Eligibility criteria and enrollment of a diverse racial and ethnic population in multiple myeloma clinical trials.

The narrow eligibility criteria may contribute to the underrepresentation of racial and ethnic subgroups in cancer clinical trials. We conducted a retrospective pooled analysis of multicenter global clinical trials submitted to the US Food and Drug Administration between 2006 and 2019 to support the approval of the use of multiple myeloma (MM) therapies that analyze the rates and reasons for trial ineligibility based on race and ethnicity in MM clinical trials. Race and ethnicity were coded per Office of Management and Budget standards. Patients flagged as having screen failures were identified as ineligible. Ineligibility rates were calculated as the percentage of patients who were ineligible compared with the screened population within the respective racial and ethnic subgroups. Trial eligibility criteria were grouped into specific categories to analyze the reasons for trial ineligibility. Black patients (24%) and other (23%) race subgroups had higher ineligibility rates than White patients (17%). The Asian race had the lowest ineligibility rate (12%) among all racial subgroups. Failure to meet the hematologic laboratory criteria (19%) and treatment-related criteria (17%) were the most common reasons for ineligibility among Black patients and were more common in Black patients than in other races. Failure to meet disease-related criteria was the most common reason for ineligibility among White (28%) and Asian (29%) participants. Our analysis indicates that specific eligibility criteria may contribute to enrollment disparities for racial and ethnic subgroups in MM clinical trials. However, the small number of screened patients in the underrepresented racial and ethnic subgroups limits definitive conclusions.

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

BACKGROUND: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling. METHODS: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma. RESULTS: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed. CONCLUSIONS: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).

Minimal Residual Disease Data in Hematologic Malignancy Drug Applications and Labeling: An FDA Perspective.

Minimal residual disease (MRD) is increasingly used as a prognostic biomarker, a measure of clinical efficacy, and a guide for treatment decisions in various hematologic malignancies. We sought to characterize MRD data in registrational trials in hematologic malignancies submitted to the U.S. Food and Drug Administration (FDA) with the ultimate goal of expanding the utility of MRD data in future drug applications. We descriptively analyzed MRD data collected in registrational trials, including the type of MRD endpoint, assay, disease compartment(s) assessed, and the acceptance of MRD data in the U.S. prescribing information (USPI). Of 196 drug applications submitted between January 2014 and February 2021, 55 (28%) included MRD data. Of the 55 applications, MRD data was proposed by the Applicant for inclusion in the USPI in 41 (75%) applications but was included in only 24 (59%). Despite an increasing number of applications that proposed to include MRD data in the USPI, the acceptance rate decreased over time. Although MRD data have the potential to expedite drug development, our analysis identified challenges and specific areas for improvement, including assay validation, standardization of collection methods to optimize performance, and considerations in trial design and statistical methodology.

FDA Approval Summary: Belantamab Mafodotin for Patients with Relapsed or Refractory Multiple Myeloma.

On August 5, 2020, the FDA granted accelerated approval to belantamab mafodotin-blmf (BLENREP; GlaxoSmithKline) for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. Substantial evidence of effectiveness was obtained from the phase II, multicenter DREAMM-2 trial. Patients received belantamab mafodotin 2.5 or 3.4 mg/kg intravenously once every 3 weeks until disease progression or unacceptable toxicity. The trial demonstrated an overall response rate of 31% in the 2.5 mg/kg cohort and 34% in the 3.4 mg/kg cohort. Keratopathy was the most frequent adverse event, occurring in 71% and 77% of patients, respectively. Other ocular toxicities included changes in visual acuity, blurred vision, and dry eye. The U.S. prescribing information for belantamab mafodotin includes a boxed warning for ocular toxicity, and belantamab mafodotin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy. This article summarizes the data and the FDA review process supporting accelerated approval of belantamab mafodotin 2.5 mg/kg intravenously once every 3 weeks. This approval may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Perspectives on Drug Development in Multiple Myeloma-Looking Forward to 2025.

The multiple myeloma treatment landscape has evolved considerably over the last 20 years with the development of multiple therapies with novel mechanisms of action and new combination regimens. However, the recent failure of several large phase III trials, coupled with an increased understanding of the mutational landscape of multiple myeloma has provided opportunities to explore optimal strategies for future multiple myeloma drug development. The Office of Oncologic Diseases at the FDA held an educational symposium, "Drug Development in MM-Project 2025," in November 2019. The symposium brought together select U.S.-based academic thought leaders in the field of multiple myeloma to explore issues relevant to regulatory science in the field, including considerations for trial design, combination strategies, control arms, and precision medicine. This article summarizes the highlights of this educational symposium held at the FDA, including discussions on the future development of novel drugs and drug combinations and biomarker-directed therapies for patients with multiple myeloma.

