AMG 386, a selective angiopoietin 1/2-neutralizing peptibody, in combination with chemotherapy in adult patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14033-14033 ◽  
Author(s):  
A. C. Mita ◽  
D. Wang ◽  
C. H. Takimoto ◽  
E. Malseed ◽  
L. Nguyen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Neutralizing Antibodies ◽  
Tumor Response ◽  
Adult Patients ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Amg 386 ◽  
Angiopoietin 1

14033 Introduction: AMG 386 is a selective angiopoietin 1 /2-neutralizing peptibody that inhibits angiogenesis by preventing interaction between angiopoietins and Tie2 receptors. This open-label study evaluated the safety, pharmacokinetics (PK), and antitumor activity of AMG 386 in combination with FOLFOX-4 (F), carboplatin + paclitaxel (CP), or docetaxel (D) in adult patients (pts) with advanced solid tumors. Methods: Three cohorts of 6–9 pts received 1 full cycle of chemotherapy (2 weeks of F or 3 weeks of D 75 mg/m2 or CP). Administration of AMG 386 10 mg/kg IV weekly was started on day 1 of cycle 2 for patients who did not experience a dose-limiting toxicity (DLT) to chemotherapy during cycle 1, and continued until disease progression or intolerance. Safety and tolerability, tumor response (RECIST every 8 weeks), PK profiles of AMG 386 and chemotherapy agents, and formation of antibodies to AMG 386 were assessed. Results: As of October 2, 2006, 16 pts have received AMG 386: 6 pts in the F cohort, 5 in CP, and 5 in D; 7 pts were men, median age 59.5 years (range, 44- 75 years). No AMG 386-related serious AEs or DLTs were reported. AEs related to chemotherapy + AMG 386 in = 2 pts were neutropenia (n = 3), thrombocytopenia (n=2), diarrhea (n=2), and vomiting (n=2). No neutralizing antibodies were observed. F, CP, and D coadministered with AMG 386 did not appear to affect the PK profile of AMG 386, and AMG 386 had no apparent effect on the PK profile of 5 FU, leucovorin, C, P, or D. Tumor response data are available for 6 pts. One pt receiving CP+ AMG 386 for bladder cancer refractory to gemcitabine/cisplatin had a complete response (CR) at week 8, confirmed at week 16. Stable disease in 4 pts and progressive disease in 1 pt were also observed. Conclusions: Weekly administration of AMG 386 in combination with F, CP, or D appears to be safe and well tolerated. A CR in bladder cancer suggests promising antitumor activity of AMG 386 in combination with chemotherapy. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. [Table: see text]

Phase I trial of trebananib (AMG 386) plus temsirolimus (Tr + T) in patients (pts) with advanced solid tumors (PJC-008/NCI#9041).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2534-2534
Author(s):  
David Shao Peng Tan ◽  
Christian K. Kollmannsberger ◽  
Sebastien J. Hotte ◽  
David W. Cescon ◽  
Ivan Diaz-Padilla ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Antitumor Activity ◽  
Solid Tumors ◽  
Tumor Response ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Treatment Benefit ◽  
Amg 386 ◽  
Anti Cancer ◽  
Limb Edema

