Trials In Lymphoma Research Articles

Geographic Trends in Clinical Trials in Lymphoma, 1997-2017

BackgroundIn order to fulfil their medical and academic mission, clinical trials have to be available to the very populations they are intended to serve. A broad and homogenous geographic distribution is thus paramount to ensure patient fairness as well as to allow optimal generalizability of trial results to real-world populations. We aimed to investigate trends in the geographic distribution of clinical trials in lymphoma performed over the past 2 decades.MethodsWe systematically searched the Clinicaltrials.gov registry for phase 3 and 4 clinical trials in lymphoma conducted between 01/01/1997 and 12/31/2017. We divided the time period into two intervals and analysed the geographic distribution of trials during these time periods. The Gini coefficient, a statistical measure of inequality ranging from 0 (equal distribution) to 1 (most unequal distribution), was calculated for each period.ResultsWe found 633 clinical trials in lymphoma conducted between 1997 and 2017 globally. 284 and 349 trials were performed in the 1997-2007 and 2008-2017 time periods, respectively. 127 (50%) and 138 (39.5%) of the trials were done in the US. Hodgkin Lymphoma accounted for 55 (19.3%) and 42 (12.0%) studies in the two time periods. CA, TX, IL and NY were consistently in the upper one-fifth of trial-abundant states (each accounting for 3.5-4.5% of all trials). AK, WY, MT and RI were consistently in the lower one-fifth of trial-abundant states (each accounting for 0.13-0.84% of trials). The trial participation of NY and AK mildly increased during the time period while that of TX and RI decreased. In each of the time periods, the 12 most trial-intense states accounted for 41.5% of all investigations. The 12 least trial-intense states were responsible for 8.8% of all the trials. The extent of geographic inequality increased over the years with the Gini coefficient rising from 0.246 to 0.3 between the first and second study period. The geographical pattern of state-specific trial intensity was strongly mitigated after adjusting for each state's population size.ConclusionsThe geographic distribution of clinical trials in lymphoma in the U.S is not uniform. Our data suggests that the trend of geographic mal-distribution is worsening, a phenomenon that may lead to deleterious public health outcomes. As patients' enrolment continues to be linked to geographic factors, patients' ability to enter clinical trials may be limited and the representation of real-world participants may be skewed (towards particular zip codes, socio-economical status and education levels, etc), consequently affecting the yield and generalizability of clinical trials. Innovative solutions must be devised to minimise any barriers to trial participation for suitable patients. DisclosuresNo relevant conflicts of interest to declare.

Encouraging Clinical Outcomes for Lymphoma Patients Participating in Early Phase Clinical Trials in the Current Era: A Single Institution and a Global Perspective

Encouraging Clinical Outcomes for Lymphoma Patients Participating in Early Phase Clinical Trials in the Current Era: A Single Institution and a Global Perspective

Assessing the Need for a Biosimilar: A Systematic Literature Review of the Treatment Burden of Rituximab in Hematological Malignancies

