IAG933 for Mesothelioma

Not currently recruiting at 28 trial locations

Overseen By Novartis Pharmaceuticals

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Novartis Pharmaceuticals

Must not be taking: TEAD inhibitors

Disqualifiers: Other malignancies, Cardiac disease, 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 IAG933, a potential drug, to determine its safety and how patients with certain types of cancer respond. It targets individuals with mesothelioma, tumors with mutations in the NF2/LATS1/LATS2 genes, or tumors with YAP/TAZ fusions. Suitable participants have advanced cancer that cannot be surgically removed or has spread, and they have exhausted all standard treatments without success. The trial aims to identify the optimal dose that is both safe and effective. As a Phase 1 trial, participants will be among the first to receive this treatment, aiding researchers in understanding its effects in people.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, there are specific timeframes for stopping certain cancer treatments before starting the trial, such as a 4-week period for some therapies. It's best to discuss your current medications with the trial team.

Is there any evidence suggesting that IAG933 is likely to be safe for humans?

Research has shown that IAG933 is safe and well-tolerated in early studies. These studies reported good disease control with manageable side effects, indicating the drug is generally well-received by patients, which is a positive sign for its safety.

Although detailed information on specific side effects is not yet available, these early studies primarily focus on safety and tolerability. The treatment has not caused any severe issues that would halt the trials.

IAG933 is currently in the first phase of testing for mesothelioma and similar conditions, so researchers are still gathering information about its safety in humans. However, the evidence so far suggests it has a manageable safety profile. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for mesothelioma?

Most treatments for mesothelioma, like chemotherapy and surgery, aim to remove or shrink tumors but can have significant side effects and limited effectiveness. IAG933 offers a fresh approach by targeting specific genetic alterations associated with mesothelioma, such as NF2 truncating mutations and YAP/TAZ fusions, which are not directly addressed by current therapies. This targeted action could mean more precise treatment with potentially fewer side effects. Researchers are excited because IAG933 may open new avenues for treating not just mesothelioma but also other cancers with similar genetic profiles.

What evidence suggests that IAG933 might be an effective treatment for mesothelioma?

Research has shown that IAG933 may help treat mesothelioma and other types of tumors. In this trial, participants will be divided into groups based on their specific conditions. For instance, one group will include mesothelioma patients; previous studies showed that 4 out of 30 patients experienced tumor shrinkage after using IAG933. Another group will focus on tumors with NF2 mutations, as IAG933 targets a specific process called YAP–TEAD, which aids tumor growth. In lab tests, IAG933 almost completely stopped the activity of genes that promote tumor growth. These findings suggest that IAG933 could be a promising option for managing these types of cancers. ^{1 2 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced mesothelioma or solid tumors that have specific genetic mutations (NF2, LATS1/LATS2) or YAP/TAZ fusions. Participants must have tried all standard treatments without success, be unable to tolerate them, or no standard treatment exists. They should also be able to undergo a tumor biopsy and not have other serious health issues like poor bone marrow, kidney, liver function, significant heart disease risks, active COVID-19 infection or a history of certain lung diseases.

Inclusion Criteria

I have advanced mesothelioma and standard treatments haven't worked or aren't suitable for me.

I have an advanced solid tumor with an NF2 mutation and can't use standard treatments.

I have an advanced cancer that cannot be surgically removed.

Exclusion Criteria

My bone marrow is not working well.

I have had a serious lung condition from medication or other causes.

My kidneys are not working well.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Characterize the safety and tolerability of IAG933 and determine the maximum tolerated dose or recommended dose

1 year

Dose Expansion

Assess the preliminary anti-tumor activity and further assess the safety and tolerability at the recommended dose/maximum tolerated dose

2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

What Are the Treatments Tested in This Trial?

Interventions

• IAG933

Trial Overview The study tests IAG933's safety and tolerability in patients with advanced mesothelioma and other solid tumors. It aims to find the highest dose patients can take without severe side effects (maximum tolerated dose) and suggest an optimal dose for further studies.

How Is the Trial Designed?

Group I: Group 4 Experimental Treatment 1 Intervention

Non-pleural mesothelioma

Group II: Group 3 Experimental Treatment 1 Intervention

Solid tumors with functional YAP/TAZ fusions

Group III: Group 2 Experimental Treatment 1 Intervention

NF2 truncating mutations or deletions

Group IV: Group 1 Experimental Treatment 1 Intervention

Malignant pleural mesothelioma

Who Is Running the Clinical Trial?

Novartis Pharmaceuticals

Lead Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

Malignant mesothelioma, while not typically immunogenic, shows immune recognition, and patients exhibit impaired immune responses, making it a valuable model for studying immune-related biomarkers.

