4 for subsequent cycles. Inclusion criteria were > 2 prior lines of systemic therapy, creatinine clearance >20 ml/min, platelets >50,000/mm3, and neutrophils >1000/mm3. Primary endpoint was overall response with secondary endpoints of time to progression, incidence of AEs and SAEs. Results: Thirty-nine pts received at least 1 infusion of CNTO328 in combination with dex - median age 66 yrs (range 43–89), median disease duration 4.2 yrs (1–13), median lines of prior therapy 5 (2–9) including bortezomib (100%), IMIDs (87%), and ASCT (59%). The median duration of therapy was 3.3 months (0.5–21+). Of the 36 pts who were evaluable, the overall response rate (CR+PR+MR) using EBMT criteria was 31% (7PR, 4MR). An additional 4 uMR and 4 SD lasting ≥3 months have been reported. PRs were durable; 6 out of 7 pts had responses ranging from 3 months to up to more than 1 year (with 1 still ongoing for more than 1 year). Duration of MRs ranged from 2–5 months. Responses were seen in pts relapsing after and refractory to at least one other prior treatment including bortezomib, IMIDs, or steroids. Median time to disease progression (PD) was 3.7 months (0.3–18+). Main reasons for treatment discontinuation were PD (24) and AEs (6). Hematologic toxicities Grade ≥ 3 were common though not dose-limiting. Three pts had Grade ≥ 3 infections considered reasonably related to CNTO328. Conclusions: CNTO 328 in combination with dex shows promising preliminary activity in this heavily pretreated patient population with an acceptable safety profile. Further investigation is ongoing. No significant financial relationships to disclose.

Pharmacokinetics and safety of an oral ALK inhibitor, ASP3026, observed in a phase I dose escalation trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2602-2602 ◽  
Author(s):  
Amita Patnaik ◽  
Patricia LoRusso ◽  
Howard A. Ball ◽  
Erkut Bahceci ◽  
Geoffrey Yuen ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Expansion Phase ◽  
Advanced Malignancies ◽  
Grade 3 ◽  
Ecog Ps ◽  
Clinical Trial Information

2602 Background: ASP3026 (3026) is a selective, potent, ATP-competitive, small molecule oral inhibitor of ALK receptor tyrosine kinase that has not previously been tested in humans. A Phase 1 dose-escalation trial, using a 3+3 design, evaluating 3026 as an oral single agent was conducted to investigate PK (Day 1 and Day 28), safety and clinical activity in patients (pts) with advanced malignancies (excluding leukemias) of ECOG PS 2 or less. Methods: 3026 was administered under fasting conditions on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 25 mg QD to 800 mg QD. Results: Thirty pts were enrolled into the dose escalation part of the study. The MTD was determined based on DLT data from cycle 1. Three DLTs were observed: grade 2 nausea and vomiting leading to dose reduction at 525 mg QD; grade 3 rash leading to dose reduction, and grade 3 ALT/AST increase leading to study withdrawal at 800 mg QD. The most common AEs were constipation, vomiting, diarrhea, nausea and abdominal pain, and all AEs were manageable and reversible. Median AUC and Cmax increased proportionally with dose from 25 mg QD to 800 mg QD. There was no evidence of non-linear PK at ASP3026 doses >25 mg QD. The median terminal half-life was approximately 10 - 41 hours. Overall, A3026 appears well absorbed with median Tmax around 3 hours for both Day 1 and Day 28. Terminal T1/2 appears adequate for one daily dosing with median values ranging from approximately 18 to 34 hours. Based on visual inspection of pre-dose (trough) values from Days 8, 15, 22, and 28 it appears that steady-state conditions are achieved by day 28. Conclusions: The MTD of 3026 is 525 mg QD. Treatment with 3026 resulted in a promising safety and PK profile in pts with advanced malignancies. Further evaluation of 3026 in pts with tumors harboring gene mutation or ALK fusion genes in the cohort expansion phase at the MTD is ongoing. Clinical trial information: NCT01401504.

