
Maja J A de JongeErasmus University Rotterdam | EUR · Erasmus Medical Center (MC)
Maja J A de Jonge
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221
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Publications (221)
Background
Immune checkpoint inhibitors (ICIs) are effective treatments for patients with metastatic melanoma, including patients with brain metastasis (BM). However, half of patients with melanoma BM have intracranial progression within six months after the start of ICIs. We investigated whether size affects response to ICIs in patients with melan...
Purpose:
Treatment efficacy of nivolumab was evaluated in patients with advanced, treatment-refractory solid dMMR/MSI tumors and in-depth biomarker analyses were performed to inform precision immunotherapy approaches.
Patients and methods:
Patients with dMMR/MSI tumors who exhausted standard-of-care treatment options were enrolled in the Drug Re...
Advances in therapeutic approaches for melanoma urge the need for biomarkers that can identify patients at risk for recurrence and to guide treatment. The potential use of liquid biopsies in identifying biomarkers is increasingly being recognized. Here, we present a head‐to‐head comparison of several techniques to analyze circulating tumor cells (C...
Background
Patients with irresectable stage III or metastatic melanoma presenting with poor prognostic factors are usually treated with a combination of immune checkpoint inhibitors (ICIs), consisting of ipilimumab and nivolumab. This combination therapy is associated with severe immune related adverse events (irAEs) in about 60% of patients. In cu...
A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single‐center cohort study, we assessed the impact of different initial treatment str...
Purpose
To evaluate the efficacy of pembrolizumab across multiple cancer types harboring different levels of whole-genome sequencing–based tumor mutational load (TML; total of nonsynonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234).
Experimental Design
Patients with solid, treatment-refractory...
Background
Patients with advanced cancer who no longer have standard treatment options available may decide to participate in early phase clinical trials (i.e. experimental treatments with uncertain outcomes). Shared decision-making (SDM) models help to understand considerations that influence patients’ decision. Discussion of patient values is ess...
BACKGROUND
Brain metastases (BM) significantly impact quality of life and survival in patients with metastatic renal cell cancer (mRCC). Based on the International Metastatic RCC Database Consortium (IMDC) risk classification, treatment strategies for patients with mRCC vary from systemic treatment with vascular endothelial growth factor receptor-t...
BACKGROUND
Metastatic renal cell cancer (mRCC) is known for its variable disease course and can be categorized according to the International Metastatic RCC Database Consortium (IMDC) criteria. As patients with mRCC who have a favorable IMDC score and/or a low tumor burden usually have an indolent disease course, watchful waiting is often considere...
Background
Patients with advanced cancer who have no standard treatment options anymore can sometimes decide to participate in early phase clinical trials (i.e. experimental treatments with uncertain outcomes). Shared decision-making models consider discussing patient values essential, but such communication is often limited in this context and may...
BRAFV600E alterations are prevalent across multiple tumors. Here we present final efficacy and safety results of a phase 2 basket trial of dabrafenib (BRAF kinase inhibitor) plus trametinib (MEK inhibitor) in eight cohorts of patients with BRAFV600E-mutated advanced rare cancers: anaplastic thyroid carcinoma (n = 36), biliary tract cancer (n = 43),...
Background
In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based...
Background:
Melanoma brain metastasis (MBM) is associated with poor outcome, but targeted therapies (TTs) and immune checkpoint inhibitors (ICIs) have revolutionized treatment over the past decade. We assessed the impact of these treatments in a real-world setting.
Methods:
A single-center cohort study was performed at a large, tertiary referral...
Background:
The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is consid...
BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase II study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine...
Objective
This article identifies the core values that play a role in patients’ decision-making process about participation in early-phase clinical cancer trials.
Methods
Face-to-face, semi-structured serial interviews (n = 22) were performed with thirteen patients with advanced cancer recruited in two Dutch specialized cancer centers. In a cyclic...
