A phase I study of the tolerability, safety, pharmacokinetics and preliminary antitumor effects of KBP-5209, a novel pan-HER inhibitor, in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2565-2565
Author(s):  
Sarina Anne Piha-Paul ◽  
Sunil Sharma ◽  
Chengkon Shih ◽  
Bert H. O'Neil ◽  
Qinghong Zhou ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Study Drug ◽  
Nausea And Vomiting ◽  
Advanced Solid Tumors ◽  
Irreversible Inhibitor ◽  
Antitumor Effects ◽  
Serious Adverse Events

2565 Background: KBP-5209 is a novel potent and irreversible inhibitor of tyrosine kinases of the human epidermal growth factor receptor (EGFR) family that preclinically has demonstrated potent antitumor activities in esophageal and gastric cancers and NSCLC. Methods: This first-in-human study (NCT02442414) was conducted to determine tolerability, safety, pharmacokinetics and antitumor activity of KBP-5209 administered QD or BID in patients (pts) with advanced solid tumors. Dose escalation (DE) initially was based on a modified accelerated titration plan and then shifted to a standard 3+3 design. The starting dose was 20 mg QD. Eligible patients were adults with advanced, refractory solid tumors with ECOG PS < 1. A cycle was 28 days. DLTs were evaluated for during the first cycle. DE enriched for patients with tumors having molecular alterations in EGFR or HER2/3. Dose escalation continues so dose expansion has not initiated. Results: As of 26 Nov, 2016, 23 pts (15 females, 8 males) are a part of the evaluable population with a median age 57 (37-79) treated at doses of 20mg (1), 40mg (3), 60mg (7), 70mg (4), 80mg (6) QD and 20mg BID (2).Tumor types included breast (6), CRC (4), ovarian (3), H&N (2), sarcoma (2), and NSCLC, sinus, gastric, gallbladder, pancreas, CUP tumor (1 each). Tumor genetic profiles were available for 20 pts. DLTs were G3 diarrhea, nausea, and vomiting, which occurred in 1 pt at 80mg QD and G3 Diarrhea, occurring in 1pt at 80mg QD. The most common adverse events related to study drug were diarrhea (60.9%), nausea (47.8%), vomiting (43.5%), fatigue (21.7%), decreased appetite (17.4%) and lipase increased (17.4%). Serious adverse events (SAEs) related to study drug were reported in 4pts: diarrhea (1 pt, 70mg QD; 1pt, 80mg QD), nausea and vomiting (1pt, 70mg QD), and diarrhea, nausea and vomiting (1 pt, 80mg QD). Stable disease has been observed in 7pts up to 24 weeks, in which 2/28 pts (7%) achieved tumor shrinkage. Conclusions: Based on the present data, KBP-5209 has been well tolerated with a safety profile similar to other pan-HER inhibitors. For QD dosing, maximum tolerated dose has been identified as 70mg QD. The BID dose escalation continues. Clinical trial information: NCT02442414.

Phase I trial of the programmed death receptor 1 (PD-1) inhibitor, BI 754091, in patients (pts) with advanced solid tumors.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 212-212 ◽  
Author(s):  
Melissa Lynne Johnson ◽  
Manish R. Patel ◽  
Lillian L. Siu ◽  
Mark Kozloff ◽  
Raid Aljumaily ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Activated T Cells ◽  
Serious Adverse Events ◽  
Anti Tumor Activity

