Pediatric Cancer Drug Development: Leveraging Insights in Cancer Biology and the Evolving Regulatory Landscape to Address Challenges and Guide Further Progress.

The discovery and development of anticancer drugs for pediatric patients have historically languished when compared to both past and recent activity in drug development for adult patients, notably the dramatic spike of targeted and immune-oncology therapies. The reasons for this difference are multifactorial. Recent changes in the regulatory landscape surrounding pediatric cancer drug development and the understanding that some pediatric cancers are driven by genetic perturbations that also drive disparate adult cancers afford new opportunities. The unique cancer-initiating events and dependencies of many pediatric cancers, however, require additional pediatric-specific strategies. Research efforts to unravel the underlying biology of pediatric cancers, innovative clinical trial designs, model-informed drug development, extrapolation from adult data, addressing the unique considerations in pediatric patients, and use of pediatric appropriate formulations, should all be considered for efficient development and dosage optimization of anticancer drugs for pediatric patients.

FDA Approval Summary: Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma.

In January 2023, the FDA granted accelerated approval to pirtobrutinib for the treatment of adult patients with relapsed or refractory mantle cell lymphoma (MCL) after at least two lines of systemic therapy, including a Bruton tyrosine kinase (BTK) inhibitor. Approval was based on BRUIN, a single-arm study of pirtobrutinib monotherapy in patients with B-cell malignancies. Efficacy was based on independent review committee-assessed overall response rate (ORR) supported by durability of response in 120 patients with relapsed or refractory MCL who had received a prior BTK inhibitor and received the approved pirtobrutinib dosage of 200 mg once daily. The ORR was 50% [95% confidence interval (CI), 41-59], and the complete response rate was 13% (95% CI, 7-20), with an estimated median duration of response of 8.3 months. The most common nonhematologic adverse reactions were fatigue, musculoskeletal pain, diarrhea, edema, dyspnea, pneumonia, and bruising. Warnings and Precautions in labeling include infection, hemorrhage, cytopenias, atrial arrhythmias, and second primary malignancies. Postmarketing studies were required to evaluate longer-term safety of pirtobrutinib and to verify the clinical benefit of pirtobrutinib. This article summarizes key aspects of the regulatory review, including the indication statement, efficacy and safety considerations, and postmarketing requirements.

Physiologically Based Pharmacokinetic Modeling of Nilotinib for Drug-Drug Interactions, Pediatric Patients, and Pregnancy and Lactation.

Nilotinib is a second-generation BCR-ABL tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia in both adult and pediatric patients. The pharmacokinetics (PK) of nilotinib in specific populations such as pregnant and lactating people remain poorly understood. Therefore, the objectives of the current study were to develop a physiologically based pharmacokinetic (PBPK) model to predict nilotinib PK in virtual drug-drug interaction (DDI) studies, as well as in pediatric, pregnant, and lactating populations. The nilotinib PBPK model was built in PK-Sim, which is part of the free and open-source software Open Systems Pharmacology. The observed clinical data for the validation of the nilotinib models were obtained from the literature. The model reasonably predicted nilotinib concentrations in the adult population; the DDIs between nilotinib and rifampin or ketoconazole in the adult population; and the PK in the pediatric, pregnant, and lactating populations, although in the latter 2 populations plasma concentrations were slightly underestimated. The ratio of predicted versus observed PK parameters for the adult model ranged from 0.71 to 1.11 for area under the concentration-time curve and 0.55 to 0.95 for maximum concentration. For the DDI, the predicted area under the concentration-time curve ratio and maximum concentration ratio fell within the Guest criterion. The current study demonstrated the utility of using PBPK modeling to understand the mechanistic basis of PK differences between adults and specific populations, such as pediatrics, and pregnant and lactating individuals, indicating that this technology can potentially inform or optimize dosing conditions in specific populations.

Utility of Physiologically Based Pharmacokinetic Modeling to Investigate the Impact of Physiological Changes of Pregnancy and Cancer on Oncology Drug Pharmacokinetics.

