Provider communication is extremely important, especially when dealing with a pediatric cancer diagnosis. In this episode of “The Vitals,” Bryan A. Sisk, MD, MSCI, assistant professor of pediatric hematology and oncology at the Washington University School of Medicine discusses his recent research on communication barriers between healthcare providers and children with cancer and their families.

While some of these issues can be found in the broader cancer space, others – like how much information to give a 6-year-old versus a 16-year-old – align more with the intricacies of pediatrics. Sisk talks about this, and the improvements he hopes to see in this space in years to come.

Podcasts

A Chat on Communication Barriers in Childhood Cancer

The FDA has granted a rare pediatric disease (RPD) designation to the p-STAT3 inhibitor WP1066 for the treatment of patients with ependymoma, a rare type of tumor that can develop in the brain or the spinal cord.

“The FDA’s recognition of the high prevalence and unmet needs in the treatment landscape for ependymoma, especially in pediatric patients is a significant milestone as we continue to advance and expand the WP1066 development program,” Walter Klemp, chairman and chief executive officer of Moleculin, stated in a press release. “We currently have orphan drug designation for WP1066 for the treatment of brain tumors, as well as RPD designation for 3 other pediatric indications, and believe that ependymoma represents another important rare indication.”

In January 2021, WP1066, which is an agent that appears to directly elicit tumor cell death and rouse the immune system to eliminate tumors, was granted 3 

 designations in diffuse intrinsic pontine glioma, medulloblastoma, and atypical teratoid rhabdoid tumor.

Waldemar Priebe, PhD, professor of medicinal chemistry in the Department of Experimental Therapeutics of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, made the discovery that led to the development of the agent.

Priebe examined naturally-occurring compounds in propolis, which offered the opportunity to evaluate the ability of caffeic acid benzyl ester (CABE) to inhibit p-STAT3, which is an important target for cancer therapeutics.

By looking at CABE, Priebe was able to identify novel compounds that could more strongly inhibit p-STAT3. WP1066 moved to the head of the pack after it proved to be able to successfully inhibit p-STAT3 and other important oncogenic transcription factors like c-Myc, HIF-1α and HIF-2α.

WP1066 has been shown to have antitumor efficacy spanning a wide array of tumor cell lines; the agent has also resulted in a survival benefit in several animal models. Moreover, WP1066 can enhance antitumor effects of the immune system and its response to tumor activity. Investigators postulate that the agent may have a dual-action mechanism that permits it to treat an array of resistant tumors and to be more amenable to be paired in novel combinations for unresponsive tumors.

Additionally, the addition of WP1066 to checkpoint inhibitors could lead to additive or synergistic effects that could improve outcomes in patients who are receiving the immunotherapy, according to Moleculin Biotech, the drug developer.

In ATL-T, SLVL, and human brain malignant cell lines, WP1066 was found to significantly abrogate PD-L1/2 expression in a recent study. Incubation of the drug obstructed the growth of lymphoma cells and induced cell apoptosis.

 Results from another study suggested that the agent could have efficacy when paired with a CTLA-4 inhibitor, as CTLA-4–induced immune suppression mostly occurs via the STAT3 pathway.

“We continue to be encouraged by the data WP1066 has demonstrated to date and believe it has potential to be an effective therapy for pediatric patients with ependymoma,” Klemp added in the release. Ependymoma begins in the ependymal cells within the brain and spinal cord that line the passageways where cerebrospinal fluid flows. Although this disease can present at any age, it is mostly reported in young children.

The RPD Priority Review Voucher Program was developed as a way to incentivize the development of novel treatments for pediatric patients with rare diseases. Under the FDA’s rare pediatric disease designation program, the regulatory agency can grant a priority review voucher to a sponsor who receives an approval for a product for a rare pediatric disease, which is defined as a serious or life-threatening disease that primarily impacts those up to 18 years of age.

If WP1066 is approved for this indication, the pharmaceutical company would be able to receive a voucher that could be redeemed to receive priority review for a subsequent marketing application for a different product candidate or that could be either sold or transferred.

Moleculin awarded new rare pediatric disease designation from US FDA for WP1066 for the treatment of ependymoma. News release. Moleculin Biotech, Inc. April 14, 2021. Accessed April 14, 2021. 

Moleculin announces FDA approves 3 rare pediatric disease designations for WP1066. News release. Moleculin Biotech, Inc. December 1, 2020. Accessed April 14, 2021. 

WP1066. Moleculin Biotech, Inc website. Accessed April 14, 2021. 

Technology. Moleculin Biotech, Inc website. Accessed April 14, 2021. 

