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  • 1
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    Abstract LB-197: First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-197-LB-197
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. LB-197-LB-197
    Abstract: Background: ARQ 092 is an oral allosteric, ATP-independent, potent and selective inhibitor of AKT. Preclinical data from human cell lines and xenograft models support the exploration of anti-tumor activity of ARQ 092 across a broad range of human solid and hematological malignancies. The safety and preliminary activity of ARQ 092 in patients with advanced/metastatic solid tumors are presented. Methods: Adults patients (pts) were enrolled into this multi-cohort phase 1 trial at the starting dose of 10 mg/QOD. Cohorts of 3 or 6 patients were based on a 3+3 dose escalation schedule. Dose was to be doubled for the first 5 cohorts, then increased according to a modified Fibonacci scheme. Treatment was continued until disease progression or unacceptable toxicity. Diabetic patients requiring insulin were excluded. Dose Limiting Toxicity (DLT) definition included grade ≥3 toxicities, grade 2 liver dysfunction, and grade 3 hyperglycemia requiring insulin (uncontrolled by metformin) during the first 28 days of treatment. Results: As of October 20th, 2012, 22 ECOG PS1 pts (8 male; median age 63.3 yrs), with advanced/metastatic solid tumors were enrolled at doses/schedules ranging from 10 mg/QOD to 80mg/QD. Colorectal (N=4), endometrial (N=4) and neuroendocrine (N=3) were the most frequent tumors. Treatment-emergent adverse events (TEAEs) were reported in 20 (90.9%) pts. The most frequent ( & gt;10%) included nausea, fatigue (both in 10 pts, 45.4%) and anorexia (7 pts, 31.8%). Grade 3 maculo-papular rash with pruritis occurred in 2 pts in the 80mg/QD cohort, triggering one DLT. Eight pts experienced 17 SAEs including diarrhea, tricuspid regurgitation, dyspnea and metabolic encephalopathy. Drug-related SAEs include: Grade 3 hyperglycemia, in 3 pts at 80mg/QD (1 constituted DLT, another was not a DLT because it was not treated with metformin, and the third, managed with insulin, occurred after 28 days). A DLT of congestive heart failure developed in a subject previously exposed to radiation and adriamycin. The MTD has not been reached, but the 80mg QD continuous dose/schedule was deemed not to be well tolerated. A cohort of 60mg QD is under evaluation. Currently, 6 pts remain stable for & gt; 4 months and 3 pts are still on therapy (1 pt on 80mg/QD, 2 pts on 20mg/QD); a 20% reduction in tumor burden was achieved in a pt with concomitant reduction of circulating pAKT expression. The study is ongoing with 7 pts on ARQ 092. PK analysis and PD results based on tumor biomarker expression and on plasma pAKT are pending. Conclusions: A formal MTD has not yet been reached. Rash preceded by hyperglycemia and preliminary signs of activity as single agent may represent a differential feature of ARQ 092 in this class. Exploratory efficacy in a selected population over-expressing AKT will be pursued at the defined recommended phase 2 dose. Citation Format: Mansoor Saleh, Kyri Papadopoulos, Alireza Arabnia, Amita Patnaik, Robin M. Stein, Federica Cattaneo, Giovanni Abbadessa, Jonathan Greenberg, Stephen Warren, Anthony Tolcher. First-in-human study with ARQ 092, a novel pan AKT-inhibitor: Results from the advanced solid tumors cohorts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-197. doi:10.1158/1538-7445.AM2013-LB-197
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-LB-197
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
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  • 2
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    Abstract CT056: A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT056-CT056
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. CT056-CT056