BACKGROUND: Advanced targeted therapies have improved survivals and efficacies in patients with certain hematology conditions. However, the treatment costs and safety are some concerns among healthcare providers, patients, and payers.OBJECTIVES: To identify and characterize the treatment burden of rituximab, focusing on drug cost, toxicity, and other treatment-related costs in hematological malignancies, given the anticipated market entry of biosimilar products.[1]METHODS: We conducted a systematic literature review (SLR) using the online version of Index Medicus identified relevant publications using pertinent search terms (see Table) to capture treatment-related cost and non-cost burden publications in English language, publication dates 01/01/2010 to 01/24/2018.RESULTS: Of the 704 publications returned in the search, a total of 28 US and ex-US treatment burden studies (9 cost, 16 non-cost, and 3 drug route comparison studies) were included in the review. US (4) and ex-US (5) treatment cost studies found that direct medical costs of care were dramatically increased with the addition of rituximab or that rituximab represented a large proportion of total costs of care. For publications with calculated benefits associated with treatment, the addition of rituximab to CT was coupled with life-year gains and lower mortality. A large observational study found no difference in all-cause hospitalization rates in the 12 months following rituximab treatment. While studies designed to evaluate rituximab toxicity have found the addition of rituximab to CT to be associated with a general increase in incidence of adverse events (AEs) overall, 1 prospective study found no subsequent decline in quality of life (QOL), and another prospective study observed a significant increase in time without disease symptoms or toxicity (8.33 months) and less time spent in relapse. Both rituximab maintenance (after successful induction) and retreatment at progression were associated with a decline in illness-related anxiety (1randomized, Phase III trial in indolent non-Hodgkin lymphoma), while rituximab maintenance was associated with significantly decreased pain and other illness-related symptoms vs observation (2 studies). Five studies (3 US; 2 ex-US) analyzed infusion-related reactions (IRRs) and/or rapid infusion use. Overall, IRRs, especially with first infusions, were common (40%-63%), but primarily low-grade (I-II), and rituximab was usually well-tolerated on same-day rechallenge. Marked patient time was saved with rapid infusion. An SLR and meta-analysis of rapid rituximab infusion further characterized rapid infusion, identifying all IRRs as Grade I or II with a pooled incidence of 2.6%. Three ex-US studies evaluated economic endpoints comparing intravenous and subcutaneous (SC) preparation and administration of rituximab. One study calculated higher labor costs for SC rituximab, while 2 studies calculated lower staff time for SC rituximab; all studies identified shorter patient treatment/chair time for SC rituximab.CONCLUSIONS: We found that the treatment-related cost burden of rituximab in malignant conditions is substantial, while its associated toxicity is relatively low, and patient QOL is maintained or improved. Incident and increased toxicities associated with rituximab added to CT may or may not be exclusively attributable to rituximab. Administration rate and route influence economic endpoints with rituximab use. These findings highlight the potential economic benefit of lower-cost biosimilar rituximab products for patients, health care systems, and payers.[1] This Abstract is not intended to refer to any particular biosimilar product or use thereof. DisclosuresJames:Teva: Consultancy; Roche: Consultancy. Trautman:Teva: Consultancy; Roche: Consultancy. Hoehn:Teva: Employment. Szabo:Teva: Employment. Tang:Teva: Employment.

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

The Novel SYK/JAK Inhibitor Cerdulatinib Demonstrates Good Tolerability and Clinical Response in a Phase 2a Study in Relapsed/Refractory Peripheral T-Cell Lymphoma and Cutaneous T-Cell Lymphoma

Molecular Characteristics of Diffuse Large B-Cell Lymphoma and Correlation with Baseline Metabolic Tumor Volume (MTV), Interim Positron Emission Tomography (iPET) and Outcome in the PETAL Trial