BACKGROUND: The treatment of cancer during pregnancy remains challenging with knowledge gaps in drug dosage, safety, and efficacy due to the under-representation of this population in clinical trials. Our aim was to investigate physiological changes reported in both pregnancy and cancer populations into a PBPK modeling framework that allows for a more accurate estimation of PK changes in pregnant patients with cancer. METHODS: Paclitaxel and docetaxel were selected to validate a population model using clinical data from pregnant patients with cancer. The validated population model was subsequently used to predict the PK of acalabrutinib in pregnant patients with cancer. RESULTS: The Simcyp pregnancy population model reasonably predicted the PK of docetaxel in pregnant patients with cancer, while a modified model that included a 2.5-fold increase in CYP2C8 abundance, consistent with the increased expression during pregnancy, was needed to reasonably predict the PK of paclitaxel in pregnant patients with cancer. Changes in protein binding levels of patients with cancer had a minimal impact on the predicted clearance of paclitaxel and docetaxel. PBPK modeling predicted approximately 60% lower AUC and Cmax for acalabrutinib in pregnant versus non-pregnant patients with cancer. CONCLUSIONS: Our results suggest that PBPK modeling is a promising approach to investigate the effects of pregnancy and cancer on the PK of oncology drugs and potentially inform dosing for pregnant patients with cancer. Further evaluation and refinement of the population model are needed for pregnant patients with cancer with additional compounds and clinical PK data.

Landscape and Regulatory Perspective on Oncology Drugs in Pregnancy.

Cancers affecting pregnant women include breast cancer, melanoma, thyroid cancer, cervical cancer, lymphomas, and leukemias. The medical management of cancer during pregnancy with molecularly targeted oncology drugs remains quite challenging, with knowledge gaps about the drugs' safety and efficacy due to exclusion of pregnant women from cancer clinical trials, discontinuation of individuals who become pregnant during clinical trials, and limited information on appropriate dosing of molecularly targeted oncology drugs during pregnancy. Physiological changes occur during pregnancy and may result in alterations in the absorption, distribution, metabolism, and excretion of drugs used in pregnant women. Physiologically based pharmacokinetic modeling that incorporates physiological changes induced by both the cancer disease state and pregnancy has the potential to inform dosing of molecularly targeted oncology drugs for pregnant women, improve our understanding of the pharmacokinetic changes associated with pregnancy in patients with cancer, facilitate the design of potential studies of molecularly targeted oncology drugs in pregnant women to support dosing recommendations, and provide model-informed pharmacokinetic data to support regulatory decision making.

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

FDA Approval Summary: Ruxolitinib for Treatment of Chronic Graft-Versus-Host Disease after Failure of One or Two Lines of Systemic Therapy.

On September 22, 2021, the Food and Drug Administration approved ruxolitinib for the treatment of chronic graft-versus-host disease (cGVHD) after the failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-365 (REACH-3; CINC424D2301; NCT03112603), a randomized, open-label, multicenter trial of ruxolitinib in comparison to best available therapy (BAT) for the treatment of corticosteroid-refractory cGVHD occurring after the allogeneic hematopoietic stem cell transplantation. A total of 329 patients were randomized 1:1 to receive either ruxolitinib 10 mg twice daily (n = 165) or BAT (n = 164). BAT was selected by the investigator prior to randomization. The overall response rate through Cycle 7 Day 1 was 70% (95% CI, 63-77) in the ruxolitinib arm, and 57% (95% CI, 49-65) in the BAT arm. The median duration of response, calculated from first response to progression, death, or initiation of new systemic therapies for cGVHD, was 4.2 months (95% CI, 3.2-6.7) for the ruxolitinib arm and 2.1 months (95% CI, 1.6-3.2) for the BAT arm; and the median time from first response to death or initiation of new systemic therapies for cGVHD was 25 months (95% CI, 16.8-not estimable) for the ruxolitinib arm and 5.6 months (95% CI, 4.1-7.8) for the BAT arm. Common adverse reactions included anemia, thrombocytopenia, and infections. Given the observed response rate with durability, the clinical benefit of ruxolitinib appears to outweigh the risks of treatment for cGVHD after the failure of one or two lines of systemic therapy.

FDA Approval Summary: Oral Azacitidine for Continued Treatment of Adults with Acute Myeloid Leukemia Unable to Complete Intensive Curative Therapy.

On September 1, 2020, the FDA granted approval for oral azacitidine (Onureg, CC-486) for continued treatment of adult patients with acute myeloid leukemia (AML) who achieved complete remission (CR) or complete remission with incomplete blood count recovery (CRi) following intensive induction chemotherapy and who are not able to complete intensive curative therapy. Approval was based on improvement in overall survival using CC-486 300 mg daily in a 2 weeks on/2 weeks off schedule in comparison with placebo (HR, 0.69; 95% confidence interval, 0.55-0.86; P = 0.0009) in the randomized trial CC-486-AML-001 (QUAZAR) in adults ≥ 55 years old with AML in CR/CRi who did not complete standard intensive induction and postremission therapy. Of note, the study was not designed to test CC-486 as maintenance after standard postremission therapy or as an alternative to standard postremission therapy. Gastrointestinal toxicities, fatigue, and pneumonia were more common in patients treated with CC-486 compared with placebo. Additional studies are needed to establish safe dosing for patients with hepatic impairment. The pharmacokinetic parameters, recommended dose, and recommended schedule of CC-486 differ substantially from those of other azacitidine formulations; therefore, inappropriate substitutions between formulations pose a considerable risk for harm.