    Abstract: Background AVID100, a rationally designed anti-EGFR-DM1 conjugate, showed potent activity in preclinical models, including cancer cell lines resistant to approved anti-EGFR monoclonal antibodies. In addition, AVID100 showed increased toxicity on tumor cells compared to the unconjugated antibody. There was no increased AVID100-mediated toxicity on keratinocytes. Methods In the completed Phase Ia segment, 24 patients with advanced or metastatic epithelial malignancies without available standard of care therapy and likely to express EGFR were enrolled into sequential dose-escalation cohorts to assess safety, tolerability, pharmacokinetic (PK) parameters, and to identify the recommended Phase II dose (R2PD) of 2 hour infusions on an every 3 week schedule. In the ongoing Phase IIa segment, preliminary antitumor activity is being assessed in expansion cohorts of patients with high EGFR expression, including triple-negative breast cancer (TNBC) (2+ expression in ≥75% or 3+ in ≥50% of tumor cells) or either squamous cell carcinoma of the head and neck (SCCHN) or squamous non-small cell lung carcinoma (sqNSCLC) (3+ expression in ≥ 50% of tumor cells). The DAKO PharmDx assay was validated and used for screening intensity of EGFR protein expression. Results During Phase Ia, no Cycle 1 dose limiting toxicities (DLTs) were observed in Cohorts 1-6 at doses (N) of 20 (1), 40 (1), 80 (3), 120 (3), 180 (3), and 220 (6) mg/m2. In Cohort 7 (6) (270 mg/m2; ~ 7.3 mg/kg) two patients experienced Cycle 1 DLTs (G3 asymptomatic lipase elevation, G4 reversible thrombocytopenia), exceeding the maximally tolerated dose. A third patient developed G3 reversible pneumonitis. As a result, 220 mg/m2 (~6 mg/kg) was selected as the R2PD. Tumor types in greater than one patient included: colorectal (13), breast (4), and ovarian (2). Preliminary PK results at the R2PD revealed exposure exceeding preclinically predicted therapeutic levels. Cmax increased proportionally with dose, plasma half-life was ~50 hours at the R2PD, and clearance decreased with increasing doses with saturation observed between 180-270 mg/m2. Safety and tolerability were acceptable. Other treatment-related adverse events included: infusion-related reactions that were ameliorated by premedication and infusion prolongation, rash, nausea, vomiting, fatigue, headache, anorexia, mucositis, punctate keratitis, diarrhea, elevated amylase, reversible transaminase and alkaline phosphatase elevations without other evidence of hepatotoxicity, hypomagnesemia, and hypokalemia. Prolonged disease stabilization was observed in 3 of these patients not selected for EGFR overexpression (colorectal, ovarian, cervical). Conclusions AVID100 is a well-tolerated anti-EGFR-DM1 conjugate with evidence for exposure levels at or above those observed for cetuximab and ado-trastuzumab emtansine. Antitumor activity is currently being evaluated in EGFR-overexpressing patients in Phase IIa. Citation Format: Nehal Lakhani, Sreenivasa Chandana, Anthony Tolcher, Yvette Cole, Karla Rivas, Sandra Sinclair, Paul I. Nadler, Debra L. Wood, Kyri P. Papadopoulos. A Phase Ia/IIa trial of AVID100, an anti-EGFR antibody-drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT056.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-CT056
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Phase I First-in-Human Study of CUDC-101, a Multitargeted Inhibitor of HDACs, EGFR, and HER2 in Patients with Advanced Solid Tumors
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 19 ( 2014-10-01), p. 5032-5040
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 19 ( 2014-10-01), p. 5032-5040
    Abstract: Purpose: This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose (RD) for CUDC-101, a multitargeted inhibitor of HDACs, EGFR, and HER2 as a 1-hour intravenous (i.v.) infusion for 5 consecutive days every 2 weeks. Experimental Design: Twenty-five patients with advanced solid tumors received escalating doses of CUDC-101 (range, 75–300 mg/m2/day) following a standard 3 + 3 dose escalation design. Results: The MTD was determined to be 275 mg/m2. Common grade 1/2 adverse events included nausea, fatigue, vomiting, dyspnea, pyrexia, and dry skin. DLTs occurred in 1 patient in the 275-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 1) and 3 patients in the 300-mg/m2 dose cohort (grade 2 serum creatinine elevation, n = 2; pericarditis, n = 1), all of which were transient and reversible. CUDC-101 exposure increased linearly with the mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vdss), area under curve (AUC), and terminal elimination half-life (t1/2) at the MTD dose of 9.3 mg/L, 51.2 L/h, 39.6 L, 9.95 h·ng/mL and 4.4 hours, respectively. Acetylated histone H3 induction was observed in posttreatment skin samples from 3 patients in the 275-mg/m2 dose cohort, suggesting adequate systemic exposure and target inhibition. One patient with gastric cancer had a partial response and 6 patients had stable disease. Conclusion: CUDC-101 administered by 1-hour i.v. infusion for 5 consecutive days every 2 weeks was generally well tolerated with preliminary evidence of antitumor activity. A dose of 275 mg/m2 is recommended for further clinical testing. Clin Cancer Res; 20(19); 5032–40. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-14-0570