Introduction: Treatment results in diffuse large B-cell lymphoma (DLBCL) are heterogeneous. Established risk models like the International Prognostic Index (IPI) and molecular lymphoma features such as MYC translocations and the cell of origin (COO) subtype are prognostic of outcome. A positive iPET scan after 2 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has recently been shown to predict poor outcome independent of the IPI (Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas trial [PETAL]; Dührsen et al., J Clin Oncol 36:2024, 2018). Another PET-derived parameter of potential prognostic significance is baseline MTV. This retrospective analysis of lymphoma biopsies from the PETAL trial investigated the relationship between molecular lymphoma features and PET parameters.Methods: Available lymphoma specimens were analyzed for COO by immunohistochemistry employing the Hans-classifier (HC) and by gene expression (GE) using the HTG EdgeSeq System (HTG Molecular Diagnostics). MYC and BCL2 and/or BCL6 translocations (“double-hit” [DH]) were assessed by fluorescence in situ hybridization (FISH). MTV was determined applying the 41% SUVmax segmentation method, and iPET was evaluated using the deltaSUVmax method. Association between iPET result and molecular lymphoma features was assessed by risk ratios (RR). Survival curves of time-to-event endpoints were compared using hazard ratios (HR) from Cox regression and the log-rank test.Results: Of 609 DLBCL patients treated in the PETAL trial, 63 had a positive iPET. 134 of 267 DLBCL biopsies available for HC analysis (50.2%) were classified as non-germinal center B-cell (non-GCB) and 133 (49.8%) as GCB. COO analysis by GE revealed an activated B-cell (ABC) type in 122 (51.1%) and a GCB type in 102 (42.7%) of 239 available biopsies (n=7 [2.9%] unclassified, n=8 [3.3%] failed quality control). Concordance between HC and GE was found in 165 of 197 biopsies studied by both methods (83.8%). MYC breaks were found in 27 (10.7%) and MYC amplifications in 48 (19.0%) of 253 cases studied by FISH. A DH lymphoma was diagnosed in 16 of 253 cases (6.3%). Complete information on HC, GE and DH status was available for 170 cases. The relationship is depicted in figure 1. COO classification by either HC or GE was not correlated with baseline MTV, iPET result, event-free (EFS) survival or overall (OS) survival. By contrast, DH status was correlated with positive iPET (RR 2.30 [95% CI, 0.76 to 6.96]) and inferior outcome as shown in figure 2 (EFS: HR 2.04 [95% CI, 1.02 to 4.07]; p=.044; OS: HR 3.00 [95% CI, 1.34 to 6.71]; p=.007). There was no correlation between DH status and MTV. iPET-positive DLBCL harbored MYC breaks more frequently than iPET-negative DLBCL (RR 3.29 [95% CI, 1.40 to 7.77]). A similar trend was observed in 72 cases tested for BCL2 breaks (RR 1.30 [95% CI, 0.44 to 3.84]) and 74 cases tested for BCL6 breaks (RR 1.85 [95% CI, 0.59 to 5.80]).Conclusion: HC and GE showed good concordance with respect to COO classification, but COO was not correlated with MTV, iPET, EFS or OS. By contrast, MYC-rearranged lymphomas with or without BCL2 or BCL6 breaks were statistically significantly associated with a positive iPET, and DH lymphomas were correlated with poor outcome. Yet, the unfavorable prognosis of iPET-positive DLBCL cannot solely be explained by MYC translocations because most iPET-positive lymphomas lacked this genetic anomaly. Our results strengthen the role of iPET as a prognostic tool, independent not only of IPI, but also of COO status and MYC translocation. [Display omitted] DisclosuresRichter:HTG Molecular Diagnostics, Inc.: Research Funding. Hüttmann:Celgene: Other: Travel expenses; Roche: Other: Travel expenses. Gärtner:HTG Molecular Diagnostics, Inc.: Employment. Duehrsen:Amgen: Research Funding; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Klapper:HTG Molecular Diagnostics, Inc.: Research Funding; Amgen: Honoraria, Research Funding; Regeneron: Honoraria, Research Funding; F.Hoffman-La Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding.

Brentuximab Vedotin: A Nursing Perspective on Best Practices and Management of Associated Adverse Events.

Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30-expressing cells. This article assesses the occurrence and management of the most frequent and clinically relevant BV-associated adverse events (AEs), with a focus on Hodgkin lymphoma and systemic anaplastic large cell lymphoma trials, and shares practical tips that may help decrease occurrence and severity. Peer-reviewed literature was surveyed to collect safety data from sponsored clinical trials of BV and to compile associated management guidelines. Peripheral neuropathy was the most common BV-associated AE across clinical trials. Other clinically relevant AEs included neutropenia, infection, and infusion-related reactions. Awareness of and preparedness for these common BV-associated AEs and other less common but significant AEs will help nurse clinicians and patients maximize the clinical benefit for patients receiving BV.

Report of the 14th International Conference on Malignant Lymphoma (ICML) Closed Workshop on Future Design of Clinical Trials in Lymphomas.

The 14th ICML held in Lugano in June 2017 was preceded by a closed workshop (organized in collaboration with the American Association for Cancer Research and the European School of Oncology) where experts in preclinical and clinical research in lymphomas met to discuss the current drug development landscape focusing on critical open questions that need to be addressed in the future to permit a more efficient drug development paradigm in lymphoma. Topics discussed included both preclinical models that can be used to test new drugs and drug combinations, as well as the optimal design of clinical trials and the endpoints that should be used to facilitate accelerated progress. This report represents a summary of the workshop. Clin Cancer Res; 24(13); 2993-8. ©2018 AACR.

