X

Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Online Resource
    Online Resource
    Abstract CT109: Radiomic features in tumor assessment, preliminary results from a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with anti PD1 refractory melanoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT109-CT109
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT109-CT109
    Abstract: Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. Immunohistochemistry and gene sequencing are frequently assessed as part of clinical research. Radiomic signatures may also add valuable information, based on parameters which can be related to immune infiltration, therefore defining an imaging biomarkers panel for this clinical scenario. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. The role of imaging biomarkers is being explored in the present phase II clinical trial. Study design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. As part of exploratory objectives, a radiomics analysis was performed to detect changes in lesion texture features. Quantitative features were obtained by using Quibim Precision 2.9 platform (Quibim, Valencia, Spain) after the manual delineation of lesions on the CT study of each subject at each timepoint to obtain information about injected/non-injected lesions. Images were normalized by taking into account Hounsfield Units (HU) bias across scanners in a cross-calibration phantom and the Z-score. The difference (Delta) in the features between baseline and week 8 was calculated. Results: Studies were assessed based on event (progression) and based on whether lesions had been injected. Patients with only cutaneous disease were not included in this analysis. Out of 23 patients who had at least two imaging assessments, 6 developed progressive disease by week 8, and 17 subjects had no event by that time. Due to the small sample size, the radiomic analysis was based on hypothesis testing. With regards to volume, 50% of the non-progressing lesions reduced their value from that of the baseline. Regarding injected versus non-injected changes, up to 50% of injected lesions decreased their volume after 8 weeks of injected treatment whereas in non-injected lesions volume decreased in less than 25% of lesions. From the independent sample t-test of delta radiomics features against the injected/non-injected lesions variable, there were 4 features with a statistically significant difference between groups; all of them related to the Low Grey-Level Zone Emphasis. Specifically, Delta original GLRLM Low Grey-Level Run Emphasis showed the highest significant difference between injected and non-injected lesions (p=0.004), with higher and positive delta values in the injected group (75% injected lesions were above 0). Conclusions: Imaging biomarkers provide a large number of quantitative image features with a wide span of information, from size to heterogeneity of the tissue which may be indicator of tumor progression and immune infiltrate. In the analysis of radiomics features, delta GLRLM low grey-level zone emphasis was sensitive to the tumoral changes happening in injected lesions at week 8. This might add insights into the imaging-based evaluation of immune infiltration in intratumoral immunotherapy and the creation of associated imaging biomarkers panels. Citation Format: Paula Moreno, Philippe Saiag, Luis de la Cruz Merino, Caroline Dutriaux, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, Henry Montaudié, Miguel F. Sanmamed, María González Cao, María Pilar López Criado, Julie Charles, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Pablo Sau Llanas, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martin-Liberal, Ángel Alberich-Bayarri, Javier Sánchez López, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle, Iván Márquez-Rodas. Radiomic features in tumor assessment, preliminary results from a phase 2 study of intratumoral administration of BO-112 with pembrolizumab in patients with anti PD1 refractory melanoma [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 CT109.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT109
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 2
    Online Resource
    Online Resource
    Abstract CT107: Correlation of biomarkers and clinical benefit of intratumoral BO112 and pembrolizumab in patients with anti PD1 refractory melanoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT107-CT107
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT107-CT107