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
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    Abstract B181: Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B181-B181
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. B181-B181
    Abstract: Background: The AKT pathway is critical in cancer initiation and progression, it can be constitutively activated by mutations in AKT (8% breast, 6% colorectal, 6.8% meningioma) and PIK3CA (27% breast, 28% endometrial, 13% colorectal)12. ARQ 092 is a potent and selective AKT inhibitor in phase 1 clinical development. Also, ARQ 092 has been shown to have anti-growth activity in cells from patients with Proteus syndrome, a non-cancer disease solely driven by AKT1E17K3. Methods: Biochemical IC50 for AKT 1/2/3 and the selectivity profile of ARQ 092 or ARQ 751 (more potent next generation AKT inhibitor) against over 300 kinases were determined. The binding of both inhibitors to wild-type AKT1 and AKT1E17K was assessed using intrinsic tryptophan fluorescence quench. Inhibitory effect on AKT1E17K was determined in transient transfection cell system. AKT1 membrane translocation was performed in cells transiently transfected with GFP-fused AKT1 or AKT1E17K. AKT pathway in select cell lines was assessed using Western blot analysis. Anti-proliferative effects were tested in a panel of 18 breast cancer cell lines, 4 with H1047R. In vivo efficacy was tested in 2 mouse xenografts and 2 patient-derived tumors with endometrial and breast cancer cells bearing AKT1E17K or PIK3CAH1047R mutations. In a phase 1 clinical trial, patients have been enrolled to receive oral ARQ 092 at multiple doses and schedules4. Results: ARQ 092 inhibited AKT1, 2, and 3 activity with IC50 values of 5.0, 4.5, and 16 nM, respectively whereas ARQ 751 had IC50 values of 0.54, 0.79, and 1.3 nM, respectively; MK-2206 exerted less potency (40.5, 29.5 and 36.4 nM) and GDC-0068 showed potency of 2.0, 27.0, and 6.3 nM. For the AKT1E17K mutant, Kd values were 42 and 8.6 nM for ARQ 092 and ARQ 751 respectively, accompanied with inhibition of its phosphorylation; whereas over 1 μM for MK-2206. ARQ 092 and ARQ 751 but not MK-2206 at 1 μM blocked AKT1E17K membrane translocation. ARQ 092 and ARQ 751 were efficacious on all 4 PIK3CAH1047R cells with GI50 of less than 1 μM. In an endometrial PDX model bearing AKT1E17K, ARQ 092 at 100 mg/kg and ARQ 751 at 75 mg/kg obtained respectively 78% and 98% tumor growth inhibition. In vivo models with PIK3CAH1047R treated with ARQ 092 at 100-120 mg/Kg exhibited tumor growth inhibition between 32% and 84%. In the ongoing clinical trial, in 7 patients with AKT1E17K enrolled at doses close to MTD for each schedule, 2 RECIST partial responses (breast cancer and follicular lymphoma), 2 minor responses (parotid cancer, 19.3% tumor reduction; endometrial cancer, 17.5% reduction), 3 stable diseases (ovarian, neuroendocrine, meningioma, 120-277 days on therapy) were observed. One patient with PIK3CAH1047R mutant endometrial carcinoma was treated and obtained a partial response. Conclusions: ARQ 092, and the next generation ARQ 751, are potent, selective allosteric AKT inhibitors. They both bind tightly to and inhibit membrane translocation and activation of AKT1E17K and of PI3K-stimulated AKT. Preclinical and clinical findings from oncology and non-oncology studies show that AKT1 E17K and PIK3CAH1047R mutations may be used for patient selection. 1Kim MS, Br J Cancer 2008. 2Yuan TL, Oncogene 2008. 3Biesecker L, ASHG 2014 4Tolcher A, ESMO 2015. Citation Format: Giovanni Abbadessa, Yi Yu, Sudharshan Eathiraj, Justin Meade, Michael J. Wick, Anthony Tolcher, Kyri Papadopoulos, Mansoor Saleh, Jasgit Sachdev, Feng Chai, Brian Schwartz. Association of AKT1E17K and PIK3CAH1047R mutations with efficacy of ARQ 092 in vitro, in vivo and in patients. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B181.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-B181
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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  • 5
