ABSTRACT
Myelodysplastic syndromes (MDS) have historically been challenging diseases for drug development due to their biology, preclinical modeling, and the affected patient population. In April 2022, the FDA convened a panel of regulators and academic experts in MDS to discuss approaches to improve MDS drug development. The panel reviewed challenges in MDS clinical trial design and endpoints and outlined considerations for future trial design in MDS to facilitate drug development to meaningfully meet patient needs. Challenges for defining clinical benefit in patients with MDS include cumbersome response criteria, standardized transfusion thresholds, and application and validation of patient reported outcome instruments. Clinical trials should reflect the biology of disease evolution, the advanced age of patients with MDS, and how patients are treated in real-world settings to maximize the likelihood of identifying active drugs. In patients with lower-risk disease, response criteria for anemic patients should be based on baseline transfusion dependency, improvement in symptoms, and quality of life. For higher-risk patients with MDS, trials should include guidance to prevent dose reductions or delays that could limit efficacy, specify minimal durations of treatment (in the absence of toxicity or progression), and have endpoints focused on overall survival and durable responses. MDS trials should be designed from the outset to allow the practicable application of new therapies in this high-needs population, with drugs that can be administered and tolerated in community settings, and with endpoints that meaningfully improve patients' lives over existing therapies.
Subject(s)
Myelodysplastic Syndromes , Quality of Life , Humans , Myelodysplastic Syndromes/therapyABSTRACT
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.
Subject(s)
Hematologic Neoplasms , Humans , United States , Pharmaceutical Preparations , Neoplasm, Residual/drug therapy , Neoplasm, Residual/pathology , United States Food and Drug Administration , Hematologic Neoplasms/drug therapyABSTRACT
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.
Subject(s)
Azacitidine , Leukemia, Myeloid, Acute , Adult , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/etiology , Middle Aged , Remission InductionABSTRACT
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.
Subject(s)
Dendritic Cells/drug effects , Drug Approval , Hematologic Neoplasms/drug therapy , Interleukin-3 Receptor alpha Subunit/metabolism , Plasmacytoma/drug therapy , Recombinant Fusion Proteins/administration & dosage , Adult , Aged , Aged, 80 and over , Clinical Trials as Topic , Dendritic Cells/metabolism , Dendritic Cells/pathology , Female , Hematologic Neoplasms/pathology , Humans , Male , Middle Aged , Patient Safety , Plasmacytoma/pathology , Treatment Outcome , United States , Young AdultABSTRACT
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%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP ALL. The basis for this accelerated approval was a single-arm trial. For the 86 patients in first and second complete remission with MRD ≥ 0.1%, conversion to MRD < 0.01% was achieved after one cycle of blinatumomab by 85.2% [95% confidence interval (CI): 73.8%, 93.0%] and 72.0% (95% CI: 50.6%, 87.9%), respectively, and the estimated median hematologic relapse-free survivals (RFS) were 35.2 months (95% CI: 0.4-53.5) and 12.3 months (95% CI: 0.7-42.3), respectively. Hematologic RFS was considered substantial independent of whether patients underwent subsequent allogeneic stem cell transplantation. The safety profile for blinatumomab was established in prior studies, and no new safety signals were observed in the new population. Cytokine release syndrome and neurotoxicity remain significant risks. The FDA is requiring confirmation of clinical benefit in a randomized trial.