2534 Background: Preclinical data suggest that combined Ang1/2 and mTOR blockade has synergistic anti-cancer activity. The combination of Tr (inhibits angiogenesis by preventing interaction of Ang1/2 with Tie2) with the mTOR inhibitor T was evaluated in pts with advanced solid tumors to determine safety, tolerability, maximum tolerated dose (MTD), pharmacodynamics and preliminary antitumor activity. Methods: Pts were enrolled using 3+3 design. Tr and T were dosed on Day 1 (D1), 8, 15 and 22 of a 28-day cycle. Peripheral blood was collected for evaluation of Tie2-expressing monocytes (TEMs) and thymidine phosphorylase (TP) (an angiogenic enzyme increased in TEMs upon Tie2 stimulation) by flow cytometry. Tumor response was assessed every 2 cycles. Results: 13 pts have been enrolled, 6 at dose level (DL) 1 (15mg/kg Tr + 25mg T) and 7 (1 died from disease before DLT assessment) at DL -1 (15mg/kg Tr + 20mg T). Median age was 57yrs, ECOG 0-1, median previous chemotherapy lines 3 (range 1-8). In DL 1, 1/6 pts experienced DLT (Grade (Gr) 2 pneumonitis). In view of frequent Gr2 adverse events (AEs) in DL 1, DL -1 was evaluated with DLTs in 2/6 evaluable pts (Gr3 mucositis and intolerable Gr2 limb edema preventing start of cycle 2 within 14 days). The most common related AEs (all Gr across both DL) were: fatigue (77%), edema (69%), anorexia (62%), and nausea (54%). Common Gr≥3 AEs included lymphopenia (23%) and fatigue (23%). Of 10 evaluable pts, best RECIST responses were: 1 breast cancer pt (ER+/ HER2-/ PIK3CA mutant) with PR (now in cycle 9), 7 pts with SD, and 2 pts with PD. Four pts with ovarian cancer (1 PIK3CAmutant) had SD ≥11weeks with 2/3 pts (1 not evaluable) demonstrating GCIG response (>50% decrease in CA125). In preliminary analyses, TP expression in TEMs was decreased (mean -18%) in 4pts with tumor shrinkage, but increased (+6%) in 1pt with tumor growth, suggesting a trend between reduced TP and tumor response. Conclusions: The MTD was exceeded at 15mg/kg Tr and 20mg T weekly. The safety of 10mg/kg Tr and 20mg T weekly is currently being evaluated. The combination of Tr and T shows early signs of antitumor activity. TP expression in TEMs by flow cytometry as an early marker of treatment benefit warrants further evaluation. Clinical trial information: NCT01548482.

Safety, pharmacokinetics, and antitumor activity of MEDI-573, an investigational monoclonal antibody that targets IGF-I and IGF-II, in adult patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2618-TPS2618 ◽  
Author(s):  
Paul Haluska ◽  
Michael E. Menefee ◽  
Elizabeth R. Plimack ◽  
Jonathan E. Rosenberg ◽  
Donald W. Northfelt ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Level ◽  
Glucose Homeostasis ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Adult Patients ◽  
Human Antibody ◽  
Advanced Solid Tumors ◽  
Igf I

TPS2618 Background: MEDI-573 is an investigational dual-targeting human antibody that neutralizes IGF-I/-II ligands and inhibits IGF‑1R and insulin receptor-A (IR-A) signaling pathways. By sparing IR-B and its hybrid receptors, MEDI-573 may achieve antitumor activity without perturbing glucose homeostasis. Objectives of this phase 1 dose-escalation and expansion study are to evaluate safety and determine the maximum tolerated dose (MTD), optimal biologically effective dose, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI-573 in adult patients with solid tumors. Methods: Patients with advanced solid tumors, Karnofsky status ≥60, and adequate organ function were treated with escalating doses of MEDI-573 IV once weekly (0.5 to 15 mg/kg) or every 3 weeks (30 or 45 mg/kg q3w) using a 3+3 design. Three patients per dose level were evaluated for safety. A biomarker-rich dose-expansion arm tested weekly 5 or 15 mg/kg MEDI‑573 in patients with advanced bladder cancer. Results: Preliminary data are presented for 43 patients (25 M, 18 F), median age 64 years. No dose-limiting toxicities or serious toxicity patterns occurred at any dose level. Drug-related adverse events occurring in ≥10% of patients were fatigue (28%), decreased appetite (23%), nausea (16%), diarrhea (14%), and anemia (12%); the majority were ≤ grade 2. Perturbations in insulin and growth hormone were not observed. Clinically significant changes in serum glucose were rare. The MTD was not reached after completely enrolling patients through the highest dose, 45 mg/kg IV q3w. Serum exposure of MEDI-573 increased with increasing dose. Full suppression of IGF‑I/-II was achieved with weekly and q3w dosing. No neutralizing antibodies against MEDI‑573 were detected. Of 43 patients, 8 (19%) had stable disease ≥12 weeks. The longest exposure was 21 months in a patient with well-differentiated liposarcoma. Conclusions: MEDI-573 demonstrated an acceptable safety profile at all doses tested. No dose-limiting toxicity or serious toxicities, including those related to glucose homeostasis, were detected. These preliminary results support further clinical development.

Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors

2009 ◽  
Vol 27 (21) ◽  
pp. 3557-3565 ◽  
Author(s):  
Roy S. Herbst ◽  
David Hong ◽  
Linnea Chap ◽  
Razelle Kurzrock ◽  
Edward Jackson ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Partial Response ◽  
Solid Tumors ◽  
Neutralizing Antibodies ◽  
Human Study ◽  
Terminal Phase ◽  
Advanced Solid Tumors ◽  
Transfer Constant ◽  
Tumor Vascularity ◽  
Amg 386

Purpose AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. Patients and Methods Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.3, 1, 3, 10, or 30 mg/kg. Results Thirty-two patients were enrolled on the study and received AMG 386. One occurrence of dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest, which likely was caused by tumor burden that was possibly related to AMG 386. The most common toxicities were fatigue and peripheral edema. Proteinuria (n = 11) was observed without clinical sequelae. Only four patients (12%) experienced treatment-related toxicities greater than grade 1. A maximum-tolerated dose was not reached. PK was dose-linear and the mean terminal-phase elimination half-life values ranged from 3.1 to 6.3 days. Serum AMG 386 levels appeared to reach steady-state after four weekly doses, and there was minimal accumulation. No anti–AMG 386 neutralizing antibodies were detected. Reductions in volume transfer constant (Ktrans; measured by dynamic contrast-enhanced magnetic resonance imaging) were observed in 10 patients (13 lesions) 48 hours to 8 weeks after treatment. One patient with refractory ovarian cancer achieved a confirmed partial response (ie, 32.5% reduction by Response Evaluation Criteria in Solid Tumors) and withdrew from the study with a partial response after 156 weeks of treatment; four patients experienced stable disease for at least 16 weeks. Conclusion Weekly AMG 386 appeared well tolerated, and its safety profile appeared distinct from that of vascular endothelial growth factor–axis inhibitors. AMG 386 also appeared to impact tumor vascularity and showed antitumor activity in this patient population.

A phase 1b, open-label, dose-escalation study to evaluate camidanlumab tesirine (Cami) as monotherapy in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2556-2556
Author(s):  
Igor Puzanov ◽  
Patricia LoRusso ◽  
Kyriakos P. Papadopoulos ◽  
Christopher T. Chen ◽  
Yvan LeBruchec ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Single Agent ◽  
Treatment Withdrawal ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1B ◽  
Grade 3

