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  • 1
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    Interim safety and efficacy results from a phase 1 study of NT219 in adults with advanced solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3096-3096
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3096-3096
    Abstract: 3096 Background: NT219 is a small molecule, effecting IRS1/2 degradation and inhibiting STAT3 phosphorylation. IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, altered during epithelial to mesenchymal transition (EMT) and drug resistance, and play an important role in the tumor and its microenvironment. A Phase 1/2 study (NCT04474470) includes a dose escalation of NT219 administered weekly for the treatment of relapsed and/or refractory cancer patients. Methods: In the dose escalation part of the study involving a conventional 3+3 design, patients with recurrent and/or metastatic solid tumors were administered intravenously with NT219 at 3, 6, 12 and 24mg/kg. Safety was assessed according to CTCAE v5 and anti-tumor activity was assessed by the investigators according to RECISTv1.1 using CT/MRI. The primary objectives of this part of the study are to evaluate safety, tolerability, PK and determine the recommended Phase 2 dose (RP2D). The study includes evaluation of potential biomarkers including measurements of STAT3, IRS1/2 phosphorylation, and TILs in biopsy specimens. Results: As of data cutoff date of February 8, 2022, a total of 13 patients were enrolled to 4 NT219 dose levels (3 - 24mg/kg) in the dose escalation phase, of which 11 were evaluable for dose limiting toxicity (DLT) determination, including 4 with colorectal cancer (CRC), 2 with pancreatic cancer, 2 with breast cancer, and one of each of the following cancers: gastroesophageal junction (GEJ), esophageal, appendiceal, papillary thyroid, and mesothelioma. Median number of prior treatment regimens for metastatic disease was 4 (2-11). Six Grade 3 adverse events (AEs) were observed, including alkaline phosphatase increase, aspartate aminotransferase increase, toxic encephalopathy, worsening back pain, abdominopelvic ascites, closed displaced fracture of right femoral neck, with the first 2 considered as possibly related to NT219. No Grade 4 AEs or treatment related deaths were reported. For the 11 evaluable patients, best overall response included one confirmed PR (GEJ patient, 5.5 months duration of response), and 3 SD (3 of 4 CRC patients; duration of 5.2, 4, and 2 months with ongoing follow up) with two patients awaiting follow up MRI/CT scans. As of the cutoff date, 9/11 patients that completed the DLT period are either on treatment or in follow up (range 1.1 to 14.7 months). Conclusions: Interim analysis of safety results obtained in 4 NT219 dose levels found NT219 to be well tolerated without DLTs in advanced cancer patients. The observed durable PR in a GEJ patient and SDs in 3 CRC patients are an encouraging initial signal of efficacy. Combination treatment of cetuximab with escalating NT219 doses in patients with recurrent/metastatic CRC and squamous cell carcinoma of the head and neck (SCCHN) has begun. An expansion cohort in patients with recurrent/metastatic SCCHN will be initiated at the conclusion of this part. Clinical trial information: NCT04474470.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3096
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 2
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    The bi-steric mTORC1-selective inhibitor RMC-5552 in tumors with activation of mTOR signaling: Preclinical activity in combination with RAS(ON) inhibitors in RAS-addicted tumors, and initial clinical findings from a single agent phase 1/1b study.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 3098-3098
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 3098-3098
    Abstract: 3098 Background: RMC-5552 is a potent bi-steric mTORC1-selective inhibitor that activates the downstream tumor suppressor 4EBP1, thereby inhibiting initiation of protein translation. This novel therapeutic moiety addresses a key limitation of rapalogs, which do not effectively inhibit phosphorylation of 4EBP1. RMC-5552 has previously demonstrated significant anti-tumor activity in preclinical models of human cancers with mTOR pathway activation. Additionally, mTOR signaling plays a key role in therapeutic response and resistance in RAS-addicted cancers, which represent a significant unmet medical need. Methods: We examined the combination of bi-steric mTORC1 inhibitors (RMC-5552 and the research tool compound RMC-6272) with direct inhibitors of active RAS (RAS(ON) inhibitors) in mutant KRAS-driven models. To enable the clinical testing of RMC-5552 as a companion inhibitor for RAS(ON) inhibitors, a Phase 1/1b dose-escalation trial of RMC-5552 monotherapy is currently testing a once-a-week IV schedule. Results: RMC-5552 and RMC-6272 demonstrated marked combinatorial anti-tumor activity with RAS(ON) inhibitors across a series of preclinical models of KRAS mutated non-small cell lung cancer. The combination enhanced tumor apoptosis and resulted in durable tumor regressions as compared to tumor growth inhibition resulting from single agents alone. As of 13 January 2022, a total of 14 patients with solid tumors have been evaluated in an ongoing Phase 1/1b trial over 5 dose levels ranging from 1.6 to 12 mg IV weekly. Median age was 62 years and the majority received ≥3 prior therapies. The most common ( 〉 25%) drug-related adverse events were mucositis/stomatitis (43%) and decreased appetite (29%). The most common grade 3 drug-related adverse events were mucositis/stomatitis observed in 3 patients in dose levels ≥ 10 mg (21%) and were dose-limiting. The dose of 6 mg IV weekly was well tolerated. Plasma exposures of RMC-5552 were dose-proportionate at lower dose levels up to 6 mg but increased above dose proportionality with higher dose levels. Plasma exposures at 6 mg and above were consistent with those resulting in inhibition of tumor p4EBP1 in preclinical models. Of 5 patients evaluable for efficacy at doses of 6 mg and higher, one confirmed PR was observed in a patient with head and neck cancer with a pathogenic mutation in PTEN (ORR 20%) and 3 patients had a best response of SD. Dose-optimization is ongoing. Conclusions: RMC-5552 is clinically active in tumors with mTORC1 signaling activation at a tolerable dose and schedule and has the potential to be a companion inhibitor of choice for RAS(ON) inhibitors in RAS-addicted tumors. Clinical trial information: NCT04774952.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.3098
    RVK:
    XA 52760
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    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 3
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    Trial in progress: Phase I study of SY-5609, a potent, selective CDK7 inhibitor, with initial expansion in adults with metastatic pancreatic cancer.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4180-TPS4180
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. TPS4180-TPS4180
    Abstract: TPS4180 Background: SY-5609 is an oral, selective, potent CDK7 inhibitor that targets two fundamental processes in cancer: transcription and cell cycle control. Early results from the Phase 1 dose escalation portion in patients (pts) with advanced solid tumors reported improved tolerability of the intermittent 7 days on followed by 7 days off (7/7) schedule with ongoing dose escalation beyond the continuous daily dosing maximum tolerated dose. Single-agent clinical activity was demonstrated with durable stable disease, target lesion regressions, and reduction in tumor markers observed in multiple tumor types, notably in pancreatic cancer with a disease control rate (DCR) of 38.5% (Sharma 2021). Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 11% (ACS Cancer Facts and figures, 2022) with limited treatment options and therefore, is a disease in need of novel effective therapies. Oncogenic KRAS mutations are prevalent in PDAC. Mutant KRAS is a potent stimulator of mitogenic MAPK signaling and downstream transcriptional programs for cell proliferation. Preclinical studies have shown that CDK7 inhibition via SY-5609 inhibits tumor growth in KRAS mutant PDAC xenograft models, in many cases leading to regressions. SY-5609 also potentiates gemcitabine (gem) activity in PDAC cells in vitro and in xenografts in vivo (Henry 2021). Therefore, combining SY-5609 with gem +/- nab-paclitaxel (nab-pac) offers a potential new treatment strategy for metastatic PDAC (mPDAC). The expansion portion of this Phase 1 study will evaluate SY-5609 in combination with gem +/- nab-pac in mPDAC pts. Gem +/- nab-pac will be administered on a biweekly schedule as it has shown better tolerability and similar clinical activity compared to the standard of care (SOC) administration schedule (Rehman 2020). Methods: This is an ongoing Phase 1, multi-center study in select solid tumors, amended to open expansion cohorts for mPDAC and expected to enroll approximately 80 mPDAC pts who have