Abstract 4861: Initial preclinical evaluation of a novel inhibitor of mitochondrial metabolism against prostate cancer

Abstract CPI-613 is a novel inhibitor of mitochondrial metabolism that has recently shown promise in early stage clinical trials for pancreatic cancer, lymphoma, and leukemia. It is a lipoate analogue that selectively inhibits pyruvate dehydrogenase (PDH) and alpha-ketoglutarate dehydrogenase (KGDH) complexes in tumor cells (reviewed in Exp.Rev.Clin.Pharma. 7, 837). Since these two enzymes control the vast majority of carbon flow into the tricarboxylic acid (TCA) cycle, CPI-613 significantly inhibits mitochondrial metabolism. Importantly, it has demonstrated a favorable safety profile in clinical trials, presumably due to its documented selectivity to cancer metabolism. Early phase clinical trials with CPI-613 have demonstrated very promising clinical responses in pancreatic cancer, leukemia, and lymphoma when used in combination with standard chemotherapy. For example, in a recently published Phase I clinical trial in 18 patients with Stage 4 pancreatic cancer in combination with a modified FOLFIRINOX regiment, three (17%) had a complete response, eight (44%) had a partial response, three (17%) had stable disease, and four (22%) had progressive disease. Since altered cancer metabolism is a hallmark of cancer in general, we hypothesized that CPI-613 should have efficacy in other cancers, including prostate cancer, which is the second most common malignancy in men that affects over 160,000 men in the U.S annually. To test our hypothesis, we treated prostate cancer cell lines with CPI-613 in vitro and in vivo in a preclinical murine flank model. We found that CPI-613 was highly effective at killing prostate cancer cells in vitro, which was similar to its previously published potency in pancreatic cancer cells. Furthermore, we found in vitro therapeutic synergy with docotaxel, a standard of care treatment of advanced prostate cancer. We therefore tested CPI-613 in a preclinical Pc-3 flank model of androgen-resistant prostate cancer. Groups of mice (n=8) were treated 2-3 times per a week for 5 weeks with 2.5mg/kg of CPI-613, 10mg/kg of CPI-613 and control saline after tumors reached approximately 40mm3. CPI-613 was formulated in the same manner as it was for clinical trials. Both groups of mice treated with CPI-613 demonstrated a significant decrease in tumor growth without any toxicity. There was no observed difference between doses, which may be due to having crossed the threshold of drug uptake and concentration required in the mitochondria for a response. Furthermore, there was a significant increase in survival between treated groups and the control group, again without a dose effect. These results for the first time indicate biological activity of CPI-613 both in vitro and in vivo against prostate cancer and therefore warrants further investigation in representative preclinical prostate cancer models and in combination with standard-of-care therapies. Citation Format: Kiran K. Solingapuram Sai, Anirudh Sattiraju, Zuzana Zachar, Michael S. Dahan, Robert Shorr, Timothy S. Pardee, Paul M. Bingham, Akiva Mintz. Initial preclinical evaluation of a novel inhibitor of mitochondrial metabolism against prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4861.

Precision medicine and lymphoma.

The treatment of the germinal center lymphomas, diffuse large B cell (DLBCL) and follicular lymphoma, has changed little beyond the introduction of immunochemotherapies. However, there exists a substantial group of patients within both diseases for which improvements in care will involve appropriate tailoring of treatment. DLBCL consists of two major subtypes with striking differences in their clinical outcomes paralleling their underlying genetic heterogeneity. Recent studies have seen advances in the stratification of germinal center lymphomas, through comprehensive profiling of 1001 DLBCLs alongside refinements in the identification of high-risk follicular lymphoma patients using m7-FLIPI and 23G models. A new wave of novel therapeutic agents is now undergoing clinical trials for germinal center lymphomas, with BCR and EZH2 inhibitors demonstrating preferential benefit in subgroups of patients. The emergence of cell-free DNA has raised the possibility of dynamic disease monitoring to potentially mitigate the complexity of spatial and temporal heterogeneity, whilst predicting tumor evolution in real time. Altogether knowledge of the genomic landscape of germinal center lymphomas is offering welcome opportunities in patient risk stratification and therapeutics. The challenge ahead is to establish how best to combine upfront or dynamic prognostication with precision therapies, while retaining practicality in clinical trials and the real-world setting.

