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  • American Association for Cancer Research (AACR)  (9)
  • 1
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    Abstract P2-14-12: Eflapegrastim, a novel long-acting granulocyte-colony stimulating factor: Integrated safety results in patients with early-stage breast cancer treated with TC chemotherapy
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-14-12-P2-14-12
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-14-12-P2-14-12
    Abstract: Background: Eflapegrastim (E) represents the first myeloid growth factor innovation in more than 15 years. A novel, long-acting recombinant human granulocyte-colony stimulating factor (rhG-CSF), E consists of a rhG-CSF analog conjugated to a human IgG4 Fc fragment via a polyethylene glycol linker. Preclinical and Phase I and II pharmacodynamic and pharmacokinetic data showed increased potency for E versus pegfilgrastim (P). Two independent randomized Phase III trials comparing fixed dose E and P (E 3.6 mg G-CSF and P 6.0 mg G-CSF) for the management of chemotherapy-induced neutropenia (CIN) have recently been completed. Both trials met the primary endpoint of non-inferiority for E vs P in Cycle 1 duration of severe neutropenia (P & lt;.001). Here we provide an integrated summary of the safety of E administered at a fixed dose in a pre-filled syringe. Patients and Methods: Patients with early-stage breast cancer (ESBC) who were candidates for adjuvant or neoadjuvant chemotherapy were randomized 1:1 in two open-label Phase III trials to E 13.2 mg (3.6 mg G-CSF) or standard P (6 mg G-CSF) administered on Day 2 following TC (docetaxel/cyclophosphamide) chemotherapy on Day 1 of each of 4 cycles. Blood for CBC and serum chemistry was collected in every cycle. Safety assessments began with the first dose of TC and continued for one year after the last dose of study drug. AEs and laboratory values were graded according to NCI CTCAE version 4.03. Immunogenicity was assessed from blood samples collected on Day 1 of each cycle, at the end-of-treatment visit, and at 6- and 12-month follow-up visits. Results: A total of 660 patients who received at least one dose of eflapegrastim (n=334) or pegfilgrastim (n=326) were included in this integrated safety analysis. The two treatment groups were well balanced for demographics and baseline disease characteristics. The mean age was 59y, ~40% were aged & gt;65y, ~54% weighed & gt;75kg, and ~80% were treated in the adjuvant setting. Median relative dose intensity for T and C was & gt;99% for both groups. A similar percentage of patients in both treatment groups discontinued treatment due to AEs (4% E vs 6% P), with 2% in each group discontinuing due to AEs related to E or P. Serious AEs were similar in both groups (15% each). Incidence of AEs irrespective of causality were also similar between groups (74% E vs. 72% P). No notable differences between groups were observed in the types of study-drug-related AEs. The majority of study-drug-related AEs occurred with an incidence ≤10% for both E and P. As expected with myeloid growth factors, study-drug-related AEs occurring in & gt;10% in either group were bone pain (E vs P: 33% vs 34%), arthralgia (15% vs 10%), back pain (14% vs 9%), myalgia (14% vs 9%), and headache (11% vs 8%). Incidence of febrile neutropenia and neutropenic complications were similar and less than 5% in each treatment group. No leukocytosis, splenic rupture, or anaphylaxis was reported in any patient receiving E or P. The overall incidence of immunogenicity was similar in both groups and there was no demonstrable impact on clinical safety or efficacy. Conclusions: Two large, randomized Phase III trials (Total n=660) of E vs P administered once-per-cycle showed E at a lower G-CSF dose to be safe and effective for the prophylaxis of CIN in patients with ESBC receiving TC chemotherapy. E is a novel long-acting rhG-CSF with increased potency and similar toxicity to P and may provide an attractive alternative for growth factor support of patients at high risk for CIN-related complications. Citation Format: Lee S Schwartzberg, Gajanan Bhat, Julio Peguero, Richy Agajanian, Jayaram Bharadwaj, Alvaro Restrepo, Osama Hlalah, Inderjit Mehmi, Shanta Chawla, Francois Lebel, Patrick W Cobb. Eflapegrastim, a novel long-acting granulocyte-colony stimulating factor: Integrated safety results in patients with early-stage breast cancer treated with TC chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-14-12.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P2-14-12