Analysis of racial and ethnic disparities in multiple myeloma US FDA drug approval trials.

African Americans (AAs) have a higher incidence of multiple myeloma (MM) than White patients. Mortality is also higher in AAs compared with White patients. AAs more commonly have immunoglobulin H translocations t(11;14) and t(14;16) compared with White patients. We sought to characterize the demographic representation in MM clinical trials and evaluate outcomes based on race and ethnicity. We conducted a pooled analysis of all trials submitted to the US Food and Drug Administration (FDA) to support approval of a MM therapeutic between 2006 and 2019. Demographic characteristics were analyzed descriptively. An age-adjusted stratified Cox regression model was used to evaluate the relationship between time-to-event outcomes and race and ethnicity. Nineteen global trials comprising 10 157 patients were pooled. White, Asian, and Black patients comprised 84%, 7%, and 4% of the dataset, respectively; Hispanic patients comprised 4%. The age-adjusted overall survival hazard ratio (HR) for Black compared with White patients was 0.89 (95% confidence interval [CI], 0.75-1.05). The age-adjusted HR for US Black vs US White patients was 0.82 (95% CI, 0.66-1.02). For rest-of-world (RoW) Black vs RoW White patients, the HR was 1.31 (95% CI, 0.97-1.77). Black and Hispanic patients were underrepresented in the trials supporting FDA approval of MM drugs. Black patients were primarily enrolled in the United States. Outcomes in US patients were more favorable compared with those in patients in the RoW. Given the higher incidence of MM in AAs and the different disease characteristics, efforts should be made to improve representation of AAs in MM clinical trials.

Future challenges in analysis and treatment of human immune senescence.

Immune functions decline with age; immunorestorative approaches have been explored in laboratory animals and humans with definite, but limited success. In the clinical setting, the age-associated immune deficiency (immunesenescence) is compounded by the presence of comorbidities that are associated with a functional decline in immunity. Thus, any successful immune reconstitution strategy for humans must involve treatment of the underlying diseases. Furthermore, general health measures such as nutrition and exercises may have powerful effects on restoring immunity, to the extent that malnutrition and a sedentary lifestyle have contributed to existing immune deficiency. More selective approaches, such as with specific cytokines or organ transplantation are of experimental interest but are quite distant from achieving clinical applicability as interventions to restore immunity in the frail elderly.

Quantitative determination of mithramycin in human plasma by a novel, sensitive ultra-HPLC-MS/MS method for clinical pharmacokinetic application.

Mithramycin is a neoplastic antibiotic synthesized by various Streptomyces bacteria. It is under investigation as a chemotherapeutic treatment for a wide variety of cancers. Ongoing and forthcoming clinical trials will require pharmacokinetic analysis of mithramycin in humans, both to see if target concentrations are achieved and to optimize dosing and correlate outcomes (response/toxicity) with pharmacokinetics. Two published methods for mithramycin quantitation exist, but both are immunoassays that lack current bioanalytical standards of selectivity and sensitivity. To provide an upgraded and more widely applicable assay, a UPLC-MS/MS method for quantitation of mithramycin in human plasma was developed. Solid-phase extraction allowed for excellent recoveries (>90%) necessary for high throughput analyses on sensitive instrumentation. However, a ∼55% reduction in analyte signal was observed as a result of plasma matrix effects. Mithramycin and the internal standard chromomycin were separated on a Waters Acquity BEH C18 column (2.1×50 mm, 1.7 µm) and detected using electrospray ionization operated in the negative mode at mass transitions m/z 1083.5→268.9 and 1181.5→269.0, respectively, on an AB Sciex QTrap 5500. The assay range was 0.5-500 ng/mL and proved to be linear (r(2)>0.996), accurate (≤10% deviation), and precise (CV<15%). Mithramycin was stable in plasma at room temperature for 24 h, as well as through three freeze-thaw cycles. This method was subsequently used to quantitate mithramycin plasma concentrations from patients enrolled on two clinical trials at the NCI.