Eftozanermin alfa (eftoza), a second-generation tumor necrosis factor-related apoptosis-inducing ligand receptor (TRAIL-R) agonist, induces apoptosis in tumor cells by activation of death receptors 4/5. This phase 1 dose-escalation/dose-optimization study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary activity of eftoza i...
2645
Background: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-CLEVER-1 IgG4-antibody capable of inducing a phenotypic M2 to M1 immune switch of tumor-associated ma...
When standard treatment options are not available anymore, patients with advanced
cancer may participate in early phase clinical trials. Improving this complex decision-making process may improve their quality of life. Therefore, this prospective multicenter study with questionnaires untangles several contributing factors to decisional conflict (wh...
Purpose:
Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell-targeting therapies. Thus, agents able to reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Inhibition of a macrophage scavenger receptor Clever-1 has shown be...
Background
For many patients with advanced cancer, the decision whether to participate in early phase clinical trials or not is complex. The decision-making process requires an in-depth discussion of patient values. We therefore aimed to synthesize and describe patient values that may affect early phase clinical trial participation.
Methods
We con...
Macrophages are critical in driving an immunosuppressive tumor microenvironment that counteracts the efficacy of T-cell targeting therapies. Thus, agents that can reprogram macrophages towards a proinflammatory state hold promise as novel immunotherapies for solid cancers. Here, we report that immunotherapeutic targeting of the macrophage scavenger...
Background
This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/p...
Background:
Among patients with non-small-cell lung cancer (NSCLC), MET exon 14 skipping mutations occur in 3 to 4% and MET amplifications occur in 1 to 6%. Capmatinib, a selective inhibitor of the MET receptor, has shown activity in cancer models with various types of MET activation.
Methods:
We conducted a multiple-cohort, phase 2 study evalua...
Background: Capmatinib is a highly selective and potent MET inhibitor that crosses the blood-brain barrier. In the GEOMETRY study, capmatinib showed clinically meaningful response rates in pts with advanced NSCLC harboring METex14 skipping mutations, including activity in pts with baseline BM, and also demonstrated manageable safety. Here, we prese...
Background In the first part of this extensive phase I study (NCT00516724), continuous olaparib twice daily (bid) with carboplatin and/or paclitaxel resulted in myelosuppression and dose modifications. Here, we report the safety, tolerability, and efficacy of intermittent olaparib dosing combined with carboplatin and paclitaxel. Methods Patients wi...
Background The PARP inhibitor olaparib has shown acceptable toxicity at doses of up to 400 mg twice daily (bid; capsule formulation) with encouraging signs of antitumor activity. Based on its mode of action, olaparib may sensitize tumor cells to DNA-damaging agents. This Phase I trial (NCT00516724) evaluated the safety, pharmacokinetics (PK) and pr...
e15668
Background: Eftozanermin alfa (eftoza; formerly known as ABBV-621), a 2nd-generation tumor necrosis factor-related apoptosis-inducing ligand receptor agonist, is being evaluated in previously treated solid and hematologic malignancies (NCT03082209). In a dose-expansion cohort, patients (pts) with KRAS-mutant colorectal cancer (n = 24) and pa...
3097
Background: The scavenger receptor CLEVER-1 mediates the clearance of “unwanted” self-components and is highly expressed on tumor associated macrophages (TAMs). CLEVER-1 expression is associated with immunotherapy resistance and poor survival in several cancers. Pre-clinical studies demonstrate that CLEVER-1 inhibition increases TAM pro-inflam...
Introduction:
Apalutamide is a next-generation androgen receptor (AR) inhibitor approved for patients with nonmetastatic castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer. We evaluated the pharmacokinetics, safety, and antitumor activity of apalutamide combined with abiraterone acetate plus prednisone...
Background
Dysregulation of receptor tyrosine kinase MET by various mechanisms occurs in 3–4% of NSCLC and is associated with unfavorable prognosis. While MET is a validated drug target in lung cancer the best biomarker strategy for enrichment of susceptible patient population still remains to be defined. Towards this end we analyze here primary da...
