An ongoing, phase 1 dose-escalation study investigating XB002, Exelixis’ next-generation tissue factor-targeting antibody-drug conjugate (ADC) for the treatment of patients with advanced solid tumors, has shown promising results.

The results of the open-label, multi-center, first-in-human phase 1 study, called JEWEL-101, were presented during the Antibody-drug Conjugates Poster Session (abstract 256) at the 34th Symposium on Molecular Targets and Cancer Therapeutics hosted by the European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR).

The JEWEL-101 is expected to enroll approximately 450 patients and is divided into two parts: a dose-escalation stage and an expansion cohort stage. Expansion cohorts are planned for cervical cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, pancreatic cancer and several other cancers.

Tissue factor
XB002 is a next-generation antibody-drug conjugate that targets tissue factor (also known as platelet tissue factor, factor VIII, TF or CD142),a transmembrane glycoprotein that localizes the coagulation serine protease factor VII/VIIa (FVII/VIIa) to the cell surface, which is over-expressed in a variety of solid tumors. [1]

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The primary function of TF is to activate the clotting cascade. The TF:FVIIa complex also activates cells by cleavage of a G-protein coupled receptor called protease-activated receptor 2 (PAR2).[1]

Research has shown that there is a strong relationship between tissue factor (TF) and cancer. And many cancer cells express high levels of both full-length TF and alternatively spliced TF (asTF). In general, TF expression in cancer is associated with poor prognosis. [2]

Tissue factor gene expression in cancer is regulated via a variety of different signaling pathways, transcription factors and micro ribonucleic acids. The TF/factor VIIa complex is known to enhance tumor growth by activating PAR2 signaling and by increasing the expression of angiogenic factors, such as vascular endothelial growth factor (VEGF). AsTF increases tumor growth by enhancing integrin β1 signaling. Both TF and asTF contribute to metastasis via multiple thrombin-dependent and independent mechanisms that include protecting tumor cells from natural killer cells.[2].

For example, the non-coagulant, asTF retains an integrin-binding site and, upon deposition into the tumor stroma, stimulates angiogenesis by ligating endothelial integrins αvβ3 and α6β1. On tumor cells, full-length TF is constitutively associated with laminin-binding β1 integrins that support TF-VIIa-PAR2 signaling leading to upregulation of pro-angiogenic and immune modulatory cytokines and growth factors.[3]

XB002, a novel, investigational ADC, is using tumor TF as a target to deliver cytotoxic drugs to the tumor. After binding to tissue factor on tumor cells, XB002 is internalized, and the cytotoxic agent is released, resulting in targeted tumor cell death.

XB002 is currently being developed for advanced solid tumors. Preclinical findings demonstrate that XB002 binds tissue factor without affecting the coagulation cascade — a limitation of prior tissue-factor-targeting molecules.

Susanna Ulahannan MD is Assistant Professor Internal Medicine in the Section of Hematology/Oncology, University of Oklahoma College of Medicine and Associate Director of Oklahoma TSET Phase 1 Program, OU Health Stephenson Cancer Center at the OU Health Sciences Center.

Encouraging development
“Following promising preclinical data, it is encouraging to see that XB002 was well-tolerated across multiple dose levels with a pharmacokinetic analysis supporting the ability of XB002 to remain stable after infusion and reach its target before releasing its cytotoxic payload,” said Susanna Ulahannan, M.D., M.Med., Assistant Professor of Medicine in the Section of Hematology/Oncology, University of Oklahoma College of Medicine and Associate Director of Oklahoma TSET Phase 1 Program, OU Health Stephenson Cancer Center at the OU Health Sciences Center.

“As the dose-escalation phase progresses, and we initiate enrollment into tumor specific cohorts, I look forward to learning more about how XB002 may benefit people with advanced solid tumors, in particular in tumor types with high unmet need.”

Participating patients
JEWEL-101 is enrolling patients with advanced solid tumors for which therapies are unavailable, ineffective or intolerable. A total of 19 patients were enrolled across five initial escalating doses: 0.16 mg/kg (n=3), 0.5 mg/kg (n=3), 1.0 mg/kg (n=6), 1.5 mg/kg (n=3) and 2.0 mg/kg (n=4). The most common types of cancer for patients enrolled were pancreatic cancer, colorectal cancer, cervical cancer and prostate cancer. Median age was 63 years, and 63% of patients had an Eastern Cooperative Oncology Group score of 1. Seventy-nine percent of patients had at least three prior lines of therapy.