Ma C, Horlad H, Pan C, et al. Stat3 inhibitor abrogates the expression of PD-1 ligands on lymphoma cell lines. 

. 2017;57(1):21-25. doi:10.3960/jslrt.17006

Herrmann A, Lahtz C, Nagao T, et al. CTLA4 promotes Tyk2-STAT3–dependent B-cell oncogenicity. 

. 2017;77(18). doi:10.1158/0008-5472.CAN-16-0342

This article was originally published on OncLive as, "

FDA Grants Rare Pediatric Disease Designation to WP1066 for Ependymoma

Articles

The FDA has granted a rare pediatric disease designation to the p-STAT3 inhibitor WP1066 for the treatment of patients with ependymoma, a rare type of tumor that can develop in the brain or the spinal cord.

Rare Pediatric Disease Designation Granted to WP1066 for Ependymoma

Adavosertib plus irinotecan showed early activity in a cohort of pediatric patients with neuroblastoma, thus meeting the protocol-defined efficacy end point of the 1/2 ADVL1312 trial (NCT02095132), which was presented virtually during the AACR Annual Meeting 2021.

Moreover, adavosertib plus irinotecan also showed the potential to benefit patients with 

-mutant tumors, with further validation required for this effect.

“In order to look for an early signal of activity and to obtain more information regarding toxicity of the recommended phase 2 dose, the ADVL1312 trial proceeded with a phase 2 expansion in 3 pediatric disease-specific cohorts,” presenting author Kristina A. Cole, MD, PhD, of Children’s Hospital of Philadelphia and Perelman School of Medicine of the University of Pennsylvania, said in the presentation of the data.

The 3 pediatric cohorts analyzed in the expansion phase of this trial included neuroblastoma (n = 20), medulloblastoma with central nervous system (CNS) embryonal tumors (n = 10), and rhabdomyosarcoma (n = 10).

Overall, 3 objective responses were recorded from 16 eligible patients in the neuroblastoma cohort, which met the protocol-defined efficacy end point. Meanwhile, there was 1 recorded objective response in the group with medulloblastoma and CNS embryonal tumors and no responses with rhabdomyosarcoma, respectively.

The investigative team also sought to determine factors correlated with clinical response, focusing on the 

 chromatin remodeler gene. Twelve of the archival ADVL1312 tumors were evaluated.

Ultrabright telomeric foci (UBTF) were present in tumors from 2 of the 3 patients who experienced an objective response. More, ATRX deficiency was present in 4 of the 9 patients with clinical response or stable disease.

Common grade 3 or higher adverse events included neutropenia (5 events in the neuroblastoma cohort; 4 events in medulloblastoma; and 3 events in rhabdomyosarcoma), lymphopenia (4 events; 2 events; and 1 event, respectively), and leukopenia (2 events vs 2 events vs 0 events).

More, the toxicity profile of ADVL1312 featured no dose-limiting toxicities at cycle 1 or later at the maximum-tolerated dose. Regardless of this finding, and although the combination was well tolerated, the investigative team notes that oral irinotecan is not palatable.

The investigative team utilized the phase 2 data from irinotecan to inform the efficacy end point for the combination therapy analyzed in the expansion portion of ADVL1312. In order to define the therapy as effective in the neuroblastoma and rhabdomyosarcoma cohorts, 3 objective responses out of 20 eligible patients were required. More, 6 response out of 19 eligible patients were required for efficacy in the medulloblastoma with CNS embryonal tumors cohort.

“Several of the limitations of this study relate to the fact that it was a phase 2 expansion,” explained Cole. “For example, patients were eligible for response regardless of if they completed a cycle of therapy or had their disease reevaluated. One-third of patients discontinued therapy with stable disease or better.”

Median age for patients in the neuroblastoma cohort was 9 years (range, 6-19), with a majority of patients being male (65%) and White (60%). In the medulloblastoma cohort, the median age was 13.5 years (range, 6-20), with a majority of patients female (60%) and White (70%). Lastly, the rhabdomyosarcoma cohort reported a median age of 11 years (range, 4-16) with 80% of patients reporting as male and 90% of patients reporting as White.

Looking ahead, because of the satisfaction with the preliminary findings in this expansion trial, Cole noted that an adavosertib pediatric development plan is being discussed.

Cole KA, et al. Pediatric phase 2 trial of the WEE1 inhibitor adavosertib (AZD1775) and irinotecan; A Children’s Oncology Group Study (ADVL1312). Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual. Abstract CT029.

Adavosertib/Irinotecan Shows Early Activity in Pediatric Neuroblastoma

Overall, 3 objective responses were recorded from 16 eligible patients in the neuroblastoma cohort, which met the protocol-defined efficacy end point.