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 2
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    Abstract CT144: Intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT144-CT144
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. CT144-CT144
    Abstract: Background: CMP-001 comprises a CpG-A oligodeoxynucleotide packaged within a virus-like particle. It is designed to activate tumor-associated plasmacytoid dendritic cells via TLR9 inducing an interferon-rich tumor microenvironment and anti-tumor CD8+ T cell responses. Materials and Methods: CMP-001-001 is an ongoing phase Ib trial evaluating intratumoral (IT) CMP-001 in combination with pembrolizumab (administered per label) in subjects with advanced melanoma resistant (either did not respond or progressed) on prior anti-PD-1 monotherapy or in combination. During dose escalation, subjects were enrolled to cohorts of ≥ 3 subjects at CMP-001 doses of 1, 3, 5, 7.5, and 10 mg in two dosing schedules (weekly for 7w, followed by q3w; or weekly for 2w, followed by q3w). CMP-001 was administered IT into an accessible lesion(s), and response assessed in all target lesions (injected and non-injected) by RECIST v1.1. Study therapy was continued until progression, toxicity, investigator decision or withdrawal of consent. Baseline and on-therapy serum was collected for cytokine analysis. Immunohistochemical and RNA-Seq analysis was performed on available pre- and post-treatment tumor biopsies. Results: As of December 31, 2017, 68 subjects have been treated (44 in Escalation and 24 in Expansion). Safety data from 63 subjects demonstrated a manageable acute toxicity profile consisting predominately of fever, N/V, headache, hypotension and rigors. Grade 3/4 related AEs reported in ≥1 subject; hypotension (n=7), anemia (n=2), chills (n=2), hypertension (n=2) and fever (n=2). The Objective Response Rates (ORR) across all dose cohorts on weekly (n=40) and q3week schedules (n=13) were 22.5% (9/40; 95 % CI 11-39%) and 7.7%% (1/13; 95% CI 0-36%) respectively. For subjects dosed weekly at 3 and 5 mg, the ORR was 33.3% (6/18 95% CI 13-59%). Of the 10 responders, 1 progressed (w36), 2 withdrew consent (w13, w25), 7 remain on study with 2 subjects maintaining their response though w72. Regression of non-injected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases. CMP-001 induced TLR9 activation with a median 5.9 fold increase in serum CXCL10 (range of 0.9 - 276.3; mean fold increase of 21.8 with SD=48.8; n=39). Immunohistochemical and RNA-Seq analysis of tumor biopsies revealed increases in tumor-infiltrating CD8 T cells ( & gt;5 fold), PD-L1 expression ( & gt;3 fold increase in H score), and transcriptional signature of inflammation in 2/4 subjects with analyzable pre-and post-treatment samples. Conclusions: CMP-001 in combination with pembrolizumab resulted in objective, durable tumor responses with tolerable toxicities in subjects with advanced melanoma resistant to prior anti-PD-1 therapy. CMP-001 dosing at 5 mg/weekly has been selected for further evaluation in the ongoing dose expansion phase of this study. Citation Format: Mohammed Milhem, Rene Gonzales, Theresa Medina, John M. Kirkwood, Elizabeth Buchbinder, Inderjit Mehmi, Jiaxin Niu, Montaser Shaheen, Ryan Weight, Kim Margolin, Jason Luke, Aaron Morris, David Mauro, Arthur M. Krieg, Antoni Ribas. Intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT144.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-CT144
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
