HemOnc Today's PharmAnalysis

HemOnc Today's PharmAnalysis

December 05, 2017
4 min read

High failure rate of phase 3 glioblastoma trials highlights need for greater reliability of earlier studies

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Jacob J. Mandel

Results of a study published in Neuro-Oncology indicate a high failure rate of phase 3 trials for glioblastoma, the most common primary malignant brain tumor among adults.

The failure of these trials occurred even in cases when preceding phase 2 trials were positive.

“The high failure rate of phase 3 trials demonstrates the urgent need to increase the reliability of phase 2 trials of treatments for glioblastoma,” Jacob J. Mandel, MD, assistant professor of neurology at Baylor College of Medicine, and colleagues wrote. “Strategies such as the use of adaptive trial designs, Bayesian statistics, biomarkers, volumetric imaging and mathematical modeling warrant testing.”

Mandel and colleagues searched PubMed for phase 3 clinical trials conducted within the previous 25 years that included patients with newly diagnosed or recurrent glioblastoma. Researchers excluded trials that did not assess the efficacy of chemotherapy or another agent, stopped early due to toxicities or did not have a prior phase 2 trial. They also excluded trials for which the preceding phase 2 trial was negative.

Eleven studies — seven in newly diagnosed glioblastoma and four in recurrent disease — met study inclusion criteria. Of these, only one phase 3 trial showed a statistically significant OS improvement with the investigational treatment.

HemOnc Today spoke with Mandel about the study results, the need for more effective treatments for this patient population, and potential strategies to improve the success of late-stage glioblastoma trials.


Question: What prompted this research?

Answer: I am in charge of grand rounds of neurology at Baylor College of Medicine. A colleague of mine who conducted research on stroke mentioned several different positive phase 2 trials that had failed when they went on to phase 3. He discussed some of the reasons why they may have failed. This sparked my curiosity because, in glioblastoma, there have been several recent phase 2 trials that appeared promising, only to have a subsequent negative phase 3 trial. I was intrigued, and I wanted to see if there were any patterns I could identify for why this was occurring.


Q: What did you find?

A: We found that, during the past 25 years, using positive phase 2 clinical trials as predictors of subsequent positive phase 3 clinical trials was very poor for patients with glioblastoma. We tried to limit our examination to only include phase 3 studies that had prior positive phase 2 studies. However, even then, we found that only one of the 11 studies achieved statistically significant results.



Q: What are the potential clinical implications of these phase 3 trial failures ?

A: One of the most important things is trying to make sure we limit the potential exposure of toxicities to patients on clinical trials. Using treatments above standard of care, if it is not necessary, can potentially expose patients to a more toxic treatment than if they had just received the standard of care. One of the concerns when dealing with a phase 2 study that should not go on to phase 3 is that we are exposing that drug to hundreds of patients who should not have been exposed to that treatment. Additionally, the cost of research for an oncology trial — especially a large phase 3 trial — is extremely expensive, and we have very limited resources in the field of neuro-oncology. We need to be mindful of conducting trials that have the most potential to benefit our patients.


Q: Can you describe the need for new, more effective treatments for this patient population?

A: Glioblastoma is extremely difficult to treat. Patients have a poor prognosis despite treatment with radiation, chemotherapy and surgery. Unfortunately, there is no cure for these tumors. The median OS is around 15 months and the 2-year survival is around 25% for patients who are eligible for clinical trials. Sometimes we see patients who are not eligible for clinical trials, and their prognosis is even worse. When these tumors do recur, treatment options are often limited and there really are no treatments that have proven to improve OS. There are several possible reasons for why these tumors are resistant to therapy, including the difficulty of delivering drugs adequately to the brain, as well as the overlapping and redundant signaling pathways. It is important to look at what we can do to improve these trials to help these patients.


Q: Can you summarize some of the suggested strategies to improve the success of phase 3 trials?

A: Our findings did not support the common practice of initiating phase 3 studies based upon the results of single-arm phase 2 studies that compared their outcomes to historical benchmarks. With phase 2 studies, especially with a disease in which it is difficult to put patients on clinical trials, there is a lot of debate about the necessity of a control group. With the advancement of molecular markers, there appears to be an importance in making sure these patients are being compared with patients with similar genetic makeups of their tumors. Additionally, moving therapies directly into phase 3 trials in newly diagnosed disease based off of promising phase 2 studies in recurrent disease seems to be of questionable benefit.


Q: Is there anything else that you would like to mention?

A: Although the results of phase 3 studies have not been encouraging for glioblastoma, I certainly am optimistic that we are learning more every day about these tumors, and there are people working on new exciting therapies every day. I hope that we soon will be able to have more encouraging results to offer patients with this devastating disease. – by Jennifer Southall



Mandel JJ, et al. Neuro-Oncol. 2017;doi:10.1093/neuonc/nox144.


For more information:

Jacob J. Mandel, MD, can be reached at Baylor College of Medicine Medical Center, McNair Campus, 7200 Cambridge St., 9th Floor, MS: BCM609, Houston, TX 77030; email: jacob.mandel@bcm.edu.


Disclosure: Mandel reports no relevant financial disclosures.