Drug Combo Shows Early Activity in Pediatric Neuroblastoma Treatment

The National Comprehensive Cancer Network (NCCN) has issued guidelines for the management of children with a rare type of kidney cancer referred to as Wilms Tumor, or nephroblastoma.

The document highlights evidence-based recommendations for how to maximize benefits while minimizing toxicities in this patient population. Notably, the guidance comprises critical information for providers who treat pediatric tumors, hematologic malignancies, and other blood disorders that may be encountered relatively infrequently. The guidelines also contain diagnostic information for primary care pediatricians to ensure that the cancer is identified early and managed in a way that results in fewer toxicities for the patients.

“Keeping up with all of the current literature for the broad array of children’s oncologic and hematologic malignancies can be daunting. The NCCN Guidelines for Wilms Tumor provide compiled, annotated, and vetted recommendations for diagnosis, treatment, and follow up—in keeping with NCCN’s goals for streamlining and improving care so that patients can live better lives,” Elizabeth Mullen, MD, of Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who is also a member of the NCCN Guidelines Panel for Wilms Tumor, stated in a press release.

Wilms tumor is the most common cancer of the kidneys in children and it is known to affect those between the ages of 3 years and 4 years.3 In the majority of patients, the tumor will present in just 1 kidney, although it has been identified in both kidneys at the same time.

One factor that may increase the risk of Wilms tumor is African-American race; these children tend to be at a slightly higher risk for this cancer compared with other races. Additionally, Asian-American children may be at lower risk than children of other races. Another risk factor is having a familial history of the cancer.

Wilms tumor is also known to occur more commonly in children with aniridia or hemihypertrophy at birth; it has also been shown to occur as part of other rare syndromes like WAGR syndrome, Denys-Drash syndrome, and Beckwith-Wiedemann syndrome.

“The treatment of Wilms tumor is guided by the results of a series of sequential clinical trials that started back in the 1960s,” Frank M. Balis, MD, professor of pediatrics, Louis and Amelia Canuso Family Endowed Chair for Clinical Research in Oncology, of the Children’s Hospital of Philadelphia/Abramson Cancer Center at the University of Pennsylvania, and chair of the NCCN Guidelines Panel for Wilms Tumor, added in the release. “Treatment approaches have been refined through these clinical trials, making treatment selection more and more complex and nuanced.”

Balis added that treatment decisions should be based on clinical and biological risk factors, the presence of unilateral versus bilateral disease, and patient response to treatment.

NCCN clinical practice guidelines in oncology (NCCN guidelines): Wilms tumor. National Comprehensive Cancer Network. Accessed February 17, 2021.

New NCCN guidelines analyze evidence for cancer type found almost exclusively in children. News release. National Comprehensive Cancer Network. February 17, 2021. Accessed February 17, 2021. 

Wilms’ tumor. Mayo Clinic website. Updated April 24, 2020. Accessed February 17, 2021. 

NCCN Issues First-Ever Guidance for Pediatric Solid Tumor

The National Comprehensive Cancer Network has issued guidelines for the management of children with a rare type of kidney cancer referred to as Wilms Tumor, or nephroblastoma.

NCCN Publishes Guidelines for Pediatric Solid Tumor

Parents of pediatric patients with cancer were found to be more likely to believe misinformation about the coronavirus disease 2019 (COVID-19) than parents of children without a cancer history, according to recent research published in 

This puts oncology nurses in the prime position to talk with caregivers of pediatric patients, and show them where to find reliable information on COVID-19.

The researchers surveyed 735 parents of children between the ages of 2 and 17 – 315 parents had children who were currently in cancer treatment, while 420 had children without a cancer history. In the survey, participants were asked to rate COVID-19 information based on whether they thought it was “definitely untrue,” “likely untrue,” “not sure if untrue/true,” “likely true,” and “definitely true.” The survey included 17 common and untrue COVID-19 myths from the World Health Organization’s website.

“For the correct pieces of information, there was no difference between the parents of kids with cancer and the parent control group,” said Jeanine P.D. Guidry, PhD, assistant professor at the Virginia Commonwealth University Robertson School of Media and Culture and director of the Media+Health Lab said in an interview with 

“For the pieces of misinformation, parents of pediatric cancer patients were more likely to say, ‘this is correct information,” Guidry explained.

Eating garlic can help prevent infection with the COVID-19 virus

Gargling with or swallowing bleach will help get rid of COVID-19

Drinking a sip of water every 15 minutes can prevent COVID-19

While eating garlic or drinking water every 15 minutes are not unhealthy actions, they can become harmful if a person believes that they are protected from COVID-19 and, as a result, does not follow CDC guidelines. Drinking bleach, however, is outright dangerous, Guidry said.