Subject(s)
Antibodies, Bispecific/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Drug Approval , Neoplasm, Residual/drug therapy , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Adult , Aged , Aged, 80 and over , Antibodies, Bispecific/administration & dosage , Antibodies, Bispecific/adverse effects , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Neoplasm, Residual/diagnosis , Neoplasm, Residual/mortality , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Prognosis , Remission Induction , Treatment Outcome , Young AdultABSTRACT
On September 1, 2017, the FDA granted approval for gemtuzumab ozogamicin (Mylotarg; Pfizer Inc.) in combination with daunorubicin and cytarabine and as a monotherapy for the treatment of adult patients with newly diagnosed CD33-positive acute myeloid leukemia (AML). Gemtuzumab ozogamicin is a CD33-targeted antibody-drug conjugate joined to calicheamicin. Approval of gemtuzumab ozogamicin combination treatment was based on a randomized trial of 271 patients with newly diagnosed AML treated with daunorubicin and cytarabine with or without 3 mg/m2 fractionated gemtuzumab ozogamicin, which resulted in an event-free survival (EFS) of 13.6 months for gemtuzumab ozogamicin + daunorubicin and cytarabine and 8.8 months for daunorubicin and cytarabine alone [HR = 0.68 (95% confidence interval (CI), 0.51-0.91)]. Hemorrhage, prolonged thrombocytopenia, and veno-occlusive disease were serious toxicities that were more common in patients treated with gemtuzumab ozogamicin + daunorubicin and cytarabine. Approval of gemtuzumab ozogamicin monotherapy was based on a randomized trial of 237 patients with newly diagnosed AML treated without curative intent. Median overall survival (OS) was 4.9 months with gemtuzumab ozogamicin versus 3.6 months on best supportive care [HR = 0.69 (95% CI, 0.53-0.90)]. Adverse events were similar on both arms. Postapproval, several studies are required including evaluation of fractionated gemtuzumab ozogamicin pharmacokinetics, safety of combination gemtuzumab ozogamicin in the pediatric population, immunogenicity, and the effects of gemtuzumab ozogamicin on platelet function. Clin Cancer Res; 24(14); 3242-6. ©2018 AACR.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Drug Approval , Gemtuzumab/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/metabolism , Sialic Acid Binding Ig-like Lectin 3/metabolism , Adult , Antineoplastic Agents, Immunological/pharmacology , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gemtuzumab/pharmacology , Humans , Leukemia, Myeloid, Acute/diagnosis , Treatment OutcomeABSTRACT
The deregulation of the sonic hedgehog (shh) signaling pathway in epidermal keratinocytes is a primary event leading to the formation of basal cell carcinoma (BCC). The mechanisms by which this pathway exerts this effect remain largely undefined. We demonstrate that overexpression of shh in HaCaT keratinocytes grown in organotypic cultures induced a basal cell phenotype, as evidenced by their morphology, trans-epithelial staining of cytokeratin 14, and suprabasalar proliferation. Shh also induced keratinocyte infiltration into the underlying collagen matrix. Constitutive shh expression was associated with increased phosphorylation of the epidermal growth factor receptor (EGFR) as well as jnk and raf. Additionally, levels of c-jun and matrix metalloproteinase-9 (MMP-9) protein were elevated in shh-expressing cells. Inhibition of EGFR activity with either the tyrphostin, AG1478, or blocking receptor-ligand interaction with the monoclonal antibody, C-225, blocked matrix infiltration. In contrast, exogenously supplied EGF significantly augmented the invasiveness of the HaCaT cells. These observations provide insight into the impact of deregulated shh on epidermal homeostasis. The findings further suggest that an intact EGF signaling axis cooperates with shh and is a critical mediator of matrix invasion in a tumor type characterized by disrupted shh.
Subject(s)
Epidermal Growth Factor/metabolism , Keratinocytes/metabolism , Signal Transduction/physiology , Trans-Activators/genetics , Trans-Activators/metabolism , Carcinoma, Basal Cell/physiopathology , Cell Line , Extracellular Matrix/metabolism , Gene Expression , Hedgehog Proteins , Humans , Keratinocytes/cytology , Organ Culture Techniques , Phenotype , Skin Neoplasms/physiopathology , TransfectionABSTRACT
Melanoma is notoriously resistant to chemotherapy, but variable responses to biotherapies, including the IFNs and IL-2, provide intriguing avenues for further study. Systemic IL-2 treatment has provided significant clinical benefit in a minority of patients with metastatic melanoma, leading to long-term survival in a few cases. We hypothesize that one previously unidentified mechanism of effective IL-2 therapy is through direct upregulation of the tumor suppressor IL-24 in melanoma tumor cells resulting in growth suppression. In this study, five melanoma cell lines were treated with high dose recombinant human IL-2. Three (A375, WM1341, WM793) showed statistically significant increases in IL-24 protein; two (WM35, MeWo) remained negative for IL-24 message and protein. This increase was abolished by preincubating with anti-IL-2 antibody or blocking with antibodies against the IL-2 receptor chains. These IL-2 responsive melanoma cell lines expressed IL-2Rß and IL-2Rγ mRNA. The IL-2Rßγ complex was functional, as measured by IL-2-induced signal transducers and activators of transcription activation as well as IL-15 signaling through its shared receptor complex. IL-24 upregulation was observed in response to either IL-2 or IL-15. Cell growth was significantly decreased by treatment of IL-24-positive cells with IL-2 or IL-15, whereas no effect was seen in negative cells. Incubating the IL-24 inducible-cells with anti-IL-24 antibody as well as transfecting with IL-24 small interfering RNA effectively reversed the growth suppression seen with IL-2. Thus, we have shown that one mechanism of clinically effective IL-2 therapy may be the direct action of IL-2 on a biologically distinct subset of melanoma cells leading to upregulation of the tumor suppressor IL-24.