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Testing PI3K Inhibitor BKM120 in Recurrent Glioblastoma

Glioblastoma multiforme (GBM), or grade 4 glioma, is an aggressive brain tumor that is resistant to chemotherapy and radiation, and is almost always fatal. The median survival is 15 months and the five-year survival is just 10 percent. Approximately 10,000 people will receive a new diagnosis of GBM in the US each year. GBM arises from astrocytes, a type of glial cell that support and nourish neurons. It produces tumors that invade diffusely into surrounding tissue and so cannot be completely excised surgically. This diffuse growth contributes to tumor recurrence after surgery.

Traditionally, the treatment for GBM was surgery followed by radiation therapy focused on the tumor and a 2cm margin. In 2005, the FDA approved temozolomide (Temador), a chemotherapeutic that crosses the blood brain barrier. However, the medium time to progression following treatment with radiation therapy and this cytotoxic agent is only seven months. Treatment options for patients with recurrent GBM is very poor. Bevacizumab (Avastin) has modest activity but most other chemotherapeutic agents are ineffective. The medium survival for recurrent GBM is five to nine months.

In the past decade, researchers have made progress in understanding the molecular pathogenesis of GBM, the sequential accumulation of genetic aberrations, and the dysregulation of growth factor signaling pathways. In about 15 percent of GBM tumors, phosphatidylinositol 3-kinase (PI3K) plays a central role in cancer growth, survival, motility, metabolism, and angiogenesis. Angiogenesis, or the growth of new blood vessels, is significant since GBM tumors are highly vascularized and require an expanded blood supply to support their rapid growth.

Another 40 percent of GBM patients lack a functioning tumor suppressor, PTEN (phosphatase and tensin homolog), which shuts off the PI3K pathway. Preliminary evidence suggested that PI3K pathway activation and PTEN inactivation indicate poor prognostic outcome in many cancers and that inhibiting the PI3K pathway may provide therapeutic benefit in those same cancers.

Putting the PI3K Hypothesis to the Test

Previously, a Phase I trial testing PI3K inhibition in all cancers showed that a new PI3K inhibitor, BKM120, helped slow or stop tumor growth in some patients. The current Phase II trial in recurrent GBM, which is open and accruing at multiple sites, proposes to test BKM120 specifically in patients with recurrent GBM who have PI3K pathway activation or and/or loss of PTEN function.

The rationale for the trial is to test whether PI3K inhibition stops malignant glioma cells from growing and prolongs progression-free survival. The trial design includes two arms, both using BKM120 as a single agent. The first arm will include 15 patients who require surgery to remove a relapsed tumor. About one third of relapsed GBM patients do require such surgery.  These participants will receive 100mg of BKM120 orally once a day for 8 to 12 days prior to surgery, and a tumor sample from the surgery will be used for research purposes. After recovery from surgery, participants will resume taking BKM120 on a continuous once-daily dosing schedule. The primary endpoints are to determine if an effective level of BKM120 penetrated the brain and if the inhibitor modulated PI3K pathway activity. Investigators will also evaluate the safety profile and pharmacokinetics of BKM120, as well as the effect of down-regulating the PI3K pathway on tumor cell proliferation.  A secondary endpoint is whether FDG-PET imaging may be a pharmacological marker for PI3K/AKT response during treatment.

The second arm will include 50 relapsed GBM patients who do not need further surgery. These participants will receive BKM120 at the same dose on a continuous basis.  The primary endpoint is progression free survival at six months compared to historical data. “There is no control,” explains Patrick Wen, MD (DFCI), who designed and leads the study," because we have good data for the baseline on standard therapy.” Secondary endpoints are median progression free survival and overall survival. Participants may continue on the therapy as long as it is tolerated and the tumor is controlled. All participants will be followed through medical records for information on post-treatment therapies, progression, and survival.

About BKM120

The PI3K signaling molecule comprises a family of eight members grouped into three classes. Of those, Class I PI3K is involved in the PI3K-PDK1-AKT pathway that regulates cell proliferation, growth, survival and apoptosis, as well as mediating the transforming and growth-stimulating potential of common oncogenes that contribute to solid tumors.  BKM120 is a new pan-Class I PI3K inhibitor that was extensively evaluated in human glioblastoma cells. As a small lipophilic molecule, it can cross the blood brain barrier. Preclinical studies show that BKM120 decreases the phosphorylation of downstream effectors of AKT in cancer cells lacking PTEN, and also produces changes in vascular function but does not impair wound healing. It is rapidly absorbed orally. In addition to common side effects of targeted therapies, it can raise glucose levels and produce some mild mood changes.

“This trial is an important first step towards a much needed new treatment for glioblastoma,” says Wen. “We think blocking PI3K is important, but we do not expect it will be sufficient.” In the lab, PI3K blockage is just cytostatic, meaning it stops cell growth but does not kill the cell. Wen is also investigating the optimal combination of cytotoxic agents and complementary targeted molecular drugs with this PI3K inhibitor in concurrent clinical trials. Luckily, he says, the regulatory climate is now more amenable to combination trials of experimental agents, and hopefully this will accelerate the rate of developing new treatments for brain cancer patients who currently have very limited options.

Title:
Phase II Study of BKM120 for Subjects With Recurrent Glioblastoma

DF/HCC Protocol:
11-033

Principal Investigator:
Patrick Y. Wen, MD (DFCI)

More Information:
The trial is open and accruing. For information on ClinicalTrials.gov, go to NCT01339052

Funding:
The Catherine and Ben Ivy Foundation