Guidry explained that parents of pediatric patients with cancer already are experiencing the stress of a diagnosis, and as a result may be more included to believe in quick fixes to mitigate the anxiety of COVID-19.

Study findings supported this: Those who reported that they were more stressed were also more likely to believe misinformation about COVID-19.

“For people who are already in a very stressful situation in their lives, [the COVID-19 pandemic] just adds to it,” she said. “And the desire to see things resolved and to not have this additional level of uncertainty may make people more vulnerable to believing misinformation, because it gives a sense of reassurance.”

The development of COVID-19 vaccines is another area that is abound with myths and misinformation around it.

“I think one of the areas with misinformation that we have to be really careful of is, of course, misinformation related to the vaccine. We have a way out of this pandemic,” Guidry said, explaining that the high efficacy rates seen with the FDA-approved vaccines are very exciting.

“This is a better outcome vaccine-wise than we thought we would get. But that doesn’t mean anything if the vaccinations don’t get in people’s arms.”

Guidry said that some vaccine misconceptions are easier to dispel. For example, if a person is worried that it was not studied enough or corners were cut in the quick development process, they can be given scientific literature to read. But other theories – like powerful people putting microchips in the vaccine to track us – might be a bit harder to approach.

“Misinformation really just plays into our fears,” Guidry said.

Oncology Nurses Can Promote Reliable Info

Since oncology nurses are typically on the frontlines of communication with patients and their caregivers, they are in an ideal spot to talk about COVID-19 misinformation and how it can be harmful – especially in more vulnerable populations like children with cancer.

“Being aware that this is an issue is probably the biggest thing,” Guidry said. “People may be more vulnerable; keep an eye on that. Talk to them about preventative measures, talk to them about the vaccine. Right now, we’re not vaccinating children, but we are vaccinating parents.”

On a broader level, Guidry concluded, “If there’s 1 thing I would wish for our society, it’s a greater trust in science. It’s not perfect, but it’s the best we have.”

Guidry J, Miller CA, Ksinan AJ, et al. COVID-19–Related Misinformation among Parents of Patients with Pediatric Cancer. 

. 2021;27(2):650-652. doi:10.3201/eid2702.203285.

Parents of pediatric patients with cancer were more likely to believe COVID-19 misinformation than parents of children without cancer. 

COVID-19 Misinformation: Parents of Patients May Fall for It 

Ruxolitinib (Jakafi), when administered using a pediatric dosing algorithm, was found to elicit responses in patients with chronic graft-versus-host disease (GVHD) with acceptable safety, according to preliminary findings from a retro review presented during the 2021 Transplantation & Cellular Therapy Meeting.1

The FDA approved ruxolitinib for the treatment of steroid-refractory acute GVHD in adult and pediatric patients 12 years and older in 2019 based on its ability to achieve a high rate of objective responses, as seen in Study INCB 18424-271 (NCT02953678). Despite this progress, there are limited data and understanding on how to administer ruxolitinib in patients with chronic disease and specifically how to dose the drug.2

A retrospective review of 20 patients with chronic GVHD, 4 of whom presented with overlap syndrome was conducted with the goal of providing more understanding on dosing ruxolitinib in pediatric patients with chronic GVHD. Investigators led by YunZu Michele Wang, MD, member, Division of Bone Marrow Transplantation and Immune Deficiency and instructor, Department of Pediatrics at the University of Cincinnati in Ohio, followed a weight-based dosing algorithm by which patients < 25 kg received 2.5 mg of ruxolitinib twice daily and those whose weight was ≥ 25 kg received at 5 mg dose of ruxolitinib twice daily. Patients in the study who were also being treated with tri-azole antifungal therapy had a 50% dose reduction of ruxolitinib upfront. The study protocol allowed for progressive dose increases of up to 10 mg twice daily. Response to ruxolitinib was assessed at the time of therapy initiation as well as a minimum of 30 days after treatment was initiated. Responses were evaluated per the National Institutes of Health 2014 Criteria.

The study population was compiled of patients aged 5 to 26 years. At baseline, information obtained for each patient showed that the underlying disease in the population was beta-thalassemia, DNA ligase intravenous deficiency, chronic neutrophilic leukemia, myelodysplastic syndrome, B-cell acute lymphoblastic leukemia (ALL), Epstein-Barr Virus, and hemophagocytic lymphohistiocytosis, acute myeloid leukemia, chronic disease, hemoglobin sickle cell disease, T-cell ALL, hyper-IgM syndrome, Fanconi anemia, and chronic myeloid leukemia.

