Synovial Sarcomas (SS) are rare tumors occurring predominantly in adolescent and young adults with a dismal prognosis in advanced phases. We report a first-in-human phase I of monoclonal antibody ...(OTSA-101) targeting FZD10, overexpressed in most SS but not present in normal tissues, labelled with radioisotopes and used as a molecular vehicle to specifically deliver radiation to FZD10 expressing SS lesions.
Patients with progressive advanced SS were included. In the first step of this trial, OTSA-101 in vivo bio-distribution and lesions uptake were evaluated by repeated whole body planar and SPECT-CT scintigraphies from H1 till H144 after IV injection of 187 MBq of
In-OTSA-101. A 2D dosimetry study also evaluated the liver absorbed dose when using
Y-OTSA-101. In the second step, those patients with significant tumor uptake were randomized between 370 MBq (Arm A) and 1110 MBq (Arm B) of
Y-OTSA-101 for radionuclide therapy.
From January 2012 to June 2015, 20 pts. (median age 43 years 21-67) with advanced SS were enrolled. Even though
In-OTSA-101 liver uptake appeared to be intense, estimated absorbed liver dose was less than 20 Gy for each patient. Tracer intensity was greater than mediastinum in 10 patients consistent with sufficient tumor uptake to proceed to treatment with
Y-OTSA-101: 8 were randomized (Arm A: 3 patients and Arm B: 5 patients) and 2 were not randomized due to worsening PS. The most common Grade ≥ 3 AEs were reversible hematological disorders, which were more frequent in Arm B. No objective response was observed. Best response was stable disease in 3/8 patients lasting up to 21 weeks for 1 patient.
Radioimmunotherapy targeting FZD10 is feasible in SS patients as all patients presented at least one lesion with
In-OTSA-101 uptake. Tumor uptake was heterogeneous but sufficient to select 50% of pts. for
Y-OTSA-101 treatment. The recommended activity for further clinical investigations is 1110 MBq of
Y-OTSA-101. However, because of hematological toxicity, less energetic particle emitter radioisopotes such as Lutetium 177 may be a better option to wider the therapeutic index.
The study was registered on the NCT01469975 website with a registration code NCT01469975 on November the third, 2011.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background:
Stabilized mutant p53 protein (mutp53) is a novel target in epithelial ovarian cancer. Due to aberrant conformation, mutp53 proteins depend on folding support by the Hsp90 chaperone. ...Hsp90 blockade induces degradation of mutp53, resulting in tumor cell cytotoxicity and increased sensitivity to chemotherapeutics. Preclinical synergy of the Hsp90 inhibitor ganetespib combined with paclitaxel provided the rationale for testing the combination in platinum-resistant ovarian cancer (PROC) patients in the GANNET53 trial (NCT02012192).
Methods:
Eligible patients had high-grade PROC with ≤ 4 prior lines of chemotherapy. Weekly paclitaxel (80 mg/m
2
) and increasing doses of ganetespib (100, 150 mg/m
2
) were given i.v. on days 1, 8, 15 in a 28 days cycle until disease progression or unacceptable toxicity. Endpoints were safety and determination of phase II dose. Dose limiting toxicity (DLT) was defined as grade 4 toxicity (with exceptions) occurring in cycles 1&2.
Results:
Ten patients (median age 59 years; range 43–70) were enrolled. No DLT occurred in cohort 1 (4 patients treated with paclitaxel + ganetespib 100 mg/m
2
), nor in cohorts 2 and 3 (6 patients treated with paclitaxel + ganetespib 150 mg/m
2
). The most common adverse event (AE) related to ganetespib was transient grade 1/2 diarrhea (
n
= 6). Related grade 1/2 AEs in >2 patients included QTc prolongation (
n
= 4), nausea (
n
= 3), anemia (
n
= 3), headache (
n
= 3), fatigue (
n
= 3), and dyspnoea (
n
= 3). Most frequently related grade 3/4 AEs were diarrhea (
n
= 3) and neutropenia (
n
= 2). There was 1 death on study due to hemorrhage from a duodenal ulcer. Three patients discontinued study treatment due to serious AEs (digestive hemorrhage
n
= 1, cardiac failure
n
= 1, abdominal pain and vomiting
n
= 1), 6 due to progressive disease, one due to investigator and patient decision. Two patients achieved a partial response (ORR 20%) and 4 patients a stable disease (disease control rate of 60%). Median PFS was 2.9 months (1.6 months in cohort 1 at 100 mg/m
2
ganetespib, 5.1 months in cohorts 2+3 at 150 mg/m
2
ganetespib).