2556 Background: Depletion of tumor-infiltrating CD25+ regulatory T cells (Tregs), which inhibit tumor-specific immune responses, could contribute to tumor eradication. Cami (ADCT-301), an anti-CD25, pyrrolobenzodiazepine-based antibody-drug conjugate, targets CD25+ Tregs. A mouse surrogate has shown potent antitumor activity in solid tumor models. Here we report preliminary data from the monotherapy arm of a phase 1b trial of Cami in pts with selected advanced solid tumors. Methods: The monotherapy dose-escalation part of this open-label study enrolled pts (aged ≥18 years) with selected advanced solid tumors and no suitable existing therapy. The primary objective was to characterize safety and tolerability, and to identify the recommended phase 2 dose of Cami monotherapy. Secondary and exploratory objectives included evaluation of preliminary antitumor activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity. Pts received Cami every 3 weeks (1 cycle) with dose escalation per a 3+3 design. Disease control rate (DCR) was assessed (complete and partial responses [CR, PR] and stable disease). Results: At data cut-off (Dec 17, 2020), 44 pts were enrolled, with primary tumor types (stage IVA/B: 27 pts; 61.4%) of colorectal (15 pts; 34.1%), pancreatic (14 pts; 31.8%), head and neck, ovarian/fallopian tube, and renal cell carcinoma (all 3 pts; 6.8%), non-small cell lung cancer (2 pts; 4.5%), gastric, esophageal/GEJ, melanoma, and triple-negative breast cancer (each 1 pt; 2.3%). Median (range) age was 60.5 (33–82) years; median (range) number of prior systemic therapies was 4 (1–9). Pts received a median (range) of 2 (1–6) Cami cycles at doses of 20–150 µg/kg. Median (range) treatment duration was 22 (1–178) days. No dose-limiting toxicities were reported. The maximum tolerated dose (MTD) was not reached. All-grade treatment-emergent adverse events (TEAEs) in ≥20% pts were nausea (18 pts; 40.9%), decreased appetite and fatigue (each 16 pts; 36.4%), constipation (13 pts; 29.5%), abdominal pain (11 pts; 25%), and rash (10 pts; 22.7%). The only Grade ≥3 TEAE in ≥10% pts was anemia (5 pts; 11.4%). Grade 3 autoimmune AEs (colitis, immune-mediated AE, systemic inflammatory response syndrome) and neurologic AEs (dysphagia and asthenia, but not GBS) were reported in 3 (6.8%) and 2 (4.5%) pts, respectively. 1 (2.3%) Cami-related TEAE led to treatment withdrawal; no Cami-related TEAEs were fatal. DCR was 25% (95% CI: 11.1, 34.7); 11/44 pts attained stable disease. No pts had CR or PR. Conclusions: Dose escalation of Cami monotherapy is complete. The safety profile is encouraging and MTD was not reached. PK/PD data will be presented. 150 µg/kg is the highest dose investigated for single-agent Cami and the highest to be investigated combined with pembrolizumab in selected advanced solid tumors in the current protocol. Funding: ADC Therapeutics SA NCT03621982. Clinical trial information: NCT03621982.

scholarly journals Tislelizumab in Chinese patients with advanced solid tumors: an open-label, non-comparative, phase 1/2 study

2020 ◽  
Vol 8 (1) ◽  
pp. e000437
Author(s):  
Lin Shen ◽  
Jun Guo ◽  
Qingyuan Zhang ◽  
Hongming Pan ◽  
Ying Yuan ◽  
...  
Keyword(s):  
Cell Death ◽  
Antitumor Activity ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Phase 1 ◽  
Chinese Patients ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Dose Verification ◽  
Open Label

BackgroundTislelizumab is an investigational, humanized, IgG4 monoclonal antibody with high affinity and binding specificity for programmed cell death-1 (PD-1) that was engineered to minimize binding to FcγR on macrophages in order to abrogate antibody-dependent phagocytosis, a mechanism of T-cell clearance and potential resistance to anti-PD-1 therapy.MethodsThe purpose of this phase 1/2, open-label, non-comparative study was to examine the safety, tolerability, and antitumor activity of tislelizumab in adult (≥18 years) Chinese patients with histologically or cytologically confirmed advanced solid tumors with measurable disease. The phase 1 portion of the study consisted of a dose-verification study and a pharmacokinetic (PK) substudy; phase 2 was an indication-expansion study including 11 solid tumor cohorts. Patients previously treated with therapies targeting PD-1 or its ligand, programmed cell death ligand-1 were excluded. During dose-verification, dose-limiting toxicities (DLTs) were monitored; safety and tolerability were examined and the previously determined recommended phase 2 dose (RP2D) was verified. The primary endpoint of phase 2 was investigator-assessed objective response rate per Response Evaluation Criteria in Solid Tumors V.1.1.ResultsAs of December 1, 2018, 300 patients were treated with tislelizumab 200 mg intravenously once every 3 weeks (Q3W). Median duration of follow-up was 8.1 months (range 0.2–21.9). No DLTs were reported during the phase 1 dose-verification study and the RP2D was confirmed to be 200 mg intravenously Q3W. Most treatment-related adverse events (62%) were grade 1 or 2, with the most common being anemia (n=70; 23%) and increased aspartate aminotransferase (n=67; 22%). Of the 251 efficacy evaluable patients, 45 (18%) achieved a confirmed clinical response, including one patient from the PK substudy who achieved a complete response. Median duration of response was not reached for all except the nasopharyngeal carcinoma cohort (8.3 months). Antitumor responses were observed in multiple tumor types.ConclusionsTislelizumab was generally well tolerated among Chinese patients. Antitumor activity was observed in patients with multiple solid tumors.Trial registration numberCTR20160872.