Sixteen of the patients were steroid-refractory, but there were also 4 steroid-dependent patients included in the study. As prior systemic therapy, patients received a wide range of agents, some of which were rituximab (Rituxan), imatinib (Gleevec), infliximab (Remicade), and ibrutinib (Imbruvica). Most patients had also received a steroid.

Further assessment of disease characteristics in these patients showed that for the majority, chronic GVHD had affected major organs. The skin was the site of the most impact, which was observed in 11 patients. In addition, the eyes or sclerotic skin were impacted in 7 patients each, the gastrointestinal tract was affected in 6 patients, and the lungs, liver, and genitourinary system were impacted in 3 patients each. There were 2 patients whose joints were affected by their chronic GVHD and 1 whose muscles were compromised.

At the time of ruxolitinib initiation, 16 patients were also on treatment with prednisone at a median dose of 0.5 mg/kg daily (range, 0.08 mg-1.5 mg). The median time from diagnosis to ruxolitinib dosing was 181 days (range, 17-1792 days). Ruxolitinib was administered at a median dose level of 5 mg daily (range, 2.5 mg-10 mg). Notably, 6 patients in the study received the maximum daily ruxolitinib allotment of 20 mg.

Wang et al observed a response to ruxolitinib in the skin, joints, gastrointestinal tract, liver, and muscles. A 100% response rate was observed in the group of patients with sclerotic skin chronic GVHD. In addition, 2 out of 3 patients who had lung involvement experienced pulmonary function test stabilization following treatment with ruxolitinib.

Of the responses elicited by ruxolitinib therapy, 2 were complete responses in the skin, and 12 were partial responses that occurred a median of 48 days from the time ruxolitinib was first dosed. The overall response rate observed with ruxolitinib in this study was 70%. Durable responses were achieved by 13 of the 14 responders at a median of 411 days. There was also 1 patient who achieved stable disease. In the group of 16 patients who were on steroids at the time of ruxolitinib initiation, 13 patients were in the process of being weaned or were off steroids at data cutoff. Overall, 18 patients from the 20-patient cohort were still alive at data cutoff. Wang et al observed progressive disease in 4 of the study subjects, and 2 patients died from chronic GVHD that had severely progressed.

Ruxolitinib demonstrated some ability to activate the JAK/STAT pathway in this study, according to flow cytometry histograms taken before treatment and after initiation of treatment. The 

data showed fewer cases of progressive disease after ruxolitinib.

Ten patients in the study experienced adverse events (AEs) of any grade. In some cases of grade 3 or higher AEs, Wang et al intervened by holding off on treatment. In the case of grade 3 neutropenia, however, the dose of ruxolitinib was reduced. Another intervention involved holding the concurrent myelosuppressive agent in a patient who had 

, grade 3 thrombocytopenia, and grade 4 neutropenia. The final intervention of note involved starting a patient with an 

 colitis, grade 4 thrombocytopenia, and grade 2 neutropenia on a thrombopoietin receptor agonist.

Notably, none of the study subjects developed a fungal infection or pneumocystis pneumonia while receiving ruxolitinib. There was also no infection caused by neutropenia or bleeding caused by thrombocytopenia.

Findings from this retrospective analysis imply that ruxolitinib is safe and tolerable in children with chronic GVHD. Wang et al note that high infection rates are an ongoing problem for the chronic GVHD population and based on this analysis, it is still unclear whether or not ruxolitinib increases the rate of infection for patients with chronic GVHD.

Wang YM, Teusink-Cross A, Elborai Y, et al. Ruxolitinib for the treatment of chronic gvhd in children and young adults. Presented at: Presented at: 2021 Transplantation & Cellular Therapy Meetings; February 8-12, 2021; virtual. Abstract 298.

FDA approves ruxolitinib for acute graft-versus-host disease. New release. FDA. May 24, 2019. Accessed February 9, 2021. 


This article was originally published on OncLive as, "Ruxolitinib Showcases Early Efficacy, Safety in Pediatric Chronic GVHD."

Ruxolitinib Is Promising in Pediatric Chronic GVHD

The FDA has approved crizotinib (Xalkori) for the treatment of pediatric patients 1 year of age and older and young adults with ALK-positive relapsed or refractory, systemic anaplastic large cell lymphoma (ALCL).

The regulatory decision was based on data from Study ADVL0912 (NCT00939770), which showed encouraging antitumor activity with crizotinib in pediatric and adult patients with relapsed/refractory ALCL.

“We are proud to deliver the first biomarker-driven therapy for children and young adults with ALCL. [Crizotinib] offers a meaningful new treatment option for young patients with relapsed or refractory ALK-positive ALCL,” Chris Boshoff, MD, PhD, chief development officer, Oncology, Pfizer Global Product Development, stated in a press release. “[Crizotinib] transformed the treatment of ALK-positive non-small cell lung cancer as the first biomarker-driven therapy for that disease, and this approval is a notable milestone in our journey to continue to follow the science to address cancers with significant unmet need.”

