Dosage Optimization: A Regulatory Perspective for Developing Oncology Drugs.

Optimized dosages provide a secure foundation for the development of well-tolerated and effective oncology drugs. Project Optimus, an initiative within the Oncology Center of Excellence, strives to reform the dosage optimization and dosage selection paradigm in oncology. This initiative stems from the availability of targeted drugs and from the demand for more tolerable dosages from patients, caregivers, and advocates.

Perspectives on Drug Development for the Treatment of Chronic Myeloid Leukemia in Pregnant Patients and Patients Who Are Breastfeeding.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous.

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.

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.

FDA Approval Summary: Dabrafenib in Combination with Trametinib for BRAFV600E Mutation-Positive Low-Grade Glioma.

On March 16, 2023, the FDA approved dabrafenib in combination with trametinib (Tafinlar, Mekinist; Novartis Pharmaceuticals Corporation) for the treatment of pediatric patients with low-grade glioma (LGG) with a BRAFV600E mutation who require systemic therapy. FDA also approved oral formulations of both drugs suitable for patients who cannot swallow pills. This approval was based on the LGG cohort from study CDRB436G2201 (NCT02684058), a multicenter, open-label trial in which pediatric patients with LGG with a BRAFV600E mutation were randomly assigned 2:1 to dabrafenib plus trametinib (D+T) or carboplatin plus vincristine (C+V).

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.

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.

FDA Oncology Center of Excellence Project Renewal: Engaging the Oncology Community to Update Product Labeling for Older Oncology Drugs.

The FDA conducts independent reviews of scientific data obtained with investigational drug products to ensure that they are safe and effective. As a result of this process, FDA-approved product labeling is generated that is considered one of the most trusted sources of information for use of an approved drug. But FDA approval is only the beginning of the life cycle of a new drug; the first oncology drugs now have more than 7 decades of clinical experience in the postmarketing setting.

FDA Approval Summary: (Daunorubicin and Cytarabine) Liposome for Injection for the Treatment of Adults with High-Risk Acute Myeloid Leukemia.

On August 3, 2017, the FDA granted regular approval to Vyxeos (also known as CPX-351; Jazz Pharmaceuticals), a liposomal formulation of daunorubicin and cytarabine in a fixed combination, for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia (t-AML) or acute myeloid leukemia (AML) with myelodysplasia-related changes (AML-MRC). Approval was based on data from Study CLTR0310-301, a randomized, multicenter, open-label, active-controlled trial comparing Vyxeos with a standard combination of daunorubicin and cytarabine ("7+3") in 309 patients 60-75 years of age with newly diagnosed t-AML or AML-MRC. Because of elemental copper concerns with the Vyxeos formulation, patients with Wilson disease were excluded from the study.

FDA Approval Summary: Vemurafenib for the Treatment of Patients with Erdheim-Chester Disease with the V600 Mutation.

On November 6, 2017, the U.S. Food and Drug Administration (FDA) granted regular approval to vemurafenib for the treatment of adult patients with Erdheim-Chester disease (ECD) with V600 mutation.

FDA Approval Summary: Midostaurin for the Treatment of Advanced Systemic Mastocytosis.

In April 2017, the U.S. Food and Drug Administration granted regular approval to midostaurin for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome.

Unlabelled: On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc.

FDA Approval Summary: Daratumumab for Treatment of Multiple Myeloma After One Prior Therapy.

Unlabelled: On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy.

FDA Approval Summary: Sonidegib for Locally Advanced Basal Cell Carcinoma.

On July 24, 2015, the FDA approved sonidegib (ODOMZO; Novartis) for the treatment of patients with locally advanced basal cell carcinoma (laBCC) not amenable to curative surgery or radiotherapy. The approval was based on data from one randomized, double-blind, noncomparative trial of two doses of sonidegib administered to 230 hedgehog inhibitor-naïve patients with metastatic basal cell carcinoma (mBCC, = 36) or laBCC ( = 194). Patients were randomized 2:1 to receive sonidegib 800 mg ( = 151) or 200 mg ( = 79) daily.

FDA Approval: Alectinib for the Treatment of Metastatic, ALK-Positive Non-Small Cell Lung Cancer Following Crizotinib.

On December 11, 2015, the FDA granted accelerated approval to alectinib (Alecensa; Genentech) for the treatment of patients with anaplastic lymphoma receptor tyrosine kinase (ALK)-positive, metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib. This approval was based on two single-arm trials including 225 patients treated with alectinib 600 mg orally twice daily. The objective response rates (ORR) by an independent review committee in these studies were 38% [95% confidence interval (CI), 28-49] and 44% (95% CI, 36-53); the median durations of response (DOR) were 7.

FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma.

On July 23, 2014, the FDA granted accelerated approval to idelalisib (Zydelig tablets; Gilead Sciences, Inc.) for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies. In a multicenter, single-arm trial, 123 patients with relapsed indolent non-Hodgkin lymphomas received idelalisib, 150 mg orally twice daily.

Epigenetics and oncology.

Epigenetic modifications play a critical role in the development of pediatric and adult cancers, contributing to the cumulative changes observed as normal cells undergo malignant transformation. These modifications have been studied to develop epigenome-targeted therapies and new diagnostic tools. The U.

Are hepatic impairment studies necessary for therapeutic proteins?

Objective: This study assessed whether trials to investigate the effect of hepatic impairment on the pharmacokinetics of therapeutic proteins (TPs), which are conducted for small molecule drugs, are necessary.

Methods: The product labeling for 91 TPs that have been approved by the US Food and Drug Administration were reviewed. A PubMed search was also conducted to identify completed studies that assessed the effect of hepatic impairment on the pharmacokinetics of TPs.

Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper.

Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker. These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs. Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges.

Approval summary: Cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer.

On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab in combination with cisplatin or carboplatin and 5-fluorouracil for the first-line treatment of patients with recurrent locoregional or metastatic squamous cell head and neck cancer.

Desired professional development pathways for clinical pharmacists.

The 2012 American College of Clinical Pharmacy (ACCP) Certification Affairs Committee was charged with developing guidelines for the desired professional development pathways for clinical pharmacists. This document summarizes recommendations for postgraduate education and training for graduates of U.S.