Safety Analysis of Brentuximab Vedotin from the Phase III AETHERA Trial in Hodgkin Lymphoma in the Post-Transplant Consolidation Setting

The phase III AETHERA trial demonstrated the efficacy of brentuximab vedotin (BV) as consolidation therapy in patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression after autologous hematopoietic stem cell transplantation (auto-HSCT; hazard ratio, .57; P < .001). The objective of this analysis is to provide further detail on the most common and clinically important treatment-emergent adverse events (AEs) in the AETHERA BV arm including their occurrence and management. AEs of clinical importance occurring in patients who participated in AETHERA (BV + best supportive care [BSC], n = 165; placebo + BSC, n = 164) were evaluated for time to onset, manageability through dose modification, and resolution. As previously reported, peripheral neuropathy (PN; 67%), infections (60%), and neutropenia (35%) were the most common BV-associated treatment-emergent AEs. Neutropenia was managed with dose delays and granulocyte colony-stimulating factor; no dose reductions or discontinuations were required. Most PN cases (57%) were managed with dose delays and reductions. The median time to PN onset was 13.7 weeks (range, .1 to 47.4). After the end of treatment, PN continued to resolve; symptom resolution was similar to that in the placebo arm at 3 years, demonstrating reversibility. BV had no significant impact on pre-existing PN. Patients with PN-related dose modifications had progression-free survival (PFS) comparable with patients without. Other less common but serious AEs, including pulmonary toxicities, hepatotoxicity, and cardiotoxicity, were rare in both arms and were managed with BV dose modifications or discontinuations. Secondary malignancies were rare and reported in patients with comorbidities or other risk factors. Consolidation therapy with BV for patients with HL at high risk of relapse after auto-HSCT is associated with sustained PFS. The most common AEs in the BV arm were manageable and reversible. Awareness of these AEs and management approaches will enable healthcare providers and patients to plan the safest and most effective treatment plan.

Diagnosis-to-Treatment Interval Is an Important Clinical Factor in Newly Diagnosed Diffuse Large B-Cell Lymphoma and Has Implication for Bias in Clinical Trials.

Purpose Selection bias in clinical trials has consequences for scientific validity and applicability of study results to the general population. There is concern that patients with clinically aggressive disease may not have enrolled in recent diffuse large B-cell lymphoma (DLBCL) trials due to the consent process and the inability to delay therapy for eligibility evaluation. We have examined the diagnosis-to-treatment interval (DTI) and its association with clinical factors and outcome in a clinic-based observational cohort of patients with DLBCL from the United States. Validation of results was performed in an independent, clinical trial-based cohort from Europe. Patients and Methods Patients were prospectively enrolled in the University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource (MER; N = 986) or the Lymphoma Study Association (LYSA) LNH-2003 clinical trials program (N = 1,444). All patients received anthracycline-based immunochemotherapy at initial diagnosis. Associations of DTI with clinical factors and outcome were examined. Outcome was assessed using event-free survival at 24 months from diagnosis (EFS24). Results Median (range) DTI was 15 days (0 to 155 days in the MER and 23 days (0 to 215 days) in LYSA. Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B symptoms, and higher International Prognostic Index in both cohorts (all P < .001). Longer DTI was associated with improved EFS24 in both the MER (per-week odds ratio, 0.80; 95% CI, 0.74 to .0.87) and LYSA (per-week odds ratio, 0.90; 95% CI, 0.86 to 0.94); association with EFS24 remained significant after adjustment for International Prognostic Index. Conclusion DTI is strongly associated with prognostic clinical factors and outcome in newly diagnosed DLBCL. DTI should be reported in all clinical trials of newly diagnosed DLBCL and future trials should take steps to avoid selection bias due to treatment delay.

Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition.

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Rapid, real time pathology review for ECOG/ACRIN 1412: a novel and successful paradigm for future lymphoma clinical trials in the precision medicine era

ECOG/ACRIN 1412 (E1412) is a randomized, phase II open-label study of lenalidomide/RCHOP vs. RCHOP alone in adults with newly diagnosed de novo diffuse large B-cell lymphoma (DLBCL) and requires NanoString gene expression profiling (GEP) for cell-of-origin testing. Because of high ineligibility rate on retrospective expert central pathology review (ECPR), real-time (RT) ECPR was instituted to confirm diagnosis and ensure adequate tissue for GEP prior to study enrollment. Goal was notification of eligibility within 2 working days (WD). Initially, 208 patients were enrolled, 74 (35.6%) of whom were deemed ineligible by retrospective ECPR. After initiation of RT-ECPR, 219 patients were registered. Of these, 73 (33.3%) were ineligible and were declined enrollment; 47 (21.5% of total) had an ineligible diagnosis on RT-ECPR, and 26 (11.9% of total) had inadequate tissue. Because the 73 ineligible patients were never enrolled, no study slots were “lost” during this phase. Notification of eligibility occurred in an average of 1 WD (Range 0–4) with 97.3% within 2 WD. This novel RT-ECPR serves as a model for future lymphoma trials. Real-time ECPR can help to reduce costs and ensure that study slots accurately reflect the targeted population. In the precision-medicine era, rapid collection of relevant pathology/biomarker data is essential to trial success.