    Abstract: Background: There is a lack of predictive biomarkers for immunotherapy in melanoma. In terms of IHC, there is no strong rational to support the use of PD-L1 expression. BRAF mutations occur in 40-50% of melanomas and the MAPK pathway may also be activated by NRAS mutations. Patients harboring these mutations face usually a worse prognosis. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that, by mimicking the effect of a viral infection, mobilizes the immune system. Prior data from a phase I trial (NCT02828098) suggest that, when administered intratumorally, it causes an increase in CD8 infiltration and PD-L1 expression. The role of these and other biomarkers is being explored in the present phase II clinical trial. Study Design: Single arm study with BO-112 plus pembrolizumab (NCT04570332) in patients with advanced melanoma in progression to anti-PD1 therapy. Tumors were genotyped by next generation sequencing, whole exome sequencing and tumor mutation burden. Antitumor and immunological effects of the treatment in the tumor microenvironment were assessed by PDL1 and CD8 immunohistochemistry with a paired biopsy performed after 21 days of treatment. Results: A preliminary analysis has been performed, based on patients evaluable for clinical benefit (defined as response or stable disease & gt;16 weeks). Samples from 35 patients have been analyzed, with 24 patients paired biopsies available. Patients with “cold” tumors (PD-L1 negative and CD8 low) at baseline had a trend to lack of clinical benefit. Only basal PD-L1 in the inflammatory component showed a statistically significant correlation with clinical outcome (4/20 (25%) tumors PDL1 IC negative had benefit versus 10/15 (67%) positive), p=0.0053. Fifteen patients had an increase in PD-L1 and 14 patients had increase in CD8 infiltrate after BO-112 treatment; the lack of increase in PDL1 and CD8 after treatment was also predictive of lack of response (p=0.04). BRAF/NRAS driver mutations correlated with positive outcome. Clinical benefit was observed in 4 of 17 (24%) patients not carrying activating mutations whereas 11 out of 18 (61%) patients with BRAF/NRAS activating mutations had clinical benefit (p=0.02), mainly in cutaneous histology (14% versus 65%, p=0.02). Mucosal melanoma patients (n=3) achieved an ORR 66.7% and DCR 100%. The two mucosal melanoma patients with partial response harbored SETD2 mutations and one of them showed extensive cyclic nucleotide-gated (CNGs), indicative of defects in DNA repair pathways. Regarding acral melanoma patients (n=9), no responses were observed, even in the single case with a NRAS mutation. The only patient achieving clinical benefit, with stable disease & gt;16 weeks; had a unique mutation profile, with TP53 (inactivating) and KIT (activating) mutations. Conclusions: Patients basal mutant BRAF/NRAS could have more probability of benefit from BO-112 and pembrolizumab combination. PD-L1 and/or CD8 increase is an early marker of response. These findings could help to select patients in future clinical trials. Further investigation into predictive biomarkers is warranted. Citation Format: Ruth Roman, Philippe Saiag, Caroline Dutriaux, Luis de la Cruz Merino, Eduardo Castanon, Miguel F. Sanmamed, Caroline Robert, Juan F. Rodríguez-Moreno, Pablo Cerezuela-Fuentes, Ana M. Arance, María González Cao, Henry Montaudié, María Pilar López Criado, Julie Charles, Alfonso Berrocal, María del Carmen Álamo de la Gala, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, Eva Muñoz-Couselo, Delvys Rodríguez Abreu, Juan Martín-Liberal, Helena Escuin-Ordinas, Mark Branum, Sonia Macia, Marisol Quintero, Javier Sánchez López, Marya F. Chaney, Beatriz García-Peláez, Marta Vives-Usano, Miguel Ángel Molina, Stéphane Dalle, Iván Márquez-Rodas. Correlation of biomarkers and clinical benefit of intratumoral BO112 and pembrolizumab in patients with anti PD1 refractory melanoma [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 CT107.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT107
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 3
    Online Resource
    Online Resource
    Abstract CT014: Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: Final results of SPOTLIGHT203 phase 2 study
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT014-CT014
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT014-CT014
    Abstract: Background: BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine that mimics a viral infection. Through dendritic cells activation, increase in CD8 T-cell infiltration and interferons induction, it produces an immunogenic cell death. Phase 1 study (NCT02828098) showed ORR 20% in patients (pts) with anti PD-1 resistant melanoma (mel). Hence phase 2 trial was designed. Study design: Single arm study (NCT04570332) with intratumoral BO-112 plus intravenous pembrolizumab in pts with mel (cutaneous, acral or mucosal) and confirmed progressive disease (PD) while on anti-PD1 based therapy. Pts were treated with BO-112, 1-2 mg on a weekly basis for 7 weeks and thereafter Q3W in 1-8 different lesions. Pembrolizumab 200 mg was administered Q3W. Primary endpoint was overall response rate (ORR) by RECIST 1.1 by independent reviewer. Secondary endpoints included disease control rate (DCR), progression free survival (PFS) and safety. Exploratory objectives included radiomic signatures, itRECIST and evaluation of tumor microenvironment. At least 20% of pts had to achieve response in order to consider primary endpoint met. Results: Recruitment was completed 24th August 2021 with 42 pts; female 43%; median age 66 (rank 27-88). Table summarizes basal characteristics. With 40 evaluable for response pts, 10 achieved response (25%): 3 complete response (CR) and 7 partial response (PR). 