Recommendations for Dose Selection for Adolescent Patients in Relevant Adult Oncology Clinical Trials.

Our research supported the dose selection recommendations for adolescents in the US Food and Drug Administration (FDA) Guidance on Inclusion of Adolescent Patients in Adult Oncology Clinical Trials. The FDA Guidance states that for drugs administered as a flat dose in adults and data showing no clinically meaningful effect of body size on drug exposure and toxicity in adults, a minimum body weight threshold may need to be defined to prevent adolescents who have a lower body weight from exceeding adult exposures. Our review of adult population pharmacokinetic analyses of new molecular entities approved for oncology between January 2015 and March 2021 suggested that 40 kg (the approximate median body weight of a 12-year-old) is generally the lower end of the body weight range that has no clinically relevant effect on drug pharmacokinetics or safety. The minimum body weight threshold and selection of an appropriate dose for adolescents in relevant adult oncology clinical trials should ultimately be determined based on available data on pharmacokinetics or pharmacodynamics of the investigational drug with consideration of body size effect on drug exposure, toxicity, and efficacy data (if available), the therapeutic index of the drug, and dose- and exposure-response relationships in adults.

Fusion Oncoproteins in Childhood Cancers: Potential Role in Targeted Therapy.

Cancer remains the leading cause of death from disease in children. Historically, in contrast to their adult counterparts, the causes of pediatric malignancies have remained largely unknown, with most pediatric cancers displaying low mutational burdens. Research related to molecular genetics in pediatric cancers is advancing our understanding of potential drivers of tumorigenesis and opening new opportunities for targeted therapies. One such area is fusion oncoproteins, which are a product of chromosomal rearrangements resulting in the fusion of different genes. They have been identified as oncogenic drivers in several sarcomas and leukemias. Continued advancement in the understanding of the biology of fusion oncoproteins will contribute to the discovery and development of new therapies for childhood cancers. Here we review the current scientific knowledge on fusion oncoproteins, focusing on pediatric sarcomas and hematologic cancers, and highlight the challenges and current efforts in developing drugs to target fusion oncoproteins.

FDA Approval Summary: Selumetinib for Plexiform Neurofibroma.

On April 10, 2020, the FDA approved selumetinib (KOSELUGO, AstraZeneca) for the treatment of pediatric patients 2 years of age and older with neurofibromatosis type 1 who have symptomatic, inoperable plexiform neurofibromas. Approval was based on demonstration of a durable overall response rate per Response Evaluation in Neurofibromatosis and Schwannomatosis criteria and supported by observed clinical improvements in plexiform neurofibroma-related symptoms and functional impairments in 50 pediatric patients with inoperable plexiform neurofibromas in a single-arm, multicenter trial. The overall reponse rate per NCI investigator assessment was 66% (95% confidence interval, 51-79) with at least 12 months of follow-up. The median duration of response was not reached, and 82% of responding patients experienced duration of response ≥12 months. Clinical outcome assessment endpoints provided supportive efficacy data. Risks of selumetinib are consistent with MAPK (MEK) inhibitor class effects, including ocular, cardiac, musculoskeletal, gastrointestinal, and dermatologic toxicities. Safety was assessed across a pooled database of 74 pediatric patients with plexiform neurofibromas and supported by adult and pediatric selumetinib clinical trial data in cancer indications. The benefit-risk assessment for selumetinib in patients with inoperable plexiform neurofibromas was considered favorable.

FDA Approval Summary: Ruxolitinib for Treatment of Steroid-Refractory Acute Graft-Versus-Host Disease.

