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  • American Society of Clinical Oncology (ASCO)  (10)
  • 1
    Online Resource
    Online Resource
    A phase I, first-in-human clinical trial of the GDF-15 neutralizing antibody CTL-002 in subjects with advanced-stage solid tumors (ACRONYM: GDFATHER).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS2658-TPS2658
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS2658-TPS2658
    Abstract: TPS2658 Background: Growth and differentiation factor 15 (GDF-15) is a TGF-β superfamily member physiologically expressed mainly in placenta and linked to feto-maternal tolerance. Under pathophysiologic conditions, prevention of excessive immune cell infiltration during tissue damage and cachexia induction have been ascribed to GDF-15. A recent study [Haake et al. AACR2020; Abstract #5597] elucidated a mechanism by which GDF-15 inhibits LFA-1 activation on CD8+ T cells, thus interfering with effector T cell recruitment to tissues. Importantly, several cancer entities secrete high levels of GDF-15, correlating with poor prognosis and reduced overall survival [reviewed in Front Immunol 2020 May 19;11:951] . To block this effect the GDF-15 neutralizing antibody CTL-002 was generated. In preclinical models CTL-002 demonstrated potent effector T cell shifting into tumor tissue by neutralizing GDF-15. Methods: This is a phase 1, first-in-human (FIH), two-part, open-label clinical trial of intravenous (IV) administration of CTL-002 given as monotherapy and in combination with an anti-PD-1 antibody in subjects with advanced-stage, relapsed/refractory solid tumors who relapsed post or were refractory to a prior anti-PD-1/PD-L1 therapy. Eligible subjects have exhausted all available approved standard treatments. Further key eligibility criteria include having received at least one prior anti-PD1/-PD-L1 treatment and having relapsed on or after it or having been refractory to it, and presenting with a biopsy-accessible tumor for serial biopsy taking. The trial is termed GDFATHER, for “GDF-15 Antibody-mediaTed Effector cell Relocation”. Main endpoints are safety of CTL-002 monotherapy and CTL-002 combination with an anti-PD-1 antibody, pharmacokinetics, pharmacodynamics (e.g. degree of GDF-15 neutralization achieved and change in immune-cell number and composition in the tumor tissue) as well as preliminary clinical efficacy (tumor mass reduction; anticachexia effect) In part A of the trial (dose escalation) up to 24 subjects will receive escalating doses of CTL-002 IV (0.3 – 20 mg/kg) in a „mono-followed-by-combination“-design with CTL-002 given as monotherapy and followed by combination with an anti-PD-1 checkpoint inhibitor. In part B (expansion) up to 5 cohorts with up to 25 subjects per cohort with defined tumor entities expected to be GDF-15 dependent will be treated to determine the recommended phase 2 dose (RP2D) and further evaluate safety and preliminary efficacy of CTL-002 monotherapy and the combination. The study was initiated in December 2020 and enrolled the first patient on Dec 09, 2020. Cohort 1 has been completed without DLT and enrollment for cohort 2 began in February 2021. Clinical trial information: NCT04725474.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.TPS2658
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Initial results from the phase 2A trial of visugromab (CTL-002) + nivolumab in advanced/metastatic anti-PD1/-L1 relapsed/refractory solid tumors (The GDFATHER-TRIAL).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 2501-2501
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 2501-2501
    Abstract: 2501 Background: Increasing evidence has emerged that Growth and Differentiation Factor 15 (GDF-15) plays a critical role in tumoral immunosuppression. Apart from blocking immune-cell entry into the tumor microenvironment, GDF-15 also has a major impact on the formation of the immune synapse. Many tumors overexpress GDF-15 and have hijacked this mechanism to block immunotherapy success. Here we report initial results of the phase 2a part of the GDF-15 neutralizing antibody visugromab (CTL-002) in combination with nivolumab. Methods: At cut-off date (06-Feb-2023), a total of 79 pts with advanced/metastatic solid tumors have been enrolled and were treated with visugromab 10 mg/kg Q2W in combination with nivolumab 240 mg Q2W in the phase 2a expansion part of the CTL-002-001 phase 1/2 trial (NCT04725474). The primary endpoint of the phase 2a expansion is the Objective Response Rate (ORR) according to RECIST v1.1. Tumor assessments were performed every 8 weeks and patients had to be relapsed/refractory to a minimum of 12 weeks continuous prior anti-PD1/-PD-L1-containing therapy, with relapse or progression after initial response to have occurred on continued anti-PD1/PDL1 therapy. Phase 2a contained several indication-specific expansion cohorts (e.g. NSCLC, Bladder Cancer, HCC, Melanoma), following a Simon 2-stage design, and two cohorts were already expanded to stage 2 in light of initial responses observed. An additional expansion cohort is a pan-tumor basket cohort with sequential tumor biopsies for biomarker analyses. A key component of this multi-arm trial is an extensive translational research program to identify response-predictive tumor and immunologic marker and pattern. Results: Across several