TRIDENT-1: A global, multicenter, open-label Phase II study investigating the activity of repotrectinib in advanced solid tumors harboring ROS1 or NTRK1-3 rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS9637-TPS9637
Author(s):  
Robert Charles Doebele ◽  
Jessica Jiyeong Lin ◽  
Misako Nagasaka ◽  
Viola Weijia Zhu ◽  
Nashat Y. Gabrail ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Phase 1 ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Advanced Solid Tumors ◽  
Phase 2 ◽  
Resistance Mutations ◽  
Open Label ◽  
Phase 2 Study

TPS9637 Background: Repotrectinib is a next-generation ROS1/TRK inhibitor with > 90-fold greater potency than crizotinib against ROS1 and > 100-fold greater potency than larotrectinib against TRK. Preclinical studies demonstrated inhibitory activity of repotrectinib against ROS1 resistance mutations, including the solvent-front mutation (SFM) G2032R. In the phase 1 portion of the study, repotrectinib was found to be well tolerated with encouraging antitumor activity including a 91% confirmed overall response (cORR) in TKI-naïve ROS1+ NSCLC pts. In ROS1+ NSCLC pts who received 1 prior chemo and 1 prior TKI, the cORR was 57% at the clinical dose of 160 mg QD or above. Intra-cranial (IC) activity was observed in ROS1+ NSCLC pts with measurable CNS disease (100% IC-ORR in TKI-naïve and 75% IC-ORR in patients with 1 prior TKI). Encouraging antitumor activity was observed in pts with NTRK+ solid tumors. Methods: A global phase 2 study was initiated and is actively enrolling. The primary endpoint for the Phase 2 study is cORR assessed by BICR (Blinded Independent Central Review) using RECIST v1.1, in each expansion cohort in pts with advanced solid tumors that harbor a ROS1 or NTRK1/2/3 gene fusion. Secondary endpoints include duration of response (DOR), progression-free survival (PFS), overall survival (OS), IC-ORR, IC-PFS, and quality of life assessments. All pts need to have RECIST 1.1 measurable disease confirmed by BICR and ECOG performance score ≤1. Repotrectinib is administered at 160 mg QD for 14 days and, if tolerated, the dose can be increased to 160 mg BID. Approximately 320 pts (≥12 years old) will be enrolled into 6 defined expansion cohorts, depending on the status of previous treatment with TKIs and cancer types (see table below). Clinical trial information: NCT03093116 . [Table: see text]

scholarly journals Surufatinib Plus Toripalimab in Patients with Advanced Solid Tumors: A Single-Arm, Open-Label, Phase 1 Trial

2020 ◽  
Author(s):  
Yanshuo Cao ◽  
Ming Lu ◽  
Yu Sun ◽  
Jifang Gong ◽  
Jie Li ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Phase 1 Trial ◽  
Open Label Phase ◽  
Grade 3