“We are pleased to present the first clinical profile of XB002 at ENA 2022, representing an important milestone for our first biologic in clinical development,” said Vicki L. Goodman, M.D., Executive Vice President, Product Development & Medical Affairs, and Chief Medical Officer, Exelixis.

“We are eager to proceed to the expansion cohort stage of JEWEL-101 once the recommended dose is determined, as we aim to further understand the activity of this molecule as a potential new treatment for people who have difficult-to-treat tumors with limited treatment options,” Goodman added.

Interim study results
The recommended dose and maximum tolerated dose for XB002 have not yet been determined. As of the data cutoff, there were no dose-limiting toxicities. The primary reasons for treatment discontinuation included radiographic progression (47%), treatment-emergent adverse events (AEs; 11%), lack of clinical benefit (11%) and patient request other than AEs (16%).

A pharmacokinetic analysis demonstrated that XB002 exposure increased more than or proportionately to a dose increase from 0.16 mg/kg to 2.0 mg/kg. XB002 total antibody and intact antibody-drug conjugate pharmacokinetics were similar, suggesting XB002 is stable after infusion. Levels of free payload remained low (<1 ng/mL) at all dose levels. At 2.0 mg/kg, mean AUC0-t was 121 μg∙day/mL for intact antibody-drug conjugate and 4.21 ng∙day/mL for free payload; mean Cmax was 46.6 μg/mL and 0.809 ng/mL, respectively.

Adverse events
The results of the dose escalation phase of the study confirmed that 42% of participating patients experienced grade 3 treatment-emergent AEs; there were no grade 4 or 5 treatment-emergent AEs. Treatment-related AEs were experienced by 63% of patients; all were grade 2 or lower, except for one grade 3 event (hypertension), and improved or resolved prior to the next XB002 dose. Serious AEs were experienced by 16% of patients, and all were considered unrelated to XB002; two patients had grade 3 events (COVID-19 pneumonia and diarrhea), and one patient had grade 2 bacteremia. No bleeding events occurred despite the use of anticoagulant agents in 8 patients (42%).

Ocular treatment-emergent AEs were experienced by 42% of patients, with noninfective conjunctivitis (26%) and dry eye (16%) considered related to XB002 treatment. Incidence of ocular events was higher at the 2 mg/kg dose level (75%) than at the other dose levels (33%). No corneal toxicity was observed. All ocular events were reversible with supportive care, which included lubricating, vasoconstrictive, corticosteroid and/or antibiotic eyedrops.

No objective responses were observed.

Three patients with stable disease remain on treatment with XB002: one each with metastatic castration-resistant prostate cancer, appendiceal adenocarcinoma and pancreatic adenocarcinoma, at treatment durations of 42 weeks, 10 weeks and 7 weeks, respectively. One additional patient with uterine carcinosarcoma who achieved stable disease as the best response discontinued XB002 at 15 weeks.

In the upcoming cohort-expansion stage, the efficacy of XB002 will be further evaluated as a single agent and in combination with nivolumab (Opdivo®; Bristol-Myers Squibb).

Clinical trial
Study of XB002 in Subjects With Solid Tumors (JEWEL-101) – NCT04925284

Highlights of Prescribing information
Nivolumab (Opdivo®; Bristol-Myers Squibb) [Prescription Information]

[1] Kasthuri RS, Taubman MB, Mackman N. Role of tissue factor in cancer. J Clin Oncol. 2009 Oct 10;27(29):4834-8. doi: 10.1200/JCO.2009.22.6324. Epub 2009 Sep 8. PMID: 19738116; PMCID: PMC2764391.
[2] Hisada Y, Mackman N. Tissue Factor and Cancer: Regulation, Tumor Growth, and Metastasis. Semin Thromb Hemost. 2019 Jun;45(4):385-395. doi: 10.1055/s-0039-1687894. Epub 2019 May 16. PMID: 31096306; PMCID: PMC6546519.
[3] Ruf W, Yokota N, Schaffner F. Tissue factor in cancer progression and angiogenesis. Thromb Res. 2010 Apr;125 Suppl 2(0 2):S36-8. doi: 10.1016/S0049-3848(10)70010-4. PMID: 20434002; PMCID: PMC3827916

Featured Image: Exelixis laboratory. Courtesy: © 2010 – 2022 Exelixis. Used with permission.


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