Showing papers by "Albiruni Ryan Abdul Razak published in 2018"
TL;DR: Sustained partial responses in two patients with immune checkpoint inhibition treated with either durvalumab alone or in combination with tremelimumab (anti–CTLA-4), which appeared unrelated to tumor immune infiltrates or mutational burden suggest that immune checkpoint blockade may be a useful therapeutic strategy for ASPS.
Abstract: Alveolar soft-part sarcoma (ASPS) is a morphologically distinctive mesenchymal tumor characterized by a canonical ASPL-TFE3 fusion product. In the metastatic setting, standard cytotoxic chemotherapies are typically ineffective. Studies have suggested modest clinical response to multitargeted receptor tyrosine kinase inhibitors. Here, we report sustained partial responses in two patients with immune checkpoint inhibition treated with either durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4), which appeared unrelated to tumor immune infiltrates or mutational burden. Genomic analysis of these patients, and other cases of ASPS, demonstrated molecular mismatch-repair deficiency signatures. These findings suggest that immune checkpoint blockade may be a useful therapeutic strategy for ASPS. Cancer Immunol Res; 6(9); 1001-7. ©2018 AACR.
42 citations
TL;DR: Tumour necrosis <90% following neoadjuvant therapy is associated with increased recurrence risk and inferior OS in patients with STS, and ILP was associated with higher odds of achieving ≥90% necrosis.
40 citations
New York University1, Mayo Clinic2, University Hospitals of Cleveland3, City of Hope National Medical Center4, Memorial Sloan Kettering Cancer Center5, Greenville Health System6, University of Michigan7, University of Toledo8, University of California, San Diego9, MedImmune10, University of Chicago11
TL;DR: Current treatment options for ED-SCLC are limited, with standard first-line platinum and etoposide and second-line topotecan having limited clinical activity.
Abstract: 8517Background: Treatment options for ED-SCLC are limited, with standard first-line platinum and etoposide and second-line topotecan having limited clinical activity Beyond these agents, no approv
31 citations
25 citations
TL;DR: This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings and indicates that more comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations.
Abstract: Next-generation sequencing (NGS) has identified recurrent genomic alterations in metastatic breast cancer (MBC); however, the clinical utility of incorporating routine sequencing to guide treatment decisions in this setting is unclear. We examine the frequency of genomic alterations in MBC patients from academic and community hospitals and correlate with clinical outcomes. MBC patients with good performance status were prospectively recruited at the Princess Margaret Cancer Centre (PM) in Canada. Molecular profiling on DNA extracted from FFPE archival tissues was performed on the Sequenom MassArray platform or the TruSeq Amplicon Cancer Panel (TSACP) on the MiSeq platform. Clinical trial outcomes by RECIST 1.1 and time on treatment were reviewed retrospectively. From January 2012 to November 2015, 483 MBC patients were enrolled and 440 were genotyped. At least one somatic mutation was identified in 46% of patients, most commonly in PIK3CA (28%) or TP53 (13%). Of 203 patients with ≥ 1 mutation(s), 15% were treated on genotype-matched and 9% on non-matched trials. There was no significant difference for median time on treatment for patients treated on matched vs. non-matched therapies (3.6 vs. 3.8 months; p = 0.89). This study provides real-world outcomes on hotspot genotyping and small targeted panel sequencing of MBC patients from academic and community settings. Few patients were matched to clinical trials with targeted therapies. More comprehensive profiling and improved access to clinical trials may increase therapeutic options for patients with actionable mutations. Further studies are needed to evaluate if this approach leads to improved clinical outcomes.
25 citations
TL;DR: Data from this study do not support the routine use of targeted NGS panels outside of research protocols in UPS, and three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, however few had targetable driver mutations.
Abstract: There are limited data regarding the molecular characterization of undifferentiated pleomorphic sarcomas (UPS; formerly malignant fibrous histiocytoma). This study aimed to investigate the utility of next generation sequencing (NGS) in UPS to identify subsets of patients who harbour actionable mutations. Patients diagnosed with UPS underwent pathological re-evaluation by a pathologist specializing in sarcoma. Tumor DNA was isolated from archived fresh frozen tissue samples and genotyped using NGS with the Illumina MiSeq TruSeq Amplicon Cancer Panel (48 genes, 212 amplicons). In total, 95 patients initially classified with UPS were identified. Following pathology re-review the histological subtypes were reclassified to include: Myxofibrosarcoma (MFS, N = 44); UPS(N = 18); and Others (N = 27; including undifferentiated spindle cell sarcoma (N = 15) and dedifferentiated liposarcoma (N = 6)). Seven cases were excluded from further analysis for other reasons. Baseline demographics of the finalized cohort (N = 88) showed a median age of 66 years (32-95), primarily with stage I-III disease (92%) and high-grade (86%) lesions. Somatic mutations were identified in 31 cases (35%)(Total mutations = 36: solitary mutation(n = 27); two mutations( =n = 3); three mutations(n = 1)). The most commonly identified mutations were in TP53 (n = 24), ATM (n = 3) and PIK3CA (n = 2). Three of 43 patients with MFS and one of 18 patients with UPS had clinically relevant mutations, mainly related to biomarkers of prediction of response; however few had targetable driver mutations. Somatic mutation status did not influence disease free or overall survival. Based on the small number of clinically relevant mutations, these data do not support the routine use of targeted NGS panels outside of research protocols in UPS.