expansion cohorts, durable tumor regressions were observed, including several partial responses (PR) and one complete response (CR) in heavily pretreated patients with a median of 3 prior lines of systemic therapy for advanced/metastatic cancer, including at least one prior line of anti-PD1/-PD-L1 therapy and being relapsed/refractory to it. In NSCLC, so far 13 pts underwent at least one tumor assessment. Of these, two experienced a PR (one confirmed), three additional tumor shrinkage 〉 5% (TS) and one longer-term SD (LT-SD) were seen. In bladder cancer, 7 patients underwent at least one tumor assessment with 1 confirmed CR, 1 TS and 1 LT-SD. The treatment was overall well tolerated. Conclusions: These initial phase 2a results demonstrate promising clinical activity for the combination of visugromab and nivolumab in heavily pretreated anti-PD1/-PD-L1 refractory/relapsed solid tumor patients across various indications, including induction of confirmed partial and complete responses. Extensive biomarker evaluations are ongoing to further evaluate potential response-predictive markers identified during phase 1 development. Clinical trial information: NCT04725474 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.2501
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
    Online Resource
    Online Resource
    Phase 1 study of pasotuxizumab (BAY 2010112), a PSMA-targeting Bispecific T cell Engager (BiTE) immunotherapy for metastatic castration-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. 5034-5034
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. 5034-5034
    Abstract: 5034 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC, and pasotuxizumab is a PSMA x CD3 BiTE that mediates tumor cell killing. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received pasotuxizumab as a continuous intravenous infusion in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology design. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n = 3; 10 µg/d, n = 4; 20 µg/d, n = 3; 40 µg/d, n = 4; 80 µg/d, n = 2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious AE related to study drug was reported for 1 pt (fatigue, 20 µg/d). No anti-drug antibodies were observed. Recruitment was stopped before MTD was reached to facilitate initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort versus baseline of +0.74% (5 µg/d), –17.9% (10 µg/d), –37.4% (20 µg/d), –42.5% (40 µg/d) and –54.9% (80 µg/d). PSA decreases of ≥50% occurred in 3 pts (n = 1 each in 20 µg/d, 40 µg/d, and 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases as assessed by PSMA-PET/CT, 〉 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immunotherapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.5034
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T-cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC).
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 6_suppl ( 2020-02-20), p. 124-124
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 6_suppl ( 2020-02-20), p. 124-124
    Abstract: 124 Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC. Pasotuxizumab is a PSMA x CD3 BiTE immune therapy that mediates killing of tumor cells by T cells. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received continuous IV infusion of pasotuxizumab in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n=3; 10 µg/d, n=4; 20 µg/d, n=3; 40 µg/d, n=4; 80 µg/d, n=2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious drug-related AE was reported for 1 pt (fatigue, 20 µg/d). No antidrug antibodies were observed. Recruitment was stopped before MTD was reached to allow initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort vs baseline of +0.74% (5 µg/d), −17.9% (10 µg/d), −37.4% (20 µg/d), −42.5% (40 µg/d) and −54.9% (80 µg/d). PSA decreases ≥50% occurred in 3 pts (n=1 each in 20 µg/d, 40 µg/d, 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases by PSMA-PET/CT, 〉 90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immune therapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.6_suppl.124
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    ATR-101 phase 1 clinical study for adrenocortical carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. TPS4585-TPS4585
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. TPS4585-TPS4585
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.tps4585
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Online Resource
    Objective response and prolonged stable disease in refractory adrenocortical carcinoma treated with cabozantinib: An international case series and protocols of phase II clinical trials.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 15_suppl ( 2019-05-20), p. e16118-e16118
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 15_suppl ( 2019-05-20), p. e16118-e16118