212 Background: Tumors may achieve immune evasion by expressing PD ligand-1 (PDL-1) to bind to PD-1 expressed on activated T cells, initiating immunosuppressive signals within the tumor. Pro-inflammatory anti-tumor activity can be restored when this interaction is blocked by therapeutic PD-1 or PDL-1 inhibition. BI 754091 is a monoclonal IgG4Pro antibody directed against PD-1 that has demonstrated anti-tumor activity in vitro and in vivo. We present the results of the first in human study evaluating BI 754091 in patients with advanced solid tumors. Methods: Patients who had exhausted standard treatment (tx) options, including prior anti-PD-1 tx, were enrolled to receive BI 754091 IV every 3 weeks (Q3W) in one of 3 sequential dose escalation cohorts (80, 240 and 400 mg), 3 patients/cohort, to evaluate the safety and tolerability and establish the maximum-tolerated dose (MTD) or recommended Phase II Dose (RPIID). Additional anti-PD-1 naïve patients with select solid tumors are being enrolled in dose expansion to be treated with the selected RPIID. The objectives of the dose expansion cohort are to evaluate the safety, tolerability, PK and preliminary efficacy of the RPIID of BI 754091, in patients with advanced solid tumors. Results: 17 patients have enrolled to date, 9 patients in the dose escalation and 8 patients in the dose expansion cohorts. Both, safety and PK profile supported a RPIID of 240 mg. The most common all grade Treatment Related Adverse Events (TRAE) were fatigue 35% (6 patients), decreased appetite 18% (3 patients) and arthralgia 12% (2 patients). There were no dose-limiting toxicities, tx-related serious adverse events, or TRAEs ≥Grade 3 reported. To date, one patient (gastric cancer) has had a partial response, 8 had stable disease, and 8 patients continue on treatment. Additional efficacy data among patients in dose-expansion will be reported. Conclusions: BI 754091 is safe and well-tolerated across all dose levels tested for advanced solid tumors, with preliminary evidence of activity. A dose of 240 mg Q3W was selected for dose expansion and RPIID based upon the available safety and PK data. Clinical trial information: NCT02952248.

A phase I, first-in-human study to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of IMGN853 in patients (Pts) with epithelial ovarian cancer (EOC) and other FOLR1-positive solid tumors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2573-2573 ◽  
Author(s):  
Carla Kurkjian ◽  
Patricia LoRusso ◽  
Kamalesh Kumar Sankhala ◽  
Michael J. Birrer ◽  
Maurice Kirby ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Adverse Events ◽  
Solid Tumors ◽  
Dose Level ◽  
Dose Escalation ◽  
Drug Exposure ◽  
Cell Cancer ◽  
Human Study ◽  
Study Drug ◽  
Primary Study

2573 Background: IMGN853 is an antibody-drug conjugate (ADC) comprising a folate receptor 1 (FOLR1)-binding antibody and the potent maytansinoid, DM4. FOLR1 is over-expressed on many solid tumors, particularly EOC, endometrial cancer, non-small cell lung cancer (NSCLC), and clear-cell renal cell cancer. Methods: The primary study objectives are to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives include evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy. In dose escalation, patients with any type of FOLR1-expressing, refractory solid tumor may be enrolled. Once the MTD is defined, 3 expansion cohorts will evaluate patients with (1) primary platinum refractory or resistant EOC; (2) relapsed/refractory EOC, amenable to biopsy, and (3) relapsed/refractory NSCLC. Cohorts 2 and 3 will have IMGN853 PD assessment by pre-and post-dose tumor biopsy and by FLT-PET imaging, respectively. IMGN853 is given intravenously (IV) on Day 1 of each 21-day cycle. During dose escalation, an accelerated titration design was used. Responses are assessed using RECIST and GCIG criteria (as appropriate). Results: Eleven patients have been enrolled across 6 dose levels ranging from 0.15 to 5.0 mg/kg: 7 patients with EOC and 4 patients with endometrial cancer. No study drug-related serious adverse events (SAEs) or dose-limiting toxicity (DLT) have been reported. Among these 11 patients, 3 patients reported adverse events (AEs) considered study drug related; these were mild or moderate. At the 3.3 mg/kg dose level, one patient with serous EOC had an 82% reduction in CA125 (confirmation pending). The other 2 patients at this dose level, one with EOC and one with endometrial cancer, have stable disease. Drug exposure has been measured in 8 patients and has been found to generally increase linearly, with a half life at 3.3 mg/kg (3 patients) of approximately 4 days. Conclusions: IMGN853 is well tolerated at doses up to 3.3 mg/kg. Safety evaluation continues at 5 mg/kg and dose escalation is ongoing. Clinical trial information: NCT01609556.

scholarly journals First-in-Human Phase I, Dose-Escalation and -Expansion Study of Telisotuzumab Vedotin, an Antibody–Drug Conjugate Targeting c-Met, in Patients With Advanced Solid Tumors

2018 ◽  
Vol 36 (33) ◽  
pp. 3298-3306 ◽  
Author(s):  
John H. Strickler ◽  
Colin D. Weekes ◽  
John Nemunaitis ◽  
Ramesh K. Ramanathan ◽  
Rebecca S. Heist ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Antibody Drug Conjugate ◽  
Median Response ◽  
Drug Conjugate ◽  
Antibody Drug

