M22TGA: A NOVEL IN-HOUSE PHASE I CLINICAL TRIAL FOR PATIENTS WITH ADVANCED CRC AND PERITONEAL METASTASES

Medical innovations often emerge from constant dedication and original approaches. The M22TGA study, currently being conducted at the Antoni van Leeuwenhoek Hospital and the Netherlands Cancer Institute (NKI), is a great example of this spirit.

Leading this study is Ashwini Kanhailal, a distinguished young medical doctor with specialised interests in oncology and research. After an enriching experience at the OLVG hospital, Ashwini is contributing significant expertise to the M22TGA research.

"As I was interested in oncology and research I got the opportunity last year to start my PhD program at the NKI. I’m mainly focused on combination therapy in phase I clinical trials.”

Ashwini’s journey started with merging academic curiosity and practical application, which enabled her to steer the M22TGA trial with precision and innovation.

Unique In-House Development

What sets the M22TGA study apart from other trials is its origin. Unlike many clinical trials that start from large pharmaceutical companies, the M22TGA is entirely an in-house brainchild of NKI. From pre-clinical findings to study design to drug production, thanks also to the collaboration with Amsterdam UMC, NKI shows that even smaller Phase I units can be at the forefront of oncological research.

Study Rationale

Colorectal carcinomas remain one of the most diagnosed cancers globally. Despite numerous treatment avenues, its mortality rate remains distressingly high. Particularly, advanced CRC patients at stage IV have a worse prognosis than patients at an earlier stage, and the prognosis is further compounded if the tumor is of the mesenchymal subtype class 4 (CMS4). This subtype is also notorious for being chemo-resistant, primarily due to the presence of  peritoneal metastases.

But new insights emerged from preclinical research, bringing a light for hope. In several laboratories, including those of professor Rene Bernards at the Netherlands Cancer Institute and professor Jan Paul Medema at the Amsterdam University Medical Centre, it was shown that CMS4 subtype increases the activity of the TGF-ß signaling pathway, causing resistance to, among others, 5-fluorouracil (5-FU)  based chemotherapies, like capecitabine. They found out that inhibiting this signalling pathway with a TGF-ß inhibitor could restore the tumor's sensitivity to 5-FU. The pharmacy at the Antoni van Leeuwenhoek Hospital takes center stage here by producing galunisertib, a selective inhibitor of the TGF-ß receptor I kinase, which is now combined with capecitabine in this study.

Study Design

Encompassing both Phase I and II, the M22TGA study is meticulously designed. While the first phase delves into the combination therapy's safety and tolerability, the latter phase rigorously evaluates its anti-tumor prowess. In both phases, the recommended dosage of galunisertib is combined with the standard dosage of capecitabine.
Operating on a 'proof of principle' basis, this non-randomized, open-label study is currently active at the Antoni van Leeuwenhoek Hospital and will soon be available at the Amsterdam UMC.

Study population and patient referral

Adult patients in good clinical condition (WHO 0-1) with CRCs with peritoneal metastases are eligible for this study if there are no treatment lines available. Patients with a DPD deficiency, leptomeningeal, or symptomatic cerebral metastases are excluded from participation. Furthermore, phase I study treatments are intensive in nature; in this study, we will monitor patients weekly during the first cycle and then monthly. Weekly to monthly blood checks will take place, and during the first cycle, there will be two series of blood samples for pharmacokinetics. Biopsies will also be taken during the study, two of which are mandatory (screening and during treatment) and one optional (at progression).

The total number of patients that can be recruited for phase I are 6, while the other 25 are allowed on phase II. As Ashwini explained to us, there are currently just 3 spots taken out of 31.
It is now indeed a great opportunity for you to refer your patients that qualify for participation in this study.

To do so, contact the phase I department of the Antoni van Leeuwenhoek Hospital, by emailing us at fase1@nki.nl. Please, refer to the phase I email address for any questions regarding the study and/or study procedures.

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