Cancer is a disease where the genes in certain affected cells change so that the normal control of cell growth is damaged and the affected cells start to grow too much. Sometimes these cancer cells will metastasize, meaning that the cancer cells travel within the body and start to grow in new places where they are not supposed to be. The primary cancer and the metastases can interfere with normal organ function and cause people to become sick and sometimes die.

There are many genes involved in the development of cancer. In some people, the affected genes involved in the cancer are TSC1 or TSC2. These genes can be found in many types of solid tumors. Changes, called mutations, in these genes may lead to cancer of different types, including:

Aadi Bioscience is sponsoring a clinical trial called PRECISION 1 that is testing whether a medication called nab-sirolimus can affect patients with advanced or metastatic solid tumors.

In order to be eligible for the PRECISION 1 clinical trial, a patient must have a solid tumor with a mutation of the TSC1 or TSC2 gene. The approximate percentage of patients who have a mutation in one of these genes is about 8% of bladder cancer, 4.5% of cancers of the bile ducts/liver, 3% of endometrial, soft tissue sarcomas, and ovarian cancer, 2% of non-small cell lung cancer, kidney cancer, esophagus/stomach, and melanomas, and 1% of colorectal and thyroid cancers. The mutations also occur in other cancers in smaller percentages.

Who Is Eligible for the Trial?

To be eligible for the PRECISION 1 trial, a patient must:

• Be at least 12 years old
• Have not used any other mTOR inhibitors (for example, everolimus or temsirolimus)
• Be able to perform normal daily activities (measured by a doctor using the ECOG, KPS or LPPS scale)
• Have a solid tumor with the TSC1 or TSC2 mutation that is metastatic or cannot be surgically removed
• Have received all other appropriate standard treatment options as determined by your doctor

To determine whether you have a TSC1 or TSC2 mutation, a doctor will take a biopsy of the tumor and have it analyzed using a process called next generation sequencing (NGS). Some patients have already had their tumors analyzed with this method. If your doctor already has NGS results for you, you can use those results and do not need to have another biopsy.

What Happens During the Trial?

All participants in the PRECISION 1 trial will receive the study drug, nab-sirolimus, on day 1 and day 8, and then take a week off. Then the 21-day cycle repeats: Once a week for 2 weeks followed by 1 week off. The drug is given by IV infusion, which takes about 30 minutes.

If you do not tolerate the drug well, your doctor can try a lower dose. You will continue to receive the drug until your disease progresses, you experience unacceptable side effects, or you choose to stop participating.

What is nab-sirolimus?

nab-sirolimus is an mTOR inhibitor.

mTOR is a protein that helps to control the growth of both normal and cancer cells. The TSC1 and TSC2 genes are part of the mTOR pathway. A pathway is a series of actions within a cell that lead to a certain product or changes. The genes in the mTOR pathway work together to activate mTOR.

In some cancers, mTOR is overactivated, resulting in rapid growth of cancer cells. By inhibiting mTOR, mTOR inhibitors such as sirolimus can help to slow down the mTOR pathway, potentially slowing the growth of a tumor.

One problem with older forms of sirolimus is that they are not easily absorbed by the body, which limits their effectiveness.

nab technology binds sirolimus to albumin, a protein that is actively absorbed by the tumor. Pre-clinical studies have shown that nab technology delivers significantly more sirolimus to the tumor than another form of the drug, resulting in slower growth of the tumor.

nab technology binds sirolimus to albumin, a protein that is actively absorbed by the tumor. Pre-clinical studies have shown that nab technology potentially delivers significantly more sirolimus to the tumor than another form of the drug, possibly resulting in slower growth of the tumor.

mTOR=mechanistic target of rapamycin; nab=nanoparticle albumin-bound; TSC1=tuberous sclerosis 1; TSC2=tuberous sclerosis 2