ABSK121-NX for Solid Tumors

Not currently recruiting at 24 trial locations

Overseen By Yuan Lu

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Abbisko Therapeutics Co, Ltd

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Active CNS metastases, Cardiac disease, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called ABSK121-NX for individuals with advanced solid tumors, such as certain types of bladder or liver cancer. The goal is to determine a safe dose and evaluate the treatment's effectiveness against these cancers. The trial begins with participants receiving varying doses to ensure safety, followed by further testing at the optimal dose level. Individuals with advanced solid tumors that have specific FGFR genetic changes and who have not responded to standard treatments might be suitable candidates for this trial. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take potent inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of the study treatment (3 weeks for St John's Wort). Also, previous anti-cancer therapies must be stopped at least 2 to 6 weeks before starting the study treatment, depending on the type of therapy.

Is there any evidence suggesting that ABSK121-NX is likely to be safe for humans?

Research has not yet provided detailed safety information for ABSK121-NX. However, the trial is in its early stages, focusing on safety and tolerability. In these initial studies, researchers aim to find the safest dose by observing patient reactions to the treatment, identifying any side effects or issues it might cause.

Since ABSK121-NX is being tested in humans for the first time, researchers start with low doses. They carefully monitor patients as they gradually increase the dose to assess tolerance. This cautious approach helps ensure the treatment's safety for future studies.

Joining a trial involves some risks because the treatment is not fully tested in humans yet. However, this phase is dedicated to ensuring safety and determining the best dose to use. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about ABSK121-NX because it represents a novel approach to treating solid tumors. Unlike existing treatments that often rely on chemotherapy or targeted therapies, ABSK121-NX is administered orally and follows a dose escalation strategy guided by the Bayesian optimal interval design, aiming to identify the safest and most effective dose. The treatment's unique mechanism involves a preliminary washout period to assess safety and pharmacokinetics, potentially offering a more tailored and tolerable option for patients. This innovative approach could lead to better outcomes with fewer side effects, making it a promising candidate in the fight against solid tumors.

What evidence suggests that ABSK121-NX might be an effective treatment for solid tumors?

Research is investigating ABSK121-NX to determine its potential in treating advanced solid tumors. Currently, specific information on its effectiveness is unavailable. In this trial, participants receive ABSK121-NX alone in repeated cycles. The primary goal is to assess the drug's safety and tolerability. Researchers aim to find the optimal dose through dose escalation, which helps identify early signs of tumor-fighting potential. Although still in the early stages of testing, the exact effects on solid tumors remain unknown. ^{1 2 6 7 8}

Who Is on the Research Team?

Yuan Lu

Principal Investigator

Wuxi Abbisko Biomedical Technology Co., Ltd.

Are You a Good Fit for This Trial?

This trial is for adults with advanced solid tumors that have specific genetic changes in FGFR genes. Participants must be over 18, have a life expectancy of at least 3 months, measurable cancer according to certain criteria, and good organ and bone marrow function. They can't join if they've had recent cancer treatments or surgeries, are unable to swallow pills, or have other active cancers.

Inclusion Criteria

Patients should understand, sign, and date the written informed consent form prior to screening

Life expectancy ≥3 months

For the expansion Part:

Exclusion Criteria

I am scheduled for a major surgery during the study.

My phosphate levels have been high despite treatment.

Expansion part:

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Dose escalation of oral ABSK121-NX guided by the Bayesian optimal interval (BOIN) design to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD).

28-day cycles

Multiple visits for dose escalation and monitoring

RDE Confirmation

RDE-confirmation group of up to 24 patients to further evaluate safety and efficacy at the recommended dose for expansion.

28-day cycles

Regular visits for safety and efficacy evaluation

Dose Expansion

Expansion phase to evaluate safety and tolerability among selected tumor types at the recommended dose for expansion.

28-day cycles

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• ABSK121-NX

Trial Overview

ABSK121-NX is being tested in this study. It starts with dose escalation to find the safest dose that patients tolerate well and then expands to more patients at this dose. The drug is taken orally in repeated cycles every 28 days to check its safety and how it affects different types of tumors.

How Is the Trial Designed?

Group I: ABSK121-NX Experimental Treatment 1 Intervention

Dose escalation of oral ABSK121-NX will be guided by the Bayesian optimal interval (BOIN) design based on safety data collected until a maximum tolerated dose (MTD) or maximum administered dose (MAD) has been identified. Patients will receive a single dose of ABSK121-NX on Day -7 followed by a 7-day washout, as a run-in period to access the safety and PK of ABSK121-NX. Then, patients will continuously receive ABSK121-NX once daily (QD). The dose escalation will start at 3 mg QD followed by dose escalation of a total of 8 potential dose levels. Once RDE is determined, an RDE-confirmation group of up to 24 more patients may be enrolled at the selected dose levels to further evaluate safety and efficacy (up to 12 per dose level/regimen), if approved by the sponsor. In addition, a preliminary food-effect (FE) may be evaluated in at least 6 patients from the RDE- confirmation part. After the RDE is confirmed in the dose Escalation part, the dose Expansion phase will be conducted.