Conclusions:
The combination of ganetespib 150 mg/m
2
with paclitaxel 80 mg/m
2
once weekly for 3 out of 4 weeks was generally well-tolerated with no DLTs, and therefore chosen for the randomized phase II trial.
Abstract only
1
Background: For patients (pts) with ASCC, second-line or later treatment options have been limited. Pembrolizumab (pembro), an anti-PD-1 monoclonal antibody, has demonstrated ...antitumor activity in several tumor types (including ASCC) in the multicohort phase 1b KEYNOTE-028 study. KEYNOTE-158 (NCT02628067) is an open-label, phase 2, multicohort study that evaluates antitumor activity and safety of pembro in pts with previously treated advanced cancer. Results from the ASCC cohort are presented. Methods: Eligible pts were ≥18 y with histologically/cytologically documented metastatic and/or unresectable ASCC with prior treatment failure on or intolerance to standard first-line therapy, measurable disease per RECIST v1.1, ECOG PS of ≤1, and evaluable tissue sample for PD-L1 and biomarker analysis. PD-L1 expression was assessed by the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). Pts received pembro 200 mg Q3W until disease progression, unacceptable AE, or completion of 35 cycles. The primary endpoint was ORR per RECIST v1.1 (assessed every 9 wk for 12 mo, then every 12 wk thereafter) by independent central review. Secondary endpoints were DOR, OS, PFS and safety. Results: 112 pts with ASCC were enrolled (81.3% women; median age, 61 y range 32–79; ≥2 prior therapies, 73.2%). At database cutoff (Dec 6, 2018) 10 pts (8.9%) had completed 35 cycles and 102 discontinued; median follow-up was 12.0 mo (range, 0.8–33.0) Five pts had CR and 8 had PR; ORR was 11.6% (95% CI, 6.3–19.0). Median DOR was not reached (range, 6.0+ to 29.1+ mo). Responses occurred in 11/75 pts (14.7%) with PD-L1 combined positive score (CPS) ≥1 and 2/30 pts (6.7%) with PD-L1 CPS < 1. Among all pts, median OS was 12.0 mo (95% CI, 9.1–15.4), and median PFS was 2.0 mo (95% CI, 2.0–2.1). 68 (60.7%) pts had treatment-related AEs, including 21 (18.8%) who had grade 3–5 events; there were no treatment-related deaths. 4 pts (3.6%) discontinued due to treatment-related AEs. 27 pts (24.1%) had immune-mediated AEs/infusion reactions. Conclusions: Pembro demonstrated antitumor activity and manageable toxicity in pts with heavily pretreated advanced ASCC, regardless of PD-L1 status. Clinical trial information: NCT02628067.
Abstract only
11022
Background: Targeting oncogenic KIT and PDGFRA mutations revolutionized treatment of patients (pts) with advanced GIST; however, nearly all pts succumb to resistant disease. ...Avapritinib is a potent and selective kinase inhibitor with broad activity against oncogenic KIT/PDGFRA mutants, including PDGFRA D842V and other primary or secondary resistance mutations. Updated results from the phase 1 NAVIGATOR (NCT02508532) study of avapritinib in pts with advanced GIST are presented. Methods: Adult pts with unresectable PDGFRA D842V or other mutant GIST who progressed on imatinib and ≥ 1 other tyrosine kinase inhibitor (TKI) were treated with oral, daily, continuous avapritinib. Adverse events (AE) and response by mRECIST 1.1 per central radiology were assessed. Safety from the overall population (30-600 mg doses) and efficacy in the response evaluable 4L+ and PDGFRA Exon 18 (Ex 18) populations treated at the MTD (400 mg)/RP2D (300 mg) were analyzed. Results: As of 16 Nov 2018, 237 pts 172 KIT, 62 PDGFRA Ex 18 (56 D842V, 6 non-D842V), 2 PDGFRA N659K, 1 missing were enrolled including 111 in the 4L+ population (primarily KIT, median 4 prior TKI) and 43 in the Ex 18 population (median 1 prior TKI). The 4L+ ORR was 22% 1 CR, 23 PR (1 pending), and 52 SD with median duration of response (mDOR) of 10.2 months (95% CI: 7.2-NE). The Ex 18 ORR was 86% 3 CR, 34 PR (1 pending) and 5 SD; mDOR was not reached (95% CI: 11.3-NE). Most AE were grade 1-2, most commonly nausea (63%), fatigue (58%), anemia (49%), periorbital edema (42%), diarrhea (40%), vomiting (40%), decreased appetite (38%), increased lacrimation (33%), peripheral edema (33%) and memory impairment (most common cognitive AE, 29%). 10% of pts discontinued due to a related AE. Grade 3-4 related AE ≥ 2% were anemia, fatigue, hypophosphatemia, hyperbilirubinemia, neutropenia, and diarrhea. Conclusions: Avapritinib has important clinical activity in pts with advanced GIST who have no effective therapies. The ORR and DOR of avapritinib in 4L+ exceeds that of approved 2
nd
and 3
rd
line therapies and shows unprecedented activity in D842V and other Ex 18 mutant PDGFRA GIST. Results suggest avapritinib has the potential to change the treatment paradigm of pts with advanced GIST. Clinical trial information: NCT02508532.