On May 24, 2019, the Food and Drug Administration approved ruxolitinib for steroid-refractory acute graft-versus-host disease (SR-aGVHD) in adult and pediatric patients 12 years and older. Approval was based on Study INCB 18424-271 (REACH-1; NCT02953678), an open-label, single-arm, multicenter trial that included 49 patients with grades 2-4 SR-aGVHD occurring after allogeneic hematopoietic stem cell transplantation. Ruxolitinib was administered at 5 mg twice daily, with dose increases to 10 mg twice daily permitted after 3 days in the absence of toxicity. The Day-28 overall response rate was 57.1% (95% confidence interval [CI]: 42.2-71.2). The median duration of response was 0.5 months (95% CI: 0.3-2.7), and the median time from Day-28 response to either death or need for new therapy for acute GVHD was 5.7 months (95% CI: 2.2 to not estimable). Common adverse reactions included anemia, thrombocytopenia, neutropenia, infections, edema, bleeding, and elevated transaminases. Ruxolitinib is the first drug approved for treatment of SR-aGVHD. IMPLICATIONS FOR PRACTICE: Ruxolitinib is the first Food and Drug Administration-approved treatment for steroid-refractory acute graft-versus-host disease in adult and pediatric patients 12 years and older. Its approval provides a treatment option for the 60% of those patients who do not respond to steroid therapy.

FDA Approval Summary: Tagraxofusp-erzs For Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%-81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2-12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN.

FDA Approval Summary: Glasdegib for Newly Diagnosed Acute Myeloid Leukemia.

On November 21, 2018, the FDA approved glasdegib (Daurismo; Pfizer), a small-molecule Hedgehog inhibitor, in combination with low-dose cytarabine (LDAC) for treatment of newly diagnosed acute myeloid leukemia (AML) in adults ≥ 75 years or with comorbidities that preclude use of intensive induction chemotherapy. Evidence of clinical benefit came from Study BRIGHT AML 1003, a randomized trial comparing glasdegib+LDAC with LDAC alone for treatment of newly diagnosed AML in 115 patients either ≥ 75 years old or ≥ 55 years old with preexisting comorbidities. Efficacy was established by improved overall survival (OS) with the combination compared with LDAC alone (HR, 0.46; 95% confidence interval, 0.30-0.71; one-sided stratified log-rank P = 0.0002). Median OS was 8.3 months with the combination and 4.3 months with LDAC alone. Common adverse reactions included cytopenias, fatigue, hemorrhage, febrile neutropenia, musculoskeletal pain, nausea, edema, dyspnea, decreased appetite, dysgeusia, mucositis, constipation, and rash. The label includes a boxed warning for embryo-fetal toxicity and a warning for QT interval prolongation. There is a limitation of use for patients with moderate-to-severe hepatic and severe renal impairment; trials studying glasdegib in these patient populations are required as a condition of this approval.See related commentary by Fathi, p. 6015.

Pediatric Development of Molecularly Targeted Oncology Drugs.

Oncology products developed for adult cancers often receive full waivers of pediatric studies. This analysis retrospectively identified products with potential pediatric development opportunities despite a full waiver. Initial pediatric study plans submitted to the US Food and Drug Administration from 2012 to 2016 for oncology products with plans to request full waivers of pediatric studies were reviewed to determine if a scientific rationale existed for pediatric evaluation based on the molecular mechanism of action (MOA), clinical experience, nonclinical evidence, or published genome sequencing data. Of the 98 oncology products reviewed, pediatric studies were eventually conducted in 55 (56%) despite having a waiver, 33 additional (34%) products were considered to have a rationale for pediatric evaluation but were not studied, and 10 (10%) products had no current evidence to support pediatric development. Conducting pediatric studies based on molecular MOA, rather than indication, provides opportunities to evaluate products earlier and accelerate pediatric oncology drug development.

Bridging Adult Experience to Pediatrics in Oncology Drug Development.

Pediatric drug development in the United States has grown under the current regulations made permanent by the Food and Drug Administration Safety and Innovation Act of 2012. Over 1200 pediatric studies have now been submitted to the US FDA, but there is still a high rate of failure to obtain pediatric labeling for the indication pursued. Pediatric oncology represents special problems in that the disease is most often dissimilar to any cancer found in the adult population. Therefore, the development of drug dosing in pediatric oncology patients represents a special challenge. Potential approaches to pediatric dosing in oncology patients include extrapolation of efficacy from adult studies in those few cases where the disease is similar, inclusion of adolescent patients in adult trials when possible, and bridging the adult dose to the pediatric dose. An analysis of the recommended phase 2 dose for 40 molecularly targeted agents in pediatric patients provides some insight into current practices. Increased knowledge of tumor biology and efforts to identify and validate molecular targets and genetic abnormalities that drive childhood cancers can lead to increased opportunities for precision medicine in the treatment of pediatric cancers.

Induction dosing of peginterferon alfa-2a (40 KD) and/or high-dose ribavirin in genotype 1 CHC patients with difficult-to-treat characteristics: pharmacokinetic and viral kinetic (PK/VK) assessment from PROGRESS.