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    Abstract CT032: CMP-001 demonstrates improved response in noninflamed anti-PD-1 refractory melanoma and response is associated with serum CXCL10
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT032-CT032
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT032-CT032
    Abstract: Background In the treatment-naive setting, PD-1 blockade is associated with greater response in T cell-inflamed vs non-T cell-inflamed tumors. CMP-001 is a CpG-A oligonucleotide TLR9 agonist in a virus-like particle that is hypothesized to activate tumor-associated plasmacytoid dendritic cells (pDCs) to secrete type I interferons. Through this activity, CMP-001 may convert the tumor microenvironment to a Th1-like chemokine milieu (eg, increased CXCL10) and induce an antitumor CD8+ T-cell response. We have recently reported that intratumoral injection of CMP-001 + IV pembrolizumab (pembro) had an acceptable safety profile and can reverse PD-1 blockade resistance in patients (pts) with melanoma (Milhem et al, SITC 2019). Regression was observed in injected and uninjected lesions. Herein we report pharmacodynamic and translational data. Methods This 2-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled pts with metastatic/unresectable melanoma and stable disease (SD) or progressive disease (PD) on/after anti−PD-1 therapy. In part 1 (3+3 dose-escalation and dose-expansion), pts received CMP-001 + pembro. In part 2, pts received CMP-001 monotherapy. Determination of safety and clinical activity were the study's main objectives. Prespecified pharmacodynamic and translational studies evaluated serum chemokines and evaluated tumor biopsies using RNA and/or whole exome sequencing and immunohistochemistry for PD-L1 (reported as H-score), CD8, and CD303 (pDC marker). Results As of September 30, 2020, 159 pts (part 1) and 40 pts (part 2) have been treated. A greater median fold increase of serum CXCL10 (a marker of innate immunity, n=40) was observed in responders (R) to CMP-001 + pembro (18.8x) vs nonresponders (NR) after treatment (9.9x in SD; 6.15x in PD; differences were not statistically significant). Preliminary analyses showed that interferon gene expression distinguished R vs NR. Tumor biopsy analyses (part 1, n=139; part 2, n=34) showed that pts with high PD-L1, high CD8+ T cells, or inflamed transcriptional signatures at baseline were less likely to respond to CMP-001 + pembro vs pts without inflammation markers at baseline. Baseline mean PD-L1 expression (H-score) was 8.1 in R (n=10) vs 21.8 in NR (n=49). Posttreatment biopsies generally showed increased PD-L1, CD8+ T cells, and inflamed transcriptional signatures in R vs NR. Neither tumor mutational burden nor baseline pDC density distinguished R vs NR. Conclusions In pts with anti-PD-1 refractory melanoma, intratumoral CMP-001 ± pembro appears to disproportionately induce antitumor responses in noninflamed tumors. Clinical response to CMP-001 ± pembro was associated with induction of markers of both innate and adaptive antitumor immunity. Citation Format: Jason John Luke, Riyue Bao, John M. Kirkwood, Yousef Zakharia, Diwakar Davar, Elizabeth Buchbinder, Theresa Medina, Adil Daud, Antoni Ribas, Jiaxin Niu, Geoffrey Gibney, Kim Margolin, Anthony J. Olszanski, Inderjit Mehmi, Takami Sato, Montaser Shaheen, Aaron Morris, Dmitri Bobilev, Katie Campbell, George Weiner, James E. Wooldridge, Arthur M. Krieg, Mohammed Milhem. CMP-001 demonstrates improved response in noninflamed anti-PD-1 refractory melanoma and response is associated with serum CXCL10 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT032.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT032
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 4
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    Longitudinal SARS-CoV-2 mRNA Vaccine-Induced Humoral Immune Responses in Patients with Cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 24 ( 2021-12-15), p. 6273-6280