Purpose This first-in-human study evaluated telisotuzumab vedotin (Teliso-V), formerly called ABBV-399, an antibody–drug conjugate of the anti–c-Met monoclonal antibody ABT-700 and monomethyl auristatin E. Materials and Methods For dose escalation, three to six patients with advanced solid tumors were enrolled in eight cohorts (0.15 to 3.3 mg/kg). The dose-expansion phase enrolled patients with non–small-cell lung cancer (NSCLC) with c-Met–overexpressing tumors (c-Met positive; immunohistochemistry membrane H-score ≥ 150). Patients received Teliso-V monotherapy intravenously on day 1 once every 3 weeks. Safety, tolerability, pharmacokinetics, and maximum tolerated dose were determined. Results Forty-eight patients were enrolled (median age, 65 years; 35.4% NSCLC; median four prior therapies). One patient each in the 3.0-mg/kg (n = 9) and 3.3-mg/kg (n = 3) cohorts experienced dose-limiting toxicities. Although the maximum tolerated dose was not formally identified, the recommended phase II dose was defined as 2.7 mg/kg on the basis of overall safety and tolerability. The most frequent treatment-emergent adverse events (any grade) were fatigue (42%), nausea (27%), constipation (27%), decreased appetite (23%), vomiting (21%), dyspnea (21%), diarrhea (19%), peripheral edema (19%), and neuropathy (17%). The most frequent Teliso-V–related grade ≥ 3 adverse events were fatigue, anemia, neutropenia, and hypoalbuminemia (4% each). Teliso-V and total antibody pharmacokinetics were approximately dose proportional, with a mean harmonic half-life of 2 to 4 days each. Prospective screening identified 35 (60%) of 58 patients with c-Met–positive NSCLC. Of 16 patients with c-Met–positive NSCLC who were treated with Teliso-V 2.4 to 3.0 mg/kg, three (18.8%; 95% CI, 4.1% to 45.7%) achieved a partial response (median response duration, 4.8 months; median progression-free survival, 5.7 months; 95% CI, 1.2 months to 15.4 months). No other patients experienced a response. Conclusion Teliso-V monotherapy demonstrated favorable safety and tolerability profiles, with encouraging evidence of antitumor activity in patients with c-Met–positive NSCLC.

scholarly journals Clinical Trial Results from the Subgroup of Lymphoma/CLL in a Phase 1 Study of ARQ 092, a Novel Pan AKT-Inhibitor

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5116-5116 ◽  
Author(s):  
Wael Harb ◽  
Mansoor N. Saleh ◽  
Kyriakos P Papadopoulos ◽  
Feng Chai ◽  
Maria Larmar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Malignant Lymphoma ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Human Study ◽  
Advanced Solid Tumors ◽  
Akt Inhibitor ◽  
Dosing Schedule ◽  
Mantle Cell ◽  
Expansion Cohort

