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Precision Drug Trial Shows Solid Tumor Shrinkage

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(Nick Youngson,

26 Oct. 2020. Partial results from a clinical trial show a drug to stop specific cancer-causing proteins shrinks advanced tumors in some patients across several tumor types. The findings were reported yesterday at the online Symposium on Molecular Targets and Cancer Therapeutics, sponsored by European Organisation for Research and Treatment of Cancer, or Eortc, American Association for Cancer Research, and National Cancer Institute, part of National Institutes of Health.

Researchers from MD Anderson Cancer Center in Houston, part of the University of Texas system, and colleagues from other institutions, reported on a clinical trial testing the drug code-named PLX8394, designed to block actions that result from mutations in the BRAF gene. The BRAF gene codes for proteins that help transmit chemical signals from outside cells to the cell nucleus, and are part of a larger RAS/MAPK pathway regulating many basic cellular functions.

The BRAF gene is known as an oncogene, which means it can mutate and produce proteins that cause normal cells to become cancerous. BRAF gene mutations are associated with many common and rare solid tumor cancers, such as melanoma on skin, gliomas in the brain, and ovarian cancer, as well as multiple myeloma, a blood-related cancer. Earlier BRAF inhibitors, say the researchers, work for only a limited set of solid tumor cancers and can become resistant to treatment.

“The next generation BRAF inhibitor that we gave to patients in this trial was designed to avoid those problems,” says MD Anderson cancer research and senior author Filip Janku in an Eortc statement. “These results suggest that the combination of drugs we tested is relatively safe and may be effective for some patients.”

The biotechnology company Plexxikon, in Berkeley, California, developed PLX8394 as an oral drug to treat BRAF mutations, but work with more solid tumor cancers and avoid becoming resistant. PLX8394, says Plexxikon, activates the RAS/MAPK pathway to block signals from mutated BRAF proteins, and stop uncontrolled cell division caused by those signals. In June, Plexxikon licensed PLX8394 exclusively to Novellus, a precision cancer drug development company in Jerusalem, Israel, for further research, development, and commercialization. Researchers from Plexxikon and Novellus are among the authors of the conference paper.

The early- and mid-stage clinical trial is testing PLX8394 in patients with advanced solid tumor cancers resulting from BRAF gene mutations at 13 sites in the U.S. The study team aims to enroll 100 participants in the trial, age 12 and up with cancers that so far do not respond to treatment and cannot be surgically removed.

In the first part of the study, researchers are looking primarily for safe dosage levels of PLX8394. The trial’s second part is more complex, with participants divided into two groups: (1) those with glioma tumors and a specific sub-mutation, called V600, as well as no prior treatments targeting BRAF genes, and (2) patients with BRAF mutations other than V600 and who had previous BRAF-targeting treatments. The study team is looking for PLX8394’s safety and dosage levels in patients, but also chemical activity in the body and evidence of anti-tumor response.

In addition, some patients receive the drug cobicistat, approved as supplemental treatment for HIV infections that increases the amount of primary HIV drugs in patients. In this trial, the study team is looking to see if cobicistat also increases PLX8394 in cancer patients.

In their conference paper, the researchers say 75 patients are taking part in the trial so far, and report on 45 participants with results. Of those 45 patients, 10 or 22 percent report their tumors responding to the treatments, with shrinkage of at least 30 percent. Three of the 10 patients have gliomas, two have ovarian cancer, and others have melanoma, colorectal, or thyroid cancers. Participants taking cobicistat report two to three times as much PLX8394 exposure, compared to those not taking cobicistat.

All 10 patients have taken part in the trial for at least two years. The most serious adverse affect among some patients is higher than normal levels of bilirubin and liver enzymes in blood samples indicating possible liver damage. However, no skin lesions, reported by patients receiving earlier BRAF inhibitors, were seen in these patients.

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