progressed on SOC treatments. Objectives of the expansion cohorts include evaluation of safety and efficacy of SY-5609 in combination with gem +/- nab-pac. Key objectives of the two parallel safety lead-in cohorts 1) SY-5609 + gem and 2) SY-5609 + gem + nab-pac are safety and determination of the recommended combination dose of the doublet and triplet for subsequent cohort expansions using a 3+3 escalation design. Key objectives of expansion cohorts are to describe efficacy, defined by progression-free survival, overall response rate, and DCR. Additional objectives include evaluation of pharmacokinetics and pharmacodynamics of SY-5609 in combination with gem +/- nab-pac. SY-5609 will be administered orally once daily on a 7/7 regimen and gem +/- nab-pac will be administered intravenously, in a 4-week cycle. The expansion portion is now open to enrollment. Clinical trial information: NCT04247126.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.TPS4180
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
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    Preliminary results from ERAS-007 plus palbociclib (palbo) in patients (pts) with KRAS/NRAS mutant (m) colorectal cancer (CRC) or KRASm pancreatic ductal adenocarcinoma (PDAC) in HERKULES-3 study: A phase 1b/2 study of agents targeting the mitogen-activated protein kinase (MAPK) pathway in pts with advanced gastrointestinal malignancies (GI cancers).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 3558-3558
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 3558-3558
    Abstract: 3558 Background: The RAS/MAPK pathway is dysregulated in a broad range of cancers including CRC and PDAC, resulting in downstream activation of ERK1/2. ERAS-007 is a novel, orally bioavailable inhibitor of ERK. Palbo is an oral CDK4/6 inhibitor that inhibits cellular proliferation, an essential feature of tumor growth. Both in vitro & in vivo data exploring the combination of ERAS-007 and palbo in a panel of CRC and pancreatic CDX and/or PDX models have shown promising activity to support the potential combinatorial clinical benefit in RASm CRC and PDAC pts. Methods: HERKULES-3 is a Phase 1b/2 study to assess safety, tolerability, PK, and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, and PK of escalating doses of ERAS-007 twice daily-once a week (BID-QW) (75, 100 mg) in combination with palbo once daily (QD) (75, 100, 125 mg) in pts with KRASm/NRASm CRC or KRASm PDAC. Results: As of 30 November 2022, 30 pts were dosed with the combination of palbo and ERAS-007. Treatment emergent AEs (TEAEs) occurring in ≥20% pts were diarrhea (40%), nausea (40%), anemia (33%), vision blurred (27%), fatigue (23%), and neutrophil count decreased (20%). ERAS-007 treatment related AEs (TRAEs) were reported in 19 pts (63%), with the most frequently reported as diarrhea (40%), nausea (33%), and vision blurred (27%). Grade (Gr) ≥3 TEAEs were reported in 12 pts (40%), including 3 related to ERAS-007 (neutrophil count decreased, diarrhea and dermatitis acneiform). Neutrophil count decreased and anemia were the only Gr 3 events reported in ≥2 pts. No Gr 4 events were reported. Two Gr 5 events unrelated to any drugs (hemorrhage intracranial and malignant pleural effusion) and one Gr 5 event (anemia) related to palbo were reported. Two pts discontinued ERAS-007 due to TEAEs (Gr 5 malignant pleural effusion and Gr 2 neutrophil count decreased). Three pts reported 4 DLTs: 1 pt at 75mg ERAS-007 & 125mg palbo (Gr 3 maculopapular rash & Gr 4 sepsis), 1 pt at 100mg ERAS-007 & 100mg palbo (Gr 3 dermatitis acneiform), and 1 pt at 100mg ERAS-007 & 125mg palbo (Gr 3 thrombocytopenia). Based on preliminary PK, no clinically relevant PK interactions were identified between ERAS-007 and palbo. The evaluation of clinical activity is ongoing. Conclusions: ERAS-007 in combination with palbo in pts with KRASm/NRASm CRC or KRASm PDAC shows expected preliminary safety with reversible and manageable AEs. The highest dose evaluated and cleared by the safety review committee to date is ERAS-007 100 mg BID-QW in combination with the approved monotherapy dose of palbo 125 mg QD. Clinical trial information: NCT05039177 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.3558
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
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    A pilot study of tremelimumab, a monoclonal antibody against CTLA-4, in combination with either transcatheter arterial chemoembolization (TACE) or radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC).
