Showing papers by "Albiruni Ryan Abdul Razak published in 2021"

Ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society community of experts on the incidence threshold and the list of entities

Abstract: Background Among sarcomas, which are rare cancers, many types are exceedingly rare; however, a definition of ultra-rare cancers has not been established. The problem of ultra-rare sarcomas is particularly relevant because they represent unique diseases, and their rarity poses major challenges for diagnosis, understanding disease biology, generating clinical evidence to support new drug development, and achieving formal authorization for novel therapies. Methods The Connective Tissue Oncology Society promoted a consensus effort in November 2019 to establish how to define ultra-rare sarcomas through expert consensus and epidemiologic data and to work out a comprehensive list of these diseases. The list of ultra-rare sarcomas was based on the 2020 World Health Organization classification, The incidence rates were estimated using the Information Network on Rare Cancers (RARECARENet) database and NETSARC (the French Sarcoma Network's clinical-pathologic registry). Incidence rates were further validated in collaboration with the Asian cancer registries of Japan, Korea, and Taiwan. Results It was agreed that the best criterion for a definition of ultra-rare sarcomas would be incidence. Ultra-rare sarcomas were defined as those with an incidence of approximately ≤1 per 1,000,000, to include those entities whose rarity renders them extremely difficult to conduct well powered, prospective clinical studies. On the basis of this threshold, a list of ultra-rare sarcomas was defined, which comprised 56 soft tissue sarcoma types and 21 bone sarcoma types. Conclusions Altogether, the incidence of ultra-rare sarcomas accounts for roughly 20% of all soft tissue and bone sarcomas. This confirms that the challenges inherent in ultra-rare sarcomas affect large numbers of patients.

Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts.

Abstract: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.

Pan-cancer analysis of longitudinal metastatic tumors reveals genomic alterations and immune landscape dynamics associated with pembrolizumab sensitivity.

Abstract: Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.

The role of Denosumab in joint preservation for patients with giant cell tumour of bone.

Abstract: Aims Local recurrence remains a challenging and common problem following curettage and joint-sparing surgery for giant cell tumour of bone (GCTB). We previously reported a 15% local recurrence rate...

Lineage-defined leiomyosarcoma subtypes emerge years before diagnosis and determine patient survival.

Abstract: Leiomyosarcomas (LMS) are genetically heterogeneous tumors differentiating along smooth muscle lines. Currently, LMS treatment is not informed by molecular subtyping and is associated with highly variable survival. While disease site continues to dictate clinical management, the contribution of genetic factors to LMS subtype, origins, and timing are unknown. Here we analyze 70 genomes and 130 transcriptomes of LMS, including multiple tumor regions and paired metastases. Molecular profiling highlight the very early origins of LMS. We uncover three specific subtypes of LMS that likely develop from distinct lineages of smooth muscle cells. Of these, dedifferentiated LMS with high immune infiltration and tumors primarily of gynecological origin harbor genomic dystrophin deletions and/or loss of dystrophin expression, acquire the highest burden of genomic mutation, and are associated with worse survival. Homologous recombination defects lead to genome-wide mutational signatures, and a corresponding sensitivity to PARP trappers and other DNA damage response inhibitors, suggesting a promising therapeutic strategy for LMS. Finally, by phylogenetic reconstruction, we present evidence that clones seeding lethal metastases arise decades prior to LMS diagnosis. Heterogeneity in leiomyosarcomas (LMS) makes treatment of the disease challenging. Here the authors analyze LMS heterogeneity and molecular LMS subtypes using genomics and transcriptomics, finding origins in distinct lineages and associations with survival, in addition to the early emergence of metastatic clones.

SPEARHEAD-1: A phase 2 trial of afamitresgene autoleucel (Formerly ADP-A2M4) in patients with advanced synovial sarcoma or myxoid/round cell liposarcoma.

Abstract: 11504Background: This phase 2, open-label trial (SPEARHEAD-1; NCT04044768) is designed to evaluate the efficacy, safety, and tolerability of afamitresgene autoleucel in 45 patients (pts) with advan...

Underreporting of Symptomatic Adverse Events in Phase I Clinical Trials.

