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Finding a Cure for Children With CNS Neuroblastoma

Holt, Chuck

doi: 10.1097/01.COT.0000577040.72719.6f
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2019 Excellence in Oncology; CNS Neuroblastoma

2019 Excellence in Oncology; CNS Neuroblastoma

In the late 1990s, pediatric oncologist Kim Kramer, MD, and her colleagues at Memorial Sloan Kettering Cancer Center (MSKCC) in New York City began observing that children with central nervous system (CNS) neuroblastoma increasingly were developing isolated brain metastases.

This new type of CNS relapse identified by the MSKCC researchers had not been seen before because children with neuroblastoma treated with conventional therapies, such as chemotherapy, radiation therapy, and surgery, were not living long enough to develop the late complication of the disease, Kramer said. Researchers at MSKCC previously had shown it to be a fatal type of recurrence with a median survival of only 5.5 months.

“In the past, it was very difficult to treat children with neuroblastoma in the rest of the body. But as therapies for systemic neuroblastoma were being improved, we found there were more and more children suffering from isolated CNS relapse, which meant that the therapies we were giving them did not adequately address microscopic metastases in the brain,” Kramer told Oncology Times. “So the need to develop better-targeted therapies specifically directed at brain metastases was obviously necessary to cure these children who were otherwise remaining free of neuroblastoma.”

Toward that end, the MSKCC team initiated a clinical trial to examine the toxicity, dosimetry, and therapeutic effect of intraventricular 131I-labeled monoclonal antibody 8H9. Developed at MSKCC in the laboratory of Nai-Kong Cheung, MD, PhD, 8H9 (omburtamab) is an antibody that targets the surface glycoprotein B7-H3 overexpressed on CNS neuroblastoma tumors.

The results of the study would show that, when combined with conventional therapies, the new drug not only significantly improved survival rates, but also provided the first-ever curative approach to CNS neuroblastoma, said Kramer, whose team presented the study's findings at the 2018 Advances in Neuroblastoma Research Association Meeting in San Francisco.

“The most important finding is that targeted therapy delivered into the intrathecal space can effectively eliminate micrometastatic disease and cure children,” she said. “Long term, we found these children at 13, 14, and 15 years old. And, in fact, many of these children are cured with no late recurrence of brain metastasis.”

The dramatic improvement in survival rates for children with CNS neuroblastoma in the clinical trial at MSKCC led to a multicenter, international consortium study now under way. Additionally, the FDA recently granted a Breakthrough Therapy designation to intraventricular 131I-labeled monoclonal antibody 8H9 (omburtamab) for children with CNS neuroblastoma.

What's more, the groundbreaking translational research also has earned Kramer and her team at MSKCC a 2019 Excellence in Oncology award from the Oncology Times.

“In pediatrics, we are a small part of the whole oncology community. So, having Oncology Times highlight a rare subset of a rare disease that we are proud to say we have made great strides in is just tremendously exciting,” Kramer said. “My entire team is proud that you recognized us.”

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A Well-Mapped Plan

According to the American Cancer Society, about 800 new cases of neuroblastoma are diagnosed annually in the U.S., typically in children under age 2. In about two out of three cases, the disease has already metastasized to the lymph nodes or elsewhere before it is diagnosed.

Neuroblastoma metastatic to the brain only occurs in up to 15 percent of children with stage IV neuroblastoma and most often in children who are otherwise in systemic remission, Kramer said.

In the MSKCC study led by Kramer, a total of 93 children with CNS neuroblastoma included in the study received 2-4 injections of intraventricular 124I-8H9 or 131I-8H9. More than 52 percent of the children (48) were still alive 4.8-152 months later with a median of 58 months, 56 percent at 36 months, and 29 percent after 60 months. Following the administration of conventional therapies combined with intraventricular 131I-8H9, long-term survival was noted in patients as long as 14 years since CNS metastases were diagnosed.

Immunohistochemistry was used to assess tumor B7-H3 expression and the flow of cerebral spinal fluid was determined by 111indium-DTPA cisternography, according to the researchers. Overall, 131 patients received 2 mCi tracer of intra-Ommaya 124I-8H9 or 131I-8H9 for nuclear imaging, which was followed by a therapeutic injection (10-80 mCi, dose levels 1-8 in 10 mCi increments for phase I patients; expanded cohort 50 mCi/injection) 131I-8H9.

The researchers studied the pharmacokinetics of the new drug over 48 hours using serial CSF and blood samplings. The dosimetry was based on pharmacokinetics and region of interest analyses on serial nuclear imaging scans. Toxicity was defined by the CTCAE v.3.0. After 1 month, and if no serious adverse events or progressive disease ensued, the 8H9 dosimetry and therapy injections were repeated. Tumor response was determined by clinical, radiographic, cytologic criteria, and overall survival was noted.

