Feature

Study assesses immunotherapies for precancerous cervical lesions, advanced disease

Lynda Diane Roman

Researchers at USC Norris Comprehensive Cancer Center are conducting two clinical trials designed to investigate a form of immunotherapy for patients at both the precancerous and most advanced stage of cervical cancer.

Lynda Diane Roman, MD, and colleagues are recruiting patients with squamous cervical intraepithelial neoplasia 3 (CIN3), as well as those with vulvar intraepithelial neoplasia 3 (VIN3).

The investigators will assess the utility of IRX-2 (IRX Therapeutics) — a primary, cell-derived biologic with multiple active cytokine components that act on various parts of the immune system — for both groups of patients.

In the double-blind, randomized, placebo-controlled trials, patients will receive cyclophosphamide on day 1. Three days later, they will begin treatment with IRX-2 daily for 4 days, as well as indomethacin, zinc with multivitamins, and a proton pump inhibitor — omeprazole — for 21 days. This regimen will be repeated at 6-week intervals for two cycles.

Study protocols call for a 2:1 randomization of active therapy to placebo.

The researchers hope to enroll 30 patients each in the CIN3 and VIN3 cohorts. Pathological objective response at 25 weeks will serve as the primary outcome measure.

HemOnc Today spoke to Roman about the study, what the research team expects to find, and the role of immunotherapy for cervical cancer.

 

Question: How did the study come about?

Answer: The IRX-2 study is for women who have precancerous, squamous lesions of the cervix. The idea behind the study is that the large majority of these lesions are caused by HPV, meaning they are virally induced. We also know that, if these lesions aren’t treated and you wait, they eventually will become cancer. These lesions can occur in young women. It is not uncommon to see 20- and 30-year-olds with precancers of the cervix. Of course, we can treat them by excising them, but we are looking for other options. The problem is, surgery might get rid of the lesion but it doesn’t get rid of the virus. The virus is there to stay. Once you get an infection and it takes hold, we don’t have a way to clear the virus. Also, once someone has an infection, they are at risk for the long term to have recurring problems with cervical or vaginal cancers. If someone is especially prone to malignancy, they may need multiple procedures and it could interfere with fertility.

 

Q: Can you elaborate on the role of the immune system in this process?

A: There may be a weakness in the local immune system — in the area of the cervix or the vulva — that prevents patients from clearing HPV. A lot of research in this area has been done at USC, which helped develop this trial. USC scientists were asking questions about how to boost the immune system to help clear this virus — not just clear the lesion, but get rid of the virus. In this way, we could make an impact before cancer actually happens, by treating precancerous lesions by targeting the virus that causes them.

 

Q: Can you describe how this study will be conducted?

A: If a woman is found to have CIN3 or VIN3, she will be eligible. They will be treated in two sessions. The first part involves a very low dose of cyclophosphamide, and with some ancillary drugs, including indomethacin, zinc and an antacid. The idea is that part of the immune system can actually get in the way of an effective immune response. The initial drugs are given to try to suppress the part of the immune system that interferes with the immune response needed to clear HPV. In the second phase, the lesions are injected with study drug. The drug is aiming to boost the immune response in the deficient area so HPV can be cleared by the body. This is a randomized trial in which patients get study drug in a 2:1 ratio, where two get study drug and one gets placebo. During this period, patients get Pap smears and examinations. They are given several months for the treatment to take effect. After 6 months, they undergo definitive treatment. If there has been a response, the excision might be smaller than it would have been if they were never on study. There also is a translational science component to this study, in which people in the lab are looking at what immune response is generated and seeing what happens to the HPV virus at various phases. There is also a safety component. If there’s any concern that things are getting worse, we stop.

Q: Do you anticipate any safety concerns?

A: There have been big previous trials in this group of patients, and it is extremely rare that someone develops cancer while on such a study. Women with cervical dysplasia are generally observed all through pregnancy, for example, so we have a lot of experience observing patients with high-grade dysplasias for long periods of time. We know it’s pretty rare that someone gets cancer. With what we know from the past, we expect it to be safe.

Q: How many patients are you going to accrue?

A: The goal is 60 — 40 with cervical lesions and 20 with vulvar. We are looking to have another site — The University of Oklahoma — work with us. We’re already up and running.

 

Q: What is the timeline?

A: It will depend on what happens in Oklahoma, but the plan is 2 years.

 

Q: What do you expect the results will show?

A: This is obviously something very new. As a researcher, I’ve done this long enough that I manage expectations. I can’t say definitely, but the likelihood that we do harm is low. As far as how well this approach works, it would be satisfying if it does work because this is big problem that I don’t see going away in the near future. I look at the science and it makes sense to me, so it would be amazing if that happens. You have to try it. I tell patients we know what happens without this treatment. We watch it, and eventually you get an excision, and another, and another. But hopefully it will be worth it if the science holds up in real time. – by Rob Volansky

 

For more information:

Lynda Diane Roman, MD, can be reached at Obstetrics & Gynecology, IRD 520 2020 Zonal Ave., Off Campus, Los Angeles, CA, 90032; email: lroman@usc.edu.