Lymphoma epidemiology in Korea and the real clinical field including the Consortium for Improving Survival of Lymphoma (CISL) trial.

Lymphomas are a heterogeneous group of disease entities with well-defined clinical, morphological, immunophenotypic, and cytogenetic characteristics. Moreover, regional and racial differences have been reported in their incidence and subtype compositions. Here, we reviewed the epidemiology of lymphomas and summarized the recent achievements in specific subtypes prevalent in Korean population, focusing on clinical studies conducted by the Consortium for Improving Survival of Lymphoma (CISL) of the Korean Society of Hematology Lymphoma Working Party (KSH-LWP).

Enrollment of Older Adults in Clinical Trials Evaluating Patients with Hematologic Malignancies - the Food and Drug Administration (FDA) Experience

▪Background: The majority of hematologic malignancies are most frequently diagnosed in patients over 65 years of age (1). However, older adults are underrepresented in clinical trials evaluating new cancer therapies (2). This analysis quantifies age related enrollment in trials evaluating patients with hematologic malignancies submitted to FDA in support of drug approval.Methods: We retrospectively analyzed demographic datasets of patients enrolled to trials submitted to FDA in support of approval of new or supplemental indications for hematologic cancer therapies from 2005-2015. Patients enrolled in trials for hematologic malignancies were grouped into disease categories based on the diagnosis specified for trial entry and analyzed according to age distributions of <65, 65-74 and ≥ 75 years. The rates of enrollment for patients with chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and lymphomas (Hodgkin's and non-Hodgkin's lymphoma excluding CLL) were compared with the age distribution of incidence cases by site derived from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute 2010-2014 (1).Results: We identified a total of 44,144 patients enrolled in clinical trials evaluating hematologic malignancies. Forty five percent (19908) of the patients were enrolled in lymphoma trials, 24% (10465) in chronic myeloid leukemia (CML) trials, 22% (9605) in multiple myeloma (MM) trials, 2% (1052) in acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) trials and 6% were enrolled in trials classified as “other” (includes myeloproliferative neoplasms and trials enrolling multiple malignancies). Less than 1% (403) of patients were enrolled in acute lymphoblastic leukemia (ALL) trials. Greater than 50% of the patients with the exception of those enrolled in CLL and AML/MDS trials were <65 years of age. Greater than 85% of the participants in ALL trials were < 65 years of age.Compared to the U.S cancer population, clinical trials for lymphomas, CLL, CML and MM enrolled a disproportionately higher percentage of patients <65 years of age (Table 2). For participants ≥65 years in the lymphoma and CML trials, enrollment in the 65-74 year old age group was lower than the SEER incidence cases (24.6% versus 23.1% for lymphoma and 16.5% versus 20.7% for CML respectively); but the difference was less than 5%. CLL and MM trials enrolled a higher percentage of patients in the 65-74 year old age group compared with the SEER data. Patients ≥75 years of age were consistently underrepresented in lymphoma, CLL, CML and MM trials compared to the SEER incidence cases in the same age group. The greatest difference was seen for patients in CML trials: only 3.8% were ≥75 years of age compared with SEER incidence of 28.6%.Conclusion: Older adults 65-74 years of age were adequately represented in hematologic malignancy trials submitted to support approval of new or supplemental indications of cancer therapies. Despite a high number of incident cases diagnosed in this age group, adults ≥ 75 years of age were disproportionately underrepresented in malignant hematology clinical trials. The FDA has encouraged sponsors to design trials to enroll patients who are representative of their intended population. Additional strategies to increase clinical trial participation may be needed to enhance the quantity and quality of information needed to treat adults ≥75 years of age and provide an appropriate benefit-risk profile in the population that is likely to receive the treatment. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Immucillins in Infectious Diseases.

