Safety and pharmacokinetics (PK) of AMG 706 in combination with gemcitabine for the treatment of patients (pts) with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14005-14005 ◽  
Author(s):  
T. J. Price ◽  
L. Lipton ◽  
J. Williams ◽  
J. McGreivy ◽  
S. McCoy ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Vein Thrombosis ◽  
Finding Study ◽  
Label Dose ◽  
Grade 3 ◽  
Deep Vein

14005 Background: AMG 706 is an oral, investigational multikinase inhibitor (MKI) with antiangiogenic and direct antitumor activity achieved by selectively targeting VEGF, PDGF and Kit receptors. Methods: This is a fully enrolled, phase 1b, open-label, dose- finding study. The objectives are to determine the maximum tolerated dose and to assess safety and PK of AMG 706 in pts with solid tumors receiving AMG 706 plus gemcitabine. Pts =18 years with ECOG 0–2 and no prior treatment with bevacizumab or VEGFr MKIs were assigned to cohorts receiving escalating doses of AMG 706 (50mg QD, 125mg QD or 75mg BID continuously from day 2 of cycle 1) plus gemcitabine (1000mg/m2 weekly for 7/8 wks, then 3/4 wks per cycle) for up to 11 cycles. Assessments include dose-limiting toxicities (DLT) (weeks 1–4) and tumor response (every 3 months). Results: 26 pts were enrolled and received at least 1 dose of AMG 706 (50mg QD n=11; 125mg QD n=6; 75mg BID n=9). All but 2 pts have completed the study. Median (range) age was 57 (25–77) yrs. 65% of pts received prior chemotherapy; 4 pts received prior gemcitabine (50mg QD n=2; 125mg QD n=1; 75mg BID n=1). There were 2 DLTs: grade 4 neutropenia (125mg QD), grade 3 deep vein thrombosis (75mg BID). Treatment-related adverse events (AE) occurring in = 10% of pts are shown in the table . The mean AMG 706 PK profiles were not markedly different when AMG 706 was dosed on the same day or 24 hours after gemcitabine administration. Objective tumor responses per RECIST for 26 evaluable pts were: 2 unconfirmed PR (50mg QD n=1; 125mg QD n=1), 7 SD (50mg QD n=3; 125mg QD n=1; 75mg BID n=3), 11 PD (50mg QD n=7; 125mg QD n=3; 75mg BID n=1), and 6 not available (125mg QD n=1; 75mg BID n=5). Conclusions: These preliminary data suggest that, in pts with solid tumors, AMG 706 combined with gemcitabine had an expected AE profile at the target once-daily dose of 125mg QD, with little effect on AMG 706 PK. The data provide a foundation for conducting further trials, potentially including biliary tumors. Final data will be presented. [Table: see text] No significant financial relationships to disclose.

Safety and pharmacokinetics (PK) of AMG 706 with panitumumab plus FOLFIRI or FOLFOX for the treatment of patients (pts) with metastatic colorectal cancer (mCRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4081-4081 ◽  
Author(s):  
L. S. Schwartzberg ◽  
H. Hurwitz ◽  
J. Stephenson ◽  
D. Kotasek ◽  
D. Goldstein ◽  
...  
Keyword(s):  
Tumor Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Prior Chemotherapy ◽  
Prior Therapy ◽  
Vein Thrombosis ◽  
Finding Study ◽  
Label Dose ◽  
Grade 3

4081 Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity, selectively targeting VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 with panitumumab plus FOLFIRI or FOLFOX in pts with mCRC. Objectives are to establish safety, PK, and the maximum tolerated dose of AMG 706 with this regimen. Pts =18 yrs with mCRC, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti-EGFR therapy, received either FOLFIRI or FOLFOX (based on prior therapy) plus panitumumab (6mg/kg IV day 1 of each 2-wk cycle), and escalating doses of AMG 706 (50, 75, 125mg QD; 75mg BID) given continuously from day 3 of cycle 1. Assessments included dose-limiting toxicities (DLT) during the first 2 cycles and tumor response (every 6–8 wks from wk 6). Results: As of Nov 2006, 45 pts were enrolled and received at least 1 dose of AMG 706 (FOLFIRI/FOLFOX n=33/12); 64% had prior chemotherapy. There were 6 DLTs: FOLFIRI n=4, all grade 3 (diarrhea n=2: 50mg QD, 75mg BID; deep vein thrombosis n=1: 75mg QD; high GI output n=1: 75mg BID); FOLFOX n=2 (all fatigue, grade 3: 50mg QD). Treatment-related adverse events (AE) occurring in =10% of pts included: any AE, FOLFIRI/FOLFOX 88/92% of pts (grade 3, 21/58%); fatigue 55/58% (12/33%), anorexia 24/50% (0/0%), diarrhea 24/33% (0/8%), epistaxis 27/0% (0/0%) and hypertension 15/8% (0/0%). There were no grade 4/5 AEs. 2 cases of cholecystitis (grade 3, n=1) occurred. Preliminary data showed that AMG 706 PK at 50mg QD (FOLFOX) and 50–125mg QD (FOLFIRI) was comparable to data from monotherapy studies at the same dose levels. AMG 706 did not markedly alter the PK profiles of irinotecan or its metabolites. Objective tumor response per RECIST is shown in the table . Conclusions: In this study of pts with mCRC, AMG 706 was tolerable when combined with panitumumab and FOLFIRI or FOLFOX, with little effect on AMG 706 PK. [Table: see text] No significant financial relationships to disclose.