22 citations
TL;DR: Newly diagnosed patients with head and neck cancer may be at risk for impaired neurocognitive function (NCF) due to disease, treatment, and lifestyle factors.
Abstract: BACKGROUND Newly diagnosed patients with head and neck cancer may be at risk for impaired neurocognitive function (NCF) due to disease, treatment, and lifestyle factors. METHODS Eighty pretreatment patients with head and neck cancer and 40 control patients without cancer completed assessment of NCF and self-reported cognition, fatigue, and mood. Blood samples to evaluate organ reserves, hormones, and cytokines were collected. RESULTS Patients experienced worse symptoms of cognitive dysfunction, fatigue, and anxiety than controls. In contrast, NCF was equivalent for patients and controls. Using published norms as comparison, groups had similar high rates of impairment in performance (9/80 patients and 3/40 controls scored in the abnormal range). CONCLUSION Pretreatment patients with head and neck cancer reported cognitive disturbance. The frequency of impaired performance, albeit high, was consistent with the literature demonstrating false-positive "abnormal" neuropsychological test performance is not uncommon. Inclusion of a noncancer patient control cohort is essential because using solely normative data as a comparison may foster erroneous interpretation.
16 citations
TL;DR: Multi-agent chemotherapy is associated with a modest, but statistically significant improvement in outcomes in STS and combining chemotherapy with non-cytotoxic agents might represent a promising strategy.
16 citations
Memorial Sloan Kettering Cancer Center1, University of Texas MD Anderson Cancer Center2, Mayo Clinic3, University of Colorado Denver4, University of California, Los Angeles5, University of Pittsburgh6, Columbia University Medical Center7, Duke University8, Fox Chase Cancer Center9, Harvard University10, Ottawa Hospital11, Princess Margaret Cancer Centre12
TL;DR: This data indicates that prophylactic use of Selinexor (S) in combination with chemotherapy or a combination of chemotherapy and palliative therapies is likely to improve survival in patients with locally advanced DDLS.
Abstract: 11512Background: Locally advanced DDLS is incurable with an overall survival of 11 – 20 mo with palliative therapies. Ideal imaging criteria for efficacy is currently undefined. Selinexor (S) is an...
16 citations
TL;DR: HMM201 + ribociclib demonstrated a manageable safety profile and preliminary efficacy in pts with locally advanced or metastatic WDLPS/DDLPS, with hematologic toxicities being dose limiting.