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 24 ( 2021-12-15), p. 6273-6280
    Abstract: Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher (P = 0.002) and remained higher after 4 to 6 months (P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels (P = 0.001) and sustained levels after 4 to 6 months (P & lt; 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak (P = 0.001) and sustained antibody responses (P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination (P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. Significance: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-21-3554
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 5
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    Abstract CT183: First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT183-CT183
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT183-CT183
    Abstract: Background: IL-12 is a key mediator of antitumor immune response. In preclinical models, IT IL-12 mRNA led to IFNγ release and CD8+ T cell-dependent tumor regression and potentiated PD-L1 blockade. MEDI1191, a lipid nanoparticle-formulated mRNA encoding IL-12 delivered by IT injection, drives IL-12 production and enhances antitumor immune response with improved tolerability. We hypothesized that combining MEDI1191 with PD-L1 blockade would augment antitumor immunity in vivo. Here we report updated results from the dose-escalation phase of the first-in-human study of IT MEDI1191 and IV durvalumab (D; anti-PD-L1) for advanced/metastatic solid tumors (NCT03946800). Methods: In this multicenter, open-label study, MEDI1191 was dosed sequentially (seq, Part 1A) or concurrently (conc, Part 1B) with D. In Part 1A, MEDI1191 was given IT on Days 1 and 22 followed by D 1500 mg on day 43 and then Q4W IV. In Part 1B, MEDI1191 was given IT on Days 1, 29, 57 and then Q8W, along with D on Day 1 and then Q4W. Treatment continued until progression or unacceptable toxicity for up to 2 years. Eligible adult pts had any solid tumor with cutaneous or subcutaneous lesions suitable for IT injection and progression on standard therapy for recurrent/metastatic disease. Primary objectives were safety and tolerability and determination of maximum tolerated dose (MTD); secondary objectives included preliminary antitumor activity by RECIST v1.1. Results: Starting in May 2019, 31 pts received seq MEDI1191 with D (Part 1A cohorts 0.1-12 μg; n=20) or conc MEDI1191 with D (Part 1B cohorts 1.0-3.0 μg; n=11); 23 pts had received prior anti-PD-1/PD-L1 therapy. Most common tumor types were melanoma, n=8; head and neck cancer, n=4; and breast cancer, n=4. At the data cutoff of Dec 7, 2021, there were no dose-limiting toxicities and no MTD was identified. One pt (3.2%) had a Gr ≥3 MEDI1191-related AE (Gr 3 pyrexia, resolved within 24 hr) and 1 (3.2%) had a MEDI1191-related serious AE (SAE; Gr 2 confusion). Two pts had Gr 3 D-related AEs (6.5%, pyrexia also related to MEDI1191 and pruritus; each n=1); none had a D-related SAE. There were no Gr 4 related AEs. 3 pts had partial responses (PR): 1 with head and neck cancer (unconfirmed, off study) and 2 with anti-PD-1 resistant melanoma (1 confirmed, & gt;12 months on treatment; 1 unconfirmed, off study); 10 pts had stable disease (including the 2 unconfirmed PRs). Among pts with available biomarker data (up to 3 μg in Part 1A and 1 μg in Part 1B), MEDI1191 increased serum IL-12 in 15/17 pts, increased CD8+ T cell tumor infiltration by & gt;2-fold in 8/14 pts and increased tumor PD-L1 expression in 6/14 pts. Conclusions: IT MEDI1191 plus systemic anti-PD-L1 was safe and feasible. Preliminary antitumor efficacy and pharmacodynamics, including tumor CD8+ T cell recruitment, were consistent with expected mechanism of action. Pts with injectable deep visceral and superficial lesions are being recruited. Citation Format: Benedito A. Carneiro, Dmitriy Zamarin, Thomas Marron, Inderjit Mehmi, Sandip P. Patel, Vivek Subbiah, Anthony El-Khoueiry, David Grand, Kirema Garcia-Reyes, Sanjay Goel, Phillip Martin, Jixin Wang, Yuling Wu, Steven Eck, Benjamin Ridgway, Nairouz Elgeioushi, Jim Eyles, Nicholas Durham, Analia Azaro, Omid Hamid. First-in-human study of MEDI1191 (mRNA encoding IL-12) plus durvalumab in patients (pts) with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT183.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT183
