MTAP-Homozygous Deletion Solid Tumors: BMS-986504 Phase II Trial Opens Recruitment

Shanghai GOBROAD Cancer Hospital, affiliated with China Pharmaceutical University, is currently conducting a Phase II, open-label, multicentre study evaluating BMS-986504 as monotherapy and in combination with other agents in participants with advanced and/or metastatic solid tumors that carry a homozygous MTAP deletion (study code MountainTap-5). The trial has been approved by the National Medical Products Administration and by the Ethics Committee of the hospital, and is now recruiting eligible participants on a voluntary basis.

The design reflects a change in how trials are written for molecularly defined populations: eligibility is decided less by where a tumor started than by what has been deleted inside it. A patient whose sequencing report shows homozygous loss of MTAP can therefore be considered for this study whatever the primary site, provided the disease is advanced or metastatic and has already been treated.

Why MTAP Loss Creates a Target

MTAP sits immediately beside CDKN2A on the short arm of chromosome 9, and the two genes are frequently lost together. CDKN2A loss removes a brake on the cell cycle and is one of the commonest events in cancer; because the two loci are so close, homozygous deletion of MTAP accompanies a large share of CDKN2A deletions. Complete loss of MTAP is reported across a wide range of solid tumors, with the highest frequencies described in mesothelioma, pancreatic cancer, urothelial carcinoma and non-small cell lung cancer.

Losing MTAP leaves a cell unable to recycle a metabolite called methylthioadenosine, or MTA, which then accumulates. Accumulated MTA partially inhibits PRMT5, an arginine methyltransferase that tumor cells need in order to splice RNA and to proliferate. Rather than dying, the MTAP-deleted cell adapts and comes to depend on the PRMT5 activity that remains, which is why the deletion converts a metabolic accident into a selective vulnerability: an inhibitor that binds PRMT5 more effectively when MTA is present — an MTA-cooperative inhibitor — acts far more strongly on MTAP-deleted cells than on cells in which the pathway is intact. This is the principle known as synthetic lethality, and it is the rationale behind the study.

The hospital's recruitment notice describes BMS-986504 as a selective MTA-cooperative PRMT5 inhibitor that blocks PRMT5 in MTAP-deleted tumor cells while leaving normal cells, in which MTAP is intact, comparatively spared. The Phase II design tests both single-agent activity and combinations with other agents, so that the contribution of the drug itself can be separated from the contribution of the partner regimen.

The Study at a Glance

• Phase II, open-label, multicentre design
• BMS-986504 given as monotherapy and in combination with other agents
• Adults aged 18 years or older, of any sex
• Advanced and/or metastatic solid tumors with homozygous MTAP deletion or MTAP loss, previously treated, in the second- or third-line setting
• Oral tablets, swallowed whole and not chewed or crushed
• Approved by the National Medical Products Administration and the hospital ethics committee

Key Inclusion Criteria

1. Age 18 years or older, of any sex.
2. An advanced or metastatic solid tumor with homozygous MTAP deletion or MTAP loss, previously treated and in the second- or third-line setting. Metastatic means that the cancer has already spread to other parts of the body. Participants must have recovered from the side effects of previous treatment by the time they enroll, and radiotherapy must have stopped at least two weeks before the first dose of study treatment.
3. Able to swallow tablets whole, without chewing or crushing them.

Key Exclusion Criteria

1. Active brain metastases or carcinomatous meningitis. Participants whose brain metastases have been adequately treated may still be eligible if they have been neurologically stable for at least two weeks before enrollment and are either not taking corticosteroids or are on a stable or tapering dose of no more than 10 mg per day of prednisone, or an equivalent. For glioblastoma multiforme the threshold is no more than 20 mg per day of prednisone or no more than 3 mg per day of dexamethasone, or an equivalent.
2. A history, within the six months before enrollment, of a gastrointestinal disorder that could change absorption of the study drug or make oral medication impossible, including uncontrolled nausea, vomiting, malabsorption syndrome, a non-gastrointestinal fistula, gastrointestinal perforation or an intra-abdominal abscess.
3. Cardiac abnormalities, including a left ventricular ejection fraction below 50 percent; a history of QT prolongation, or of a heart-rate-corrected QT interval above 480 ms by the Fridericia formula, other than in right bundle branch block; or uncontrolled, symptomatic or clinically significant cardiovascular disease within the six months before enrollment.
4. Previous treatment with a PRMT5 inhibitor or with an inhibitor of methionine adenosyltransferase 2A, also known as MAT2A.

What Eligibility Actually Depends On

The criteria above are a summary, and the hospital says so explicitly alongside them. Whether a particular patient can take part is settled by a complete set of examinations and by the assessment of the study investigator. In practice the decisive document is the molecular report: a sequencing or copy-number result that documents homozygous deletion of MTAP, because it is the deletion rather than the tumor type that defines the population the study was written for.

Two further points follow from the protocol. The disease has to be advanced or metastatic and already treated with standard therapy, so this is not a first-line option. And the treatment is oral, taken as whole tablets, which rules out patients who cannot swallow them or whose digestive tract cannot be relied on to absorb them.

How to Express Interest

Patients and families outside China can approach this study through the MedTourChina central line given below. The referral team reviews the pathology report, the molecular profiling report and the treatment history with the hospital's clinical research office, and then advises whether a screening visit is worth arranging. Enquiries are handled in English, and the trial brief can be sent before any commitment to travel is made.

Please have the sequencing report to hand. A report that states homozygous MTAP deletion, or loss of MTAP on copy-number analysis, is the single most useful document at this stage; without it the study team cannot confirm that a patient sits inside the population being studied.

About the Principal Investigator

Dr. Zhou Jun is Medical Vice President and Director of the Department of Digestive Oncology at Shanghai GOBROAD Cancer Hospital, and a former chief physician at Oriental Hospital, affiliated with Tongji University. He is a chief physician and a master's supervisor. His clinical work covers tumors of the digestive system, with a focus on gastric cancer, colorectal cancer and hepatobiliary and pancreatic malignancies, and on cell therapy, molecular targeted therapy, immunotherapy and early-phase clinical research of new anticancer drugs.

He holds a number of national roles, among them council member of the Chinese Society of Clinical Oncology (CSCO), standing committee member of the CSCO Gastric Cancer Expert Committee, and member of the CSCO expert committees on colorectal cancer, biliary tract tumors, interventional radiology and smart healthcare. He is a standing committee member of the antitumor drug clinical research committee of the China Pharmaceutical Innovation and Research Development Association, a member of the editorial board of the Chinese Journal of Clinical Oncology, and was named a People's Renowned Doctor in the fifth national selection. His outpatient sessions are on Tuesday mornings and Sunday afternoons.

About the Hospital

Shanghai GOBROAD Cancer Hospital is located at 170 Taibei East Road in the Pudong New Area of Shanghai. It is a tertiary medical insurance designated institution with a total floor area of around 70,000 square metres. Four hundred beds are open in the first phase, a second phase is under construction and is expected to come into use in 2027, and the two phases together will provide around 700 beds.

The hospital concentrates on solid tumors, brings in established expert teams from China and abroad, and is built around clinical research and public-benefit services rather than around routine care alone. Studies such as MountainTap-5 are the reason that orientation matters to patients: for a molecularly defined group with no approved matched therapy, an open trial can be the only route to a drug that is not yet commercially available.

References

1. Kryukov GV, Wilson FH, Ruth JR, et al. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science. 2016;351(6278):1214-1218.
2. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, et al. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science. 2016;351(6278):1218-1223.
3. Marjon K, Cameron MJ, Quang P, et al. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Reports. 2016;15(3):574-587.