Abstract only
11078
Background: TGCTis a proliferative, neoplastic joint disease that presents as single nodule (local) or multiple nodules (diffuse D-TGCT). Localized overexpression of colony ...stimulating factor 1 (CSF1) leads to recruitment of cells expressing the CSF1 receptor (CSF1R), formation of a tumor and inflammation of joints and tendons. Cabira is a monoclonal antibody that inhibits the interaction of the CSF1 and IL-34 ligands with their shared receptor CSF1R. Methods: This Ph 1/2 study is evaluating the safety and efficacy of cabira monotherapy administered IV Q 2wk for 6 mo in patients (pts) with D-TGCT. Eligible pts have inoperable D-TGCT or tumor for which resection would cause unacceptable morbidity. Response is evaluated by MRI, pt reported outcomes, and Ogilvie-Harris (O-H) score (which combines pain, synovitis, range of motion and functional capacity on a scale of 0-12). Results: As of 15 Dec 2016, 22 pts received ≥ 1 dose of cabira at 1, 2 or 4mg/kg. Dose-related exposure increase and significant reduction in target peripheral monocytes were observed. No dose limiting toxicity was identified. 4 mg/kg was chosen for Ph2 based on efficacy, tolerability, and PK. AEs ≥ Gr 2 ( > 10%) were CK elevation 46%, rash and other skin disorders 36%, fatigue 23%, and periorbital/peripheral/face edema 18% each. Gr 3 AEs in ≥ 2 pt were CK elevation (n = 8) and periorbital edema (n = 2). Four drug-related SAEs were reported in 3 pts; hypertension, fever, CRP elevation, and myocarditis. AEs of CK elevation were asymptomatic, improved to < 2X ULN after protocol mandated drug discontinuation and are a known on-target effect of CSF1R inhibition. An amendment was made during Phase 2 to allow dosing with higher CK levels Activity at 4 mg/kg was: 1PR and 1 CK discontinuation in 3 pts in Ph1; 4 PRs in 7 evaluable pts with 6 additional ongoing in Ph2. Positive functional status improvements by O-H score were noted in objective responders (from 2 to 7). Conclusions: The initial demonstration of objective and functional activity supports further development of cabiralizumab in pts with D-TGCT. Updated data from the ongoing Ph2 will be presented. NCT02471716 . Clinical trial information: NCT02471716.
Pigmented villonodular synovitis (alternatively known as diffuse-type giant cell tumour) is a rare, locally aggressive tumour driven by a specific translocation resulting in the overexpression of ...colony-stimulating factor 1 (CSF1). CSF1 receptor (CSF1R) inhibitors (ie, tyrosine kinase inhibitors and antibodies) induce a response in patients with pigmented villonodular synovitis. We investigated the safety and efficacy of a CSF1R tyrosine kinase inhibitor, nilotinib, in patients with locally advanced non-resectable pigmented villonodular synovitis.
In this phase 2, open-label, single-arm study, we enrolled patients from 11 cancer centres of hospitals in four countries (France, Netherlands, Italy, and Australia). Eligible patients were aged at least 18 years with a WHO performance status of 2 or less, and histologically confirmed progressive or relapsing pigmented villonodular synovitis that was inoperable, or resectable only with mutilating surgery. Patients received oral nilotinib (400 mg twice per day) until disease progression, unacceptable toxicity, or completion of 1 year of treatment. The primary endpoint was the proportion of patients who were progression free at 12 weeks, which was centrally assessed according to Response Evaluation Criteria in Solid Tumors version 1.1. Analyses were by modified intention to treat (ie, all patients with no major protocol violations who were treated with nilotinib for at least 3 weeks were included). All participants who received at least one dose of study drug were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT01261429, and the results presented here are the final analysis of the trial.