Who Is Running the Clinical Trial?

Abbisko Therapeutics Co, Ltd

Lead Sponsor

Trials

26

Recruited

1,700+

Published Research Related to This Trial

ALK tyrosine kinase inhibitors (TKIs) are associated with significantly higher cardiovascular toxicities compared to chemotherapy, with a risk ratio of 5.03, indicating a serious safety concern for patients with advanced ALK-positive non-small cell lung cancer (NSCLC).

Among the ALK-TKIs, crizotinib specifically poses increased risks for cardiac disorders and venous thromboembolic events (VTEs), with risk ratios of 1.75 and 3.97, respectively, highlighting the need for careful monitoring in patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risks of cardiovascular toxicities associated with ALK tyrosine kinase inhibitors in patients with non-small-cell lung cancer: a meta-analysis of randomized control trials. Zhao, J., Ma, Z., Li, H., et al.[2023]

A study analyzing 4708 cardiac adverse event reports from the FDA's database found that hypertension is the most common cardiac issue associated with tyrosine kinase inhibitors (TKIs), particularly with lenvatinib, which also showed a high risk for cardiac failure and acute coronary syndrome.

Lenvatinib and sorafenib were linked to serious cardiac events, including acute myocardial infarction and aortic dissections, indicating that patients on these medications require careful monitoring and management of cardiac health, especially within the first 30 days of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiovascular toxicities following the use of tyrosine kinase inhibitors in hepatocellular cancer patients: a retrospective, pharmacovigilance study. Lai, X., Wan, Q., Jiao, SF., et al.[2023]

The selective pan-NTRK inhibitor AZD7451 significantly inhibited the growth of colorectal cancer cells with an NTRK1 fusion (KM12) at a low concentration of 2 nM, demonstrating its potential as an effective treatment for tumors with NTRK fusions.

In contrast, AZD7451 had no inhibitory effect on the H810 cell line, which expressed low levels of NTRK1-3, suggesting that the efficacy of NTRK inhibitors may depend on the presence of specific NTRK fusions or expressions in lung cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of neurotrophic tyrosine kinase receptor 1 fusions and neurotrophic tyrosine kinase receptor family expression in non-small-cell lung cancer and sensitivity to AZD7451 in vitro. Tatematsu, T., Sasaki, H., Shimizu, S., et al.[2021]

The antibody-drug conjugate AXL-107-MMAE effectively targets AXL-high cancer cells, showing strong anti-tumor activity in various cancers, including melanoma and lung cancer, in patient-derived xenograft models.

Combining AXL-107-MMAE with MAPK pathway inhibitors enhances tumor growth inhibition by targeting different cell populations within heterogeneous tumors, suggesting a promising strategy for treating both treatment-naive and drug-resistant cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cooperative targeting of melanoma heterogeneity with an AXL antibody-drug conjugate and BRAF/MEK inhibitors. Boshuizen, J., Koopman, LA., Krijgsman, O., et al.[2022]

In a study of 332 ductal breast cancer patients, the phosphorylation of the androgen receptor at ser515 (AR-515) combined with pERK1/2 was linked to improved cancer-specific survival and better tumor characteristics in estrogen receptor-positive (ER+) tumors.

Conversely, in triple negative breast cancer (TNBC) patients, AR-515 phosphorylation was associated with poorer cancer-specific survival, suggesting it may play a role in inflammation regulation and could serve as a prognostic marker and therapeutic target for TNBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phosphorylation of androgen receptors at serine 515 is a potential prognostic marker for triple negative breast cancer. Roseweir, AK., McCall, P., Scott, A., et al.[2018]

Axl receptor tyrosine kinases are found to be upregulated in drug-resistant cancer cells, indicating their role in cancer progression and treatment resistance.

Reducing Axl expression in drug-resistant cancer cells improved their sensitivity to chemotherapy and enhanced the effectiveness of cancer treatments in animal models, suggesting Axl could be a key target for overcoming multidrug resistance in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential expression of Axl and correlation with invasion and multidrug resistance in cancer cells. Zhao, Y., Sun, X., Jiang, L., et al.[2022]

Ulixertinib, an ERK1/2 kinase inhibitor, was tested in a phase I trial with 135 patients, establishing a recommended phase II dose of 600 mg twice daily, which effectively inhibited ERK activity in blood samples.