Various innovative treatments, including gene therapies and targeted inhibitors like ZD1839 and STI-571, are being tested in clinical trials, suggesting that a combination of therapies may be necessary for effective treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. Nowak, AK., Lake, RA., Kindler, HL., et al.[2019]

In a pilot study involving 19 patients with early-stage malignant pleural mesothelioma, the combination of intrapleural autologous activated macrophages (AM Phi) and gamma-interferon was well tolerated, with no major adverse effects reported during treatment.

The overall response rate to this therapy was limited, with only 14% of treated patients showing a response, although one patient remained disease-free for 69 months, indicating some potential for long-term benefit despite the low overall efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intrapleural infusion of activated macrophages and gamma-interferon in malignant pleural mesothelioma: a phase II study. Monnet, I., Breau, JL., Moro, D., et al.[2019]

HEG1 is a highly effective marker for identifying malignant mesothelioma (MM) in effusion cytology, showing positive results in all tested cases of MM, while being negative in most carcinomas.

The study found that loss of BAP1 and MTAP, along with homozygous deletion of CDKN2A, are common in MM, suggesting that these markers can help differentiate malignant from reactive mesothelial cells, enhancing diagnostic accuracy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

HEG1, BAP1, and MTAP are useful in cytologic diagnosis of malignant mesothelioma with effusion. Hiroshima, K., Wu, D., Hamakawa, S., et al.[2021]

Malignant mesothelioma is a challenging cancer primarily caused by environmental factors like asbestos, and most patients are not suitable for surgery or radiation, leaving cytotoxic agents as the main treatment option.

Recent trials have shown that pemetrexed, when combined with cisplatin, can achieve a response rate of 14.1% and a 1-year survival rate of 47.8%, indicating potential efficacy in treating this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging insights into the biology and therapy of malignant mesothelioma. Vogelzang, NJ.[2022]

Malignant pleural mesothelioma (MPM) is a rare but increasing cancer linked to asbestos exposure, with a significantly higher incidence in occupationally exposed populations (100 cases/million/year) compared to the general population (1 case/million/year).

First-line treatment for MPM involves a combination of pemetrexed and cisplatin, which has been shown to improve overall survival and quality of life in phase 3 trials, while ongoing studies are exploring the potential of antiangiogenic agents like bevacizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Epidemiology, molecular biology, diagnostic and therapeutic strategy of malignant pleural mesothelioma in 2007 - an update]. Porret, E., Madelaine, J., Galateau-Sallé, F., et al.[2008]

Citations

1. novartis.com novartis.com/clinicaltrials/study/nct04857372

A Phase I Study of IAG933 in Patients With Advanced ... The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04857372?term=AREA%5BConditionSearch%5D(Neurofibromatosis%20type%202%20OR%20%22bilateral%20acoustic%20neurofibromatosis%22%20OR%20%22%20central%20neurofibromatosis%22%20OR%20%22%20full%20neurofibromatosis%20type%202%22%20OR%20%22%20full%20NF2%22%20OR%20%22%20neurofibromatosis%202%22%20OR%20%22%20NF2%22%20OR%20%22%20NF2-related%20schwannomatosis%22%20OR%20%22%20nonmosaic%20neurofibromatosis%20type%202%22%20OR%20%22%20nonmosaic%20NF2-related%20schwannomatosis%22)%20AND%20AREA%5BOverallStatus%5D(NOT_YET_RECRUITING%20OR%20RECRUITING)&rank=10

A Phase I Study of IAG933 in Patients With Advanced ... The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11286534/

Direct and selective pharmacological disruption of the YAP ... Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers.

4. clinconnect.io clinconnect.io/trials/NCT04857372

A Phase I Study of IAG933 in Patients With Advanced The purpose of this study is to characterize the safety and tolerability of IAG933 in patients with mesothelioma, NF2/LATS1/LATS2 mutated tumors and tumors ...

5. researchgate.net researchgate.net/publication/370031436_Abstract_LB319_IAG933_a_selective_and_orally_efficacious_YAP1WWTR1TAZ-panTEAD_protein-protein_interaction_inhibitor_with_pre-clinical_activity_in_monotherapy_and_combinations

Abstract LB319: IAG933, a selective and orally efficacious ... Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter ...

6. nature.com nature.com/articles/s43018-024-00754-9

Direct and selective pharmacological disruption of the YAP ... We present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to ...

7. humanforschung-schweiz.ch humanforschung-schweiz.ch/en/trial-search/study-detail/58971/translate/en/?cHash=d0ebb5839e24193903c4ebedd259594d

An open-label, multicenter Phase I study of oral IAG933 in ... The purpose of this study is to find out whether IAG933 is safe and tolerable in adult study participants with advanced mesothelioma or other solid tumors. This ...

8. onderzoekmetmensen.nl onderzoekmetmensen.nl/en/node/54125/pdf

An open-label, multi-center, Phase I study of oral IAG933 in ... The purpose of this first-in-human (FIH) study is to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and ...