Between Dec 15, 2010, and Sept 28, 2012, we enrolled 56 patients with pigmented villonodular synovitis and treated them with nilotinib. Five (9%) patients discontinued study treatment before week 12; therefore, 51 patients were evaluable for the primary endpoint at 12 weeks. The estimated proportion of patients who were progression free at 12 weeks was 92·6% (95% credible interval 84·3–97·9). 54 (96%) of 56 patients had a treatment-related adverse event. Six (11%) of 56 patients had at least one grade 3 treatment-related adverse event (headache, dizziness, and hepatic disorders n=1, pruritus and toxidermia n=1, diarrhoea n=1, increased γ-glutamyl transferase concentration n=1, anorexia n=1, and increased headache n=1). No grade 4 or 5 adverse events were reported. One patient had a treatment-related serious adverse event (toxidermia) and two patients had serious adverse events not considered to be related to the study drug (borderline ovarian tumour n=1 and pilonidal cyst excision n=1).
More than 90% of patients with locally advanced unresectable progressive pigmented villonodular synovitis achieved disease control with 12 weeks of nilotinib treatment. These results indicate that CSF1R tyrosine kinase inhibitors have anti-tumour activity with manageable toxicity in patients with inoperable progressive pigmented villonodular synovitis. Randomised trials investigating the efficacy of nilotinib for patients with unresectable pigmented villonodular synovitis are warranted.
Novartis, Institut National du Cancer, EuroSARC, French National Cancer Institute, General Directorate of Care Supply, Lyon Research Innovation for Cancer, L'Agence nationale de la recherche, Laboratory of Excellence, Fondation ARC pour la recherche sur le cancer, Ligue contre le Cancer (comité de l'Ain), Info Sarcomes, and Association DAM'S.
The clinical activity of fibroblast growth factor receptor (FGFR) inhibitors seems restricted to cancers harbouring rare FGFR genetic aberrations. In preclinical studies, high tumour FGFR mRNA ...expression predicted response to rogaratinib, an oral pan-FGFR inhibitor. We aimed to assess the safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, and preliminary clinical activity of rogaratinib.
We did a phase 1 dose-escalation and dose-expansion study of rogaratinib in adults with advanced cancers at 22 sites in Germany, Switzerland, South Korea, Singapore, Spain, and France. Eligible patients were aged 18 years or older, and were ineligible for standard therapy, with an Eastern Cooperative Oncology Group performance status of 0–2, a life expectancy of at least 3 months, and at least one measurable or evaluable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. During dose escalation, rogaratinib was administered orally twice daily at 50–800 mg in continuous 21-day cycles using a model-based dose-response analysis (continuous reassessment method). In the dose-expansion phase, all patients provided an archival formalin-fixed paraffin-embedded (FFPE) tumour biopsy or consented to a new biopsy at screening for the analysis of FGFR1–3 mRNA expression. In the dose-expansion phase, rogaratinib was given at the recommended dose for expansion to patients in four cohorts: urothelial carcinoma, head and neck squamous-cell cancer (HNSCC), non-small-cell lung cancer (NSCLC), and other solid tumour types. Primary endpoints were safety and tolerability, determination of maximum tolerated dose including dose-limiting toxicities and determination of recommended phase 2 dose, and pharmacokinetics of rogaratinib. Safety analyses were reported in all patients who received at least one dose of rogaratinib. Patients who completed cycle 1 or discontinued during cycle 1 due to an adverse event or dose-limiting toxicity were included in the evaluation of recommended phase 2 dose. Efficacy analyses were reported for all patients who received at least one dose of study drug and who had available post-baseline efficacy data. This ongoing study is registered with ClinicalTrials.gov, number NCT01976741, and is fully recruited.
