Response Rate, Event-Free Survival, and Overall Survival in Newly Diagnosed Acute Myeloid Leukemia: US Food and Drug Administration Trial-Level and Patient-Level Analyses.

Purpose: To explore trial-level and patient-level associations between response (complete remission [CR] and CR + CR with incomplete hematologic [CRi] or platelet [CRp] recovery), event-free survival (EFS), and overall survival (OS) in newly diagnosed acute myeloid leukemia (AML) trials of intensive chemotherapy.

Methods: We identified data from eight randomized, active-controlled trials of intensive chemotherapy submitted to the US Food and Drug Administration for treatment of newly diagnosed AML (N = 4,482). Associations between trial-level odds ratios (ORs) for CR and CR + CRi or CRp, and hazard ratios (HRs) for EFS and OS were analyzed using weighted linear regression models.

Differentiation Syndrome with Ivosidenib and Enasidenib Treatment in Patients with Relapsed or Refractory IDH-Mutated AML: A U.S. Food and Drug Administration Systematic Analysis.

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with and -mutated acute myeloid leukemia (AML), respectively.

Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib.

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.

FDA Approval Summary: Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in Children and Young Adults.

On December 20, 2018, the Food and Drug Administration approved calaspargase pegol-mknl (CALASP), an asparagine-specific enzyme, as a component of a multi-agent chemotherapeutic regimen for acute lymphoblastic leukemia (ALL) in pediatric and young adult patients age 1 month to 21 years. Efficacy was determined on the basis of achievement and maintenance of steady-state nadir serum asparaginase activity (NSAA) above 0.1 U/mL when using CALASP, 2,500 U/m intravenously, every 3 weeks.

U.S. Food and Drug Administration Benefit-Risk Assessment of Nilotinib Treatment Discontinuation in Patients with Chronic Phase Chronic Myeloid Leukemia in a Sustained Molecular Remission.

On December 22, 2017, the U.S. Food and Drug Administration (FDA) updated the product label for nilotinib to include information for providers on how to discontinue this drug in certain patients.

FDA Approval Summary: Ivosidenib for Relapsed or Refractory Acute Myeloid Leukemia with an Isocitrate Dehydrogenase-1 Mutation.

The FDA approved ivosidenib (Tibsovo; Agios), a small-molecule inhibitor of isocitrate dehydrogenase (IDH)1 on July 20, 2018, for treatment of adults with relapsed or refractory acute myeloid leukemia (R/R AML) with susceptible IDH1 mutation as detected by an FDA-approved test. The efficacy of ivosidenib was established on the basis of complete remission (CR) + CR with partial hematologic recovery (CRh) rate, duration of CR + CRh, and conversion from transfusion dependence (TD) to transfusion independence (TI) in Study AG120-C-001, a single-arm trial. With median follow-up of 8.

FDA Approval: Blinatumomab for Patients with B-cell Precursor Acute Lymphoblastic Leukemia in Morphologic Remission with Minimal Residual Disease.

On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%.

Determination of Similarity Margin in Comparative Clinical Studies to Support the Development of Biosimilar Products of Neupogen (Filgrastim, Granulocyte Colony-Stimulating Factor [G-CSF]).

To demonstrate a biological product is biosimilar to a reference product, the applicant needs to show that the product is highly similar and has no clinically meaningful differences. Comparative clinical studies are often conducted to support the conclusion of no clinically meaningful differences, as a part of totality of evidence. The FDA has published several guidance documents to facilitate the development of biosimilar products.

Quantitative Relationship Between AUEC of Absolute Neutrophil Count and Duration of Severe Neutropenia for G-CSF in Breast Cancer Patients.

The aim of the study was to evaluate the quantitative relationship between duration of severe neutropenia (DSN, the efficacy endpoint) and area under effect curve of absolute neutrophil counts (ANC-AUEC, the pharmacodynamic endpoint), based on data from filgrastim products, a human granulocyte colony-stimulating factor (G-CSF). Clinical data from filgrastim product comparator and test arms of two randomized, parallel-group, phase III studies in breast cancer patients treated with myelosuppressive chemotherapy were utilized. A zero-inflated Poisson regression model best described the negative correlation between DSN and ANC-AUEC.

FDA Drug Approval: Elotuzumab in Combination with Lenalidomide and Dexamethasone for the Treatment of Relapsed or Refractory Multiple Myeloma.

