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  • 1
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    Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 2506-2506
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 2506-2506
    Abstract: 2506 Background: Alrizomadlin (APG-115) restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and hence may restore antitumor activity in pts with cancers failing PD-1/PD-L1 blockade. Methods: This US multicenter trial assessed alrizomadlin combined with pembrolizumab in pts with unresectable/metastatic melanoma or advanced solid tumors that had failed I-O drugs; or pts with malignant peripheral nerve sheath tumor (MPNST), liposarcoma, or ATM mutant solid tumors that had failed any standard therapy. Eligible pts had ECOG performance status of 0-2 and no CNS metastases. The phase II study cohorts included pts with melanoma, NSCLC, solid tumor with ATM mutation, well-differentiated/dedifferentiated liposarcoma, urothelial carcinoma, and MPNST. Alrizomadlin was administered orally at 150 mg once every other day for 2 consecutive weeks with 1 week off and pembrolizumab at 200 mg via IV infusion for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 25, 2020, 84 pts had been treated in 6 cohorts: melanoma (n = 26), NSCLC (n = 23), ATM mutation (n = 9), liposarcoma (n = 14), urothelial (n = 9), and MPNST (n = 3). In the PD-1/PD-L1 inhibitor-failed melanoma cohort, there was 1 confirmed partial response (PR) out of 5 pts with uveal melanoma, 2 PR (1 confirmed and 1 unconfirmed) of 5 pts with mucosal melanoma, and 1 confirmed PR of 11 pts with cutaneous melanoma. ORR in the melanoma cohort was 17.4% (4/23 evaluable pts), and the disease control rate was 60.9% (14/23). In the MPNST cohort, 1 of 3 pts had an unconfirmed ongoing PR. In I-O drug-failed NSCLC (n = 14 evaluable) and urothelial (n = 5 evaluable) cohorts, each reported 1 confirmed PR. Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs) (≥ 10%) were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade ≥ 3 TRAEs (≥ 5%) included thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). Eleven pts discontinued treatment due to AEs: 5 were treatment related, including 2 grade 4 thrombocytopenia, and 1 each of grade 2 vomiting, grade 2 fatigue, and grade 2 posterior reversible encephalopathy syndrome (PRES). Three treatment-related SAEs were PRES, pyrexia, and asthenia. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and may restore antitumor effects in pts with cancer resistant to or intolerant of I-O drugs, as suggested by preliminary antitumor activities in multiple tumor types. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.2506
    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
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    Newly updated activity results of alrizomadlin (APG-115), a novel MDM2/p53 inhibitor, plus pembrolizumab: Phase 2 study in adults and children with various solid tumors.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 9517-9517
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 9517-9517
    Abstract: 9517 Background: Alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in pts with cancers that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial evaluated alrizomadlin, an investigational MDM2-selective, small-molecule inhibitor, combined with pembrolizumab, in pts with unresectable/metastatic melanoma that progressed on I-O drugs; pts with malignant peripheral nerve sheath tumor (MPNST), well-differentiated/dedifferentiated liposarcoma, non-small cell lung cancer (NSCLC), or solid tumors with ATM mutations that progressed on available standard therapy; or pts for whom therapy was unavailable. Eligible pts had ECOG performance status of 0-2 and, if present, stable brain metastases. Alrizomadlin 150 mg PO was administered QOD for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg IV over 30 minutes on Day 1 of a 21-day cycle. Results: As of November 3, 2021, preliminary and interim results are reported for 130 pts in 6 cohorts: melanoma (n = 44), NSCLC (n = 26), ATM mutation (n = 18), liposarcoma (n = 17), urothelial (n = 13), and MPNST (n = 12). In the melanoma cohort, confirmed ORR by RECIST, (PR + CR) was 13% (2 CRs + 3 PRs/38 efficacy evaluable [EE] pts). In cutaneous and uveal melanoma subcohorts, confirmed ORR was 24% (2 CRs + 2 PRs/17 EE pts) and 9% (1 PR/11 EE pts), respectively. In the MPNST cohort, the clinical benefit rate, defined by confirmed ORR + SD of 〉 4 cycles, was 40% (4 SDs/10 EE pts). Additional confirmed PRs were reported in NSCLC, urothelial, and liposarcoma cohorts (1 each). Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs; ≥ 10%) were nausea (62%), thrombocytopenia (39%), vomiting (38%), fatigue (38%), decreased appetite (29%), diarrhea (25%), neutropenia (15%), and anemia (12%). Grade 3 + TRAEs (≥ 5%) included thrombocytopenia (23%), neutropenia (10%), and anemia (7%). A total of 16 pts discontinued treatment due to AEs; 6 were treatment related, including grade 4 thrombocytopenia (n = 3), grade 2 vomiting (n = 1), grade 2 fatigue (n = 1), and grade 2 posterior reversible encephalopathy syndrome (PRES; n = 1). A total of 10 pts reported treatment-related SAEs: 1 each of abdominal pain, asthenia, colitis, febrile neutropenia, hypophysitis, peripheral edema, overdose, PRES, pulmonary embolism, pyrexia, and thrombocytopenia. Conclusions: Alrizomadlin, combined with pembrolizumab, is well tolerated and demonstrates preliminary antitumor activity in multiple tumor types and may restore antitumor effects in pts with cancer resistant or intolerant to I-O drugs. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.9517
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 3
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    Neoadjuvant talazoparib (TALA) in patients (pts) with germline BRCA1/2 (g BRCA1/2 ) mutation-positive, early HER2-negative breast cancer (BC): Exploration of tumor BRCA mutational status and zygosity and overall mutational landscape in a phase 2 study.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 554-554
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 554-554
    Abstract: 554 Background: TALA is a poly(ADP-ribose) polymerase inhibitor approved as monotherapy for adult pts with g BRCA1/2-mutated HER2-negative locally advanced/metastatic BC. We report biomarker analyses from a phase 2, nonrandomized, single-arm, open-label study (NEOTALA; NCT03499353) evaluating the efficacy and safety of TALA in the neoadjuvant setting for pts with early g BRCA1/2-mutated HER2− BC. Efficacy and safety results are presented separately. Methods: The biomarker analysis population was all pts treated with TALA for whom biomarker results are available. To support molecular eligibility, blood was tested using BRCAnalysis CDx (Myriad Genetics). Baseline tumor tissue was retrospectively tested using FoundationOne CDx, with BRCA1/2 zygosity assessed using somatic-germline-zygosity (SGZ; Sun et al. JCO PO, 2018). Germline mutational status of 14 non- BRCA DNA damage response (DDR) genes was retrospectively assessed in baseline saliva samples using Ambry CustomNext-Cancer. Mutations were defined as known/likely pathogenic/deleterious variants, including copy number alterations (CNAs). Association between mutational status of MYC or RAD21 and primary endpoint pathological complete response (pCR) as per Independent Central Review was investigated with logistic regression. Results: Of 52 evaluable tumor samples from 61 treated pts, 39 (75%) and 13 (25%) pts exhibited BRCA1 and BRCA2 mutations, respectively; 1 (2%) pt exhibited mutations in both genes, and 1 (2%) pt had mutations in neither. BRCA loss of heterozygosity (LOH) was seen in 42/43 (98%) evaluable BRCA-mutant tumors. Of 45 pts evaluable centrally for both germline and tumor, 44/45 (98%) pts exhibited the same BRCA mutation in tumor as originally detected in germline, with the remaining pt exhibiting a g BRCA1 mutation, but lacking a tumor BRCA mutation. None of 49 saliva-evaluable pts exhibited non- BRCA germline DDR mutations. TP53 (51 [98%] pts) was the most frequently mutated gene in tumors. MYC and RAD21 (each 14 [27%] pts) were the most frequent CNAs. No evidence of association between mutational status of MYC or RAD21 and pCR was found (odds ratio=0.39, 95% CI 0.12-2.30). Based on a cutoff of ≥16%, genomic LOH was elevated in 24/27 (89%) tumors evaluable for both gLOH and pCR, precluding assessment of the potential association of gLOH high/low status with pCR. Conclusions: Tumor BRCA mutations were evident in nearly all pts in the biomarker analysis population, with BRCA LOH evident in all but 1 BRCA-mutated tumor. No pts had non- BRCA germline DDR gene mutations; tumor TP53 mutations were near-universal. MYC and RAD21 each exhibited CNAs in 27% of tumors, with no association with pCR. These results support the central role of BRCA mutations in tumor pathobiology in this indication. Clinical trial information: NCT03499353.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.554
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 4
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    Pharmacokinetic (PK)/pharmacodynamic (PD) results from a phase Ib study of pegylated hyaluronidase PH20 (PEGPH20) in combination with gemcitabine (Gem) in patients with pancreatic cancer.