Abstract: Background: Well-differentiated/dedifferentiated liposarcoma (WDLPS/DDLPS) is characterized by a consistent coamplification of human double minute 2 homolog (HDM2) and cyclin-dependent kinase 4 (CDK4) which inactivates the tumor suppressor pathways p53 and Rb, respectively. HDM201 is a selective inhibitor of the p53-HDM2 interaction and ribociclib is a CDK4/6 inhibitor. Preclinical studies suggested a synergy in in vitro and in vivo models of WDLPS/DDLPS and both agents have demonstrated single-agent clinical activity in solid tumors. We aim to determine the optimal dose and regimen of HDM201 + ribociclib and to assess the preliminary antitumor activity of this combination in patients (pts) with liposarcoma. Methods: In this multicenter, open-label, Phase Ib ongoing study, pts with locally advanced or metastatic liposarcoma that had unequivocally progressed on, or despite prior systemic therapy were treated orally with HDM201 + ribociclib. Three treatment regimens were explored: Regimen (Reg) 1 (HDM201 + ribociclib daily for the first 2 wks [QD 1st 2 wks] in a 4-wk cycle), Reg 4 (HDM201 every 3 wks + ribociclib QD 1st 2 wks in a 3-wk cycle), and Reg 5 (HDM201 every 4 wks + ribociclib QD 1st 2 wks in a 4-wk cycle). Results: As of Nov 21, 2017, 74 pts received HDM201 + ribociclib (Reg 1 n=26; Reg 4 n=29; Reg 5 n=19); 12 pts (6 each in Reg 4 and 5) were still receiving treatment. Ten pts (Reg 1 n=3; Reg 4 n=6; Reg 5 n=1) discontinued treatment due to adverse events (AEs) and 2 pts (1 each in Reg 4 and 5) died. The most common AE of any grade, regardless of cause, reported across regimens (Reg 1; Reg 4; Reg 5) was nausea (81%; 76%; 63%) which was mainly Grade 1/2 and not dose limiting. Common Grade 3/4 AEs regardless of cause included neutropenia (39%; 52%; 42%), thrombocytopenia (35%; 45%; 42%), anemia (27%; 17%; 21%), leukopenia (27%; 28%; 37%), and lymphopenia (15%; 14%; 21%). Dose-limiting toxicities were reported in 16 pts (2; 9; 5) and all except 1 (prolonged QT) were hematologic (including neutropenia [n=5], thrombocytopenia [n=4], febrile neutropenia, and anemia [n=2 each]). Partial responses were observed in 3 (4%) pts (2 in Reg 4; 1 in Reg 5). Stable disease was achieved by 36 (49%) pts (11 in Reg 1; 16 in Reg 4; 9 in Reg 5). The median progression-free survival (PFS) was 2.7 mo (95% confidence interval [CI]: 1.9-8.2 mo) in Reg 1, 4.8 mo (95% CI: 3.9 mo-not reached) in Reg 4, and 2.1 mo (95% CI: 1.4 mo-not reached) in Reg 5. Conclusions: HDM201 + ribociclib demonstrated a manageable safety profile and preliminary efficacy in pts with locally advanced or metastatic WDLPS/DDLPS, with hematologic toxicities being dose limiting. The median PFS in Reg 4 compares favorably with single-agent CDK4 inhibitors and, alongside a tolerable safety profile, suggests further exploration of this regimen may be warranted in Phase II studies of HDM201 + ribociclib in this patient population. Citation Format: Albiruni Abdul Razak, Sebastian Bauer, Jean-Yves Blay, Richard Quek, Cristina Suarez, Chia-Chi Lin, Marie L. Hutter-Kronke, Ricardo Cubedo, Stephane Ferretti, Christophe Meille, Ensar Halilovic, Giorgia Clementi, Maria Santos-Rosa, Nelson Guerreiro, Astrid Jullion, Claire Fabre, Antoine Italiano. Results of a dose- and regimen-finding Phase Ib study of HDM201 in combination with ribociclib in patients with locally advanced or metastatic liposarcoma [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 CT009.
12 citations
TL;DR: In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance.
Abstract: Idasanutlin, a selective small-molecule MDM2 antagonist in phase 3 testing for refractory/relapsed AML, is a non-genotoxic oral p53 activator. To optimize its dosing conditions, a number of clinical pharmacology characteristics were examined in this multi-center trial in patients with advanced solid tumors. This was an open-label, single-dose, crossover clinical pharmacology study investigating the effects of strong CYP3A4 inhibition with posaconazole (Part 1), two new oral formulations (Part 2), as well as high-energy/high-fat and low-energy/low-fat meals (Part 3) on the relative bioavailability of idasanutlin. After completing Part 1, 2, or 3, patients could have participated in an optional treatment with idasanutlin. Clinical endpoints were pharmacokinetics (PK), pharmacodynamics (PD) of MIC-1 elevation (Part 1 only), and safety/tolerability. The administration of posaconazole 400 mg BID × 7 days with idasanutlin 800 mg resulted in a slight decrease (7%) in Cmax and a modest increase (31%) in AUC for idasanutlin, a marked reduction in Cmax (~ 60%) and AUC0 (~ 50%) for M4 metabolite, and a minimal increase (~ 24%) in serum MIC-1 levels. Cmax and AUC were both 45% higher for the SDP formulation. While the low-fat meal caused a less than 20% increase in all PK exposure parameters with the 90% CI values just outside the upper end of the equivalence criteria (80–125%), the high-fat meal reached bioequivalence with dosing under fasting. In patients with solid tumors, multiple doses of posaconazole, a strong CYP3A4 inhibitor, minimally affected idasanutlin PK and PD without clinical significance. The SDP formulation improved rBA/exposures by ~ 50% without major food effect.