Abstract: BACKGROUND Clinician reporting of symptomatic adverse events (AEs) in phase I trials uses the Common Terminology Criteria for Adverse Events (CTCAE). The utility of the patient-reported outcomes (PROs) version of the CTCAE (PRO-CTCAE) in this setting is unknown. This prospective, observational study compared patient- and clinician-reported symptomatic AEs in phase I patients. METHODS Phase I study-eligible patients at Princess Margaret were surveyed with the PRO-CTCAE full-item library (78 symptomatic AEs) at baseline (BL), mid-cycle 1, and mid-cycle 2 (C2). Patient and trial characteristics, best response, and survival data were collected. Presence or absence of patient- (PRO-CTCAE) or clinician-reported symptomatic AEs were compared (kappa) at defined timepoints and overall (BL+ mid-cycle 1 + C2). RESULTS Of 292 patients approached from May 2017 to January 2019, a total of 265 (90.8%) were consented, with 243 (91.7%) evaluable and 552 PRO-CTCAE surveys (completion rate = 98.7%) included in analyses. Evaluation of overall patient-reported symptomatic AEs identified 50 PRO-CTCAE and 11 CTCAE items with 10% or greater reporting frequency. Nineteen CTCAE items were reported as 1% or less despite matched PRO-CTCAE items reporting as 10% or greater. Underreported categories included sexual health, bodily emissions, and cognition. Clinician- relative to patient-reporting frequency (ratio) demonstrated 9 symptomatic AEs with a 50-fold or more lower clinician reporting rate. Overall patient-clinician agreement for individual symptomatic AEs ranged from poor (κ = 0.00-0.19) to moderate (κ = 0.40-0.59), with discordance driven by lack of clinician reporting. Dyspnea (κ = 0.54) and peripheral neuropathy (κ = 0.63) at BL and limb edema (κ = 0.55) at C2 demonstrated the highest patient-clinician agreement. CONCLUSIONS Poor to moderate patient-clinician agreement for symptomatic AEs suggests clinician underreporting in phase I trials. Analyses of severity and interference PRO categories are ongoing.

Predicting Toxicity and Response to Pembrolizumab Through Germline Genomic HLA Class 1 Analysis

Abstract: Background Human leukocyte antigen class 1 (HLA-1)-dependent immune activity is linked to autoimmune diseases. HLA-1-dependent CD8+ T cells are required for immune checkpoint blockade antitumor activity. It is unknown if HLA-1 genotype is predictive of toxicity to immune checkpoint blockade. Methods Patients with advanced solid tumors stratified into 5 cohorts received single agent pembrolizumab (anti-programmed cell death-1) 200 mg intravenously every 3 weeks in an investigator-initiated phase II trial (Investigator-Initiated Phase II Study of Pembrolizumab Immunological Response Evaluation study, NCT02644369). Germline whole-exome sequencing of peripheral blood mononuclear cells was performed using the Illumina HiSeq2500 platform. HLA-1 haplotypes were predicted from whole-exome sequencing using HLAminer and HLAVBSeq. Heterozygosity of HLA-A, -B, and -C, individual HLA-1 alleles, and HLA haplotype dimorphism at positions -21 M and -21 T of the HLA-A and -B leader sequence were analyzed as predictors of toxicity defined as grade 2 or greater immune-related adverse events and clinical benefit defined as complete or partial response, or stable disease for 6 or more cycles of pembrolizumab. Statistical significance tests were 2-sided. Results In the overall cohort of 101 patients, the frequency of toxicity and clinical benefit from pembrolizumab was 22.8% and 25.7%, respectively. There was no association between any of the HLA-1 loci or alleles with toxicity. HLA-C heterozygosity had an association with decreased clinical benefit relative to HLA-C homozygosity when controlling for cohort (odds ratio = 0.28, 95% confidence interval = 0.09 to 0.91, P = .04). HLA-A and -B haplotype -21 M/T dimorphism and heterozygosity of HLA-A, -B, and -C were not predictive of outcomes. Conclusions HLA-C heterozygosity may predict decreased response to pembrolizumab. Prospective validation is required.

The Future of Clinical Trial Design in Oncology

Abstract: Clinical trials represent a fulcrum for oncology drug discovery and development to bring safe and effective medicines to patients in a timely manner Clinical trials have shifted from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to become adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in selected patient subsets This review will discuss the scientific, methodological, practical, and patient-focused considerations to transform clinical trials A call to action is proposed to establish the framework for next-generation clinical trials that strikes an optimal balance of operational efficiency, scientific impact, and value to patients SIGNIFICANCE: The future of cancer clinical trials requires a framework that can efficiently transform scientific discoveries to clinical utility through applications of innovative technologies and dynamic design methodologies Next-generation clinical trials will offer individualized strategies which ultimately contribute to globalized knowledge and collective learning, through the joint efforts of all key stakeholders including investigators and patients

A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.