    Abstract: e16118 Background: Median overall survival (OS) in advanced adrenocortical (ACC) is only 12-15 months. Previous clinical trials with oral multi-kinase inhibitors (MKI) were negative likely due to inadvertent drug interaction with mitotane. Objective: To investigate the potential of cabozantinib (CABO) monotherapy in ACC patients. Methods: Retrospective cohort study at three referral centers for ACC (U.S. and Germany). Results: Fifteen patients (13 female) with progressive disease after mitotane (14/15 patients) and three (median; range 0-8) further systemic therapies were treated with 60 mg (20-140) CABO. Mitotane had been discontinued in all patients, in 11/15 patients mitotane was stopped 〉 270 days before CABO treatment or plasma concentration documented to be 〈 2 mg/L. Adverse events (AE) of grade 1/2 and 3 were observed in 12 and 2 patients, respectively and consistent with the known safety profile of CABO. Best response was partial response in 3, stable disease in 4 and progressive disease in 8 patients. Progression-free survival (PFS) of 〉 4 months (PFS4) was observed in 7 patients. Median PFS and OS was 12 and 41 weeks, respectively. Two single center phase II trials of CABO in advanced ACC in the U.S. (NCT03370718) and Germany (NCT03612232) will accrue 18 and 37 patients, respectively. Mitotane discontinuation and plasma concentrations 〈 2 mg/L are key inclusion criteria. The primary endpoint is PFS4. Conclusions: Cabozantinib monotherapy appears to be safe and active as a monotherapy in advanced ACC. Two parallel phase II trials will investigate CABO prospectively while controlling for drug interaction with mitotane.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.15_suppl.e16118
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Online Resource
    Bispecific T-Cell Engager (BiTE) Antibody Construct Blinatumomab for the Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma: Final Results From a Phase I Study
    American Society of Clinical Oncology (ASCO) ; 2016
    In:  Journal of Clinical Oncology Vol. 34, No. 10 ( 2016-04-01), p. 1104-1111
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 10 ( 2016-04-01), p. 1104-1111
    Abstract: Blinatumomab is a CD19/CD3 BiTE (bispecific T-cell engager) antibody construct for the treatment of Philadelphia chromosome–negative acute B-lymphoblastic leukemia. We evaluated blinatumomab in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). Patients and Methods This 3 + 3 design, phase I dose-escalation study determined adverse events and the maximum tolerated dose (MTD) of continuous intravenous infusion blinatumomab in patients with relapsed/refractory NHL. Blinatumomab was administered over 4 or 8 weeks at seven different dose levels (0.5 to 90 μg/m 2 /day). End points were incidence of adverse events, pharmacokinetics, pharmacodynamics, and overall response rate. Results Between 2004 and 2011, 76 heavily pretreated patients with relapsed/refractory NHL, who included 14 with diffuse large B-cell lymphoma, were enrolled; 42 received treatment in the formal dose-escalation phase. Neurologic events were dose limiting, and 60 μg/m 2 /day was established as the MTD. Thirty-four additional patients were recruited to evaluate antilymphoma activity and strategies for mitigating neurologic events at a prespecified MTD. Stepwise dosing (5 to 60 μg/m 2 /day) plus pentosan polysulfate SP54 (n = 3) resulted in no treatment discontinuations; single-step (n = 5) and double-step (n = 24) dosing entailed two and seven treatment discontinuations due to neurologic events, respectively. Grade 3 neurologic events occurred in 22% of patients (no grade 4/5). Among patients treated at 60 μg/m 2 /day (target dose; n = 35), the overall response rate was 69% across NHL subtypes and 55% for diffuse large B-cell lymphoma (n = 11); median response duration was 404 days (95% CI, 207 to 1,129 days). Conclusion In this phase I study of relapsed/refractory NHL, continuous infusion with CD19-targeted immunotherapy blinatumomab at various doses and schedules was feasible, with an MTD of 60 μg/m 2 /day. Single-agent blinatumomab showed antilymphoma activity.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2014.59.1586
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2016
    detail.hit.zdb_id: 2005181-5
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  • 8
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    Online Resource
    Impact of unbalanced karyotypes at diagnosis on prognosis of CML.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 7041-7041
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 7041-7041
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.7041
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
    detail.hit.zdb_id: 2005181-5
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  • 9
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    Phase Ib study of the anti-TGF-β monoclonal antibody (mAb) NIS793 combined with spartalizumab (PDR001), a PD-1 inhibitor, in patients (pts) with advanced solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 2509-2509
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2509-2509