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract PS9-59: Pooled efficacy analysis from two phase 3 studies in patients receiving eflapegrastim, a novel, long-acting granulocyte-colony stimulating factor, following TC for early-stage breast cancer
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS9-59-PS9-59
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS9-59-PS9-59
    Abstract: Background: Eflapegrastim (Rolontis®, Efla) represents the first novel, long-acting granulocyte-colony stimulating factor (G-CSF) to be introduced in more than 15 years. Efla consists of a recombinant human G-CSF analog conjugated to a human IgG4 Fc fragment via a polyethylene glycol linker. Preclinical, clinical, and pharmacodynamic/pharmacokinetic data have shown increased potency for Efla versus pegfilgrastim (Peg). Both independent, randomized Phase 3 studies comparing Efla and Peg for prophylaxis of chemotherapy-induced neutropenia in patients with early-stage breast cancer (ESBC) met the primary endpoint of non-inferiority in duration of severe neutropenia (SN; ANC & lt;0.5 × 109/L) (p & lt;0.001) for Efla vs Peg in all 4 treatment cycles. Additionally, one of the studies exhibited a statistically significant reduction in the relative risk of SN in Cycle 1 with Efla. Here we provide a pooled analysis across the two pivotal studies comparing Efla vs Peg for SN in various subgroups. Methods: Patients with ESBC, who were candidates for adjuvant or neoadjuvant chemotherapy, were randomized 1:1 in two open-label Phase 3 studies to fixed-dose Efla (3.6 mg G-CSF) or standard Peg (6 mg G-CSF) administered on Day 2 following TC (docetaxel/cyclophosphamide) for a total of 4 cycles. ANCs were collected daily in Cycle 1 and 5 times in Cycles 2-4. SN was evaluated between treatment groups in Cycle 1 using Fisher’s exact test at 5% level of significance and was analyzed using multivariate logistic and Cox proportional hazards regression models. Results: A total of 643 patients who received either Efla (n=314) or Peg (n=329) were included in the analysis. The two treatment groups were well balanced for demographics and baseline characteristics. The mean age was 59 years, 38% were ≥65 years old, and 54% weighed & gt;75kg. The safety profiles, including AEs and discontinuations, for Efla and Peg were comparable, and & gt;99% of all patients received full dose of TC on schedule. The majority (67%) of patients with SN experienced a 1 day duration, occurring between Days 7 and 8 after TC. Mean duration of SN for Efla was statistically lower than for Peg (0.24 vs. 0.36 days; p=0.029). The above statistical significance was maintained for Efla after adjusting for demographic and baseline characteristics, namely age, weight, enrolling geographical region, and treatment setting in a multivariate model. Similarly, the incidence of SN for Efla was statistically lower than Peg in Cycle 1 (17.5% vs 24%; relative risk reduction [RRR]=27%; p=0.043). Univariate analysis of the incidence of SN showed a significant risk reduction in favor of Efla (8.6% vs 14.1%; p=0.034) for patients weighing & gt;75kg (p=0.034). Multivariate analysis of SN showed significant odds ratio of SN for age ≥65 years and baseline ANC & gt;6 × 109/L in favor of Efla (OR=0.42 and 0.39, respectively). The incidence of SN in Cycles 2-4 was comparable between treatment groups. Also, the incidence of febrile neutropenia and neutropenic complications was similar with & lt;5% in each treatment group. No leukocytosis, splenic rupture, or anaphylaxis was reported in any patient receiving Efla or Peg. Conclusion: A pooled analysis of two, randomized Phase 3 studies evaluating Efla vs Peg, administered once-per-cycle for prophylaxis of SN, showed