Although not dose-limiting toxicity, myelosuppression occurred in patients who had received craniospinal radiation at dose levels 6 and higher (>60 mCi). Interpatient variability for total absorbed dose to the cerebrospinal fluid (CSF) and blood was observed as well with a mean absorbed CSF dose of 104.9 cGy/mCi by CSF sampling and 2.6 cGy/mCi to the blood.

Ultimately, the researchers concluded that “intraventricular 131I-8H9 is safe, permitting favorable dosimetry to the CSF. In the phase II expansion, it demonstrated activity in improving long-term remission among patients with CNS neuroblastoma.”

Additionally, seeing how well children in the study tolerated the new drug therapy “was really a wonderful surprise” for the researchers, Kramer said.

“When antibody-based therapies for neuroblastoma are delivered intravenously, there are many acute side effects that our patients have, notably pain and allergic reaction,” she explained. “And we were prepared for those, initially thinking that the same type of acute toxicity profile may be experienced. But we have had very few cases of acute toxicities in our patients when the antibody is delivered to the intrathecal space; it's been very rare.”

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Rewarding Breakthrough

In considering intraventricular 131I-labeled monoclonal antibody 8H9 for Breakthrough Therapy designation, the FDA compared survival curves from the MSKCC clinical trial with those in the literature and reported from historical control groups, Kramer said.

“When they reviewed our results incorporating the radioimmunotherapy compared to all other published series in the literature, and also compared to series results on multi-center consortium or international studies, our survival rate was significantly better,” she stated.

The Breakthrough Therapy status awarded by the FDA is intended to attract the attention of pharmaceutical manufacturers and fast-track new drugs to market for “orphaned diseases” identified by the federal agency as lacking available treatments, including CNS neuroblastoma, Kramer noted. The designation is especially exciting “because it is a way of the FDA acknowledging that this drug is notable for improving survival rates and is on the right track for approval,” she said.

“The FDA is committed to getting drugs approved that fill an unmet need for orphaned diseases, and with only 10-15 percent of children with neuroblastoma developing brain metastases, this is clearly an unmet need,” Kramer added. “And so, to have something that can actually address an unmet need in oncology, and to have the FDA be very excited about these results and very supportive in helping us answer what needs to be done to move it forward on an international level, is tremendously rewarding.”

But while it may someday eliminate the need for other treatments, Kramer emphasized that it is important to note that the new drug currently is indicated as “an available adjuvant therapy that can successfully eradicate micro-metastatic disease and prevent further CNS complications. We have a well-mapped-out plan for when to add this therapy to conventional therapies.”

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Global Effort

Pediatrics, Neurosurgery, Radiation Therapy, Nuclear Medicine, Medical Physics, and Radiation Safety were all among the many different departments at MSKCC that had a hand in development and trial of the novel therapy now curing children with CNS neuroblastoma, Kramer acknowledged. “I am just one of many people that contributed to this particular work.”

As an example of the teamwork that was required, she pointed out that making the drug and infusing it into patients participating in the clinical trial involves multiple staff and several hospital departments. First, each antibody has to be labeled, which takes about 2-3 hours, she said. After that, Nuclear Medicine helps deliver it to the patients for another 2-3 hours.

“It's really an all-day process,” said Kramer, marveling at how one colleague would start labeling the isotopes for the clinical trial at 4 a.m. “just so that we could get it into our patients at a reasonable hour.”

Meanwhile, Kramer and her team are eagerly awaiting the results of the international consortium clinical trial gathering data on their new drug therapy for CNS neuroblastoma at multiple cancer centers throughout the U.S., such as MD Anderson Cancer Center in Houston, as well as other cancer centers around the globe, including some in Denmark and Spain.

In the “phase II/III trial of the efficacy and safety of intracerebroventricular radioimmunotherapy using 131I-omburtamab for neuroblastoma central nervous system/leptomeningeal metastases,” the researchers will assess the safety and effectiveness of the radioimmunotherapy in children and teens with neuroblastoma that has spread to the brain or spinal cord or the lining around the brain(NCT03275402).

8H9 (omburtamab) is an antibody that attaches to neuroblastoma cells. It carries radioactive iodine 131I directly to the cancer cells, killing them. In the study, patients will receive up to 2 cycles of intracerebroventricular 131I-omburtamab. The treatment is delivered by several injections into a tube that feeds into the spinal fluid surrounding the brain. Safety and efficacy will be investigated with short-term follow-up at 26 weeks and longer-term follow-up for up to 3 years after treatment.

“The first order of business is to make sure that this therapy can be successfully delivered in other institutions and that similar results can be obtained,” Kramer said, regarding the trial. “And the second order of business is to see whether this therapy can help decrease or eliminate the use of the other conventional therapies without sacrificing our cure rates.”

Chuck Holt is a contributing writer.

2019 Excellence in Oncology

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