Abstract Background: ARQ 092 is an oral allosteric, potent and selective AKT inhibitor with in vitro and in vivo activity in solid and hematological tumors. ARQ 092-101, the first clinical trial of ARQ 092, has enrolled more than 100 subjects with advanced solid tumors or recurrent malignant lymphoma. As reported previously, the dose escalation portion of the study has been completed and two dosing schedules (intermittent and weekly), are recommended for phase 2 studies. The recommended phase 2 dose (RP2D) for the intermittent dosing schedule is 200 mg once daily (QD) (one week on, one week off) and for the weekly dosing schedule is 300 mg twice daily (BID) (one day on, six days off). [1, 2] Enrollment in an expansion cohort at RP2Ds is ongoing. Here we report the results from 11 subjects with lymphoma/CLL. Material and Methods: Subjects with lymphoma/CLL have been enrolled and treated in the dose escalation and expansion cohorts with intermittent or weekly dosing schedule at the RP2Ds. Tumor responses for subjects with lymphoma were evaluated based on the Revised Response Criteria for Malignant Lymphoma. Adverse events were evaluated based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. Blood samples were collected for PK analysis. Archival or biopsy tumor tissue samples were collected for genetic analysis. Results: As of 15 Jun 2015, 11 subjects with lymphoma/CLL (73% male; median age 78 years; 5 follicular, 3 mantle cell, 2 diffuse large B cell, 1 CLL; 4 in dose escalation cohorts, 7 in expansion cohort) have been enrolled and treated at initial doses of 120 to 270 mg QD intermittently (n=7) or 300 mg BID weekly (n=4). All subjects have received at least one prior systemic therapy (median 2, range 1-6). Median duration on study treatment for all 11 subjects was 8 weeks (range 1 to 30 weeks). One subject with CLL and two with follicular lymphoma experienced durable partial responses, respectively with times to response of 8, 8 and 24 weeks and response durations of 16, 8+, and 2+ weeks. The two follicular PR subjects, one of whom had an AKT1 (E17K) mutation, remain on study treatment. In addition, one subject with follicular and one with mantle cell lymphoma experienced stable diseases. Four subjects experienced progressive diseases and two were not evaluable for tumor responses due to early consent withdrawal and clinical disease progression. Table 1. Common drug-related adverse events (≥10%) included macula-papular rash 45%, hyperglycemia 36%, mucosal inflammation 18% and stomatitis 18%. Response Follicular N=5 CLL N=1 Mantle cell N=3 Diffuse large B cell N=2 Total N=11 PR 2 1 3 SD 1 1 2 PD 1 2 1 4 NE 1 1 2 ORR 40% 100% 0% 0% 27% DCR 60% 100% 33% 0% 45% Conclusions: The safety profile of lymphoma subjects is consistent with subjects with solid tumors enrolled in this study. Preliminary signs of single agent activity have been documented with 3 PRs in heavily pretreated lymphoma/CLL including one with AKT1 (E17K) mutation. [1] First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. M. Saleh et al., Abstract LB-197, AACR 104th Annual Meeting, 6-10 Apr 2013. Washington, D.C. U.S. [2] First-in-human study with ARQ 092, a novel pan AKT-inhibitor, in subjects with advanced solid tumors or recurrent malignant lymphoma. M. Saleh et al., Abstract 320, EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics , 18-21 Nov 2014, Barcelona, Spain Disclosures Harb: Onyx Pharmaceuticals: Consultancy. Chai:ArQule, Inc.: Employment. Larmar:ArQule, Inc.: Employment. Abbadessa:ArQule, Inc.: Employment. Schwartz:ArQule, Inc.: Employment.

Phase I study of LBL-007, a novel anti-human lymphocyte activation gene 3 (LAG-3) antibody in patients with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2523-2523
Author(s):  
Yuankai Shi ◽  
Suxia Luo ◽  
Huan Zhou ◽  
Shengyu Zhou ◽  
Shan An ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Objective Response ◽  
Human Study ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Tumor Immune Escape

2523 Background: LAG-3 is an immune checkpoint receptor expressed on activated T cells to negatively regulate these cells, resulted in tumor immune escape. LBL-007, a novel anti-LAG-3 antibody, was developed by screening of a human antibody phage display library and demonstrated specific binding to human LAG-3, stimulation of IL-2 release and blockage of LAG-3 binding to its ligands including MHC II. It has shown that LBL-007 significantly inhibited tumor growth in a mouse MC38 tumor model in hLAG-3 knock-in mice with more pronounced tumor inhibition when combined with an anti-PD-1 antibody. Methods: A phase I, multicenter, open-label and first-in-human study was conducted to evaluate the safety, tolerability, and PK in patients with advanced solid tumors. The dose escalation phase was designed with 6 dose cohorts of LBL-007 at 0.05, 0.25, 1, 3, 6 and 10 mg/kg (iv every 2 weeks), using a modified 3+3 design. Key inclusion criteria included: age≥18 years, histologically/cytologically confirmed advanced solid tumors, failed ≥2 lines of prior standard therapies, ECOG of 0-1, and adequate hematologic, renal, hepatic, and cardiac function. Patients who received anticancer or immunotherapy 4 weeks from first dose of LBL-007 were excluded. The primary endpoints were tolerability and safety. Adverse events (AEs) were graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0. Any potential efficacy was assessed by objective response rate (ORR) evaluated by CT/MRI per RECIST 1.1. Results: From March 12th, 2020 to Feb 9th, 2021, 17 patients were evaluated in this study. There were no dose limiting toxicities (DLTs) at any dose cohorts, and patients were tolerated very well. Overall, there were 129 adverse events (AEs), and 8 events were serious adverse event (SAE), of which 5 were defined as suspected unexpected serious adverse reaction (SUSAR), but most unlikely treatment related AEs (TRAEs). All AEs regardless of attribution included anemia, hypocalcemia, and flu related respiratory infection, etc. The most common AEs were anemia (14, 10.9%), hypocalcemia (6, 4.7%) and thrombocytopenia (4, 3.1%). Totally, there were 8 patients without disease progression, defined as SD at the first evaluation and sustained for 3.5-9 months. The target lesions in 2 of these 8 patients were reduced by 18.9% and 23.2% (both in esophagus cancer). The progression-free survival of these 2 patients was 4.4 and 9.0 months, respectively. Patients are also being enrolled into the indication exploratory phase (3 and 6 mg/kg), testing the combination therapy with an anti-PD-1 antibody in patients with melanoma and other solid tumors. Conclusions: The dose escalation part of the study revealed tolerability of LBL-007 with an impressive safety profile, and potentially some encouraging signs of anti-tumor activities. Clinical trial: Chinaclinicaltrials.org.cn (1900025904). Clinical trial information: CTR20210196.