Efla and Peg had similar safety profiles with Efla demonstrating a statistically significant risk reduction in SN overall and in patients weighing & gt;75kg. Eflapegrastim is a novel, long-acting and potent recombinant human G-CSF which may provide an attractive option in supporting patients at risk for SN-related complications. Citation Format: Lee S Schwartzberg, Gajanan Bhat, Alvaro Restrepo, Osama Hlalah, Inderjit Mehmi, Yong Wha Moon, Seungjae Baek, Shanta Chawla, Francois Lebel, Patrick Wayne Cobb. Pooled efficacy analysis from two phase 3 studies in patients receiving eflapegrastim, a novel, long-acting granulocyte-colony stimulating factor, following TC for early-stage breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-59.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-PS9-59
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract CT002: KEYMAKER-U02 substudy 02C: neoadjuvant pembrolizumab (pembro) + vibostolimab (vibo) or gebasaxturev (geba) or pembro alone followed by adjuvant pembro for stage IIIB-D melanoma
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT002-CT002
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT002-CT002
    Abstract: Background: The phase 1/2 KEYMAKER-U02 substudy 02C (NCT04303169) is evaluating neoadjuvant pembro + investigational agents or pembro alone followed by adjuvant pembro in stage IIIB-D melanoma. Results from patients treated with neoadjuvant pembro (anti-PD-1) + vibo (anti-TIGIT; arm 1), pembro + geba (coxsackievirus A21; arm 2), or pembro alone (arm 3) are presented. Methods: Eligible patients were ≥18 y with resectable stage IIIB, IIIC, or IIID melanoma per AJCC 8th ed criteria, ≥1 measurable lesion per RECIST v1.1, and ECOG PS ≤1. Patients were randomly allocated across open investigational arms. Before resection, patients in arm 1 received 2 administrations of pembro 200 mg Q3W + vibo 200 mg Q3W (cycle 1, day 1; cycle 2, day 1); patients in arm 2 received 1 administration of pembro 400 mg (cycle 1, day 8) + 5 administrations of geba at a fixed dose of 3 × 108 tissue culture infectious dose 50% during cycle 1 (days 1, 3, 5, 8, and 22); and patients in arm 3 received 1 administration of pembro 400 mg. Surgical resection was performed at week 6. At week 12, patients started adjuvant pembro 400 mg Q6W for ≤8 administrations (total treatment duration, ~1 y). Primary end points were safety and tolerability and pCR rate by central review. Secondary end points were near pCR rate and pPR rate by central review and RFS by investigator review. ORR per RECIST v1.1 and EFS by investigator review were exploratory. Results: At data cutoff (September 9, 2022), 66 patients had been assigned to treatment (arm 1 [pembro + vibo], n = 26; arm 2 [pembro + geba] , n = 25; arm 3 [pembro alone], n = 15). Median follow-up was 14.1 mo (range, 8.0-26.1). Treatment-related AEs occurred in 92% of patients in arm 1, 84% in arm 2, and 80% in arm 3. Grade 3/4 treatment-related AEs occurred in 8%, 24%, and 7% of patients, respectively, with no grade 5 treatment-related AEs. 3 patients (12%) in arm 1, 5 (20%) in arm 2, and 0 in arm 3 discontinued any drug because of treatment-related AEs. Immune-mediated AEs or infusion reactions were reported in 31% of patients in arm 1, 32% in arm 2, and 27% in arm 3. The pCR rate was 38% (95% CI, 20-59) in arm 1, 28% (12-49) in arm 2, and 40% (16-68) in arm 3; the near pCR rate was 12% (2-30), 12% (3-31), and 7% ( & lt;1-32), respectively; and the pPR rate was 31% (14-52), 12% (3-31), and 27% (8-55), respectively. Median RFS was not reached in any arm; 18-mo RFS rates were 95% (95% CI, 70-99) in arm 1, 87% (56-97) in arm 2, and 73% (24-93) in arm 3. ORR was 50% (95% CI, 30-71), 32% (15-54), and 27% (8-55), respectively. Median EFS was not reached in any arm; 18-mo EFS rates were 81% (95% CI, 60-92), 61% (38-78), and 79% (47-93), respectively. Conclusions: Neoadjuvant pembro + vibo, pembro + geba, and pembro alone followed by adjuvant pembro had manageable safety and promising antitumor activity in patients