Abstract BackgroundPreclinical studies have supported a potential synergistic antitumor activity between surufatinib and anti-programed death ligand-1 (PD-L1). We describe here the results of a single-arm, open-label phase 1 trial to evaluate the safety, preliminary efficacy, and pharmacokinetics (PK) in patients with advanced solid tumors treated with surufatinib combined with toripalimab, an inhibitor of PD-L1.MethodsThis is an open-label, dose escalation and expansion study in patients with solid tumors who had failed standard therapies or had no effective treatment. In the dose escalation stage, 3 cohorts of patients were treated with surufatinib, at dose levels of 200, 250, or 300 mg once daily (QD) in combination with a fixed dose of toripalimab 240 mg, every 3 weeks (Q3W), to evaluate maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Additional patients were enrolled in the dose expansion phase to further assess the efficacy, safety, and PK profile.ResultsFrom April 1, 2019 to July 10, 2020, 31 patients were screened, of which 28 patients were enrolled. One patient in the 300 mg cohort experienced dose limited toxicity (DLT), a grade 3 hyperthyroidism. The top 3 most common treatment-related adverse events of ≥ grade 3 were transaminases increased (17.9%), hypertension (14.3%) and blood bilirubin increased (10.7%). No treatment-related death or treatment discontinuation was identified. The RP2D was determined to be surufatinib 250 mg QD plus toripalimab 240 mg Q3W. Overall objective response rate was 22.2% [95% confidential interval (CI) 8.6‒42.3], and disease control rate reached 81.5% (95% CI 61.9‒93.7). ConclusionsSurufatinib plus toripalimab was well-tolerated, with no unexpected safety signals, and showed promising antitumor activity in patients with advanced solid tumors. Trial registrationclinicaltrials.gov, NCT03879057; Registered March 18, 2019, https://clinicaltrials.gov/ct2/show/NCT03879057

First-in-human study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in adult patients with advanced solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3522-3522 ◽  
Author(s):  
L. S. Rosen ◽  
D. Hong ◽  
L. Chap ◽  
R. Kurzrock ◽  
A. Garcia ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Stable Disease ◽  
Fdg Pet ◽  
Tumor Response ◽  
Human Study ◽  
Laboratory Data ◽  
Ca 125 ◽  
Advanced Solid Tumors ◽  
Dce Mri ◽  
Amg 386

3522 Introduction: AMG 386 is a selective angiopoietin1/2-neutralizing peptibody that inhibits angiogenesis by preventing interaction of angiopoietins with Tie2 receptors. This first-in-human study evaluated the safety, pharmacokinetics (PK), and tumor response of AMG 386 in adults with advanced solid tumors. Methods: Patients (pts) in sequential cohorts received weekly IV AMG 386 at 0.3, 1, 3, 10, and 30 mg/kg. Safety assessments were adverse events (AEs), laboratory data, vital signs, ECGs, and anti-AMG 386 antibodies. Tumor response was assessed via RECIST criteria, DCE-MRI, FDG-PET, and volumetric CT. Results: As of Oct. 2, 2006, enrollment is complete with 32 pts (15 men, mean [SD] age 58 [12] years). One dose-limiting toxicity was seen at 30 mg/kg: respiratory arrest likely related to tumor burden, deemed possibly related to AMG 386. Other treatment-related toxicities were all = Grade 2; those observed in = 2 pts were fatigue (n=8), nausea (n=2), and peripheral edema (n=4). PK was dose-linear (mean terminal half-life, 3.1 to 6.3 days). AMG 386 appeared to reach a steady state after 3 doses, with minimal accumulation. Two pts developed binding antibodies to AMG 386; in 1 pt, they disappeared at wk 6. No neutralizing antibodies were seen. Sixteen pts had stable disease (4–52 wks, median 8 wks); 13 had progressive disease; 3 were not evaluable. One pt with ovarian cancer remains active at 52 weeks with 27% tumor shrinkage and investigator-reported reduction in serum CA-125 from 217 U/ml pretreatment to 73 U/ml (wk 4) and 31 U/ml (wk 48). A significant vascular effect (> 20% reduction) was seen by DCE-MRI in 7 of 12 (58%) evaluable subjects. Reduction in SUVmax (FDG-PET) accompanied reduction in IAUC (DCE-MRI) in 5 of 6 evaluable patients. Conclusions: Weekly administration of AMG 386 appeared to be generally well tolerated, with 1 AE > Grade 2 and no reports of the toxicities associated with VEGF blockade (hypertension, proteinuria, bleeding/clotting). Half of pts experienced stable disease; 1 has a sustained minor clinical response accompanied by a biologic response. Further clinical studies of AMG 386 in combination with chemotherapy and other targeted agents are warranted. No significant financial relationships to disclose.

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