Background:
Patients with advanced cancer for whom standard systemic treatment is no longer available may be offered participation in early phase clinical trials. In the decision making process, both medical-technical information and patient values and preferences are important. Since patients report decisional conflict after deciding on participa...
3013
Background: ABBV-621 is a potent tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor agonist fusion protein that induces apoptotic cell death, particularly in DR4/5 expressing tumor models. Methods: Patients (pts) with previously treated solid tumors and ECOG 0–2 were administered ABBV-621 (2.5–15 mg/kg IV) on day (D) 1 (d...
9004
Background: Capmatinib is a highly potent and selective MET inhibitor. Previous data of GEOMETRY mono-1 study showed a clinically meaningful overall response rate (ORR) and manageable toxicity profile in patients (pts) with METΔex14–mutated NSCLC who received 1–2 prior lines of treatment (tx) (Cohort 4) and in particular a high ORR in tx-naïve...
Objective:
Poly(ADP-ribose) polymerase (PARP) inhibitors have shown substantial activity in homologous recombination- (HR-) deficient ovarian cancer and are undergoing testing in other HR-deficient tumors. For reasons that are incompletely understood, not all patients with HR-deficient cancers respond to these agents. Preclinical studies have demo...
Background:
Overexpression/activation of focal adhesion kinase (FAK) in human malignancies has led to its evaluation as a therapeutic target. We report the first-in-human phase I study of BI 853520, a novel, potent, highly selective FAK inhibitor.
Objective:
Our objectives were to identify the maximum tolerated dose (MTD), and to evaluate safety...
BACKGROUND: Hairy cell leukemia is a rare, indolent, B-cell lymphoproliferative disease characterized by the BRAF V600E mutation in 90% to 100% of patients. Few treatment options are available for patients who progress on first-line therapy with a purine analogue and/or rituximab. The efficacy of combined BRAF and MEK inhibition is well established...
Purpose This phase 1 study examined safety, pharmacokinetics (PK), and efficacy of the poly(ADP-ribose) polymerase (PARP) inhibitor ABT-767 in patients with advanced solid tumors and BRCA1/2 mutations or with high-grade serous ovarian, fallopian tube, or primary peritoneal cancer. Methods Patients received ABT-767 monotherapy orally until disease p...
For advanced cancer patients deliberating early clinical trial participation, adequate information about expected effect on quality of life (HRQoL) and hope, may support decision making. The aim was to assess the potential relation of HRQoL to eligibility for phase‐I trial participation, and to observe the variations in patient‐reported outcomes. P...
The cover image, by Diane A. van der Biessen et al., is based on the Paper Understanding how Coping Strategies and Quality of Life maintain Hope in Patients deliberating Phase-I Trial Participation, DOI 10.1002/pon.4487.
Objective:
This study aimed to understand how hope and motivation of patients considering phase-I trial participation are affected by psychological factors such as coping strategies and locus of control (LoC), and general well-being as measured by the quality of life (QoL).
Methods:
An exploratory cross-sectional study was performed in patients...
Purpose:
This study investigated the safety, clinical activity and target-associated biomarkers of lumretuzumab, a humanized, glycoengineered, anti-HER3 monoclonal antibody (mAb), in combination with the EGFR-blocking agents erlotinib or cetuximab in patients with advanced HER3-positive carcinomas.
Experimental Design:
The study included two p...
2556
Background: Agents that generate breaks in DNA are frequently used as cancer therapeutics. These agents induce different forms of DNA damage including double-strand breaks (DSBs), which are the most lethal if left unrepaired. M3814 targets tumor cell growth and survival by inhibiting DNA-PK, which is part of a critical DSB DNA damage repair me...
Background
The discovery of novel biomarkers that predict treatment response in advanced cancer patients requires acquisition of high-quality tumor samples. As cancer evolves over time, tissue is ideally obtained before the start of each treatment. Preferably, samples are freshly frozen to allow analysis by next-generation DNA/RNA sequencing (NGS)...