Safety and early efficacy results from a phase I study of volociximab (V) in combination with carboplatin (C) and paclitaxel (P) in patients (pts) with advanced non small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13513-e13513
Author(s):  
B. Besse ◽  
S. Almokadem ◽  
D. Planchard ◽  
I. Chico ◽  
C. L. Tsao ◽  
...  
Keyword(s):  
Advanced Nsclc ◽  
Arterial Occlusion ◽  
Maximum Tolerated Dose ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study ◽  
Vein Thrombosis ◽  
Label Dose ◽  
Grade 3 ◽  
Peripheral Arterial

e13513 Background: Volociximab is a chimeric monoclonal antibody that blocks fibronectin binding to α5β1 and induces apoptosis in proliferating endothelial cells. Its anti-angiogenic actions are independent of the VEGF pathway. This is the first clinical study of voloxicimab in patients with advanced NSCLC. Methods: This phase 1b multi-center open-label, dose-escalation study was designed to determine the maximum tolerated dose of V in combination with full doses of C (AUC=6mg/ml.min) P (200mg/m2) with cycles repeated every 3 wks for a maximum of 6 cycles followed by a maintenance treatment with V alone. Eligible pts had histologically confirmed untreated stage IIIb or IV NSCLC. In cohorts 1 and 2, pts received V at 10 mg/kg and 20mg/kg IV, respectively, on days 1 and 8, of the first 21 day cycle then every 21 days. In cohort 3, pts received V 30 mg/kg IV every 21 days from day 1. We present here the interim safety analysis and RECIST response data of the combination therapy. Results: A total of 22 patients (9, 6 and 7 in cohorts 1, 2 and 3 respectively) who received at least one dose of treatment constitute the safety population. Reported salient adverse events (any grade) were constipation (68%), asthenia (64%), nausea (59%), arthralgia (55%) and paresthesia (46%). Grade 3 bowel obstruction in one patient was considered a DLT in cohort 2. No DLT's were observed in cohort 3. Seven pts reported at least one serious adverse event (all Grade 3) including deep vein thrombosis (1), peripheral arterial occlusion (1), proteinuria (1), pneumonitis (1), small intestinal obstruction (1), pleural effusion (1), hypoxia (1), dehydration (1) and orthostatic hypotension (1). Partial response was seen in 6 pts and stable disease in 12 out of 18 pts who were evaluable for response by RECIST. Conclusions: The highest dose of V tested (30 mg/kg q3w) in combination with CP appears well tolerated and the regimen has promising clinical activity in advanced NSCLC. [Table: see text]

scholarly journals An open-label, dose-finding study of the combination of satraplatin and gemcitabine in patients with advanced solid tumors

2012 ◽  
Vol 2 ◽  
Author(s):  
Eugenio Donato Di Paola ◽  
Silvia Alonso ◽  
Rosa Giuliani ◽  
Fabio Calabrò ◽  
Antonietta D’Alessio ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Finding Study ◽  
Label Dose ◽  
Dose Finding Study

scholarly journals A Phase Ib, open-label, dose-finding study of alpelisib in combination with paclitaxel in patients with advanced solid tumors

Oncotarget ◽  
2018 ◽  
Vol 9 (60) ◽  
pp. 31709-31718 ◽  
Author(s):  
Jordi Rodon ◽  
Giuseppe Curigliano ◽  
Jean-Pierre Delord ◽  
Wael Harb ◽  
Analia Azaro ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Finding ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase Ib ◽  
Finding Study ◽  
Label Dose ◽  
Dose Finding Study

scholarly journals UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis

2015 ◽  
Vol 13 (9) ◽  
pp. 1615-1622 ◽  
Author(s):  
S. H. O'Brien ◽  
D. L. Yee ◽  
J. Lira ◽  
N. A. Goldenberg ◽  
G. Young
Keyword(s):  
Deep Vein Thrombosis ◽  
Dose Finding ◽  
Open Label ◽  
Safety Study ◽  
Vein Thrombosis ◽  
Label Dose ◽  
Deep Vein

Safety and pharmacokinetics (PK) of AMG 706 in combination with panitumumab and gemcitabine-cisplatin in patients (pts) with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14057-14057 ◽  
Author(s):  
J. Crawford ◽  
H. Burris ◽  
J. Stephenson ◽  
G. Otterson ◽  
M. Stein ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Advanced Cancer ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Unknown Primary ◽  
Open Label ◽  
Prior Chemotherapy ◽  
Label Dose ◽  
Grade 3