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 15_suppl ( 2014-05-20), p. e15133-e15133
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. e15133-e15133
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2014.32.15_suppl.e15133
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 6
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    A phase II study of TR105 in patients with hepatocellular carcinoma (HCC) who have progressed on sorafenib.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. e15177-e15177
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e15177-e15177
    Abstract: e15177 Background: CD105, also known as endoglin, is an endothelial cell membrane receptor that is highly expressed on tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and tumor growth by endothelial cell growth inhibition, ADCC and apoptosis. Methods: Patients with HCC and compensated liver function (Childs Pugh A/B7), ECOG 0/1, were enrolled to a single arm phase II study of TRC105 15mg/kg IV every 2 weeks. Patients must have progressed on or been intolerant of prior sorafenib. A Simon optimal 2-stage design was employed with a 50% 4-month PFS target for progression to the second stage. Correlative biomarkers evaluated included: DCE-MRI; FDG-PET; color Doppler ultrasonography; circulating endothelial progenitor cells, plasma levels of angiogenic factors; soluble CD105 and tumor IHC for CD105. Immunogenicity studies were also performed. Results: 8 pts have been treated so far; M:F 6:2; Median age = 58 (range 24-67); 7 pts had progressed following sorafenib (N=1 intolerant). N=1 pt had fibrolammellar HCC. There were no grade 3/4 treatment-related toxicities. Most frequent toxicities were headache (G2; N=3) and epistaxis (G1; N=4). One patient with a history of ischemic heart disease developed acute cardiac syndrome during the first infusion and was replaced. No patient was progression free at 4 months by RECIST criteria. Median time on study was 8 weeks (range 4-16 weeks). Median no. of doses administered was 4 (range 2-7). Preliminary evidence of biologic response was seen on DCE-MRI in 1pt (of 3 evaluable) with a reduction in kTrans and kep and 3pts (of 3 evaluable) who demonstrated reduction in intra-tumoral color flow on color Doppler. Conclusions: TRC105 is well tolerated in this HCC population post-sorafenib. Although there was biological evidence of antiangiogenic activity it is unlikely that the study will proceed to the second stage. Full clinical and correlative data for the first stage of the study will be presented. Future role of TRC105 in HCC will most likely be as combination therapy with sorafenib or other anti-VEGF therapy. Clinical trial information: NCT01375569.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.e15177
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 7
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    A phase I, first-in-human, open-label, dose-escalation study of MGD013, a bispecific DART molecule binding PD-1 and LAG-3, in patients with unresectable or metastatic neoplasms.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3004-3004
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3004-3004
    Abstract: 3004 Background: MGD013 is an investigational, first-in-class, Fc-bearing bispecific tetravalent DART molecule designed to bind PD-1 and LAG-3 and sustain/restore the function of exhausted T cells. MGD013 demonstrates ligand blocking properties consistent with anti-PD-1 and anti-LAG-3 benchmark molecules, and improves T cell responses beyond that observed with benchmark or component antibodies alone or in combination. Methods: This study characterizes the safety, tolerability, dose-limiting toxicities, maximum tolerated dose (MTD), PK/PD, and antitumor activity of MGD013 in patients (pts) with advanced solid and hematologic malignancies. Sequential single-pt cohorts were treated with escalating flat doses of MGD013 (1-1200 mg IV every 2 weeks), followed by a 3+3 design. Tumor-specific expansion cohorts are being treated at the recommended Phase 2 dose of 600 mg. Results: At data-cutoff, 50 pts (46% checkpoint-experienced) were treated in Dose Escalation, and 157 pts (32% checkpoint-experienced) in Cohort Expansion. No MTD was defined. Treatment-related adverse events (TRAEs) occurred in 146/207 (70.5%) pts, most commonly fatigue (19%) and nausea (11%). The rate of Grade ≥ 3 TRAEs was 23.2%. Immune-related AEs were consistent with events observed with anti-PD-1 antibodies. Mean half-life was 11 days; peripheral blood flow cytometry analyses confirmed full and sustained on-target binding during treatment at doses ≥ 120 mg. Among 41 response-evaluable [RE] dose escalation pts, 3 confirmed partial responses [cPRs] (triple negative breast cancer [TNBC], mesothelioma, gastric cancer) per RECIST 1.1 were observed, while 21 pts had stable disease [SD] . Among select expansion cohorts, PRs have been observed in epithelial ovarian cancer (n=2; both cPRs, and 7 with SD among 15 RE pts) and TNBC (n=2; 1 cPR, 1 unconfirmed PR [uPR], and 5 with SD among 14 RE pts). In a cohort of pts with HER2+ tumors treated with MGD013 in combination with margetuximab (investigational anti-HER-2 antibody), 3 PRs have been observed (breast [n=2] , colorectal [n=1]; 1 cPR, 2 uPRs) and 2 pts with SD among 6 RE pts. Objective responses have been observed in several pts after prior anti-PD-1 therapy. Investigations into potential correlative biomarkers including LAG-3 and PD-1 are ongoing. Conclusions: MGD013, a novel molecule designed to coordinately block PD-1 and LAG-3, has demonstrated an acceptable safety profile and encouraging early evidence of anti-tumor activity. Clinical trial information: NCT03219268 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3004
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 8
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    Pen-866, a miniature drug conjugate of a heat shock protein 90 (HSP90) ligand linked to SN38 for patients with advanced solid malignancies: Phase I and expansion cohort results.