    American Society of Clinical Oncology (ASCO) ; 2013
    In:  Journal of Clinical Oncology Vol. 31, No. 15_suppl ( 2013-05-20), p. e15005-e15005
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 31, No. 15_suppl ( 2013-05-20), p. e15005-e15005
    Abstract: e15005 Background: Enzymatic degradation of hyaluronan (HA) is a novel strategy to target the desmoplastic stroma of pancreatic cancer. PEGPH20, a pegylated form of recombinant human hyaluronidase PH20, is an investigational drug in clinical trials. Preclinical studies demonstrate that sustained HA removal by PEGPH20 inhibits tumor growth and enhances chemotherapeutic activity in HA-rich xenografts and genetically engineered mouse tumor models. Ph1 PEGPH20 monotherapy studies show increased tumor perfusion by DCE-MRI, metabolic partial responses by FDG-PET, and stromal remodeling in tumor biopsies from selected advanced cancer patients (pts). Methods: This was a dose-escalation study to find the recommended Ph2 dose of PEGPH20 in combination with Gem in pts with Stage IV previously untreated pancreatic cancer. Pts received Gem at 1000 mg/m 2 IV qwk for Wks 1-7 plus PEGPH20 at 1, 1.6, or 3 μg/kg IV twice a week for Wks 1-4 and qwk for Wks 5-7. Wk 8 was a rest week. Thereafter, PEGPH20 + Gem were given qwk for 3 wks in 4-wk cycles. Serial plasma samples were collected and hyaluronidase activity measured by an ultrasensitive assay to assess PEGPH20 exposure. Plasma HA catabolites were measured by quantitative HPLC to assess PD. Results: 28 pts were enrolled. Plasma PEGPH20 concentrations were proportional to dose, and kinetics were well-characterized by a 2-compartment PK model. Estimates for clearance (0.5-2 mL/hr/kg) were consistent with long t 1/2 (1-2 days) previously seen with single-dose PEGPH20 monotherapy. Wks 1 and 4 PK profiles were similar, suggesting no changes to PEGPH20 clearance mechanisms after multiple doses or effects of Gem on PEGPH20 exposure. Most pretreatment plasma HA levels were 〈 1 μg/mL and increased in a time- and dose-dependent manner after dosing. Circulating HA concentration was 〉 500 µg/mL in several pts given 3 μg/kg PEGPH20. Conclusions: PEGPH20 plasma levels can be predicted using a linear PK model and circulating HA catabolites can be used as a quantitative measure of PEGPH20 PD. Results are consistent with the mechanism of action of hyaluronidase and support further study of PEGPH20 with anticancer agents. Clinical trial information: NCT01453153.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2013.31.15_suppl.e15005
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2013
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  • 5
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    Trials in progress: TAM kinase inhibitor PF-07265807 and sasanlimab plus axitinib in patients with advanced or metastatic renal cell carcinoma—A phase 1, open-label, pharmacokinetic, safety and tolerability study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. TPS743-TPS743
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. TPS743-TPS743
    Abstract: TPS743 Background: Tumor-associated macrophage kinases (TAMK) are expressed on tumor cells during malignant transformation. Inhibition of AXL and MERTK, members of the TAMK family, may lower the immune activation threshold and promote antitumor immunity. PF-07265807 (ARRY-067) is a small-molecule inhibitor of MERTK and AXL showing antitumor activity in preclinical models as monotherapy or combined with anti-programmed cell death protein 1 (anti-PD-1) antibodies (ab). Sasanlimab is an anti-PD-1 ab with acceptable safety profile being tested (300 mg SC Q4W, Phase 3) in non-muscle invasive bladder cancer. Axitinib is a VEGF inhibitor approved (single agent and combined with anti-PD-1 inhibitors) for advanced renal cell carcinoma (RCC). This first-in-human Phase 1, open-label, multi-center study (NCT04458259) will evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of PF-07265807 in patients (pts) with advanced or metastatic solid tumors as a single agent and in combination with sasanlimab with or without axitinib. We describe here the dose escalation (Part 3) and dose expansion (Part 4) for the triplet combination of PF-07265807 + sasanlimab + axitinib. Methods: Eligible participants