14057 Background: AMG 706 is an oral, investigational multikinase (MKI) inhibitor with antiangiogenic and direct antitumor activity that selectively targets VEGF, PDGF and Kit receptors. Methods: This is an ongoing phase 1b, open-label, dose-finding study of AMG 706 plus panitumumab and gemcitabine-cisplatin. Objectives are to establish the maximum tolerated dose and to assess safety, objective response and PK of AMG 706 with this regimen. Pts =18 yrs with advanced cancer, ECOG 0–1, =1 prior chemotherapy for advanced disease and no prior oral VEGFr MKIs or anti EGFR therapy, received panitumumab (9mg/kg IV day 1 of each 3-wk cycle) plus gemcitabine (1250mg/m2 IV days 1 and 8) and cisplatin (75mg/m2 IV day 1), and escalating doses of AMG 706 given continuously from day 1 of cycle 1. Assessments included dose-limiting toxicities (DLT; cycle 1), PK and tumor response (every 6–9 wks from wk 6). Results: As of Nov 2006, 36 pts (NSCLC n=19; pancreatic cancer n=4; other n=10; unknown primary n=3) were enrolled; 42% had prior chemotherapy. There was 1 DLT: pulmonary embolism, grade 5 (50mg QD). Selected treatment-related adverse events in =10% of pts are shown in the table . 39% of pts receiving AMG 706 had thromboembolic events (TE); 25% receiving study therapy without AMG 706 had TEs. There was 1 case of cholecystitis (grade 1), 1 of gallbladder pain (grade 3). Preliminary data showed that AMG 706 PK at 125 mg QD was comparable to data from monotherapy studies at the same dose level. Based on 29 pts with available response data (too early to evaluate/data unavailable n=7), objective tumor responses per RECIST were: CR n=1, 3% (breast cancer); PR n=9, 31% (NSCLC n=6; pancreatic cancer n=2; unknown primary n=1); SD n=17, 59%; PD n=1, 3%. Conclusions: In this study of pts with advanced cancer, AMG 706 was tolerable when combined with panitumumab and gemcitabine-cisplatin, with little effect on AMG 706 PK. Further studies need to determine if the observed TE rate exceeds gemcitabine-cisplatin background rates. [Table: see text] No significant financial relationships to disclose.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

Regorafenib plus nivolumab in patients with advanced gastric (GC) or colorectal cancer (CRC): An open-label, dose-finding, and dose-expansion phase 1b trial (REGONIVO, EPOC1603).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2522-2522 ◽  
Author(s):  
Shota Fukuoka ◽  
Hiroki Hara ◽  
Naoki Takahashi ◽  
Takashi Kojima ◽  
Akihito Kawazoe ◽  
...  
Keyword(s):  
Tumor Response ◽  
Maculopapular Rash ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Expansion Phase ◽  
Biomarker Analysis ◽  
Label Dose ◽  
Grade 3 ◽  
Expansion Cohort

2522 Background: Immune suppressive cells such as regulatory T cells (Tregs) or tumor-associated macrophages (TAMs) may contribute to resistance to anti-PD-1/PD-L1 inhibitors (A-PD1). Regorafenib, a potent inhibitor of angiogenic and oncogenic kinases, reduced TAMs in tumor models. The combination of regorafenib plus A-PD1 exhibited superior tumor growth suppression compared to either treatment alone in murine models. Methods: In this study, we enrolled patients (pts) with previously treated, advanced GC or CRC. The pts received regorafenib plus nivolumab in a dose-finding phase to estimate the maximum tolerated dose (MTD). Additional pts were enrolled in a dose-expansion phase to further establish the safety and determine the preliminary efficacy. Regorafenib of 80 to 160 mg was administered once daily for 21 on 7 days off with intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was dose-limiting toxicity (DLT) during cycle one (4 weeks) to estimate the MTD and the recommended dose. Results: Fifty pts were enrolled (25 GC; 25 CRC) until October 2018. The median prior treatment line was 3 (range 2-8). During dose-escalation, 3 DLTs were observed with regorafenib 160 mg, including grade (G) 3 maculopapular rash, mucositis and proteinuria, while there was no DLT with 80 or 120 mg. In the dose expansion cohort with regorafenib 120 mg, the dose was reduced to 80 mg owing to frequent G3 skin toxicities. Grade ≥ 3 treatment related adverse events occurred in 17 pts; the common events ( > 5%) being rash (14%), palmar-plantar erythrodysesthesia (10%), and proteinuria (8%). Objective tumor response was observed in 19 pts (38%) including 11 MSS GC, 7 MSS CRC and 1 MSI-H CRC for response rates of 44% in GC and 29% in MSS CRC. Three of the 7 A-PD1 pretreated GC pts achieved a partial response. The pre- and post-treatment tumor samples showed a reduction of FoxP3hiCD45RA-Tregs fraction at the tumor response. Conclusions: The combination of regorafenib 80mg plus nivolumab had a manageable safety profiles and encouraging anti-tumor activity in MSS GC and CRC pts, which warrants further investigations in a larger cohort. Updated biomarker analysis will be presented. Clinical trial information: NCT03406871.

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