On November 30, 2015, the FDA approved elotuzumab (Empliciti; Bristol-Myers Squibb) in combination with lenalidomide and dexamethasone for the treatment of patients with multiple myeloma who received one to three prior therapies. FDA approval was based primarily on the results of a phase III, randomized, open-label, multicenter trial, CA204004, which evaluated elotuzumab in combination with lenalidomide and dexamethasone (E-Ld) compared with lenalidomide and dexamethasone (Ld) alone in patients with relapsed or refractory multiple myeloma. Coprimary endpoints were progression-free survival (PFS) and overall response rate (ORR).

FDA Approval: Blinatumomab.

On December 3, 2014, the FDA granted accelerated approval of blinatumomab (Blincyto; Amgen, Inc.) for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-cell acute lymphoblastic leukemia (R/R ALL). Blinatumomab is a recombinant murine protein that acts as a bispecific CD19-directed CD3 T-cell engager.

FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease.

On April 22, 2014, the FDA granted full approval to siltuximab (SYLVANT for injection; Janssen Biotech, Inc.), a chimeric human-mouse monoclonal antibody to IL6, for the treatment of patients with multicentric Castleman disease (MCD) who are human immunodeficiency virus (HIV) negative and human herpesvirus-8 (HHV-8) negative. The approval was primarily based on the results of a randomized, double-blind trial in which 79 symptomatic patients with MCD were allocated (2:1) to siltuximab plus best supportive care (BSC) or to placebo plus BSC.

U.s. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma.

The U.S. Food and Drug Administration (FDA) review leading to accelerated approval of carfilzomib is described.

Considerations in the development of circulating tumor cell technology for clinical use.

This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development-analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

U.S. Food and Drug Administration approval: ruxolitinib for the treatment of patients with intermediate and high-risk myelofibrosis.

On November 16, 2011, the U.S. Food and Drug Administration (FDA) granted full approval to ruxolitinib, (Jakafi; Incyte Corp.

Use of adenoviral vectors to target chemotherapy to tumor vascular endothelial cells suppresses growth of breast cancer and melanoma.

To target chemotherapy to tumor vascular endothelial cells (TVECs), we created the AdTie2RprCDFib(knob-RGD+) vector by inserting into an AdEasy adenoviral vector (Ad) backbone: (i) the cytosine deaminase (CD) gene driven by the Tie2 receptor promoter (Tie2Rpr) into the E1 region of Ad; (ii) mutations that reduce binding of the fiber knob to the Coxsackie adenovirus receptor (CAR); and (iii) the RGD peptide into the H1 loop of fiber for binding to the alpha(V)beta(3) integrin receptors on TVECs. To reduce uptake of the AdTie2RprCDFib(knob-RGD+) by reticuloendothelial (RE) and liver cells, we intravenously (i.v.

EBNA1 regulates cellular gene expression by binding cellular promoters.

Epstein-Barr virus (EBV) is associated with several types of lymphomas and epithelial tumors including Burkitt's lymphoma (BL), HIV-associated lymphoma, posttransplant lymphoproliferative disorder, and nasopharyngeal carcinoma. EBV nuclear antigen 1 (EBNA1) is expressed in all EBV associated tumors and is required for latency and transformation. EBNA1 initiates latent viral replication in B cells, maintains the viral genome copy number, and regulates transcription of other EBV-encoded latent genes.

Use of CD40L immunoconjugates to overcome the defective immune response to vaccines for infections and cancer in the aged.

Multiple investigators have reported the presence of defects in the immune response of the elderly [Castle In: Clin Infect Dis 31:578, 2000; Ortqvist et al. In: Eur Respir J 30:414-422, 2007; Saurwein-Teissl et al. In: J Immunol 168:5893, 2002; Haynes et al.

Chemotherapy targeted to cancer tissue potentiates antigen-specific immune response induced by vaccine for in vivo antigen loading and activation of dendritic cells.

Our laboratory has created an Ad-sig-TAA/ecdCD40L vaccine platform designed to activate dendritic cells (DCs). Two subcutaneous (s.c.

Randomized trial of an allogeneic melanoma lysate vaccine with low-dose interferon Alfa-2b compared with high-dose interferon Alfa-2b for Resected stage III cutaneous melanoma.

Purpose: To compare the overall survival (OS) of patients with resected stage III melanoma administered active specific immunotherapy and low-dose interferon alfa-2b (IFN-alpha-2b) with the OS achieved using high-dose IFN-alpha-2b.

Patients And Methods: An Ad Hoc Melanoma Working Group of 25 investigators treated 604 patients from April 1997 to January 2003. Patients were stratified by sex and number of nodes and were randomly assigned to receive either 2 years of treatment with active specific immunotherapy with allogeneic melanoma lysates and low-dose IFN-alpha-2b (arm 1) or high-dose IFN-alpha-2b alone for 1 year (arm 2).