17 pts (44%) achieved a stable disease (SD), meaning a DCR of 68% with 18 pts still on treatment. The 4 pts with a baseline LDH & gt;3xULN developed PD no later than week 8. Responses per histology were: 66% mucosal, 28% cutaneous, 0% acral. Responses per BRAF/NRAS status were: BRAF mutant (Mut) 43%, NRAS Mut 31%, and BRAF/NRAS wild type (WT) 17%. 33 pts (79%) had at least one BO-112 related adverse event (AE) being only in 2 cases grade & gt;3 (G4 infusion reaction and G3 myalgia). Most common related AEs were asthenia, pyrexia, diarrhea, vomiting and chills. Study treatment was not discontinued in any pts due to related AE. Conclusions: The primary efficacy endpoint has been met. Additionally, disease control (PR+CR+SD) is meaningful and durable in a population with no current standard treatment options. Very high LDH levels (LDH & gt;3xULN) and acral mel could predict poor outcome. Safety profile was manageable without treatment discontinuation due to AEs. N (ITT pts, 42) (%) AJCC8 M1C/D 19 (45) BRAF Mut 7 (17) WT 35 (83) Previous treatment Ipilimumab-nivolumab 6 (15) Anti PD-1 monotherapy 33 (79) Other combo 3 (7) Prior line indication Adjuvant 11 (26) Advanced 31 (74) LDH & gt;ULN 17 (41) Best ORR (IRCR evaluable pts, N=40) Global Mucosal Cutaneous Acral ORR 10 (25) 2 (66) 8 (28) 0 PR 7 (18) 1 (33) 6 (21) 0 CR 3 (8) 1 (33) 2* (7) 0 SD 17 (43) 1 (33) 13 (45) 3 (37) PD 13 (33) 0 8 (28) 5 (63) *2 pts had pathologic CR and RECIST SD Citation Format: Iván Márquez-Rodas, Caroline Dutriaux, Philippe Saiag, Luis de la Cruz Merino, Eduardo Castanon Álvarez, Caroline Robert, Juan F. Rodríguez-Moreno, Ana M. Arance, Pablo Cerezuela-Fuentes, Henry Montaudié, Miguel F. Sanmamed, María González Cao, Julie Charles, María Pilar López Criado, Alfonso Berrocal, Enrique de Miguel, Elisa Funk-Brentano, Sorilla Prey, María del Carmen Álamo de la Gala, Javier Sánchez López, Helena Escuin-Ordinas, Sonia Macia, Marisol Quintero, Marya F. Chaney, Stéphane Dalle. Efficacy of intratumoral BO-112 with systemic pembrolizumab in patients with advanced melanoma refractory to anti-PD-1-based therapy: Final results of SPOTLIGHT203 phase 2 study [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 CT014.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT014
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 4
    Online Resource
    Online Resource
    Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE-B84).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. e18033-e18033
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e18033-e18033
    Abstract: e18033 Background: Immunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo for the first-line treatment of recurrent or metastatic (R/M) HNSCC, representative of a class of tumors that express higher levels of SEMA4D and MDSC. The primary hypothesis of this proof-of-concept study is that pepinemab in combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC. Methods: KEYNOTE-B84 (NCT04815720) is a single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG 0 or 1, are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n = 3) and dose-expansion phase (maximum n = 62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, both administered i.v. Q3W. The dose expansion phase plans to include nearly equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of 〈 20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results: The safety run-in phase (n = 3) is complete, and the combo appeared to be well-tolerated with no DLTs observed; SMC approved continuation to dose expansion. Strikingly, two of the three patients have been observed to experience a complete response (CR). Biomarker analysis revealed that tumors in both responders expressed low levels of PD-L1 (CPS 〈 20). The third patient progressed prior to first scan, suffering several unrelated SAEs attributed to a pre-existing co-morbidity. Conclusions: The ongoing KEYNOTE-B84 study completed the initial safety run-in phase, with two of three subjects achieving CR. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC. Clinical trial information: NCT04815720.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.e18033