    Abstract: 2509 Background: TGF-β plays a key role in regulating the tumor microenvironment. Emerging evidence suggests TGF-β is a key activator of cancer-associated fibroblasts, leading to fibrotic network development and immune exclusion. Preclinical data in murine models showed that TGF-β blockade alleviates intratumoral fibrosis, augmenting the efficacy of PD-1 immunotherapy. NIS793 is a human IgG2 mAb that binds to TGF-β. This study investigates NIS793 + spartalizumab in pts with advanced solid tumors. Methods: Pts initially received NIS793 (0.3–1 mg/kg Q3W) monotherapy; following evaluation of two dose levels, dose escalation continued with NIS793 + spartalizumab (NIS793 0.3–30 mg/kg Q3W + spartalizumab 300 mg Q3W; or NIS793 20–30 mg/kg Q2W + spartalizumab 400 mg Q4W) in pts with/without prior anti-PD-(L)1 therapy. In dose expansion, pts with non-small cell lung cancer (NSCLC) resistant to prior anti-PD-(L)1 or pts with microsatellite stable colorectal cancer (MSS-CRC) were treated at the recommended dose for expansion (RDE). Paired tumor biopsies were required from all pts. The primary objectives were to characterize safety and tolerability of the combination and determine the RDE. Results: By December 1, 2020, 60 pts were treated in the dose-escalation phase, mainly with NIS793 + spartalizumab (n = 49), and 60 pts were treated in dose expansion (MSS-CRC: n = 40; NSCLC: n = 20). Two pts were still receiving treatment. No dose-limiting toxicities were observed, and the RDE was established as 30 mg/kg (2100 mg) NIS793 + 300 mg spartalizumab Q3W. Overall 50% pts experienced ≥1 treatment-related AE (TRAE). The most common were rash (n = 15/120), pruritus (n = 10/120), fatigue (n = 9/120), and nausea (n = 8/120). Grade 3/4 TRAEs occurred in 11% pts, with rash (3%) being the most common. Treatment-related serious AEs were reported in 8 pts; 6 were grade 3/4 in severity. No deaths occurred due to AEs; 3 (2.5%) pts discontinued due to AEs. PK for NIS793 was linearly dose proportional with no obvious correlation between exposure and response. Two pts achieved a partial response (PR; one confirmed in clear cell renal cell carcinoma and one unconfirmed in NSCLC) during dose escalation of the combination. Two confirmed PRs were achieved in the MSS-CRC dose-expansion group. Biomarker data showed evidence of target engagement through increased TGF-β/NIS793 complexes and depleted active TGF-β in peripheral blood. Gene expression and protein analyses in tumor biopsies displayed decreased TGF-β target genes, decreased TGF-β signatures and increased immune signatures suggesting modulation of the TGF-β pathway and preliminary evidence of biological activity. Conclusions: Data showing target engagement and TGF-β pathway inhibition supported the proof of mechanism of NIS793. The RDE of the combination was established and well tolerated in pts with advanced solid tumors. Clinical trial information: NCT02947165.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.2509
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 10
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    Design and rationale of a phase 1 dose-escalation study of AMG 193, a methylthioadenosine (MTA)-cooperative PRMT5 inhibitor, in patients with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS3167-TPS3167
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS3167-TPS3167
    Abstract: TPS3167 Background: Protein arginine methyltransferase 5 (PRMT5) is an emerging target for cancer treatment. MTAP homozygous deletion occurs in 15% of cancers and often coincides with deletion of the tumor suppressor gene CDKN2A, leading to buildup of its substrate MTA. MTA shares close structural similarity to S-adenosyl methionine (SAM), the substrate methyl donor for PRMT5. By competing with SAM, MTA partially inhibits PRMT5. Thus, MTAP-null cancers are susceptible to further PRMT5 inhibition (Kryukov Science 2016). Current direct/indirect PRMT5 inhibitors (PRMT5i) showed preliminary anticancer activity, albeit with considerable toxicities due to their indiscriminate activities. AMG 193 is an MTA-cooperative PRMT5i that preferentially targets the MTA-bound state of PRMT5 that is enriched in MTAP-null tumors and represents a novel strategy to increase the therapeutic margin of this class of inhibitors. AMG 193 potently inhibits MTAP-null cancer cell lines and patient-derived xenografts. Methods: NCT05094336 is a first-in-human (FIH), multicenter, open-label, phase 1/1b/2 trial evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and efficacy of AMG 193 in patients with advanced MTAP-null solid tumors. Eligible patients (≥ 18 years) with histologically confirmed locally advanced/metastatic solid tumors not amenable to curative treatment with surgery and/or radiation, homozygous MTAP and/or CDKN2A deletion (by local next generation sequencing), or MTAP protein loss in tumors (by central immunohistochemistry), measurable disease, ECOG PS 0‒1, adequate hematopoietic, renal, liver, pulmonary, cardiac, coagulation function and glucose control will be included. The study will be conducted in 3 parts, each with subparts. Here, we describe Part 1a/b (dose exploration). Five dose levels are planned. Treatment continues until progression or withdrawal. The primary objectives are to evaluate the safety and tolerability of AMG 193 monotherapy; endpoints include dose-limiting toxicities, treatment-emergent adverse events, serious adverse events, electrocardiograms, laboratory abnormalities, and vital signs. Secondary objectives include the characterization of the PK parameters of AMG 193 including C max , T max , and AUC after single or multiple doses. This study is expected to enroll approximately 30 patients in Part 1a/b. This is the first FIH trial open for enrollment for this new class of PRMT5i and enrollment is ongoing. Clinical trial information: NCT05094336.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS3167
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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