The Immucillins are chemically stable analogues that mimic the ribocation and leaving-group features of N-ribosyltransferase transition states. Infectious disease agents often rely on ribosyltransferase chemistry in pathways involving precursor synthesis for nucleic acids, salvage of nucleic acid precursors, or synthetic pathways with nucleoside intermediates. Here, we review three infectious agents and the use of the Immucillins to taget enzymes essential to the parasites. First, DADMe-Immucillin-G is a purine nucleoside phosphorylase (PNP) inhibitor that blocks purine salvage and shows clinical potential for treatment for the malaria parasite Plasmodium falciparum, a purine auxotroph requiring hypoxanthine for purine nucleotide synthesis. Inhibition of the PNPs in the host and in parasite cells leads to apurinic starvation and death. Second, Helicobacter pylori, a causative agent of human ulcers, synthesizes menaquinone, an essential electron transfer agent, in a pathway requiring aminofutalosine nucleoside hydrolysis. Inhibitors of the H.pylori methylthioadenosine nucleosidase (MTAN) are powerful antibiotics for this organism. Synthesis of menaquinone by the aminofutalosine pathway does not occur in most bacteria populating the human gut microbiome. Thus, MTAN inhibitors provide high-specificity antibiotics for H.pylori and are not expected to disrupt the normal gut bacterial flora. Third, Immucillin-A was designed as a transition state analogue of the atypical PNP from Trichomonas vaginalis. In antiviral screens, Immucillin-A was shown to act as a prodrug. It is active against filoviruses and flaviviruses. In virus-infected cells, Immucillin-A is converted to the triphosphate, is incorporated into the viral transcript, and functions as an atypical chain-terminator for RNA-dependent RNA polymerases. Immucillin-A has entered clinical trials for use as an antiviral. We also summarize other Immucillins that have been characterized in successful clinical trials for T-cell lymphoma and gout. The human trials support the potential development of the Immucillins in infectious diseases.

Acalabrutinib: First Global Approval.

Acerta Pharma is developing the Bruton's tyrosine kinase inhibitor acalabrutinib (Calquence®) for the treatment of various haematological and solid malignancies. The drug has received accelerated approval from the US FDA for the treatment of mantle cell lymphoma based on the results of a phase II study, and phase III trials in mantle cell lymphoma and chronic lymphocytic leukaemia are currently underway. This article summarizes the milestones in the development of acalabrutinib leading to this first approval for mantle cell lymphoma.

The Search for Surrogate Endpoints in Trials in Diffuse Large B-Cell Lymphoma: The Surrogate Endpoints for Aggressive Lymphoma Project.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

Obesity negatively impacts outcome in elderly female patients with aggressive B-cell lymphomas treated with R-CHOP: results from prospective trials of the German high grade non-Hodgkin's lymphoma trial group.

To study if obesity is a risk factor in elderly patients (>60years) with aggressive B-cell lymphoma, the outcomes of 576 elderly patients treated with rituximab in the RICOVER-60 trial were analysed in a retrospective study with regard to body mass index (BMI) and gender. Of the 576 patients, 1% had low body weight (BMI<18·5), 38% were normal weight (18·5≤BMI<25), 42% were overweight (25≤BMI<30) and 19% were obese (BMI≥30). Event-free (EFS), progression-free (PFS) and overall survival (OS) according to BMI showed no significant differences for all and for male patients. EFS (P=0·041), PFS (P=0·038) and OS (P=0·031) were significantly better for female non-obese patients. A multivariate analysis adjusted for International Prognostic Index risk factors confirmed these results, with the following hazard ratios (HR) for obesity (BMI≥30) for EFS/PFS/OS: all patients - 1·4/1·4/1·4 (not significant); male patients - 1·2/1·2/1·0 (not significant) and female patients - 1·7 (P=0·032)/1·9 (P=0·022)/2·0 (P=0·017). In conclusion, obesity is a risk factor that influences treatment outcome in elderly female patients with aggressive B-cell lymphoma treated with R-CHOP (rituximab+cyclophosphamide, doxorubicin, vincristine, prednisolone). The inferior outcomes in obese female patients may be due to faster rituximab clearance in obese females.