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 5
    Online Resource
    Online Resource
    A phase 1 dose-escalation and expansion study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, given as monotherapy and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 6013-6013
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 6013-6013
    Abstract: 6013 Background: Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of attenuated human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) were evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Patients with R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy received CUE-101 monotherapy. Patients with previously untreated PD-L1+ R/M HNSCC received CUE-101 + pembrolizumab as first-line treatment. Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity were assessed. Results: As of January 12, 2023, 67 patients were enrolled. A MTD was not established in monotherapy or combination-treated patients; 4 mg/kg of CUE-101, alone or in combination with pembrolizumab, was chosen as the RP2D dose in both cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Frequent adverse events include fatigue (45%), anemia (34%), chills (27%), infusion related reactions (25%), constipation (22%), lymphopenia (22%) and nausea (22%). CUE-101 PK data demonstrate dose-dependent increases in drug exposure sustained with repeat dosing. PD data demonstrate selective expansion of HPV-16 E7 11-20 -specific CD8+ T cells, sustained increase in NK cells and transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 24.4 months (9.1, NA). Among 12 evaluable RP2D combination patients to date, 5 PRs, and 2 durable SDs have been observed, with 71% (5/7) of patients expressing PD-L1 CPS ≤ 20. Conclusions: CUE-101 facilitates the targeted delivery of high concentrations of IL-2 to relevant tumor-specific CD8+ T cells. We demonstrate safety and tolerability with encouraging PD signals and antitumor activity with monotherapy and in combination with pembrolizumab in HPV+ R/M HNSCC patients. Enrollment continues in the CUE-101 and pembrolizumab combination cohort. Clinical trial information: Clinical trial information: NCT03978689 .
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.6013
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 6
    Online Resource
    Online Resource
    Combination of radiomic and biomarker signatures as exploratory objective in a phase II trial with intratumoral BO-112 plus pembrolizumab for advanced melanoma.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS9586-TPS9586
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. TPS9586-TPS9586
    Abstract: TPS9586 Background: Intratumoral immunotherapies are gaining interest in oncology, particularly in melanoma. These therapies, however, have faced some issues. For instance, standard response criteria do not accurately describe tumor burden, and responses may differ for injected/non injected lesions. Besides, target lesions may become non evaluable. Biomarkers provide interesting information for these therapies. In addition, some radiomic signatures have been associated with CD-8 infiltration. BO-112 is a double stranded synthetic RNA formulated with polyethyleneimine (PEI) that mimics a viral infection, mobilizing the immune system and changing tumor microenvironment. Clinical data are available from a first-in-human study, which showed ORR of 11% and DCR of 46% in patients who had developed progressive disease on immunotherapy. In patients with melanoma, this ORR was 20%. A phase 2 clinical study of BO-112 with pembrolizumab in patients with liver metastases from digestive tumors is ongoing. Both studies brought up data regarding how some biomarkers are increased after a single dose of BO-112 and correlated with responses. In this phase II study in patients with pretreated melanoma (NCT04570332), we will prospectively assess CD-8 and PD-L1 by immunohistochemistry, which will be compared with multi-parametric radiologic findings and correlated with clinical benefit. In addition, retrospective DNA sequencing will be performed. This kind of exploratory analysis in intratumoral immunotherapies might be key to identify predictive and prognostic factors. Methods: Phase 2, single arm, open label study of BO-112 with pembrolizumab in patients with advanced melanoma. BO-112 is administered once weekly (QW) in 1 to 8 tumor lesions, total dose 1-2 mg (depending on the number of injected lesions), for the first 7 weeks and then once every three weeks (Q3W); pembrolizumab 200 mg will be administered Q3W. Key eligibility criteria: advanced cutaneous or mucosal melanoma; patients must have progressed on or after treatment with an antiPD-1/L1 mAb; at least one measurable lesion amenable for weekly