Mayo Clinic1, University of Texas MD Anderson Cancer Center2, University of Colorado Denver3, Chonnam National University4, Seoul National University Bundang Hospital5, Pinnacle Financial Partners6, Princess Margaret Cancer Centre7, Institut Gustave Roussy8, Catholic University of Korea9, Yonsei University10, Autonomous University of Barcelona11, MedImmune12, Netherlands Cancer Institute13
TL;DR: D+T had a manageable safety profile and encouraging antitumor activity and survival rate in previously treated mUC regardless of PD-L1 status, but patients with either tumor or immune cell expression ≥25% had numerically higher response rates and 6-month OS rates than those with Conclusions: D+.
Abstract: Background: PD-L1 blockade with durvalumab (D) is approved as second-line therapy in platinum-refractory metastatic urothelial cancer (mUC). Adding CTLA-4 blockade with tremelimumab (T) may improve responses, particularly in pts with low PD-L1 expression. Here we report safety and efficacy in the mUC cohort of the dose-expansion phase of a phase I, multicenter, open-label study of D+T in pts with advanced solid tumors (NCT02261220). Methods: Pts with platinum-refractory mUC received D 20 mg/kg + T 1 mg/kg Q4W for 4 months, followed by D 10 mg/kg Q2W for a total of 12 months of treatment. The primary objectives were safety in the mUC cohort and antitumor activity in the subgroup with tumor cell and immune cell PD-L1 expression Results: As of Oct 20 2017, 168 pts received treatment and had ≥24 weeks9 follow-up. Median age was 65.5 yr (range, 35-85), 78.0% were male, 81.0% had visceral metastases (32.1% liver metastases) and 32.1% had received >1 prior line of chemotherapy. Median duration of follow-up was 11.6 mo. Treatment-related AEs occurred in 75.6% of pts and were Grade 3-4 in 28.6%. One pt died due to a treatment-related AE (pulmonary hemorrhage). Treatment-related AEs led to discontinuation of therapy in 11.9% of pts. Confirmed objective response rate (ORR) was 35/168 (20.8%) including 4 CRs. Responses occurred early (median 1.8 mo) and are durable (median DOR not reached, range 1.9-24.9 mo). At 6 months, the PFS rate was 25.4% and the OS rate was 60.9%. Median PFS was 1.9 mo and median OS was 9.5 mo. Clinical activity was seen regardless of PD-L1 status, but patients with either tumor or immune cell expression ≥25% had numerically higher response rates (29.4% vs 15.1%) and 6-month OS rates than those with Conclusions: D+T had a manageable safety profile and encouraging antitumor activity and survival rate in previously treated mUC regardless of PD-L1 status. Citation Format: Arjun V. Balar, Amit Mahipal, Enrique Grande, Victor M. Villalobos, Sebastien Salas, Taek Won Kang, Se Hyun Kim, Thomas Powles, Frank Tsai, Aung Naing, Albiruni Razak, Yohann Loriot, Ji Youl Lee, Sang Joon Shin, Rafael Morales-Barrera, Natasha Angra, Feng Xiao, Shaad Abdullah, Michiel S. Van der Heijden. Durvalumab + tremelimumab in patients with metastatic urothelial 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 CT112.
TL;DR: Timely publishing of early cancer clinical trials results remains unsatisfactory, and industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication.
Abstract: Introduction The role of phase I cancer trials is constantly evolving and they are increasingly being used in 'go/no' decisions in drug development. As a result, there is a growing need to ensure trials are published when completed. There are limited data on the publication rate and the factors associated with publication in phase I trials. Methods The ClinicalTrials.gov database was searched for completed adult phase I cancer trials with reported results. PubMed was searched for matching publications published prior to April 1, 2017. Logistic regression was used to identify factors associated with unpublished trials. Linear regression was used to explore factors associated with time lag from study database lock to publication for published trials. Results The study cohort included 319 trials. 95 (30%) trials had no matching publication. Thirty (9%) trials were not published in abstract form as well. On multivariable analysis, the most significant factor associated with unpublished trials was industry funding (odds ratio 3.3, 95% confidence interval 1.7-6.6, p=0.019). For published trials, time lag between database lock and publication was longer by 10.9 months (standard error 3.6, p<0.001) for industry funded trials compared with medical center funded trials. Conclusions Timely publishing of early cancer clinical trials results remains unsatisfactory. Industry funded phase I cancer trials were more likely to remain unpublished, and were associated with a longer time lag from database lock to publication. Policies that promote transparency and data sharing in clinical trial research might improve accountability among industry and investigators and improve timely results publication.
TL;DR: This data indicates that a subset of patients treated with immune checkpoint inhibitors experience an accelerated tumor growth rate compared with pre-treatment kinetics, known as hyperprogressio...
