Cancer Research UK said it has launched a Phase I trial of an Eli Lilly cancer candidate, a cell division cycle 7 kinase (Cdc7) inhibitor designed to fight numerous solid-tumor cancers with mutations of the p53 gene.

LY3143921 hydrate is being studied for safety and tolerability, as well as for optimal dosage, in the trial, being carried out by Cancer Research UK’s Centre for Drug Development. Through its Clinical Development Partnership program, Cancer Research UK is partnering with Lilly to advance the drug in early-stage clinical studies.

In earlier mouse studies, LY3143921 hydrate showed promise by selectively inhibiting Cdc7, a protein that assists cells in reproduction. The Phase I trial will assess the Cdc7 inhibitor in patients with metastatic bowel cancer, squamous non-small-cell lung cancer, and high-grade serous ovarian cancer, as well as in patients with squamous carcinoma of the esophagus, squamous carcinoma of the head and neck (human papilloma virus negative), urothelial cancer, triple-negative breast cancer, and pancreatic cancer.

Lilly and Cancer Research UK reason that since cancer cells are more dependent on Cdc7 than normal cells, they would likely be more sensitive to growth inhibition by the Cdc7 inhibitor. The partners also believe that cancers with specific p53 mutations may be particularly sensitive to inhibition of Cdc7.

Several companies are pursuing development of Cdc7 inhibitors against cancer. In February, PMV Pharmaceuticals of Cranbury, NJ, completed a $74 million Series B financing, with proceeds intended for developing and advancing into clinical phases the company's pipeline of mutant p53 restoration drug candidates.

And just last week, on August 15, Sierra Oncology said it will advance SRA141, an oral small-molecule Cdc7 inhibitor now in preclinical development.

Oncology Pipeline Overhaul

LY3143921 is part of a Lilly oncology pipeline that the pharma giant said last month it would overhaul. The company said it will prioritize development of its lead cancer candidate, the CDK 4/6 inhibitor abemaciclib now awaiting FDA review, and six other Phase I and II candidates, including prexasertib.It will also pursue internal development of two Phase I and one Phase II candidates, all awaiting data from ongoing trials, as well as partnering or selling development rights to 10 other candidates in Phase I or II.

Lilly also outlined a four-pronged approach to cancer pipeline development:

  • Promote new oncology products such as Cyramza® (ramucirumab), Lartruvo (olaratumab), and abemaciclib;
  • Pursue new standard-of-care changing therapies that target tumor dependencies in molecularly enriched populations;
  • Build “rational” combination therapies that overcome resistance;
  • Develop next-generation immunotherapies.

Lilly’s LY3143921 hydrate will be delivered orally once a day for a 21-day cycle, with the cycle being repeated up to 12 times. Patients will receive increasing doses of the drug in the first part of the trial, then receive the highest tolerated dose in the second part, Cancer Research UK said. The trial will take place at four UK centers: Belfast (The Northern Ireland Cancer Centre), Edinburgh (Lothian Health Board), Glasgow (Greater Glasgow Health Board), and Newcastle (Newcastle upon Tyne Hospitals NHS Foundation Trust).

“We hope that this new cancer drug might—in the future—provide patients who have tried all available treatment options another opportunity to stop their cancer cells from multiplying and control their disease,” Richard Wilson, M.D., Cancer Research UK–funded clinical researcher and chief investigator at the Northern Ireland Cancer Centre, said in a statement.

“It’s very early days, but this trial will help us to understand whether this drug could help cancer patients and whether it has the potential to stop the growth of many different cancer types, particularly those with loss of p53 function,” Dr. Wilson added.

The Clinical Development Partnership program is a joint initiative of Cancer Research UK’s Centre for Drug Development and Commercial Partnerships team, formerly known as Cancer Research Technology. Through the program, Cancer Research UK sponsors and funds early clinical development, while companies retain all underlying rights to their programs.

At the end of those early studies, companies can decide if they wish to develop the drug further based on their trial results. If they choose not to, the Commercial Partnerships team gains rights to secure an alternative partner to continue development, with a share of future income returned to the company.

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