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    Abstract A103: Preliminary results of a phase 1 study of FP-1039 (FGFR1:Fc), a novel antagonist of multiple fibroblast growth factor (FGF) ligands, in patients with advanced malignancies
    American Association for Cancer Research (AACR) ; 2009
    In:  Molecular Cancer Therapeutics Vol. 8, No. 12_Supplement ( 2009-12-10), p. A103-A103
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 8, No. 12_Supplement ( 2009-12-10), p. A103-A103
    Abstract: Background: The human fibroblast growth factor (FGF) axis is a complex system comprised of 22 ligands that bind to various combinations of 4 distinct cell surface receptors (FGFR1-4). FGFs have been demonstrated to be involved in tumor growth promotion, tumor angiogenesis, and in tumor stem cell maintenance. FP-1039 acts as a potent ligand “trap” that sequesters multiple FGF family ligands, neutralizing their ability to bind to and activate multiple FGF receptors. FP-1039 has anti-tumor activity in multiple xenograft models both as a single agent and in combination with other anticancer agents. Study Design: We report preliminary results of a first-in-human study of FP-1039 as a single agent in patients with advanced solid malignancies. Objectives were to characterize the safety, pharmacokinetics (PK), and immunogeneicity profiles of FP-1039. Characterization of preliminary anti-tumor activity and pharmacodynamic biomarkers were exploratory objectives. Subjects received 4 once-weekly intravenous doses of FP-1039, followed by a two week observation period. In the absence of either unacceptable toxicity or progressive disease, patients were eligible to receive additional weekly doses of FP-1039. Results: To date, a total of 15 subjects have received FP-1039 at doses ranging from 0.5–1.0 mg/kg. FP-1039 was generally well tolerated at doses of 0.5 and 0.75 mg/kg. A single dose limiting toxicity (DLT) was seen at 0.75 mg/kg and two at 1 mg/kg. The DLTs were clinically distinct, no consistent pattern related to drug exposure could be discerned and confounding factors were present. Further dose exploration is ongoing. PK analysis revealed a linear, dose-dependent increase in drug exposure in the plasma compartment typical of a large protein. Cohort mean terminal half-lives ranged from 63 to 102 hours, and appeared to be similar on Day 1 and Day 22. There was accumulation after 4 weekly doses of FP-1039. Transient, weak anti-drug antibody responses were seen in 4 of 12 subjects (33%) which were not associated with changes in PK or clinical sequelae. Free plasma FGF2 levels were assessed prior to initial dosing and at multiple subsequent timepoints. All subjects had elevated FGF2 levels prior to FP-1039 treatment compared to published levels in normal individuals. Preliminary analysis demonstrated a decrease in plasma levels of free FGF2 following FP-1039 treatment at all doses. Ten subjects completed the treatment period while 5 did not due to adverse events or rapidly progressive disease. By RECIST criteria, 6 subjects had stable disease. In one of these, a subject with castration-resistant prostate cancer and progressive disease despite docetaxel treatment, a reduction in FDG PET SUV on 2- and 6-week scans and a 20% decrease in tumor size by CT scan were demonstrated. Conclusions: FP-1039 appears to be well tolerated at doses of 0.5–0.75 mg/kg, and exploration of higher doses is in progress. Preliminary PK and target engagement data (reduction in FGF2) support a weekly or longer dosing interval. Preliminary single agent activity is promising. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A103.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-09-A103
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
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  • 6
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    Abstract A96: Phase 1 study of HSP90 inhibitor MPC-3100 in subjects with refractory or recurrent cancer.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A96-A96
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A96-A96