scholarly journals Quality-of-Life (QOL) during Screening for Phase 1 Trial Studies in Patients with Advanced Solid Tumors and Its Impact on Risk for Serious Adverse Events

Cancers ◽  
2017 ◽  
Vol 9 (12) ◽  
pp. 73 ◽  
Author(s):  
Sidra Anwar ◽  
Wei Tan ◽  
Chi-Chen Hong ◽  
Sonal Admane ◽  
Askia Dozier ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Adverse Events ◽  
Solid Tumors ◽  
Phase 1 ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Phase 1 Trial

Results of two phase I dose escalation studies of the oral heat shock protein 90 (Hsp90) inhibitor SNX-5422.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2617-2617
Author(s):  
Todd Michael Bauer ◽  
Jeffrey R. Infante ◽  
Ramesh K. Ramanathan ◽  
Glen Weiss ◽  
Jasgit C. Sachdev ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Hsp90 Inhibitor ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Two Phase ◽  
Blurry Vision

2617 Background: SNX-5422 is a prodrug of SNX-2112, a highly potent, non-geldanamycin analog, HSP90 inhibitor with preclinical anti-tumor activity in multiple tumor models. These phase 1 studies were designed to evaluate safety and tolerability, determine dose limiting toxicities, maximum tolerated doses (MTDs), and describe pharmacokinetics of SNX-2112 and SNX-5422. Methods: Two phase 1, open-label, 3 + 3 dose-escalation studies evaluated SNX-5422 when given daily (QD) or every-other-day (QOD) during the first 30 days of treatment in patients (pts) with advanced solid tumors or lymphoma. Plasma concentrations of SNX-2112 and SNX-5422 were measured after the first and 11th (steady state) doses. Tumor assessments were performed every 8 weeks. Results: In both studies, pts received SNX-5422 QOD, 3 wks on/1 wk off, with doses ranging from 4 to 133 mg/m2 QOD. In one study, pts also received QD doses from 50 to 89 mg/m2, 3 wks on/1 wk off, and 50 mg/m2 QD continuously. Fifty-six pts (34M/22F; mean age 62 years) were enrolled. Treatment-related adverse events were mainly low grade (G), including diarrhea (64%), nausea (39%), vomiting (29%), fatigue (27%), abdominal pain (14%), and anorexia (14%). Reversible G 1 blurry vision, and G 1-2 blurry vision/vision darkening were reported by 1 pt on 100 mg/m2 QOD, and 4 pts treated with 50 to 89 mg/m2 QD. G 3 diarrhea was dose limiting in 2 of 3 pts (89 mg/m2 QD; 133 mg/m2 QOD). MTDs for the QOD and QD schedules were declared at100 mg/m2 and 67 mg/m2, respectively. The QD schedule was associated with higher incidences of treatment related adverse events. 38 pts were evaluable for response including 1 confirmed durable complete response, 1 unconfirmed partial response, and 17 with stable disease. Activity was seen in adrenal, lung, liver, neuroendocrine, GIST, and prostate. All but 2 were seen with the QOD schedule. Conclusions: SNX-5422 mono-therapy was generally well tolerated and showed promising signs of efficacy in pts with advanced solid tumors. Given the superior benefit-risk profile of QOD dosing over QD dosing based on these preliminary clinical findings, 100 mg/m2 QOD has been selected for further clinical testing. Clinical trial information: NCT00506805 and NCT01611623.