 

Disclosure: Roman reports no relevant financial disclosures.

Lynda Diane Roman

Researchers at USC Norris Comprehensive Cancer Center are conducting two clinical trials designed to investigate a form of immunotherapy for patients at both the precancerous and most advanced stage of cervical cancer.

Lynda Diane Roman, MD, and colleagues are recruiting patients with squamous cervical intraepithelial neoplasia 3 (CIN3), as well as those with vulvar intraepithelial neoplasia 3 (VIN3).

The investigators will assess the utility of IRX-2 (IRX Therapeutics) — a primary, cell-derived biologic with multiple active cytokine components that act on various parts of the immune system — for both groups of patients.

In the double-blind, randomized, placebo-controlled trials, patients will receive cyclophosphamide on day 1. Three days later, they will begin treatment with IRX-2 daily for 4 days, as well as indomethacin, zinc with multivitamins, and a proton pump inhibitor — omeprazole — for 21 days. This regimen will be repeated at 6-week intervals for two cycles.

Study protocols call for a 2:1 randomization of active therapy to placebo.

The researchers hope to enroll 30 patients each in the CIN3 and VIN3 cohorts. Pathological objective response at 25 weeks will serve as the primary outcome measure.

HemOnc Today spoke to Roman about the study, what the research team expects to find, and the role of immunotherapy for cervical cancer.

 

Question: How did the study come about?

Answer: The IRX-2 study is for women who have precancerous, squamous lesions of the cervix. The idea behind the study is that the large majority of these lesions are caused by HPV, meaning they are virally induced. We also know that, if these lesions aren’t treated and you wait, they eventually will become cancer. These lesions can occur in young women. It is not uncommon to see 20- and 30-year-olds with precancers of the cervix. Of course, we can treat them by excising them, but we are looking for other options. The problem is, surgery might get rid of the lesion but it doesn’t get rid of the virus. The virus is there to stay. Once you get an infection and it takes hold, we don’t have a way to clear the virus. Also, once someone has an infection, they are at risk for the long term to have recurring problems with cervical or vaginal cancers. If someone is especially prone to malignancy, they may need multiple procedures and it could interfere with fertility.

 

Q: Can you elaborate on the role of the immune system in this process?

A: There may be a weakness in the local immune system — in the area of the cervix or the vulva — that prevents patients from clearing HPV. A lot of research in this area has been done at USC, which helped develop this trial. USC scientists were asking questions about how to boost the immune system to help clear this virus — not just clear the lesion, but get rid of the virus. In this way, we could make an impact before cancer actually happens, by treating precancerous lesions by targeting the virus that causes them.

 

Q: Can you describe how this study will be conducted?

A: If a woman is found to have CIN3 or VIN3, she will be eligible. They will be treated in two sessions. The first part involves a very low dose of cyclophosphamide, and with some ancillary drugs, including indomethacin, zinc and an antacid. The idea is that part of the immune system can actually get in the way of an effective immune response. The initial drugs are given to try to suppress the part of the immune system that interferes with the immune response needed to clear HPV. In the second phase, the lesions are injected with study drug. The drug is aiming to boost the immune response in the deficient area so HPV can be cleared by the body. This is a randomized trial in which patients get study drug in a 2:1 ratio, where two get study drug and one gets placebo. During this period, patients get Pap smears and examinations. They are given several months for the treatment to take effect. After 6 months, they undergo definitive treatment. If there has been a response, the excision might be smaller than it would have been if they were never on study. There also is a translational science component to this study, in which people in the lab are looking at what immune response is generated and seeing what happens to the HPV virus at various phases. There is also a safety component. If there’s any concern that things are getting worse, we stop.

 

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Q: Do you anticipate any safety concerns?

A: There have been big previous trials in this group of patients, and it is extremely rare that someone develops cancer while on such a study. Women with cervical dysplasia are generally observed all through pregnancy, for example, so we have a lot of experience observing patients with high-grade dysplasias for long periods of time. We know it’s pretty rare that someone gets cancer. With what we know from the past, we expect it to be safe.

Q: How many patients are you going to accrue?

A: The goal is 60 — 40 with cervical lesions and 20 with vulvar. We are looking to have another site — The University of Oklahoma — work with us. We’re already up and running.

 

Q: What is the timeline?

A: It will depend on what happens in Oklahoma, but the plan is 2 years.

 

Q: What do you expect the results will show?

A: This is obviously something very new. As a researcher, I’ve done this long enough that I manage expectations. I can’t say definitely, but the likelihood that we do harm is low. As far as how well this approach works, it would be satisfying if it does work because this is big problem that I don’t see going away in the near future. I look at the science and it makes sense to me, so it would be amazing if that happens. You have to try it. I tell patients we know what happens without this treatment. We watch it, and eventually you get an excision, and another, and another. But hopefully it will be worth it if the science holds up in real time. – by Rob Volansky

 

For more information:

Lynda Diane Roman, MD, can be reached at Obstetrics & Gynecology, IRD 520 2020 Zonal Ave., Off Campus, Los Angeles, CA, 90032; email: lroman@usc.edu.

 

Disclosure: Roman reports no relevant financial disclosures.

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