Between Dec 30, 2013, and July 5, 2017, 866 patients were screened for FGFR mRNA expression, of whom 126 patients were treated (23 FGFR mRNA-unselected patients in the dose-escalation phase and 103 patients with FGFR mRNA-overexpressing tumours 52 patients with urothelial carcinoma, eight patients with HNSCC, 20 patients with NSCLC, and 23 patients with other tumour types in the dose-expansion phase). No dose-limiting toxicities were reported and the maximum tolerated dose was not reached; 800 mg twice daily was established as the recommended phase 2 dose and was selected for the dose-expansion phase. The most common adverse events of any grade were hyperphosphataemia (in 77 61% of 126 patients), diarrhoea (in 65 52%), and decreased appetite (in 48 38%); and the most common grade 3–4 adverse events were fatigue (in 11 9% of 126 patients) and asymptomatic increased lipase (in 10 8%). Serious treatment-related adverse events were reported in five patients (decreased appetite and diarrhoea in one patient with urothelial carcinoma, and acute kidney injury NSCLC, hypoglycaemia other solid tumours, retinopathy urothelial carcinoma, and vomiting urothelial carcinoma in one patient each); no treatment-related deaths occurred. Median follow-up after cessation of treatment was 32 days (IQR 25–36 days). In the expansion cohorts, 15 (15%; 95% CI 8·6–23·5) out of 100 evaluable patients achieved an objective response, with responses recorded in all four expansion cohorts (12 in the urothelial carcinoma cohort and one in each of the other three cohorts), and in ten (67%) of 15 FGFR mRNA-overexpressing tumours without apparent FGFR genetic aberration.
Rogaratinib was well tolerated and clinically active against several types of cancer. Selection by FGFR mRNA expression could be a useful additional biomarker to identify a broader patient population who could be eligible for FGFR inhibitor treatment.
Bayer AG.
3150 Background: Selpercatinib, a first-in-class highly selective and potent RET kinase inhibitor with CNS activity, is approved in multiple countries for the treatment of RET-activated cancers. ...Current indications for RET mutant disease are limited to MTC. This analysis examined if selpercatinib was effective in non-MTC, RET mutation positive tumors and whether certain RET mutations demonstrated better activity (n=23; data cut-off: 13Jan2023). Methods: The phase 1/2 LIBRETTO-001 trial (NCT03157128) enrolled pts with locally advanced/metastatic RET-altered solid tumors, including pts with RET mutations in tumors other than MTC. Mutations must be known to be activating based on activity in MTC or other published evidence. Primary endpoint was objective response rate (ORR) by independent review committee (IRC). Secondary endpoints included ORR by investigator (INV), duration of response (DoR), progression-free survival (PFS), and safety. Results: Fourteen different tumor types were identified among the 23 pts with non-MTC RET-mutated tumors. This included 8 tumors from the Multiple Endocrine Neoplasia (MEN) syndrome spectrum; adrenal (pheochromocytoma; n=5), paraganglioma (n=2), neuroendocrine (n=1) (Table). Most of the mutations were located in extracellular cysteine-rich domain (CRD) and in the tyrosine kinase domain (TKD) of RET. In 23 efficacy-evaluable pts, confirmed ORR by IRC was 21.7% (5/23, 95% CI: 7.5, 43.7). ORR by IRC for pts with MEN-associated tumors (n=8) was 37.5% while five of these pts (62.5%) had stable disease lasting at least 16 weeks (SD16+). ORR by IRC for the sub-population with pheochromocytoma (n=5) was 40.0% and for pts with tumors manifesting RET extracellular cysteine mutations (n=5) was 60.0%. Of the 15 pts with non-MEN-associated tumors, 2 pts (8.7%; mutation in TKD) had a partial response (both with NSCLC adenocarcinoma, of which one had co-existent MTC). For the overall pts, the median DoR was 12.2 months (95% CI: 3.8, NE) and median PFS was 5.5 months (95% CI: 1.8, 19.4). No new safety signals were identified compared to previous reports. One grade 5 AE, general physical health deterioration, was observed and deemed by INV as not related to selpercatinib. Conclusions: This study suggests that RET-mutated, MEN-associated cancers (adrenal, paraganglioma, neuroendocrine) may benefit from selpercatinib treatment, which could be mediated through mutations in the extracellular CRD. The non-MTC RET-mutated tumor types appear not to derive benefit from selpercatinib. Clinical trial information: NCT03157128 . Table: see text