Abstract: 3015Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal a...

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma.

Abstract: Objective: Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma. Materials & methods: HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size). Results: Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time. Conclusion: Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.

Pharmacokinetics of Selinexor: The First-in-Class Selective Inhibitor of Nuclear Export.

Abstract: The functionality of many tumor suppressor proteins (TSPs) and oncoprotein transcript RNAs largely depend on their location within the cell. The exportin 1 complex (XPO1) transports many of these molecules from the nucleus into the cytoplasm, thereby inactivating TSPs and activating oncoprotein transcript RNAs. Aberrations of these molecules or XPO1 can increase this translocation process, leading to oncogenesis. Selinexor is a selective inhibitor of nuclear export and is an active agent in various malignancies. It is currently approved for relapsed or refractory diffuse large B-cell lymphoma as well as multiple myeloma. Following oral administration, selinexor exhibits linear and time-independent pharmacokinetics (PK) across a wide dose range, with moderately rapid absorption (time to reach maximum concentration [Tmax] 2–4 h) and moderate elimination (half-life [t½] 6–8 h). Selinexor PK observed among patients with various solid tumors and hematologic malignancies is consistent irrespective of disease. Population PK analyses demonstrated the PK of selinexor is well-described by a two-compartment model, with significant relationships for body weight on apparent clearance and apparent central volume of distribution, and sex on apparent clearance, which result in clinically non-relevant changes in exposure. These analyses also suggested selinexor PK are not significantly impacted by various concomitant medications and organ dysfunction (hepatic/renal). The time course of selinexor PK appears similar between pediatric and adult patients, although higher exposures have been observed among pediatric patients relative to adults administered similar milligrams per meter squared (mg/m2) doses of selinexor.

A phase II, open-label, randomized trial of durvalumab (D) with olaparib (O) or cediranib (C) in patients (pts) with leiomyosarcoma (LMS).

Abstract: 11522Background: The use of immune checkpoint blockade (ICB) in non-inflamed (cold) tumors is associated with limited clinical efficacy. Combination of ICB with certain molecularly targeted agents ...

Selinexor, a First in Class, Nuclear Export Inhibitor for the Treatment of Advanced Malignant Peripheral Nerve Sheath Tumor.

Abstract: Malignant peripheral nerve sheath tumor (MPNST) is a highly malignant neoplasm arising from peripheral nerve or its attendant sheath and is derived from Schwann or pluripotent cells of neural crest origin. Patients with recurrent, unresectable, or advanced stage disease have limited treatment options, and current therapies are associated with little benefit. In this article, we report nine cases of MPNST treated with selinexor, an orally bioavailable, selective inhibitor of nuclear export, accompanied by tumor stabilization or regression.

Canadian consensus on TRK-inhibitor therapy for NTRK fusion-positive sarcoma.

Abstract: Malignant sarcomas are rare accounting for <1% of all adult solid malignancies and approximately 11% to 13% of all pediatric malignancies. TRK-inhibitors have demonstrated robust and long-lasting responses in patients with NTRK fusion-positive solid tumors, including sarcoma. Access to these agents in many jurisdictions such as Canada remains limited. We undertook a modified Delphi consensus to articulate and convey the clinical importance of these agents for the Canadian sarcoma community. A systematic search of published and presented literature was conducted to identify clinical trials reporting outcomes on the use of TRK-inhibitors in relapsed/refractory NTRK fusion-positive sarcoma. Three main consensus questions were identified: (a) is there currently an unmet clinical need for systemic therapy options in relapsed/refractory sarcoma? (b) do TRK-inhibitors confer a clinical benefit to patients with NTRK fusion-positive sarcoma? (c) do phase I/II basket trials provide sufficient evidence to justify funding of TRK-inhibitors in NTRK fusion-positive sarcoma? Response rates to the first and second surveys were 57% (n = 30) and 42% (n = 22), respectively. There was strong agreement among the Canadian sarcoma community that there was unmet clinical need for effective systemic therapy options in relapsed/refractory sarcoma, that TRK-inhibitors are a safe and effective treatment option for patients with NTRK fusion-positive sarcoma, and that available phase I/II basket trials provide sufficient evidence to support funding of these agents in relapsed/refractory NTRK fusion-positive sarcoma. TRK-inhibitors are a safe and effective systemic therapy option for patients with relapsed/refractory NTRK fusion-positive sarcoma.