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  Journal of Clinical Oncology Vol. 38, No. 15_suppl ( 2020-05-20), p. 3515-3515
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. 3515-3515
    Abstract: 3515 Background: PEN-866 is a miniature drug conjugate which links a HSP90 binding small molecule to a SN-38 cytotoxic payload. HSP90 is highly expressed in advanced malignancies. PEN-866 targets and binds to activated tumor HSP90 protein, releases its cytotoxic payload, and results in complete tumor regressions in multiple xenograft models. This first-in-human study assessed safety, tolerability, pharmacokinetics (PK), and preliminary efficacy of PEN-866. Methods: Patients (pts) with progressive, advanced solid malignancies were enrolled in escalating cohorts of 2-9 pts. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of PEN-866 given weekly (3 out of 4 weeks in a 28-day cycle). Results: 30 pts were treated in 8 cohorts (range 30-360 mg flat dosing or 150–200 mg/m 2 BSA-based dosing). As of 9Jan20, the total median/mean exposure was 7.05/12.4 weeks. No dose limiting toxicities (DLTs) occurred in the first 4 cohorts (30-240 mg; 14 pts). In cohort 5 (360 mg), 1 of 3 pts had a DLT of grade (G) 3 transient diarrhea, and 2 other pts had G3 uncomplicated transient neutropenia. A change to BSA-based dosing was instituted for cohort 6 (175 mg/m 2 ), on which no DLTs were observed, although 1 pt experienced G3 uncomplicated transient neutropenia. At 200 mg/m 2 , 2 of 5 pts experienced DLTs (G5 dehydration, G3 fatigue). The MTD and RP2D were determined to be 175 mg/m 2 . The most frequent (≥20% pts) related adverse events were nausea (50%), fatigue (43%), diarrhea (40%), vomiting (27%), and anemia (23%). PK was nonlinear. Plasma exposures increased greater than dose proportionally. Median t 1/2 ~7 h. Cleaved SN38 never exceeded 3% of PEN-866 plasma AUC at all dose levels. Tissue PK confirmed tumor accumulation and retention of both the conjugate and released payload. As of 9Jan20, 26 pts were evaluable for response. 11 pts had stable disease at 8 weeks, of which 7 lasted 12–58 weeks. One pt with anal squamous cell carcinoma achieved a confirmed partial response. Decreased target lesion size was observed in 6 additional pts. Conclusions: PEN-866 was well tolerated and demonstrated preliminary evidence of antitumor activity. PEN-866 will be evaluated in Phase 2a expansion cohorts enrolling multiple solid tumors (NCT03221400). Clinical trial information: NCT03221400 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2020.38.15_suppl.3515
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 9
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    A phase I/II study of TRC105 in combination with sorafenib in hepatocellular carcinoma (HCC).