with stage IIIB-D melanoma. Of the combination treatments, pembro + vibo showed the most promise. Citation Format: Reinhard Dummer, Caroline Robert, Richard A. Scolyer, Janis M. Taube, Michael T. Tetzlaff, Andrew Hill, Jean-Jacques Grob, David C. Portnoy, Celeste Lebbe, Muhammad A. Khattak, Jonathan Cohen, Gil Bar-Sela, Inderjit Mehmi, Ronnie Shapira Frommer, Nicolas Meyer, Yixin Ren, Mizuho Fukunaga-Kalabis, Clemens Krepler, Georgina V. Long. KEYMAKER-U02 substudy 02C: neoadjuvant pembrolizumab (pembro) + vibostolimab (vibo) or gebasaxturev (geba) or pembro alone followed by adjuvant pembro for stage IIIB-D melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT002.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT002
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract CT004: Intratumoral (IT) MEDI1191 + durvalumab (D): Update on the first-in-human study in advanced solid tumors
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT004-CT004
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT004-CT004
    Abstract: Background: MEDI1191 is an IT-administered lipid nanoparticle-formulated mRNA encoding IL-12. This phase 1, open-label study (NCT03946800) showed that MEDI1191 in sequential (seq) or concurrent (conc) combination with IV D (anti-PD-L1) was safe and had preliminary antitumor activity in pts with advanced/metastatic solid tumors who had progressed on SoC. Here we present updated analyses, including the first report of pts with deep-seated lesions. Methods: In Part 1A (subcutaneous/cutaneous [SC/C] lesions), pts received MEDI1191 on Days 1 and 22, followed by D 1500 mg on Day 43 then Q4W. In Parts 1B (SC/C) and 1D (deep-seated lesions), pts received MEDI1191 on Days 1, 29 and 57 then Q8W, with D on Day 1 then Q4W. Treatment continued for up to 2 years, until progression or unacceptable toxicity. Primary objectives were safety, tolerability and maximum tolerated dose (MTD); secondary objectives included preliminary antitumor activity per RECIST v1.1 in injected/non-injected lesions. Results: As of October 5, 2022, 61 pts (40 had prior anti-PD-[L]1) received seq (Part 1A 0.1-12.0 μg, n=25 [4/25 had MEDI1191 only] ) or conc (Part 1B 1.0-12.0 μg, n=27; Part 1D 1.0-3.0 μg, n=9) MEDI1191 + D. The most commonly represented cancer was melanoma (n=14). Pts in Part 1D had pancreatic (n=2), colorectal (n=2), gastric, anal, melanoma, neuroendocrine or unknown primary cancer (each n=1); all had hepatic metastases. There were no dose-limiting toxicities for MEDI1191 and no MTD was identified. Gr ≥3 MEDI1191-related AEs occurred in 3 pts (4.9%; Gr 3 asthenia and pyrexia, each n=1; Gr 4 lymphocyte count decreased, n=1); 2 pts (3.3%) had a MEDI1191-related serious AE (SAE; Gr 2 pyrexia and confusion, each n=1). Gr ≥3 D-related AEs occurred in 3 pts (4.9%; Gr 3 asthenia, pyrexia [both also MEDI1191-related] and pruritus; each n=1); 1 pt (1.6%) had a D- and MEDI1191-related SAE (Gr 2 pyrexia). In Parts 1A and 1B, 7 pts had partial responses (PRs): 5 confirmed (cPRs) in melanoma (n=2), sarcoma, breast and neuroendocrine cancer (each n=1), and 2 unconfirmed (uPRs) in melanoma and head and neck cancer (each n=1); no pts had PRs in Part 1D. 3/5 pts with cPR had prior anti-PD-(L)1; 2/3 also had prior anti-CTLA-4. For the 5 cPRs, DoR was 1.9-22.3 months (median not reached); 3 had ongoing PRs and 2 had stable disease (SD) at data cutoff. Non-target injected lesions shrank in 4 pts with cPRs. Overall, 15 pts had SD (including the 2 uPRs). MEDI1191 induced pharmacodynamic changes in the periphery and tumor microenvironment. A ≥2-fold increase in serum IL-12 levels was seen in 42/46 pts, with increases in serum IFNγ in 37/46; 9/22 pts had ≥2-fold increases in CD8+ T cell tumor infiltration and tumoral PD-L1 expression. Conclusions: MEDI1191 + D was safe and tolerable in pts with SC/C or deep-seated lesions. Antitumor activity was seen in injected and distant lesions, and pharmacodynamic activity was consistent with expectations based on mechanistic biology. Citation Format: Eduardo Castañón, Dmitriy Zamarin, Benedito A. Carneiro, Thomas Marron, Sandip Pravin Patel, Vivek Subbiah, Inderjit Mehmi, Honey Kumar Oberoi, Anthony El-Khoueiry, Benjamin Ridgway, Nairouz Elgeioushi, Nicholas M. Durham, Emily Jennings, Michael Abadier, Paula G. Fraenkel, Analia Azaro, Omid Hamid. Intratumoral (IT) MEDI1191 + durvalumab (D): Update on the first-in-human study in advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT004.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT004