    Abstract: Background: MPC-3100 is an orally-bioavailable, fully-synthetic inhibitor of the molecular chaperone HSP90. HSP90 is important for post-translational protein folding, stabilization, and function of so-called client proteins, many of which are necessary for growth and survival of cancer cells. In preclinical studies, MPC-3100 has demonstrated client protein modulation and antitumor activity against a broad range of tumor types. Methods: In this first-in-human, open label, dose escalating, 3+3 design with accelerated titration, multiple-dose study, the safety and tolerability of single agent MPC-3100 were assessed in subjects with recurrent or refractory cancer. Secondary objectives were to characterize the pharmacokinetic parameters (PK) of MPC-3100, assess antitumor activity, and evaluate pharmacodynamic (PD) biomarkers. Subjects received oral MPC-3100 once daily for 21 days followed by 7 days off at doses of 50, 100, 165, 245, or 340 mg/m2 (Cohorts 1–5, respectively) or for 28 days continuously at total daily doses of 480 mg or 640 mg administered as 240 mg or 320 mg Q12H (Cohorts 6 and 7, respectively) per 28-day cycle. Clinical examinations, blood draws for PK and PD, and tumor assessments were performed at pre-specified times during the study. Results: MPC-3100 was administered to 26 subjects [13 M, 13 F; median age 63.5 yr, range 45–85 yr; ECOG performance status 0 (n=13), 1 (n=11) and 2 (n=2) at screening; most-represented primary cancer types colon (n=6), prostate (6), and breast (3); median of 4 (range 0 to 16) prior chemotherapies]. The total number of cycles of MPC-3100 administered to all subjects was 44 (median 1, range & lt; 1 to 13). Twenty five subjects experienced at least one potentially drug-related adverse event (AE), the majority of which were Grade 1 and 2, most frequently diarrhea (56%), nausea (56%), vomiting (32%), fatigue (32%). Five potentially-related serious AEs (SAEs) were observed in four subjects: abdominal pain, supraventricular tachycardia, respiratory failure, enteritis, and renal failure. The single dose-limiting toxicity (DLT) in this study, Grade 3 supraventricular tachycardia, was observed at the 245 mg/m2 dose level. Total daily doses greater than 600 mg were not well tolerated secondary to Grade 1–3 gastrointestinal and Grade 1/2 visual adverse events that resolved following discontinuation of study drug. Hepatotoxicity was not observed in this study. Best clinical response was stable disease in 12/26 (46%) subjects with 6 subjects remaining on study for ≥ 3 cycles. PK analysis indicated that Cmax and AUC(0–12h) on Day 1 increased in a nearly dose-proportional manner. Terminal plasma half-life ranged from 4.8 to 21.4 hours (mean 11.2 hours). Day 21 exposures were 1.01 to 1.99 times those observed on Day1, indicating a modest degree of drug accumulation. Biomarker analysis demonstrated induction of HSP70 expression at 24 hours post-treatment, and an increase in the degree of HSP70 induction from Day 1 through Day 22, suggesting effective and persistent HSP90 inhibition by MPC-3100 in vivo. Conclusions: MPC-3100 appears to be safe and tolerable when administered orally at doses below 600 mg per day to subjects with recurrent or refractory cancer. Side-effects were generally manageable or reversible upon discontinuation of MPC-3100. Biomarker modulation indicates appropriate HSP90 inhibition. Nearly half of the subjects attained stable disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A96.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A96
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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    Abstract CT031: COM701 demonstrates preliminary antitumor activity as monotherapy and in combination with nivolumab in patients with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT031-CT031
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. CT031-CT031
    Abstract: Introduction: COM701 is a novel first-in-class Immune checkpoint inhibitor (ICI) that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG) blocking its interaction with its ligand, PVRL2 and regulating the activity of T/NK cells through the DNAM/TIGIT axis. In preclinical experiments inhibition of PVRIG alone and in combination with anti-PD1 and/or TIGIT leads to tumor growth inhibition and activation of T-cells in the microenvironment generating an antitumor response. Methods: A total of 28 pts (Arm A/B 16/12) with a variety of cancer types were enrolled. Hybrid accelerated (1st 4 dose cohorts in Arm A) and 3+3 study design (cohorts 5-8 in Arm A and all cohorts in Arm B). Patients with performance status ECOG 0-1 and advanced or metastatic solid tumors who failed standard of care tx were eligible. Prior ICIs were permissible. In Arm A pts received COM701 