IT injection. Primary efficacy variable is ORR by RECIST 1.1, assessed by independent central radiologist (QUIBIM Precision platform). A 1-sided alpha of 4.19% and power of 81.8% are used. If less than 8 patients out of 40 have ORR, the study will not meet the statistical bar. Secondary endpoints include clinical activity by RECIST1.1 and iRECIST, overall survival, safety and PKs. Exploratory objectives include itRECIST and evaluation of CD-8 and PD-L1 expression by immunohistochemistry (Pangaea laboratory), which will be correlated with radiomic signatures (first order and second order) from standard-of-care computed tomography (CT) images. Enrollment is open and 1 of planned 40 patients has been enrolled. Nineteen sites are planned to participate. Clinical trial information: NCT04570332.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.TPS9586
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 7
    Online Resource
    Online Resource
    Abstract CT111: Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE B84)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT111-CT111
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 12_Supplement ( 2022-06-15), p. CT111-CT111
    Abstract: Purpose: Immunosuppressive myeloid cells in the tumor microenvironment (TME) limit the efficacy of immune checkpoint inhibitors (ICIs) in head and neck squamous cell carcinoma (HNSCC). Preclinical and clinical studies demonstrated that antibody blockade of semaphorin 4D (SEMA4D) promotes tumor infiltration and activation of DCs and CD8+ T cells and reverses immunosuppression, including attenuation of MDSC recruitment and function, leading to enhanced efficacy of ICIs. Pepinemab, a humanized SEMA4D blocking antibody, in combination (combo) with avelumab provided clinical benefit in some patients with ICI-resistant and PD-L1-low NSCLC. Pembrolizumab (pembro) is approved as monotherapy or in combo with chemo for the first-line treatment of recurrent or metastatic (R/M) HNSCC. More effective treatments are, however, needed to increase the frequency and duration of responses. The primary hypothesis of this proof-of-concept study is that pepinemab in combo with pembro will yield increased clinical benefit compared to the reported activity for pembro monotherapy in R/M HNSCC. Methods: KEYNOTE B84 (NCT04815720) is a multicenter, single-arm open-label study evaluating the safety, efficacy, and PK/PD of pepinemab in combo with pembro as first-line treatment of R/M HNSCC. Subjects with measurable disease per RECIST1.1, ECOG PS of 0 or 1, and PD-L1 CPS ≥ 0 are eligible; subjects who have received prior ICIs or other systemic treatment for R/M HNSCC are excluded. The study includes a safety run-in (n=3) and dose-expansion phase (maximum n=62). Pepinemab, previously found to be well-tolerated in combo with other ICIs, will be evaluated initially at the highest intended dose of 20 mg/kg, in combo with 200 mg pembro, both administered i.v. Q3W. The dose expansion phase will include an equal distribution of subjects who have tumor PD-L1 combined positive scores (CPS) of & lt;20 and ≥20. The primary efficacy endpoint is ORR, and the secondary endpoints are PFS, DoR, and OS, as well as exploratory biomarker analyses. Pre- and on-treatment biopsies will be collected for evaluation of immune contexture in TME. Results: The safety run-in phase (n=3) was successfully completed. The combo was well tolerated with no DLTs observed. One of the three patients had a confirmed complete response, a second patient progressed with several SAEs attributed to comorbidities (diabetes) deemed unrelated to treatment, and the third patient has not yet completed tumor evaluation. The safety monitoring committee has recommended that the dose-expansion phase be initiated at 20 mg/kg pepinemab and 200 mg pembro Q3W. Conclusions: The ongoing KEYNOTE B84 study completed the initial safety run-in phase. Phase 2 will evaluate pepinemab, a SEMA4D inhibitor, as a novel strategy to potentially overcome resistance and enhance activity of pembro in R/M HNSCC. Citation Format: Terrence L. Fisher, Elizabeth E. Evans, Crystal Mallow, Amber Foster, Megan Boise, Ernest Smith, John E. Leonard, Marya F. Chaney, J. Thaddeus Beck, Steven Hager, Nabil F. Saba, Conor Steuer, Douglas Adkins, Barbara Burtness, Maurice Zauderer. Phase 1/2 study of pepinemab, an inhibitor of semaphorin 4D, in combination with pembrolizumab as first-line treatment of recurrent or metastatic head and neck cancer (KEYNOTE B84) [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 CT111.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2022-CT111
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 8
    Online Resource
    Online Resource
    Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies and dose escalation update.