Background Early signs of efficacy are critical in drug development. Response Evaluation Criteria In Solid Tumors (RECIST) are commonly
used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST however, emphasizes the value of tumor shrinkage,
whilst many targeted agents induce prolonged tumor growth arrest. This limits its u...
There are several reasons why combining an inhibitor of the vascular endothelial and the platelet-derived growth factor receptor with a taxane might induce synergistic antitumor activity. This phase I study aimed to determine the maximal tolerated dose (MTD) of the combination of pazopanib with two different schedules of docetaxel.
In a 3 + 3 + 3 d...
This multi-center Phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small cell (SCLC) and non-small cell lung (NSCLC) cancers METHODS: Consenting adult patients with good performa...
Background The folate receptor alpha is selectively over-expressed in a number of human cancers. BMS-753493 is a folate conjugate of the epothilone analog BMS-748285 that was designed to selectively target folate receptor expressing cancer cells. Methods BMS-753493 was investigated in two parallel multi-institutional first-in-human phase I/IIa stud...
Aim: To evaluate the safety profile of RG7116 in combination with cetuximab or erlotinib.
Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. RG7116 plus cetuximab (400 mg/m² followed by 250 mg/m² qw IV) and RG7116 plus erlotinib (150 mg/day p.o.) combinations were evaluated...
Background: ABT-767 is a potent oral inhibitor of PARP-1 and -2. Malignancies with defects in homologous repair are more dependent on PARP for DNA repair than normal cells. Objectives of this study are to determine safety and PK of ABT-767 in pts with high grade serous ovarian cancer (OvC), fallopian tube, or primary peritoneal cancer or with BRCA1...
Purpose:
RGB-286638 is a multitargeted inhibitor with targets comprising the family of cyclin-dependent kinases (CDK) and a range of other cancer-relevant tyrosine and serine/threonine kinases. The objectives of this first in human trial of RGB-286638, given i.v. on days 1 to 5 every 28 days, were to determine the maximum tolerated dose (MTD) and...
Background:
Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels.
Methods:
Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-...
Purpose:
The pan-Class I PI3K inhibitor buparlisib (BKM120) has shown activity in a range of preclinical cancer models. This first-in-man study was initiated to identify the maximum tolerated dose (MTD) of buparlisib (100 mg/day) and to assess safety and preliminary efficacy.
Methods:
Patients with advanced solid tumors (N = 83) enrolled in a Ph...
To assess safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of E7107 administered as 5-minute bolus infusions on days 1, 8, and 15 in a 28-day schedule.
Patients with solid tumors refractory to standard therapies or with no standard treatment available were enrolled. Dose levels of 0.6-4.5 mg/m2 were explored.
Forty pa...
e19138
Background: D is an ATP competitive pan-aurora kinases inhibitor with activity also against FGFRs, VEGFR, Ret, TrkA, Scr, and Abl. Methods: Eligible pts had NSCLC progressing for advanced/metastatic disease after 1 prior chemotherapy line (CT). Primary endpoint was progression-free survival at 4 months (PFS-4) evaluated in a Simon two-stage...
2522
Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered...
2579
Background: This three-center phase I study evaluated the PARP1/2 inhibitor olaparib (O) in combination with carboplatin (C), paclitaxel (Pa) or both (CPa) in patients (pts) with advanced solid tumors refractory to standard therapies (NCT00516724). Methods: This ongoing study consists of multiple parts (P) in which escalating doses of O capsul...
Introduction:
For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials.
Materials and methods:
Over a period of 25 months, all pat...
Vascular endothelial growth factor (VEGF) signalling plays a key role in tumour angiogenesis. Cediranib (AZD2171) is a small-molecule VEGF signalling inhibitor with potent activity against all three VEGF receptors. In this phase I, open-label, parallel-group study, adults with advanced solid tumours received a single 45 mg dose of cediranib, follow...