In the open-label, multicenter, single-arm phase 1/2 Study ADVL0912, investigators evaluated the toxicities and optimal dose of crizotinib in younger patients with solid tumors or ALCL that has relapsed after a period of improvement or has not responded to treatment.

The primary end points of this trial focused on identifying the maximum-tolerated dose of the agent, as well as determining the recommended phase 2 dose. Investigators also set out to characterize the pharmacokinetics of crizotinib in pediatric patients with refractory disease.4 Key secondary end points were to define the antitumor activity of the drug in the phase 1 portion of the research, to evaluate the relationship between ALK positivity crizotinib response, the relationship between minimal residual disease status and response, to understand the palatability of the oral formulation of the agent, and to assess potential alterations in bone growth in the patient population.

A total of 121 patients were enrolled to the trial; this included 26 pediatric patients with relapsed/refractory, systemic ALK-positive ALCL who had previously received at least 1 systemic treatment. Patients who received crizotinib experienced an ORR of 88%. Of the 23 patients who achieved a response to treatment, 39% continued to respond for at least 6 months, while 22% continued to respond for at least 12 months.

Regarding safety, the toxicity profile of the agent in children and young adults with ALK-positive ALCL proved to be comparable to its use in those with ALK-positive and ROS1-positive non—small cell lung cancer. The most frequently reported toxicities included diarrhea, vomiting, nausea, vision disorder, headache, musculoskeletal pain, stomatitis, fatigue, decreased appetite, pyrexia, abdominal pain, cough and pruritis.

Additionally, the most common adverse effect determined to be grade 3 or higher in severity comprised neutropenia, lymphopenia and thrombocytopenia. Sixty-two percent of patients experienced grade 4 neutropenia, while 35% reported grade 4 lymphopenia, and 19% experienced grade 4 thrombocytopenia. Just under half of all study participants, or 46%, experienced visual disorders with crizotinib; 65% of those with ALCL reported this toxicity.

“Crizotinib represents an exciting new development in the treatment of this disease,” Meghan Gutierrez, chief executive officer at the Lymphoma Research Foundation, added in the release. “Researchers have made significant progress in our understanding of ALCL, which we hope will continue to improve treatment strategies and the options for children with ALCL. Today’s news builds upon this progress and provides hope to pediatric patients with ALCL and their loved ones.”

1. Pfizer's Xalkori (crizotinib) approved by FDA for ALK-positive anaplastic large cell lymphoma in children and young adults. News release. Pfizer Inc. January 14, 2021. Accessed January 14, 2021. http://bit.ly/35YmdaL.

2. FDA accepts supplemental new drug application for Pfizer’s Xalkori (crizotinib) for the treatment of pediatric ALK-positive anaplastic large cell lymphoma. News release. Pfizer Inc. January 14, 2021. Accessed September 23, 2020. https://bit.ly/2RRX75J.

3. Gambacorti-Passerini C, Orlov S, Zhang L, et al. Long-term effects of crizotinib in ALK-positive tumors (excluding NSCLC): a phase 1b open-label study. Am J Hematol. 2018;93:607-614. doi:10.1002/ajh.25043

4. Crizotinib in treating younger patients with relapsed or refractory solid tumors or anaplastic large cell lymphoma. ClinicalTrials.gov. Updated June 9, 2020. Accessed September 23, 2020. https://clinicaltrials.gov/ct2/show/NCT00939770.

5. Mossé YP, Voss SD, Lim MS, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children's Oncology Group study. J Clin Oncol. 2017;35(28):3215-3221. doi:10.1200/JCO.2017.73.4830

FDA Approves Crizotinib for Pediatric and Young Adult ALK+ Anaplastic Large Cell Lymphoma

FDA Approves Crizotinib for Pediatric/Young Adult ALK+ Anaplastic Large Cell Lymphoma

Germline predisposition variants associated with cancer susceptibility syndromes can underlie the genetic risk for rhabdomyosarcoma (RMS), indicating that germline testing should be performed in accordance with RMS subtypes and irrespective of age, according to findings from a study published in the 

Journal of the National Cancer Institute.

Germline cancer-predisposition variants were identified in 45 patients with RMS across 15 autosomal dominant genes (7.3%; all FOXO1 fusion—negative). The enrichment of germline cancer-predisposition variants in this population was statistically significant compared with controls (1.4%; P = 1.3 x 10-22). The majority of the predisposition variants (73.3%) were identified in predisposition genes that have been linked to pediatric RMS risk, such as TP53 (Li-Fraumeni syndrome), NF1 (neurofibromatosis type I), HRAS, and BRCA2.