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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    Abstract CT226: Crizotinib (C) in patients (pts) with solid tumors with MET amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT226-CT226
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 8_Supplement ( 2023-04-14), p. CT226-CT226
    Abstract: Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors and MET amp or mut treated with C are reported. Methods: Eligible pts had no standard treatment (tx) options, had measurable disease, ECOG performance status (PS) 0-2, and adequate organ function. Pts with non-small cell lung cancer were excluded. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received C at 250 mg orally BID until disease progression. Low accruing histology-specific cohorts with MET amp or mut were collapsed into 1 histology-pooled cohort for analysis. Primary end point was disease control (DC) per investigator, defined as complete or partial response (PR) or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The primary end point was summarized as a proportion and the hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test with α= 0.10. Other end points were progression-free survival (PFS), overall survival (OS), duration of response and SD, and safety. Results: 31 pts with solid tumors (12 tumor types) and MET mut only (n=10), amp only (n=19), or mut and amp (n=1) were enrolled; 1 pt with overexpression was ineligible. 3 additional pts were unevaluable for efficacy. Table shows demographics and outcomes. 2 PR (both esophageal adenocarcinoma with MET amp) and 4 SD16+ (2 renal cell carcinoma, 1 with mut, 1 with amp; colorectal with amp; small intestine with amp) were observed for DC rate of 21% (1-sided 90% CI: 12%, 100%) and objective response rate of 7% (95% CI: 1%, 24%). The null DC rate was not rejected. 5 pts had ≥1 grade 3 tx-related adverse or serious adverse event. Conclusions: C did not meet prespecified criteria to declare a signal of activity in pts with solid tumors with MET amp or mut. Table: Baseline Characteristics (N=31); Efficacy Outcomes (n=28); Toxicity Outcomes (N=31) Median (Med) age, years (range) 61 (30, 82) Female, % 16 (52) ECOG PS, % 0 15 (48) 1 12 (39) 2 4 (13) Prior systemic regimens, % 1 3 (10) 2 5 (16) ≥3 23 (74) DC rate, % (OR and SD16+) (1-sided 90% CI) 21 (12, 100) Objective response rate, % (95% CI) 7 (1, 24) Med PFS, wks (95% CI) 8 (8, 13) Med OS, wks (95% CI) 37 (26, 68) Duration of response, wks (n=2) 14 and 20 Med duration SD, wks (n=4) 27 (26, 28) Number of pts1 with tx-related grade 3 adverse or any grade serious adverse event AE2 5 (16) SAE3 3 (10) 1Pts may have experienced one or more events 2ALT increase, diarrhea and all SAEs 3Acute kidney injury, ALT increase, AST increase, blood bilirubin increase, creatinine increase, dehydration, fatigue, GGT increase, hyperkalemia, nausea, sinus bradycardia Citation Format: Kathryn F. Mileham, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Herbert L. Duvivier, Carmen J. Calfa, Carrie L. Dul, Alissa S. Marr, Eugene R. Ahn, Deepti Behl, Michael J. Hall, Inderjit Mehmi, Anu Gaba, Rom Leidner, Mark M. Zalupski, Gina N. Grantham, Abigail Gregory, Susan Halabi, Richard L. Schilsky. Crizotinib (C) in patients (pts) with solid tumors with MET amplification (amp) or mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT226.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-CT226
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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