for the triplet cohorts are adult pts with confirmed unresectable advanced or metastatic clear cell RCC, with estimated creatinine clearance ≥30 mL/min and urinary protein 〈 2+ or ≥2+ but 24-h urine protein:creatinine ratio 〈 2 g/24 h. Pts for Part 4 need to have intermediate and poor risk RCC and no prior systemic therapy for metastatic disease. Other key eligibility criteria: measurable disease by RECIST 1.1 or non-measurable disease, ECOG PS 0–2, adequate bone marrow and liver function, and resolved acute effects of prior therapy. Each cycle is 21 days. Part 3 will determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) of PF-07265807 in triplet therapy using a Bayesian logistic regression model and the escalation with overdose control principle. After the MTD/RP2D is identified, Part 4 will further evaluate the safety and preliminary efficacy of PF-07265807 combined with sasanlimab and axitinib. Treatment with study drug will continue until disease progression, consent withdrawal, or unacceptable toxicity, whichever occurs first. Primary endpoints of Part 3 are incidence of dose-limiting toxicities, adverse events (AE), and laboratory (lab) abnormalities. For Part 4, the primary endpoints are objective response rate and complete response rate; secondary endpoints include disease control rate; time-to-event endpoints; AEs; lab abnormalities; concentrations of PF-07265807 and its metabolite, sasanlimab, and axitinib; and incidence and titer of anti-sasanlimab anti-drug antibodies response. The study started in late 2020 and is recruiting. Clinical trial information: NCT04458259 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.TPS743
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 6
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    Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with previously treated, recurrent or refractory ovarian cancer: A phase Ib, open-label expansion trial.
    American Society of Clinical Oncology (ASCO) ; 2015
    In:  Journal of Clinical Oncology Vol. 33, No. 15_suppl ( 2015-05-20), p. 5509-5509
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    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 5509-5509
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2015.33.15_suppl.5509
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2015
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  • 7
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    Abstract 4926: Alpelisib in combination with trastuzumab and pertuzumab as maintenance therapy in patients with HER2+, PIK3CA -mutant advanced breast cancer: EPIK-B2 Study Part 1 safety and efficacy results
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4926-4926
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4926-4926
    Abstract: Introduction: Current standard first-line (1L) treatment (tx) for patients (pts) with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) includes taxanes plus trastuzumab (T) and pertuzumab (P). Mutations (mut) in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) gene encoding PI3Kα have been reported in 12%-39% of HER2+ BCs and associated with worse prognoses and lower pathological complete response to anti-HER2 tx in the neoadjuvant setting. Alpelisib (ALP) is an oral, α-specific PI3K inhibitor approved at 300 mg per day (QD) in combination with fulvestrant in hormone receptor (HR)-positive, HER2−, PIK3CA-mut ABC following progression on/after endocrine therapy. EPIK-B2 is a 2-part Phase 3 study to evaluate ALP plus T+P as 1L maintenance tx in pts with HER2+, PIK3CA-mut ABC, without progressive disease at study entry. Here, we report results of Part 1, the safety run-in of EPIK-B2. Methods: Part 1 of EPIK-B2 was open label and assessed safety of ALP plus T+P in pts with HER2+ ABC and confirmed the recommended Phase 3 dose of ALP for the randomized Part 2. Pts with HER2+ ABC, with or without a PIK3CA mut, who had completed induction taxane chemotherapy plus T+P were eligible for Part 1. Part 2, currently enrolling, allows only PIK3CA-mut pts. Pts in Part 1 received 300 mg (Cohort A) or 250 mg (Cohort B) ALP QD plus 6 mg/kg T and 420 mg P, on Day 1 of each 21-day cycle. The primary endpoint of Part 1 was incidence of dose-limiting toxicities (DLTs) in the first 6 