monotherapy 0.01, 0.03, 0.1, 0.3, 1, 3, 10mg/kg (all IV Q 3 weeks (wks)) and 20 mg/kg (IV Q 4 wks). In Arm B, pts received COM701 at 0.3, 1 or 3mg/kg plus nivolumab 360mg IV q3 wks (3 pts/dose cohort) and 3 pts received 10mg/kg plus nivolumab 480mg IV q4 wks. Treatment emergent adverse events (TEAEs) were reported per CTCAE v4.03 and responses per RECIST v1.1. Dose-limiting toxicities (DLTs) were evaluated within a 21-day or 28-day window (for 3- or 4-wks dosing schedule respectively). Data cutoff date was January 23, 2020. Results: The median number of prior anticancer therapies were: Arm A, 7 (range 2-15), Arm B, 5 (range 2-9). No DLTs have been reported in any of the dose cohorts. Tx was well tolerated with no subjects discontinuing tx due to toxicity, the most frequent TEAEs in Arm A were fatigue (46%), nausea (31%) and anxiety (23%) - all G1-2. In Arm B ≥4 pts - anemia, lower extremity edema, rash and fatigue the majority being grade 1-2 (88%). In Arms A+B: partial response (PR) + stable disease (SD) was 57% (16/28). Of note: Arm A (COM701 20mg/kg IV q4 wks): confirmed PR in a pt with primary peritoneal cancer ongoing on tx & gt; 15 weeks. Arm B: unconfirmed PR in a pt with MSS-CRC on COM701 0.3mg/kg plus nivolumab 360mg IV q3 wks, ongoing on tx & gt;34 wks). Overall 11/28 pts remain on study tx including 3 pts who have not reached 1st imaging assessment. Conclusion: COM701 is well tolerated as monotherapy and in combination with nivolumab in a variety of heavily pretreated pts with advanced or metastatic solid tumors. COM701 demonstrates encouraging preliminary antitumor activity with objective responses as monotherapy and in combination with nivolumab in hard to treat tumor types (primary peritoneal and MSS-CRC). Citation Format: Ryan Sullivan, Drew Rasco, Emerson Lim, Manish Sharma, Dale Shepard, Amita Patnaik, Erika Hamilton, Gini Fleming, Kyri Papadopoulos, Adam ElNaggar, Adeboye Henry Adewoye, Bartosz Chmielowski, Ecaterina Dumbrava, Dan Vaena. COM701 demonstrates preliminary antitumor activity as monotherapy and in combination with nivolumab in patients with advanced solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT031.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2020-CT031
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    A first-in-human, first-in-class, phase I study of carlumab (CNTO 888), a human monoclonal antibody against CC-chemokine ligand 2 in patients with solid tumors
    Springer Science and Business Media LLC ; 2013
    In:  Cancer Chemotherapy and Pharmacology Vol. 71, No. 4 ( 2013-4), p. 1041-1050
    Details
    In: Cancer Chemotherapy and Pharmacology, Springer Science and Business Media LLC, Vol. 71, No. 4 ( 2013-4), p. 1041-1050
    Type of Medium: Online Resource
    ISSN: 0344-5704 , 1432-0843
    URL: Article
    DOI: 10.1007/s00280-013-2099-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2013
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    Abstract 5187: PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis
    American Association for Cancer Research (AACR) ; 2016
    In:  Cancer Research Vol. 76, No. 14_Supplement ( 2016-07-15), p. 5187-5187
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 76, No. 14_Supplement ( 2016-07-15), p. 5187-5187
    Abstract: Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge to obtain efficient drug delivery across the blood brain barrier (BBB). Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. Clinical PET imaging with 64Cu or 89Zr labeled trastuzumab has previously been able to visualize breast cancer brain metastases. The aim of our study was to investigate if PET imaging with 64Cu-labeled trastuzumab was predictive of the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established as an intracranial brain metastases model. Methods: The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). PET/CT imaging with 64Cu-trastuzumab was performed in animals with confirmed intracranial ST1339 tumors prior to treatment with T-DM1 (10 mg/kg/week x4). Results: T-DM1 treatment with 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals. A variable response within the treatment group was observed. Forty percent had tumor shrinkage while 60% exhibited tumor growth within the duration of the therapy. The intracranial tumors were clearly visible on the 64Cu-trastuzumab PET images co-registered with T2-weighted MR images for anatomical localization. Interestingly, the