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 3_suppl ( 2015-01-20), p. 291-291
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 291-291
    Abstract: 291 Background: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including HCC. CD105 is essential for angiogenesis and its expression is upregulated by hypoxia and VEGF inhibition. TRC105 is a chimeric IgG1 anti-CD105 monoclonal antibody that inhibits angiogenesis and causes ADCC and apoptosis of proliferating endothelium. Sorafenib is the only FDA-approved drug in HCC. Methods: Preclinical: Murine BNL HCC cells were grown subcutaneously in wildtype Balb/c mice and treated with antibody to murine CD105, (clone MJ7/18; 10-200ug) + sorafenib (10 mg/kg daily p.o.) or sorafenib alone with assessment for CD105 expression, tumor size. Clinical: Patients with HCC (Childs Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, 15mg/kg q 2wks plus sorafenib 400mg bid. Correlative biomarkers included DCE-MRI, color Doppler ultrasonography, circulating endothelial and endothelial progenitor cells, plasma levels of angiogenic factors, soluble CD105 and tumor IHC for CD105. Samples were also collected for immunogenicity and pharmacokinetics. Results: Preclinical studies: CD105 expression was increased in BNL HCC tumors by sorafenib. Anti-CD105 antibody + sorafenib reduced tumor volume compared to sorafenib alone. Clinical trial: 19 pts were enrolled; Hep B/C/NA: 2/10/7; M:F 13:6; Mean age of 60 (range 18-76); 1 DLT (increased AST) occurred at 10mg/kg. Three of 14 (21%) evaluable pts achieved PR by RECIST. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median time on study was 4 months (range 2 to 22 months). Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity was observed and the study is proceeding to the phase 2 stage. Full correlative and clinical data will be presented. Clinical trial information: NCT01306058.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.3_suppl.291
    RVK:
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    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 10
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    Phase I/II study of ISIS 183750 in combination with irinotecan for advanced solid tumors or colorectal cancer: Final results.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 3_suppl ( 2015-01-20), p. 639-639
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 3_suppl ( 2015-01-20), p. 639-639
    Abstract: 639 Background: ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of eukaryotic translation initiation factor 4E (eIF4E), a potent oncogene. In preclinical models, ISIS demonstrated enhanced activity in combination with irinotecan (Iri). The purpose of this study was to determine maximum tolerated dose (MTD) and explore efficacy in an irinotecan-refractory colorectal cancer (CRC) population. Methods: Phase (Ph) I: Patients (pts) with advanced carcinoma (ECOG 0-2) received ISIS 183750 at 800 or 1,000 mg IV q-weekly in combination with Iri 180 mg/m2 q-2weekly. Ph II: Pts with irinotecan-refractory colorectal cancer were treated with ISIS 183750 1,000mg IV q-weekly in combination with Iri 160 mg/m2. Peripheral blood was analyzed for eIF4E mRNA. Tumor biopsies were obtained at baseline and C1D15 for ISIS 183750 IHC and eIF4E mRNA quantification. Response was assessed q8weeks by RESIST criteria. Results: 24 pts (14M/10F, median age 63 (range 43-79), ECOG PS 0/1/2: 5/18/1, prior chemotherapy regiments 3 (1-7)) were treated with ISIS 183750 + Iri. Ph 1: N=14 (colorectal (9), pancreas (3), endometrial (1), small bowel (1)). Ph 2: N=10 (colorectal). Median time on treatment was 56 days (2-232). The most common grade 3-4 adverse events were neutropenia 8/24 pts (33%) and hypoalbuminemia 6/24(25%). No dose limiting toxicities were seen. Efficacy data were evaluated in 15 irinotecan-refractory CRC pts. There were no objective responses. Stable disease was seen in 7/15 (47%) patients, median time of disease control was 22.1 wks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13/19 pts. Matched pre- and post-treatment tumor biopsies showed decreased eIF4E mRNA levels in 5/9 pts. In tumor tissue, intracellular presence of ISIS 183750 was detected by IHC in all biopsied patients. Conclusions: ISIS 183750 at the maximum dose tested of 1,000 mg in combination with irinotecan was feasible and relatively well tolerated. Even though intracellular penetration of ISIS was observed, it did not result in objective tumor response. Consequently, further exploration of resistance mechanisms is needed. Clinical trial information: NCT01675128.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.3_suppl.639
    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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