“Currently, there are a limited number of genes considered to cause pediatric RMS,” said He (Hurley) Li, PhD, postdoctoral associate at the Human Genome Sequencing Center at Baylor College of Medicine and first author of the study. “But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

“Our study highlights the utility of sequencing large numbers of children diagnosed with cancer to identify these types of changes, termed pathogenic variants,” said Philip Lupo, PhD, associate professor of pediatrics, hematology and oncology at Baylor College of Medicine, and corresponding author of the study. “Understanding the frequency of these variants in children with RMS could influence strategies for genetic testing and future surveillance of patients with a pathogenic variant, as some of these variants may predispose children to multiple cancers later in life.”

RMS is an aggressive tumor and the most common soft tissue sarcoma in children. Despite its prevalence, the genetic susceptibility of the malignancy is not as well defined compared with other pediatric malignancies.

Germline DNA from 615 patients with newly diagnosed RMS, consented through the Children’s Oncology Group, underwent whole-exome sequencing. The prevalence of cancer-predisposition variants in 63 autosomal dominant cancer-predisposition genes in these patients was compared with population controls (n = 9963).

Additional findings showed that 5 patients had well-described oncogenic missense variants in HRAS (p.G12V and p.G12S) linked to Costello syndrome.

Differences in genetic etiology were reported based on histology. Specifically, germline variants were more common in patients with embryonal versus alveolar RMS (10.0% vs 3.0%, respectively; P = .02).

Furthermore, patients with a cancer-predisposition variant were found to be younger at diagnosis (P = 9.9 x 10-4), and approximately half of germline variants (40.0%) were identified in patients aged 3 years or older, contrasting current genetic testing guidelines in patients diagnosed at an early age.

“These results may change our current decisions about when to offer genetic testing for children with RMS, which right now is focused on very young patients,” concluded Sharon Plon, MD, PhD, medical geneticist on the study team and professor of pediatrics, oncology and molecular and human genetics at Baylor College of Medicine.

Li H, Sisoudiya SD, Martin-Giacalone BA, et al. Germline cancer-predisposition variants in pediatric rhabdomyosarcoma: a report from the Children’s Oncology Group. JNCI. 2020. doi:10.1093/jnci/djaa204

Genomic assessment of cancer-predisposition landscape of pediatric rhabdomyosarcoma. News release. Baylor College of Medicine. December 30, 2020. Accessed January 4, 2021. https://bit.ly/358HHkO

TP53, NF1 Among Genetic Variants Identified as Precursors to Pediatric Rhabdomyosarcoma

“But our study is pointing to new genes to consider. For example, we found that the BRCA2 gene, typically associated with adult breast and ovarian cancer, may also somehow influence the susceptibility of pediatric RMS.”

Genetic Precursors to Pediatric Rhabdomyosarcoma Identified

The FDA approved pralsetinib (Gavreto) for adults and children aged 12 or older with advanced or metastatic 

-mutant medullary thyroid cancer (MTC) who need systemic therapy or 

 fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory.

The approval is based on findings from the open-label, multi-cohort ARROW clinical trial, where the drug was administered to 55 patients with 

-mutant MTC who received prior cabozantinib or vandetanib. Overall response rate (ORR) was 60%, with 79% of responses lasting 6 or more months.

Additionally, pralsetinib was also evaluated in 29 patients with 

-mutant MTC who did not have previous cabozantinib or vandetanib. The ORR in this cohort was 66%, with 84% of responding patients having responses that lasted 6 months or longer. Finally, 9 patients who were radioactive iodine refractory received pralsetinib. Their ORR was 89%, and all responding patients had a response of 6 or more months.

It is recommended that pralsetinib be given orally once a day at a 400 mg dose. Patients should take the medication on an empty stomach, with no food intake at least 2 hours before and at least 1 hour after medication.

The most common adverse events, which occurred in 25% or more of patients included: constipation, hypertension, fatigue, musculoskeletal pain, and diarrhea. 

Common grade 3-4 laboratory abnormalities, which occurred in at least 2% of patients were: decreased lymphocytes, decreased neutrophils, decreased hemoglobin, decreased phosphate, decreased calcium (corrected), decreased sodium, increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), decreased platelets, and increased alkaline phosphatase.

The FDA made this approval 3 months ahead of schedule with the use of their Real-Time Oncology Review (RTOR) pilot program, as well as Assessment Aid. 