intracranial tumor uptake between the animals was rather heterogeneous. Conclusion: A treatment response to T-DM1 was observed in an intracranial ST1339 HER2 positive breast cancer PDX model. PET imaging with 64Cu-trastuzumab confirmed delivery of trastuzumab to the tumors. Further quantitative image analysis of the intracranial 64Cu-trastuzumab tumor uptake will reveal if the drug delivery measured by 64Cu-trastuzumab PET imaging is predictive of the efficacy of T-DM1 in a HER2 positive PDX breast cancer brain metastases model. Citation Format: Carsten Haagen Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony Tolcher, Andreas Kjaer. PET imaging of trastuzumab emtansine (T-DM1) drug delivery to intracranial patient derived xenograft (PDX) models of breast cancer metastasis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5187.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2016-5187
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 10
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    Abstract A15: Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis
    American Association for Cancer Research (AACR) ; 2015
    In:  Molecular Cancer Therapeutics Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A15-A15
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 14, No. 12_Supplement_2 ( 2015-12-01), p. A15-A15
    Abstract: Background: It is estimated that 10-30% of all breast cancer patients at some point develop brain metastases. Overexpression of the human epidermal growth factor receptor 2 (HER2) is a independent risk factor for development of brain metastases. Up to 37% of patients with HER2-positive metastatic breast cancer develop brain metastases and half of these patients die as a result of failure to control the intracranial disease. A reason for this is the challenge of efficient drug delivery across the blood brain barrier (BBB). Subcutaneous patient derived xenograft (PDX) models are increasingly used for efficacy studies in drug development. However, when targeting brain tumors or metastases, the major impact of the BBB on drug bioavailability must be taken into consideration. The aim of this study was therefore to compare the efficacy of trastuzumab emtansine (T-DM1) in a HER2 positive breast cancer PDX model established subcutaneously and as an intracranial brain metastases model. Methods: Mice were implanted subcutaneously with the HER2 positive breast cancer PDX model designated ST1339 and randomized into 3 treatment arms: Control, T-DM1 (5 mg/kg/week x4) and T-DM1 (10 mg/kg/week x4). Treatment response of subcutaneous tumors was monitored by caliper measurements. The intracranial PDX model was established by stereotactic intracranial injection of enzymatically digested ST1339 tumor tissue. At confirmed tumor take, mice were randomized into two arms: Control and T-DM1 (10 mg/kg/week x4). Treatment response was monitored by contrast-enhanced T1- and T2-weighted Magnetic Resonance Imaging (MRI) and positron emission tomography (PET) with the amino acid radiotracer O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET). Results: T-DM1 at 10 mg/kg/week x4 effectively inhibited tumor growth in the subcutaneous model whereas treatment with 5 mg/kg/week x4 did not have any effect on tumor growth. T-DM1 treatment at 10 mg/kg/week x4 of mice with intracranial tumors inhibited tumor growth and prolonged survival compared to non-treated animals. Conclusion: A treatment response to T-DM1 was observed in both the subcutaneous and intracranial ST1339 HER2 positive breast cancer PDX model. With the combination of subcutaneous and intracranial PDX models of breast cancer and breast cancer brain metastases new drugs can thus be tested in preclinical models that more closely mimic the microenvironment and the challenges of drug delivery across the BBB in patients. Citation Format: Carsten H. Nielsen, Mette K. Nedergaard, Lotte K. Kristensen, Camilla S. Knudsen, Michael J. Wick, Kyri Papadopoulos, Anthony W. Tolcher, Andreas Kjaer. Efficacy of trastuzumab emtansine (T-DM1) in subcutaneous and intracranial patient derived xenograft models of breast cancer metastasis. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A15.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-15-A15
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
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    SSG: 12
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