The treatment showed an acceptable safety profile, with common side effects including diarrhea (48%) and fatigue (42%), and demonstrated early signs of clinical activity, with partial responses in 14-17% of patients with specific genetic mutations in their tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-in-Class ERK1/2 Inhibitor Ulixertinib (BVD-523) in Patients with MAPK Mutant Advanced Solid Tumors: Results of a Phase I Dose-Escalation and Expansion Study. Sullivan, RJ., Infante, JR., Janku, F., et al.[2021]

XK469 is a novel antitumor agent that effectively induces cell cycle arrest in human U-937 leukemia cells at the G(2)/M phase, demonstrating its potential as a treatment for drug-resistant tumors.

The mechanism of action for XK469 involves the inhibition of the MEK/MAPK signaling pathways, leading to antiproliferative effects without significant cytotoxicity compared to conventional anticancer agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

XK469, a novel antitumor agent, inhibits signaling by the MEK/MAPK signaling pathway. Lin, H., Subramanian, B., Nakeff, A., et al.[2021]

NTRK1 gene rearrangements lead to aggressive cancer types, and while there are no approved inhibitors yet, several tyrosine kinase inhibitors (TKIs) like entrectinib and LOXO-101 are being tested in clinical trials.

The study identified novel mutations that confer resistance to NTRK inhibitors and found that cabozantinib, especially when combined with IGF1R inhibitors, could effectively overcome this resistance, suggesting new therapeutic strategies for treating NTRK-rearranged cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mechanisms of Resistance to NTRK Inhibitors and Therapeutic Strategies in NTRK1-Rearranged Cancers. Fuse, MJ., Okada, K., Oh-Hara, T., et al.[2020]

A meta-analysis of 19 studies found that serious adverse events (SAEs) related to ALK inhibitors occurred in over 20% of patients, with ceritinib and brigatinib showing SAEs in more than 40% of participants, highlighting significant safety concerns.

Among the ALK inhibitors analyzed, alectinib was identified as the safest option, suggesting it may be preferable for patients due to its lower incidence of SAEs, particularly lung toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The safety and serious adverse events of approved ALK inhibitors in malignancies: a meta-analysis. Hou, H., Sun, D., Liu, K., et al.[2020]

A meta-analysis of 13 randomized controlled trials involving 5164 patients found that vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are associated with a significant increase in the risk of fatal adverse events (FAEs), with a relative risk of 1.64 compared to controls.

The increased risk of FAEs was particularly significant in studies focused on renal cell carcinoma and those using placebo as a control, highlighting the need for careful monitoring of patients receiving VEGFR TKIs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment-related mortality with vascular endothelial growth factor receptor tyrosine kinase inhibitor therapy in patients with advanced solid tumors: a meta-analysis. Sivendran, S., Liu, Z., Portas, LJ., et al.[2022]

Neurotrophic tyrosine kinase (NTRK) gene fusions, although found in less than 5% of lung tumors, are significant oncogenic drivers associated with poor survival, highlighting their potential as therapeutic targets in lung cancer.

Clinical trials of NTRK inhibitors like entrectinib and LOXO-101 have shown promising responses in lung cancer patients with an acceptable safety profile, suggesting these treatments could be effective options for targeting specific lung cancer subtypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New targets bring hope in squamous cell lung cancer: neurotrophic tyrosine kinase gene fusions. Rolfo, C., Raez, L.[2023]

A novel myxofibrosarcoma (MFS) cell line, NCC-MFS6-C1, was successfully established, showing genetic abnormalities typical of MFS and aggressive growth characteristics, which can aid in future research.

Drug screening with NCC-MFS6-C1 identified gemcitabine and romidepsin as effective anticancer agents against MFS, confirming their potential for treating this rare malignancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment and characterization of NCC-MFS6-C1: a novel patient-derived cell line of myxofibrosarcoma. Yoshimatsu, Y., Noguchi, R., Sin, Y., et al.[2022]

AXL, a receptor tyrosine kinase, is expressed in Ewing sarcoma (ES) tumors, with high levels correlating to poorer overall survival, indicating its potential as a prognostic marker.

The AXL-inhibitor BGB324 effectively reduced cell viability and migration in Ewing sarcoma cell lines and enhanced the effectiveness of chemotherapy drugs, suggesting AXL as a promising therapeutic target for treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma. Fleuren, ED., Hillebrandt-Roeffen, MH., Flucke, UE., et al.[2022]

ADCT-601 is an AXL-targeted antibody-drug conjugate that effectively binds to AXL-expressing tumor cells, leading to potent antitumor activity through DNA damage and cell killing mechanisms, as demonstrated in various human cancer xenograft mouse models.

The treatment was well tolerated at doses up to 6 mg/kg and showed superior efficacy compared to other ADCs, including effectiveness in drug-resistant cancer models, suggesting its potential as a promising therapeutic option for AXL-expressing malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical Development of ADCT-601, a Novel Pyrrolobenzodiazepine Dimer-based Antibody-drug Conjugate Targeting AXL-expressing Cancers. Zammarchi, F., Havenith, KE., Chivers, S., et al.[2023]

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