Abstract: 3063Background: A subset of patients (pts) treated with immune checkpoint inhibitors experience an accelerated tumor growth rate (TGR) compared with pre-treatment kinetics, known as hyperprogressio...
TL;DR: GIST is driven by primary and secondary driver mutations in KIT/PDGFRα and cell-free tumor (ct) DNA and may provide the opportunity to assess disease status and response to therapy.
Abstract: 11511Background: GIST is driven by primary and secondary driver mutations in KIT/PDGFRα and cell-free tumor (ct) DNA may provide the opportunity to assess disease status and response to therapy. Th...
TL;DR: Selinexor is a first-in-class SINE compound with single-agent activity in STS and the safety, tolerability and efficacy of selinexor when combined with EMT is determined.
Abstract: 3123Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination...
TL;DR: The PK, safety and tolerability data presented together with efficacy data from the phase 1 trial demonstrate a favorable profile and broad therapeutic window for DCC-2618 and support the selection of 150 mg QD as the RP2D for the ongoing pivotal phase 3 INVICTUS study of DCC -2618 in pts with >4th-line GIST.
Abstract: Background: DCC-2618, a pan-KIT and PDGFRα kinase switch control inhibitor, is being studied in a pivotal, randomized phase 3 trial, INVICTUS (NCT03353753), based on encouraging disease control observed in a phase 1 trial (NCT02571036) in heavily pretreated GIST patients (pts). In the phase 1 trial, escalating doses of DCC-2618 up to 400 mg per day did not result in a DLT or MTD dose level. The RP2D of 150 mg QD was selected based on PK, efficacy and safety observed across the dose escalation cohorts before enrolling pts into expansion cohorts. Methods: Dose escalation in the phase 1 study is complete, and this study is now enrolling pts into 6 expansion cohorts, including 3 GIST cohorts. DCC-2618 was administered in 28-day cycles at daily oral doses of 20 to 200 mg BID or 100 to 250 mg QD in pts with advanced solid tumors, including GIST. The safety and tolerability of DCC-2618 will be reviewed as a function of exposure to study drug. We report PK results from all dose-escalation cohorts and the expansion phase. The impact of dose modifications including intra-patient dose escalation was assessed based on PK. Results: As of Jan 18, 2018, a total of 168 patients had been treated including 141 GIST patients. The most common treatment-emergent adverse effects (TEAE; all grades, ≥10% of patients) for the overall population across all dose levels included fatigue, myalgia, lipase increase (↑), alopecia, constipation, decreased appetite, nausea, hand-foot-syndrome, anaemia, diarrhea, dyspnea, abdominal pain, weight decrease, arthralgia, and hypertension (HTN). The most common TEAEs for the RP2D of 150 mg QD, based on 106 pts, included fatigue, myalgia, lipase ↑, alopecia, constipation and hand-foot-syndrome. G3 or G4 TEAE, regardless of attribution, occurring in ≥2% pts across all dose levels included included lipase ↑, anemia and HTN. 7.2% of patients underwent dose reductions. All patients who could have received at least 1 cycle prior to Dec 1, 2017 were included for further analysis (127 total, 114 GIST). Among these 114 GIST patients, 83 (73%) remain active on treatment, and 27, 14, 9 and 6 patients have been on DCC-2618 for more than 6, 9, 12, or 15 mo, respectively (15 pts were treated beyond progression per RECIST; a total of 21 were allowed to dose escalate while on study). The median follow up is 3.7 months with a range from 1 to 20 months. Population PK modeling using data from 67 patients demonstrated that combined exposures of DCC-2618 and its active metabolite, DP-5439, increase dose-proportionally. Dosing with a high fat meal increased exposure only slightly. The impact of dose escalation on plasma exposure will be shown. Conclusions: The PK, safety and tolerability data presented together with efficacy data from the phase 1 trial demonstrate a favorable profile and broad therapeutic window for DCC-2618 and support the selection of 150 mg QD as the RP2D for the ongoing pivotal phase 3 INVICTUS study of DCC-2618 in pts with >4th-line GIST. Citation Format: Filip Janku, Michael Heinrich, Albiruni Razak, Michael Gordon, Ping Chi, Kristen Ganjoo, Margaret von Mehren, Neeta Somaiah, Jongtae Lee, Keisuke Kuida, Rodrigo Ruiz Soto, Oliver Rosen, Suzanne George. Pharmacokinetic (PK), safety, and tolerability profile of DCC-2618 in a phase I trial supports 150mg QD selected for a pivotal phase III trial in gastrointestinal stromal tumor (GIST) [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 CT029.