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 16_suppl ( 2022-06-01), p. 2574-2574
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. 2574-2574
    Abstract: 2574 Background: LNS8801 is an oral, highly selective, small molecule agonist of the G protein-coupled estrogen receptor (GPER). LNS8801 normalizes c-Myc levels in cancer cells, inhibits proliferation, suppresses invasion, and enhances immune recognition. In preclinical models, LNS8801 has demonstrated increased activity with ICIs. In the first-in-human dose escalation study, LNS8801 was safe and tolerable alone and in combination with pembrolizumab in patients with metastatic solid tumors (NCT04130516). Methods: Patients who are relapsed and refractory (r/r) to PD-1/L1 ICIs and have measurable disease are enrolling in a Phase 1b cohort and receive LNS8801 (125 mg, QD, PO) and pembrolizumab (200 mg, Q3W, IV) (NCT04130516). The primary objective is safety and tolerability assessed according to NCI CTCAE v5.0. Secondary endpoints include pharmacokinetic, pharmacodynamics (eg., increase in serum prolactin over the initial 10 hours of dosing to assess GPER engagement), objective response rate and clinical benefit rate per RECIST v1.1. Results: Updates from the dose escalation portion of the study include long term benefit in a monotherapy patient with cutaneous melanoma on treatment for 2 years with RECIST stable, metabolically inactive disease by PET; a metastatic uveal melanoma patient on therapy for a year, and growing confidence in LNS8801’s favorable safety profile and predictive systemic biomarkers. As of 2/1/22, 13 ICI r/r patients were treated with LNS8801 and pembrolizumab, including those who entered the study directly after confirmed progression on ICIs. Cancer types include lung (3), colorectal, vaginal, nasopharyngeal, neuroendocrine, uterine, and pancreatic cancer, mesothelioma (2), and cutaneous and uveal melanoma. 46% of patients had AEs possibly related to study drugs (31% grades 1-2 and 31% grade 3), with colitis (15%) and fatigue (23%) appearing in more than 10% of patients. Of the 10 evaluable patients, 7 had stable disease (SD), with 4 patients demonstrating tumor regression. At the data cut-off, duration of treatment ranged from 0.7–7.5 months with 4 patients treated between 4.8 and 7.5 months and 4 patients continuing on treatment. All evaluated patients with SD had a prolactin response indicative of systemic target engagement. Conclusions: The combination of LNS8801 and pembrolizumab is tolerable without unanticipated toxicities and demonstrates encouraging anti-tumor activity in patients that are r/r to ICIs, including patients who enrolled immediately after confirmed progression on pembrolizumab alone. These data, as well as continued follow-up on patients with long-term benefit from dose escalation, support further development of LNS8801 as a cancer therapeutic. Clinical trial information: NCT04130516.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.16_suppl.2574
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 9
    Online Resource
    Online Resource
    A phase 1 first-in-human study of the anti-LAG-3 antibody MK4280 (favezelimab) plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3584-3584
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3584-3584
    Abstract: 3584 Background: Patients (pts) with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed on ≥2 prior therapies have limited treatment options, with median OS ranging from 6-9 months (mo). In the dose-escalation phase of this first-in-human multicohort study (NCT02720068), the anti-lymphocyte activation gene (LAG)-3 antibody favezelimab (fave) was well tolerated alone and with pembrolizumab (pembro) across all dose levels (Lakhani, SITC, 2018, abstract O26). Here, we evaluate the safety and efficacy of fave alone or in combination with pembro in pts with advanced MSS CRC from the dose confirmation phase. Methods: Eligible pts with MSS PD-1/PD-L1-treatment-naïve mCRC that progressed on prior standard-of-care (3L+) were enrolled (cohort A) to receive the RP2D of 800 mg fave alone (Arm 1), 800 mg fave + 200 mg pembro (Arm 2C), or 800 mg fave + 200 mg pembro (MK-4280A) co-formulation (Arm 5), all Q3W. Treatment continued for 35 cycles or until progression, unacceptable toxicity, or investigator/pt decision. Pts with confirmed progression per irRECIST v1.1 on fave alone could crossover to 800 mg fave + pembro. Safety was assessed in all treated pts; efficacy in the full analysis set (FAS) of all treated pts with baseline scan. Objectives included safety (primary), ORR (RECIST v1.1 by investigator [secondary] ), and DOR, PFS, and OS (exploratory). Interim analysis data cut-off was: Oct. 23, 2020. Results: A total of 20 pts received fave (Arm 1); 89 pts (including 9 crossover) received fave + pembro (Arms 2C+5); 12 pts (Arm 1) and 36 pts (Arms 2C+5), had PD-L1 CPS ≥1 tumors. At data cut-off, median follow-up was 5.8 months (mo) in Arm 1 and 6.2 mo in Arms 2C+5. Treatment-related adverse events (TRAEs) were 65% with fave (Arm 1) and 65.2% with fave + pembro (Arms 2C+5). Grade ≥3 TRAEs were 15% (Arm 1), and 20% [Arms 2C+5]). No grade 5 TRAEs were reported. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15%) with fave, and fatigue (16.9%) with fave + pembro. Confirmed ORR was 6.3% (4PR, 1CR) with fave + pembro (Arms 2C+5). No pt receiving fave alone responded. In Arms 2C+5, median DOR was 10.6 mo (range, 5.6-12.7). ORR, OS and PFS by PD-L1 status are reported in the Table. Conclusions: Favezelimab alone or in combination with pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, including with MK-4280A, compared with monotherapy most notably in pts with PD-L1 CPS ≥1 tumors. Clinical trial information: NCT02720068. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3584
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
  • 10
    Online Resource
    Online Resource
    Phase 1 trial of a novel, first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in patients with advanced or recurrent treatment-refractory solid malignancies.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 3084-3084
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 3084-3084
    Abstract: 3084 Background: The G protein-coupled estrogen receptor (GPER) is a broadly expressed G protein-coupled receptor that is tumor suppressive. LNS8801 is an oral, highly selective small molecule agonist of GPER. GPER activation results in c-Myc depletion, inhibition of tumor proliferation, and enhancement of tumor immune recognition. Preclinically, LNS8801 demonstrates potent single-agent and combinatorial anti-cancer activity and can overcome established resistance to standard-of-care anti-cancer therapies including immune checkpoint inhibitors. Methods: The primary objective of this phase 1/1B first-in-human, open-label, multicenter study (NCT04130516) was to determine the safety and tolerability and recommended phase 2 dose (RP2D) of LNS8801 in patients (pts) with locally advanced or metastatic solid tumor malignancies, both as monotherapy and in combination with the anti-PD-1 antibody, pembrolizumab. Dose levels were escalated in a 3+3 fashion and included 10, 40 and 125 mg dosed 3/7, 125 mg daily, and 125 and 250 mg twice daily. Dose limiting toxicity (DLT) was defined via NCI CTCAE v5.0 during the first 21 days of treatment. An increase in prolactin over the initial 12 hrs of dosing was measured to assess systemic GPER signaling. Tumor c-Myc expression was measured as a surrogate of treatment-related biologic response. Radiographic response (RECIST v1.1) was evaluated every 8 weeks until progression. Results: 33 pts (19 M/14 F) with median age 58.8 y and 4 (1-9) prior therapies enrolled. Median duration of treatment was 66 d (1–367+). With monotherapy (n = 28), no DLTs, treatment-related SAEs, or treatment-related study discontinuations were observed up through the maximum administered dose (250 mg bid). Possibly related AEs were grade 1 or 2 and did not correlate with dose level. Exposure was above that predicted for efficacy and t 1/2 was ̃10 hr at all doses. Of 26 evaluable monotherapy pts, 8 (27%) experienced stable disease (SD) for up to a year. All SD pts had a prolactin response. Among tumors expressing GPER, c-Myc depletion was observed in 100% (5/5) of paired pre and on-treatment biopsies. In the combination cohort (n = 5), 2/2 evaluable pts demonstrated net tumor reductions on initial f/up scans, including one RECIST partial response. Based on PK/PD data, 125 mg daily has provisionally been identified as the monotherapy and combination RP2D. Conclusions: LNS8801 is well tolerated and demonstrates signals of anti-tumor activity when administered both as monotherapy and in combination with pembrolizumab. Confirmation of RP2Ds and updated efficacy data will be presented in June. A phase 2A expansion study to evaluate these RP2Ds in clinical settings of high unmet need is now in development. Clinical trial information: NCT04130516.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.3084
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Online Resource
    Open Access Request
    Availability (electronic / print)
Nothing or not found what you are looking for? Please check your search query or use the Interlibrary Loan Search.
Close ⊗
This website uses cookies and the analysis tool Matomo. Further information can be found on the KOBV privacy pages