The FDA approved pralsetinib (Gavreto) for adults and children aged 12 or older with advanced or metastatic RET-mutant medullary thyroid cancer (MTC) who need systemic therapy or RET fusion-positive thyroid cancer who require systemic therapy and are radioactive iodine-refractory.
 

FDA Approves Pralsetinib for RET-Altered Thyroid Cancers

The FDA has granted an accelerated approval to naxitamab-gqgk (Danyelza) for use in combination with granulocyte-macrophage colony-stimulating factor as a treatment for pediatric patients 1 year of age and older and adult patients with relapsed/refractory high-risk neuroblastoma in the bone or bone marrow who have demonstrated a partial response, minor response, or stable disease to prior treatment.

The decision is supported by clinical evidence from 2 studies in patients with high-risk neuroblastoma with refractory/relapsed disease.

“Today is an important day for children living with refractory/relapsed high-risk neuroblastoma,” said Thomas Gad, founder, chairman and president, of Y-mAbs, the developer of naxitamab. “It’s very exciting to see this treatment go from being an experimental therapy used at my daughter’s bedside to now being FDA approved. On behalf of Y-mAbs, I want to thank all the patients and physicians who took part in our clinical trials and our scientific partner, Memorial Sloan Kettering, for helping us achieve this goal.”

Naxitamab is a GD2-directed monoclonal antibody, which is highly expressed in various neuroectoderm-derived tumors and sarcomas. Naxitamab is administered to patients 3 times per week in an outpatient setting and is repeated every 4 weeks.

Initial results from the Study 12-230 trial (NCT01757626) had been presented at the 2019 International Society of Pediatric Oncology Annual Congress.2 At the meeting, data from several subsets of patients who received the agent were released.

In 28 patients with primary refractory high-risk neuroblastoma, the ORR as 78% and the 2-year PFS rate was 50%. In a subset of 35 patients with relapsed neuroblastoma resistant to salvage therapy, the ORR was 37% and the 2-year PFS rate was 36%. In 44 patients with high-risk neuroblastoma in second or later complete remission and no evidence of disease, naxitamab was given in combination with GM-CSF as maintenance therapy; this resulted in a 2-year PFS rate of 52%.

Findings from a trial (NCT03363373) detailed in a poster presentation that had recently been presented at the 2020 ASCO Virtual Meeting showed that treatment with the agent in 24 patients with relapsed/refractory high-risk neuroblastoma led to a high complete response (CR) rate of 71% (95% CI, 49%-87%) and an overall objective response rate (ORR) of 79 (95% CI, 58%-93%).

Of 16 patients who were primary refractory, the ORR with naxitamab was 88% (95% CI, 62%-98%) and the CR rate was 81% (95% CI, 54%-96%). Of 8 patients who had an incomplete response to salvage treatment, the ORR and CR rates were 63% (95% CI, 24%-91%) and 50% (95% CI, 16%-84%), respectively. Thirteen of 14 patients who had bone marrow disease at baseline experienced bone marrow clearance.

The median progression-free survival (PFS) was 42 weeks (95% CI, 26—not estimable), and the median follow-up time in patients evaluable for efficacy was 30 weeks.

With regard to safety, 88% of patients experienced at least 1 related treatment-emergent adverse event (TEAE) that was grade 3/4 in severity; these events included general disorders and administration site conditions (72%), pain (72%), vascular disorders (60%), hypotension (60%), respiratory, thoracic, and mediastinal disorders (44%), skin and subcutaneous tissue disorders (40%), and urticaria (40%), among others.

Six serious related TEAEs were reported in 5 patients: anaphylactic reaction (n = 4), pyrexia (n = 1), and respiratory depression (n = 1).

The accelerated approval is contingent on the results of the confirmatory, ongoing Study 201 trial. The study will enroll a minimum of 80 patients.

1. FDA Approves Y-mAbs’ DANYELZA® (naxitamab-gqgk) for the Treatment of Neuroblastoma. News release. Y-mAbs. November 25, 2020. Accessed November 25, 2020. https://bit.ly/3nVyHGl.

2. Y-mAbs announces naxitamab update. News release. Y-mAbs Therapeutics, Inc. October 25, 2019. Accessed June 2, 2020. bit.ly/2XrflyG.

3. Mora J, Chan GC-F, Morgenstern DA, et al. Naxitamab, a new generation anti-GD2 monoclonal antibody (mAb) for treatment of relapsed/refractory high-risk neuroblastoma (HR-NB). J Clin Oncol. 2020;38(suppl 15):10543. doi:10.1200/JCO.2020.38.15_suppl.1054.

FDA Approves Naxitamab-gqgk for Relapsed/Refractory High-Risk Neuroblastoma

Childhood/AYA Cancer