wk of tx; secondary endpoints included safety/tolerability and ALP exposure by dose level. Preliminary confirmed overall response rate (ORR; best overall response [BOR] of CR/PR) and clinical benefit rate (CBR; BOR of CR/PR/SD lasting ≥24 wk) were evaluated per RECIST v1.1 during the on-treatment period. Results: Three pts in Cohort A and 12 in Cohort B received 300 mg and 250 mg ALP, respectively. DLTs, 1 event each of hyperglycemia and dermatitis acneiform, were seen in Cohort A, none were reported in Cohort B pts given 250 mg ALP; however, Part 2 of EPIK-B2 will be initiated with 200 mg ALP with the option of intrapatient dose escalation to 250 mg QD, the maximum tolerated dose, per FDA feedback to consider a lower toxicity threshold in 1L maintenance setting. No unexpected AEs were reported; most common AEs were diarrhea, decreased appetite, and hyperglycemia. Six of 15 pts (40%; 2 in Cohort A, 4 in Cohort B) had PIK3CA-mut disease. Among these, ORR was 50% (n/N=3/6) and CBR was 100% (n/N=6/6). Tumor response was maintained in 5 of 6 pts with PIK3CA mutations (83%) after ≥21 cycles of tx (range, 21-31). Conclusions: ALP plus T+P combination is safe; reported AEs align with those in previous ALP studies. Preliminary efficacy data suggest promising clinical benefit with ALP plus T+P for pts with HER2+ PIK3CA-mut disease. Citation Format: Sara A. Hurvitz, François-Clement Bidard, Wei Li, Xichun Hu, Sonia Pernas, Joseph Thaddeus Beck, Mario Campone, Kevin Punie, Michelle Miller, Mathilde Kaper, Yu Han, Farhat Ghaznawi, Guy Jerusalem. Alpelisib in combination with trastuzumab and pertuzumab as maintenance therapy in patients with HER2+, PIK3CA-mutant advanced breast cancer: EPIK-B2 Study Part 1 safety and efficacy results. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4926.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4926
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 8
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    Ramucirumab with cisplatin and fluoropyrimidine as first-line therapy in patients with metastatic gastric or junctional adenocarcinoma (RAINFALL): a double-blind, randomised, placebo-controlled, phase 3 trial
    Elsevier BV ; 2019
    In:  The Lancet Oncology Vol. 20, No. 3 ( 2019-03), p. 420-435
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    In: The Lancet Oncology, Elsevier BV, Vol. 20, No. 3 ( 2019-03), p. 420-435
    Type of Medium: Online Resource
    ISSN: 1470-2045
    URL: Article
    DOI: 10.1016/S1470-2045(18)30791-5
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
    detail.hit.zdb_id: 2049730-1
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  • 9
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    Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway: An emerging treatment strategy for squamous cell lung carcinoma
    Elsevier BV ; 2014
    In:  Cancer Treatment Reviews Vol. 40, No. 8 ( 2014-09), p. 980-989
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    In: Cancer Treatment Reviews, Elsevier BV, Vol. 40, No. 8 ( 2014-09), p. 980-989
    Type of Medium: Online Resource
    ISSN: 0305-7372
    URL: Article
    DOI: 10.1016/j.ctrv.2014.06.006
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
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  • 10
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    Preliminary Results from a Phase 1/2, Open-Label, Dose-Escalation Clinical Trial of IMO-8400 in Patients with Relapsed or Refractory Waldenstrom's Macroglobulinemia
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 1540-1540
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1540-1540
    Abstract: Introduction: Waldenström's macroglobulinemia (WM) is a rare, indolent B-cell lymphoma characterized by lymphoplasmacytic cell infiltration of bone marrow and elevated serum levels of immunoglobulin M (IgM) protein. Despite recent advances in treatment the disease relapses in most patients. About 90% of WM patients harbor the MYD88 L265P oncogenic mutation. MYD88 is an adapter protein in the Toll-like receptor (TLR) pathway. The MYD88 L265P oncoprotein has been shown to amplify TLR 7 and 9 signaling, leading to downstream activation of NF-κB and cytokine signaling pathways that promote tumor cell survival and proliferation (Lim, AACR 2013). IMO-8400 is an investigational oligonucleotide antagonist of endosomal TLRs 7, 8 and 9. In preclinical studies in a human cell line and animal models of WM, IMO-8400 inhibited key cell signaling pathways, including NF-κB, BTK, STAT-3 and IRAK-4, and inhibited tumor growth and tumor IgM production. In Phase 1 and 2 clinical trials in healthy subjects (N=30) and in patients with autoimmune disease (N=35), IMO-8400 was generally well tolerated and demonstrated evidence of clinical activity. Based on these data, we initiated a Phase 1/2 clinical trial of IMO-8400 in WM, the first study of a drug candidate specifically targeting the MYD88 L265P mutation. Methods: This Phase 1/2 multicenter, open-label, dose-escalation clinical trial continues to recruit adult patients with relapsed or refractory WM (NCT Identifier: NCT02092909). In a classic 3x3 dose escalation scheme, patients are enrolled in one of three sequential escalating dose cohorts and receive subcutaneous IMO-8400 at dosages of 0.6, 1.2 or 2.4 mg/kg per week, respectively, for 24 weeks. The presence of the MYD88 L265P mutation is assessed by PCR-based genetic screening following enrollment. Patients who complete the 24-week treatment period are eligible to enroll in an extension trial. The primary study objective is to evaluate the safety and tolerability of escalating IMO-8400 dosages. Secondary objectives include preliminary evaluation of clinical response based on international guidelines and identification of an optimal dose for further evaluation (Kimby, Clin Lymphoma Myeloma 2006). Results: Overall, 17 patients (6 female, 11 male) have been enrolled in three dose cohorts to date. Median baseline characteristics include: age 66 years, prior therapies 4 (range 1-13), serum IgM 2,225 mg/dL, serum M protein 0.96 g/dL, and B2-microglobulin 3.42 mg/L. IMO-8400 has been generally well tolerated across all dose cohorts to date, with patient exposure ranging from 2-46 weeks in the Phase 1/2 and extension trials. The most common adverse events reported to date include transient flu-like symptoms and injection site reactions. One serious adverse event of worsening grade 3 arthritis, deemed possibly related to study drug, was reported in a patient with a pre-existing history of arthritis in the 2.4 mg/kg dose cohort. This patient discontinued study treatment. To date, no other patients have discontinued treatment due to treatment-related adverse events. Preliminary evidence of clinical activity for IMO-8400 has been observed in all dose cohorts. In June 2015, an independent Data Review Committee reviewed 4-week safety data from the highest dose cohort and agreed that 2.4 mg/kg was safe for further evaluation. Safety, pharmacokinetics and preliminary activity for all three dose cohorts will be presented. Conclusions: IMO-8400 is a mutation-targeted therapy in development for the treatment of patients with relapsed or refractory WM. In an ongoing Phase 1/2 clinical trial in WM, IMO-8400 has been generally well tolerated and has demonstrated preliminary evidence of clinical activity. Safety results support continued evaluation of IMO-8400 at 2.4 mg/kg/week in this patient population. Disclosures Thomas: Novartis, Celgene, Acerta Pharmaceuticals, Idera Pharmaceuticals: Research Funding. Harb:Astex Pharmaceuticals, Inc.: Research Funding; Idera Pharmaceuticals: Research Funding. Beck:Idera Pharmaceuticals: Research Funding. Nashat:Idera Pharmaceuticals: Research Funding. Ansell:Idera Pharmaceuticals: Research Funding. Eradat:Idera Pharmaceuticals: Research Funding. Libby:Idera Pharmaceuticals: Research Funding. Hajdenberg:Celgene: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau; Gilead: Speakers Bureau; Janssen: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Heffner:Idera Pharmaceuticals: Research Funding. Hoffman:Idera Pharmaceuticals: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Simov:Idera Pharmaceuticals: Employment. Wyant:Idera Pharmaceuticals: Employment. Brevard:Idera Pharmaceuticals: Employment. O'Leary:Idera Pharmaceuticals: Employment. Agrawal:Idera Pharmaceuticals: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.1540.1540
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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