A Phase 1 Cohort Dose Escalation and Expansion Trial to Determine the Safety, Tolerance, Maximum Tolerated Dose, and Preliminary Antineoplastic Activity of IKS03 in Patients with Advanced B-Cell Non-Hodgkin Lymphomas (NHL)
Notice bibliographique
Résumé
Background: IKS03 is an antibody-drug conjugate (ADC) comprising an anti-CD19 antibody conjugated with novel ConjuALL technology to a highly potent proprietary DNA-crosslinking pyrrolobenzodiazepine (PBD) prodrug payload for the treatment of CD19-positive hematologic malignancies. Both the payload and the linker of IKS03 incorporate an innovative tumor-selective chemistry that takes advantage of the overexpression of beta glucuronidase in cancer cells compared to most normal tissues. Payload release and activation require cleavage of glucuronide moieties that are incorporated into the linker payload structure providing improvements in both efficacy and safety compared to traditional ADC formats. This “glucuronide trigger” is stable while in circulation with minimal to no systemic payload release from the ADC. Following binding and internalization of IKS03 into a CD19-positive cancer cell, beta glucuronidase can release the active PBD payload leading to cell death. Normal tissues without CD19 expression and/or with low levels of the beta glucuronidase enzyme have limited ADC uptake, are less able to process IKS03 and are differentially spared. In preclinical studies, IKS03 demonstrated significant in vivo efficacy with complete tumor regressions in CD19-positive diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) xenograft models at single doses of 0.1 to 1 mg/kg. IKS03 demonstrated greater activity than the clinical benchmark ADC loncastuximab tesirine. IKS03 is also highly effective in patient-derived xenograft models that contain some of the genetic alterations commonly found in relapsed/refractory NHL patients. Results from toxicology studies in cynomologus monkey suggest a manageable safety profile at single doses, well above those required for in vivo activity. Pharmacokinetics are favorable with a mean total ADC half-life of 8 days and undetectable levels of the active PBD payload in circulation confirming targeted delivery of the payload. Study Design and Methods: This Phase 1 multicenter, open label, non-randomized study of IKS03 will consist of two parts: dose-escalation (Part I) and dose-expansion (Part II) together enrolling approximately 140 adult patients with relapsed or refractory B-cell NHL after at least two prior lines of systemic therapy. Patients will receive repeat doses of study drug by IV infusion on Day 1 of each 21-day cycle, until disease progression, unacceptable toxicity, or another withdrawal criterion is met. Key exclusion criteria include: active central nervous system involvement with NHL; clinically significant cardiovascular, pulmonary or hepatic disease; or receipt of other CD19-directed therapy within 3 months. Part I dose escalation will enroll patients with confirmed CD19-positive, measurable or non-measurable advanced B-cell NHL. Eligible subtypes include DLBCL, MCL, FL, high-grade B-cell, and marginal zone lymphoma as per WHO 2016 classification. Patients with Burkitt's lymphoma, Waldenström macroglobulinemia, and chronic lymphocytic leukemia are excluded. In Part 1, the primary objective is establishment of the recommended Phase 2 dose (RP2D) by evaluation of safety, tolerability and the maximum tolerated dose (MTD) of IKS03. Dose escalation will follow a 3+3 design. A two cycle Dose-Limiting Toxicity (DLT) assessment period will be observed, and dose-escalation decisions will be guided by a study safety committee. Dose escalation increments will be adjusted based on occurrence of protocol-specified DLTs as well as overall tolerability. Secondary objectives include characterization of immunogenicity and pharmacokinetic (PK) profile of IKS03. Exploratory objectives include preliminary antineoplastic activity per Lugano criteria (Cheson et al, JCO 2014) and evaluation of pharmacodynamic markers. Part II will further evaluate the antineoplastic activity of IKS03 at the RP2D in expansion cohorts of patients with selected NHL subtypes and with measurable disease. Sample size will be determined for each subtype using a Simon Two-Stage design. Secondary objectives include further evaluation of safety, tolerability, immunogenicity and PK profile of IKS03 as well as confirmation of the RP2D. Clinical trial information: NCT05365659.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,003 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».