JASPAC 01: Randomized phase III trial of adjuvant chemotherapy with gemcitabine versus S-1 for patients with resected pancreatic cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 4008-4008 ◽  
Author(s):  
Akira Fukutomi ◽  
Katsuhiko Uesaka ◽  
Narikazu Boku ◽  
Hideyuki Kanemoto ◽  
Masaru Konishi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adjuvant Chemotherapy ◽  
Interim Analysis ◽  
Standard Treatment ◽  
Dose Intensity ◽  
Phase Iii ◽  
Secondary Endpoints ◽  
Full Analysis ◽  
Grade 3 ◽  
Ecog Ps

4008 Background: Adjuvant chemotherapy with gemcitabine (G) has been standard treatment for resected pancreatic cancer (PC). In the GEST study, S-1 (S) had shown non-inferiority to G in overall survival (OS) for unresectable PC. The aim of this phase III study is to investigate non-inferiority of S to G on OS as adjuvant chemotherapy for resected PC. Methods: Patients (pts) after macroscopically curative resection of PC with an ECOG PS of 0-1 and adequate organ functions were randomly assigned to G (1000 mg/m2, iv, d1, 8 and 15, q4w, for 6 courses) or S (80/100/120 mg/day based on BSA, po, d1-28, q6w, for 4 courses) with balancing by surgical margins (R), nodal status (N) and institution. Primary endpoint was OS. With 180 pts per arm, the study had 80% power to prove non-inferiority with a margin of hazard ratio (HR) 1.25 on the basis of expected HR 0.87, with 0.05 two-sided alpha. Secondary endpoints were relapse-free survival (RFS), safety, and quality of life (EQ-5D). One interim analysis was planned after 180 deaths. Results: From 4/2007 to 6/2010, 385 pts were enrolled from 33 hospitals in Japan. 378 pts (G/S: 191/187) were included in the full analysis set. Pts characteristics (G/S) were well balanced (PS0: 67%/70%, R0: 86%/88%, N0: 38%/36%). Based on the interim analysis with 205 OS events, IDMC recommended to publish the results. OS at 2-years were 53% for G and 70% for S. HR for S to G was 0.56 (95% CI, 0.42-0.74, p<0.0001 for non-inferiority, p<0.0001 for superiority). On subgroup analysis, HRs for R0/R1, N0/N1 pts were 0.57 (95% CI, 0.42-0.78)/0.53 (0.27-1.05), 0.48 (0.28-0.83)/0.58 (0.41-0.80), respectively. RFS at 2-years were 29% for G and 49% for S. HR of relapse for S to G was 0.56 (95% CI, 0.43-0.71, log-rank p<0.0001). Incidences of grade 3/4 toxicities in G/S were leukopenia 39%/9%, hemoglobin decrease 17%/13%, thrombocytopenia 9%/4%, elevated AST 5%/1%, fatigue 5%/5%, and anorexia 6%/8%. Relative dose intensity of G/S was 84%/97%. EQ-5D QOL score in S was significantly better than that in G (p<0.0001). Conclusions: S-1 adjuvant chemotherapy is shown non-inferior, and furthermore, even superior to GEM. S-1 is considered as the new standard treatment for resected PC pts. Clinical trial information: UMIN000000655.

A genotype-directed study to optimize dosing of irinotecan according to the UGT1A1 genotype.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2570-2570
Author(s):  
Federico Innocenti ◽  
Ravi Salgia ◽  
Jacqueline Ramirez ◽  
Linda A. Janisch ◽  
Samir D. Undevia ◽  
...  
Keyword(s):  
Maximum Tolerated Dose ◽  
Severe Neutropenia ◽  
Hematological Toxicity ◽  
Genotype Frequencies ◽  
Flat Dose ◽  
Starting Dose ◽  
Heavily Pretreated ◽  
Reduction Methods ◽  
Require Dose ◽  
Clinical Trial Information

2570 Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ≥4 days, G≥3N on a treatment day, G≥3 febrile N, G4 anemia or thrombocytopenia, or G≥3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, G≥3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p<0.0001). At the MTD, I AUC in *28/*28 pts was 50% and 62% lower than that of *1/*28 and *1/*1 pts (16.8±4.4, 33.4±11.9, 44.2±11.3 h*ug/ml [mean±SD], respectively). At the MTD, SN-38 AUC in *28/*28 pts was 30% and 26% lower than that of *1/*28 and *1/*1 pts (620±407, 881±715, 841±888 h*ng/ml). 3 PRs were observed (NSCLC-700 mg-*1/*28, gastric-850 mg-*1/*1, small bowel-850 mg-*1/*28). Conclusions: In a heavily pretreated population, UGT1A1*28 information can be used to individualize dosing of I. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in pts receiving I. Clinical trial information: NCT00708773.

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