11516 Background: Vascular Endothelial Growth Factor (VEGF)-driven angiogenesis is a pivotal factor in creating an immunosuppressive tumor microenvironment. Approximately 80% of Soft Tissue Sarcomas ...(STS) are characterized by a 'cold' microenvironment, lacking tertiary lymphoid structures (TLS). While the efficacy of VEGF pathway and PD-1/PD-L1 axis blockade has been established in various tumor types, their impact on 'cold' STS remains unexplored. This study aims to evaluate the synergistic effect of anti-angiogenesis and PD-1 blockade in altering the microenvironment of cold STS, potentially enhancing immune response and therapeutic efficacy. Methods: In this phase II, single-arm, open-label, multicentric trial, we explored the efficacy and safety of combining regorafenib (R) and avelumab (A) in advanced TLS-negative STS patients. Patients were administered 160 mg of R daily for 3 weeks in a 4-week cycle, alongside 10 mg/kg of A biweekly. Endpoints included high-throughput analysis of tumor and plasma samples, response rate, progression-free survival (PFS), overall survival (OS), and safety, as per the NCI-CTCAE v5.0 guidelines. Results: From May 2019 to August 2021, 49 TLS-negative STS patients were enrolled, including leiomyosarcoma (45%), synovial sarcoma (18%), and other subtypes. The median age was 57.1 years, with patients having undergone an average of 2 prior treatment lines. High-throughput analysis of sequential plasma samples indicated an upregulation of immune-inducing protein biomarkers such as CXCL10 and soluble CD8 antigen. Multiplex immunofluorescence analysis of sequential tumor samples revealed significant increase in CD8 T cell infiltration on-treatment. The most common severe adverse events were grade 1 or 2 palmar-plantar erythrodysesthesia, fatigue, and diarrhea. The median follow-up was 7.1 months, with 32.6% of patients experiencing tumor shrinkage, and a clinical benefit rate of 48.8%. The 6-month PFS was 22.1%, with a median OS of 15.1 months. Conclusions: The combination of regorafenib and avelumab demonstrates a marked mobilization of antitumor immunity in patients with TLS-negative STS. The observed efficacy appears superior to that of single-agent immune checkpoint inhibition in 'cold' STS, and higher than the 6-month PFS benchmark of 14% set by EORTC. This indicates the potential effectiveness of this treatment combination in managing advanced cold STS, marking a significant stride in precision immunotherapy for this group of tumors. Clinical trial information: NCT03475953 .
2573 Background: Major challenges of the clinical development of CD40 agonists are toxicity due to systemic CD40 activation and peripheral target-mediated drug disposition. MP0317, a CD40 agonist ...DARPin (designed ankyrin repeat protein), is exclusively activated by binding to fibroblast activation protein (FAP) on cancer-associated fibroblasts. This enables local CD40 activation in the tumor microenvironment (TME) and reduces systemic toxicity. Methods: This Phase 1, multicenter, open-label, dose-escalation study assessed safety/tolerability, pharmacokinetics/pharmacodynamics, and preliminary antitumor activity of MP0317 monotherapy (NCT05098405; data cut-off 15 Jan 2024). Eligible adults with selected advanced solid tumors (based on predicted FAP expression) were enrolled into 9 dose-escalation cohorts of MP0317 0.03–10 mg/kg administered IV 3-weekly (Q3W) or weekly (Q1W) until disease progression or unacceptable toxicity. Blood biomarkers were analyzed by immuno-assays and flow cytometry, and paired tumor biopsies by RNA sequencing and immunofluorescence. Results: Dose-escalation enrolment is complete and 46 patients received ≥1 MP0317 dose, including 24 women (52%) and 22 men (48%). Median age at enrolment was 63 years (range 35–79). Patients received a median of 4 prior treatment lines (range 1–13). Colorectal cancer was the most frequent tumor type (12 patients, 26%). MP0317 maximum tolerated dose was not reached; only one patient experienced a dose-limiting toxicity (asymptomatic Grade 3 alanine and aspartate aminotransferases elevation), at the highest planned dose of MP0317 (10 mg/kg Q3W). Grade ≤2 fatigue was the most frequent adverse reaction (15 patients, 30%), followed by Grade ≤2 infusion-related reaction, nausea and anorexia in 8, 7, and 5 patients, respectively. One patient achieved unconfirmed partial response, and stable disease was observed in 11 patients (24%). Serum PK data showed MP0317’s half-life extended properties and sustained exposure at higher doses. Paired tumor biopsies confirmed the colocalization of MP0317 with FAP and CD40. MP0317 detection in tumor biopsies at doses ≥1.5 mg/kg was associated with an increase in antigen-presenting (dendritic and B cells), plasma and T follicular helper cell abundance, as well as enhanced dendritic cell maturation and IFNγ production in the TME. CXCL10 serum level increases post MP0317 treatment supported these findings. Only minor changes were seen in pro-inflammatory cytokines. Conclusions: MP0317 had a favorable safety profile in 46 patients across all 9 dose-escalation cohorts exploring Q3W and Q1W regimens. Doses ≥1.5 mg/kg showed evidence of pharmacodynamic TME modulation, indicating tumor-localized CD40 activation. The data support further clinical evaluation of MP0317 including combination with complementary anticancer therapies. Clinical trial information: NCT05098405 .
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