BACKGROUND/AIMS: PROGRESS randomized chronic hepatitis C genotype 1 patients with a baseline viral load ≥400,000 IU/mL weighing ≥85 kg to regimens of 180 µg/week for 48 weeks or 360 µg/week for 12 weeks followed by 180 µg/week for 36 weeks peginterferon alfa-2a plus ribavirin. This analysis explored pharmacokinetics and early viral kinetics (VK) and evaluates differences between groups. METHODOLOGY: Blood samples for pharmacokinetic and VK analyses were collected from 51 patients enrolled in the PROGRESS study. RESULTS: Mean peginterferon alfa-2a trough concentration at week 12 was 11.7±4.3 ng/mL for 180 µg and 23.4±11.3 ng/mL for 360 µg. Early VK profiles suggested a trend towards an enhanced viral decline in the 360 µg groups with a mean decrease in HCV RNA at 48 hours post first dose of 1.04 log10 (IU/mL) compared with 0.76 log10 (IU/mL) in the 180 µg groups. Mean beta slope increased with dose, ranging from 0.38±0.26 log10 IU/week at 180 µg to 0.52±0.32 log10 IU/week at 360 µg. CONCLUSIONS: Early viral de clines may be enhanced with the 360 µg dose. These data may suggest the utility of high-dose peginterfer on alfa-2a plus direct-acting antivirals (DAA) in select difficult-to-treat populations.

FDA approval: ceritinib for the treatment of metastatic anaplastic lymphoma kinase-positive non-small cell lung cancer.

On April 29, 2014, the FDA granted accelerated approval to ceritinib (ZYKADIA; Novartis Pharmaceuticals Corporation), a breakthrough therapy-designated drug, for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. The approval was based on a single-arm multicenter trial enrolling 163 patients with metastatic ALK-positive NSCLC who had disease progression on (91%) or intolerance to crizotinib. Patients received ceritinib at a starting dose of 750 mg orally once daily. The objective response rate (ORR) by a blinded independent review committee was 44% (95% CI, 36-52), and the median duration of response (DOR) was 7.1 months. The ORR by investigator assessment was similar. Safety was evaluated in 255 patients. The most common adverse reactions and laboratory abnormalities included diarrhea (86%), nausea (80%), increased alanine transaminase (80%), increased aspartate transaminase (75%), vomiting (60%), increased glucose (49%), and increased lipase (28%). Although 74% of patients required at least one dose reduction or interruption due to adverse reactions, the discontinuation rate due to adverse reactions was low (10%). With this safety profile, the benefit-risk analysis was considered favorable because of the clinically meaningful ORR and DOR.

Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device.

BACKGROUND: Peginterferon alfa-2a (40 kDa) is currently administered using a prefilled syringe. The peginterferon alfa-2a disposable autoinjector is a new safety-engineered device designed to facilitate injection and reduce the risk of needlestick injuries. The analysis of two open-label Phase I trials evaluated the pharmacokinetics, successful administration, and tolerability of peginterferon alfa-2a when using the autoinjector. The studies were performed to support the filing and registration of the autoinjector device. METHODS: In trial 1, 50 healthy adult subjects received one 180 µg dose of peginterferon alfa-2a via the autoinjector. Serial blood samples were collected predose, up to 336 hours following drug administration, and at follow-up (28 ± 3 days post-dosing) for noncompartmental pharmacokinetic analysis. Trial 2 randomized 60 adult patients with chronic hepatitis C to 180 µg peginterferon alfa-2a once weekly by the autoinjector or prefilled syringe for 3 weeks followed by the alternative device (prefilled syringe or autoinjector, respectively) for 3 weeks. Patients also received ribavirin. Administration by the devices was evaluated under direct observation by a study staff member and by patient subjective assessment. RESULTS: In trial 1, following a single dose of peginterferon alfa-2a, the maximum plasma concentration was 16.1 ± 5.3 ng/mL (mean ± standard deviation), and area under the concentration time curve (0-168 hours) was 1996 ± 613 ng · hour/mL, similar to that reported using a vial/syringe or prefilled syringe. In trial 2, few patients showed handling difficulties with either device. Generally, patients were observed to be more satisfied and confident, followed instructions better, and successfully initiated injection with the autoinjector versus the prefilled syringe. Patients reported the autoinjector to be more convenient and easier to use. No pain or discomfort was experienced using the autoinjector. The autoinjector safety profile was consistent with that known for peginterferon alfa-2a/ribavirin. CONCLUSION: These results indicate that peginterferon alfa-2a can be successfully and safely delivered via the autoinjector and that the device is easy to handle.