A first-in-human phase I study of oral pan-CDK inhibitor BAY 1000394 in patients with advanced solid tumors: Dose escalation with an intermittent 3 days on/4 days off schedule.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3012-3012 ◽  
Author(s):  
Rastislav Bahleda ◽  
Anas Gazzah ◽  
Andrea Varga ◽  
Prabhu Rajagopalan ◽  
David Andrew Henderson ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Oral Solution ◽  
Tablet Formulation ◽  
Nausea And Vomiting ◽  
Cdk Inhibitor ◽  
Advanced Solid Tumors ◽  
Antiemetic Treatment ◽  
Grade 3

3012 Background: BAY 1000394 (BAY) is an oral pan-CDK inhibitor targeting CDKs 1,2,4, 7 and 9 in the low nanomolar range. A phase I dose escalation study was initiated to determine the maximum tolerated dose (MTD), pharmacokinetics (PK), and pharmacodynamics (PD) in patients (pts) with advanced solid tumors. Methods: BAY was administered twice daily in a 3 days on / 4 days off schedule (cycle length 21 days, 3+3 design). PK was evaluated on cycle 1 day 1 and day 10. Response rate was assessed according to RECIST 1.1. PD markers included CK18 fragments in plasma. Results: As of Jan 08 2011, 34 pts were treated at doses of 0.6 (3 pts), 1.2 (4), 2.4 (3), 4.8 (3), 9.6 (3), 19.2 (6) mg per day as oral solution and at doses of 10 (4), 15 (6) and 20 (2) mg per day as tablet. Tumor types included 10 colorectal, 4 mesothelioma and 20 others. Cohort 9 (20 mg tablet) is ongoing. Frequent CTCAEv4 grade 1/2 drug related AEs occurring in more than 25% of patients up to cohort 8 were asthenia, diarrhea, nausea, vomiting and anorexia. DLTs (grade 3, 1 pt each) were hyponatremia, aphtous stomatitis at 19.2 mg solution and arterial thrombosis at 15 mg tablet. Aphthous stomatitis (20%) has not been observed with the tablet formulation. Other grade 3 related AEs were asthenia in 2 and nausea and vomiting in one pt each. Nausea and vomiting on treatment days were observed despite antiemetic treatment (aprepitant +/- setron). PK was dose proportional up to 9.6 mg, T1/2 was 10 hours, and relative bioavailability of tablet formulation was excellent; major metabolite levels were low (<10%). Levels of CK18 fragments did not correlate with dose or tumor response. Stable disease (SD) lasting for 2-4 months was observed in 9 patients, among others in 4 of 4 mesothelioma and 2 of 2 ovarian pts. One additional pt with cholangiocarcinoma has ongoing SD lasting for 5 months. One of the ovarian pts had a significant decline of CA125 lasting for 3 months. Conclusions: The tablet formulation of BAY 1000394 was better tolerated than oral solution. So far, doses up to a 15 mg per day with concomitant antiemetic treatment showed an acceptable tolerability. SD was observed in 10 of 25 heavily pretreated pts across cohorts 3 – 8.

Phase I study of capecitabine, oxaliplatin, bevacizumab, and everolimus in advanced solid tumors.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
Fatima A. Rangwala ◽  
Johanna C. Bendell ◽  
Mark Kozloff ◽  
Christy Arrowood ◽  
Jennifer Meadows ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Rectovaginal Fistula ◽  
Dose Intensity ◽  
Advanced Solid Tumors ◽  
Increased Risk ◽  
Level 1 ◽  
Grade 3

