In late August, the Mesothelioma Applied Research Foundation hosted an interview as part of its Meet the Mesothelioma Experts (MTME) series to discuss a new clinical trial about gene therapy. This episode featured Dr. Daniel Sterman of NYU, the principal investigator for the study, and Dr. Steven Albelda of UPenn whose science is at the basis of the trial’s approach. In the text below, we break down the details of the study which is officially titled: Phase 3 gene therapy clinical trial evaluating the efficacy and safety of intrapleural administration of adenovirus-delivered interferon Alpha-2b (rAd-IFN) in combination with celecoxib and gemcitabine in patients with malignant pleural mesothelioma.
Who is eligible?
Patients eligible for this trial include those with pleural malignant mesothelioma of the predominantly epithelioid subtype who have undergone standard chemotherapy treatment with Alimta/cisplatin after which they progressed. The chemotherapy could have been administered before or after surgical resection and the recurrence could have occurred at that point, or potentially they could have received radiation therapy and chemotherapy for their mesothelioma and now have evidence of disease progression. Also eligible are patients who may have had a second-line treatment including immunotherapy. Currently, patients with peritoneal mesothelioma who have metastases in the chest cavity are not eligible. If interested in the study, patients should contact their oncologist or one of the study centers listed below to determine eligibility.
About the trial:
Although the title of the trial may seem intimidating, in practicality the trial is straightforward. It involves three different components: a virus that delivers the interferon gene into the tumor cells, the drug Celebrex, commonly used for arthritis, and gemcitabine, a chemotherapy drug frequently used as second-line therapy in mesothelioma.
The trial is currently open at sites including NYU, University of Maryland, UCLA, University of Kansas, and other sites internationally.
About the drugs:
- Adenovirus-delivered interferon gene: Human interferon alpha-2 is a protein secreted by cells when they are infected by a virus. In tumors, the interferon acts by disrupting cell proliferation and by activating the immune system against them. However, injecting the interferon directly into tumors is not feasible due to high toxicity of the interferon at the levels at which it would need to be administered to be effective. Instead, this study enlists the help of a cold virus (modified to not replicate) to deliver the gene for the interferon directly in the tumor cells, sort of like a trojan horse. At that point, the tumor cells become factories for the production of the interferon, thus activating a variety of immune responses within the tumor. The adenovirus-delivered interferon gene is injected into the patient’s chest cavity through a small catheter.
- Celebrex: This is a drug commonly used to treat arthritis. In this case, it is used to optimize the tumor environment to improve effectiveness of the interferon gene therapy. The Celebrex also decreases side effects such as fever and chills, which can be caused by the other two agents used in this study.
- Gemcitabine: Also known by its brand name Gemzar, gemcitabine is a chemotherapy drug typically used as second-line treatment in mesothelioma. The drug has been extensively studied as a single agent as well as in combination with cisplatin and carboplatin.
Trial design:
This clinical trial is designed to include two experimental arms: one arm is administered all three agents (adenovirus-delivered interferon gene, Celebrex, and gemcitabine). The other arm is only delivered the Celebrex and gemcitabine. Upon enrollment, patients are randomly assigned into one of the two groups.
Side effects:
The side effects of this clinical trials are relatively mild, and the agents are well-tolerated. For a duration of about 24 to 36 hours after the injection into the chest cavity, the interferon gene therapy can cause fever, chills and a slight lowering of blood pressure. Some patients also experience mild nausea and mild body aches.
The Celebrex is generally very well tolerated.
Gemcitabine side effects have been well-studied and can be controlled by pre-medicating the patient. They include flu-like symptoms, fever, fatigue, nausea and vomiting.
Study rationale:
This study is a Phase 3 study, meaning that its aim is to determine whether the randomly assigned arm receiving the adenovirus-delivered interferon gene has better overall survival rates and better progression-free rates than the arm only receiving the Celebrex and chemotherapy. The study also seeks to gain a better understanding of the safety of these agents.
This Phase 3 trial is based on previous Phase 1 and 2 trials, which focused almost exclusively on dosage and safety. Those early trials showed impressive improvement in patient survival when compared to studies looking solely into second-line chemotherapy survival. These results motivated the development of this new Phase 3 trial. It is important to note that caution should always be exercised when comparing results from different and separate studies.
This MTME broadcast was made possible by an educational grant by Trizell Ltd. A full recording and a full transcription are available on our website.
As part of the Meet the Mesothelioma Experts (MTME) series, the Meso Foundation invites specialists in the field of mesothelioma to discuss their current research interests as well as promising developments in the treatment of mesothelioma.
Interested in participating in our MTME as a guest speaker? Contact us at [email protected] or 703-879-3797.