490 Background: Everolimus (E), an oral rapamycin analogue, is a potent mTOR inhibitor. Combined inhibition of VEGF and mTOR pathways may increase anti-angiogenic and anti-tumor activity. We evaluated E in combination with capecitabine (C), oxaliplatin (O), and bevacizumab (B) in a phase I dose escalation study. Methods: Eligible patients (pts) had advanced solid tumors, adequate organ function and no increased risk for class-related toxicities. B and O were given intravenously; C and E were orally administered. Cycle length was 21 days. Doses for level 1: C 850 mg/m2 on days 1-14; O 130 mg/m2 on day one; B 7.5 mg/kg on day one; and E 5 mg three times a week. Doses for level -1: C 680 mg/m2, O100mg/m2. An intermediate dose level (-1b) of E escalated to 5 mg five times weekly was added to maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1. Concomitant administration of CYP3A4 substrates, inhibitors or inducers was prohibited. Results: Dose escalation is complete with 27 pts evaluable for toxicity and 24 evaluable for efficacy. Two DLTs (grade 2 intolerable fatigue, anorexia, vomiting and grade 3 diarrhea) were observed in 6 pts in cohort 1. No DLTs were observed in cohort -1; one DLT (rectovaginal fistula) was observed in the -1b cohort. Possible grade ≥3 treatment-related adverse events any time on study (n=1 except as indicated) included diarrhea (n=2), intestinal perforation/fistula, rectovaginal fistula, hypertriglyceridemia (n=3), hyperglycemia, hypoalbuminemia, hyponatremia, peripheral neuropathy, neutropenia (n=2), lymphopenia, thrombocytopenia, hypertension (n=3), deep vein thrombosis, and arterial thrombosis. Adverse events were consistent with known class-related toxicities. For efficacy, 10 pts had a partial response (PR); 10 had stable disease as best response. Of 13 pts with chemorefractory metastatic colorectal cancer (mCRC), 5 had a PR. Of 8 pts with chemonaive mCRC, 5 had a PR. Conclusions: E in combination with full dose C, O and B was associated with unacceptable toxicity, primarily GI toxicity. E at 5mg five times weekly, C at 680 mg/m2 on days 1-14, O at 100 mg/m2 and B at 7.5 mg/kg on day one appears well tolerated. Activity was noted in chemorefractory and chemonaive mCRC patients.

First-in-human dose escalation study of LY2875358 (LY), a bivalent MET antibody, as monotherapy and in combination with erlotinib (E) in patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8093-8093 ◽  
Author(s):  
Jonathan Wade Goldman ◽  
Lee S. Rosen ◽  
Alain Patrick Algazi ◽  
Patricia Kellie Turner ◽  
Volker Wacheck ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Advanced Nsclc ◽  
Single Agent ◽  
Primary Objective ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Dose Escalation Study ◽  
Human Dose ◽  
Recommended Phase Ii Dose

8093 Background: Activation of the hepatocyte growth factor (HGF)/MET receptor pathway promotes tumor growth, invasion and dissemination. LY is a humanized IgG4 monoclonal bivalent antibody against MET which inhibits ligand dependent- and ligand independent activation of MET. Based on preclinical results, we examined LY alone in patients with advanced solid tumors and LY+E in advanced NSCLC patients. Methods: LY monotherapy was administered 20-2,000 mg Q2W IV to 23 patients with advanced solid tumors. Combination therapy with 700-2,000 mg Q2W IV of LY and E (150 mg QD) was completed in 14 patients with advanced NSCLC. The primary objective was to determine a recommended phase II dose (RPTD) for LY and LY+E. Secondary objectives included assessment of toxicity, PK, PD (including MET extracelluar domain and HGF), and antitumor activity. Results: LY and LY+E were well tolerated. No dose-limiting toxicities, serious adverse events, or ≥ Grade 3 adverse events (AEs) possibly related to LY have been observed. The most frequent (≥5% of patients) AEs possibly related to LY2875358 monotherapy were nausea (8.7 %), vomiting (8.7%), and diarrhea (8.7%). The most frequent (≥10% of patient) grade 1 or 2 adverse event possibly related to LY2875358 in patients treated with LY+E were fatigue (21.4%) and anorexia (14.3%). Durable PR according to RECIST were observed for LY (n=1) and LY+E (n=2 out of 13 evaluable patients; both PR patients positive for MET protein expression). Conclusions: LY appears to be safe when administered as single agent and in combination with E up to 2,000 mg Q2W IV. The RPTD of LY is 750 mg Q2W IV for monotherapy and in combination with E based on PK/PD data. Clinical trial information: NTC 01287546.

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