bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase Ia/Ib study of a novel BTK inhibitor, DTRMWXHS-12 (DTRM-12), and combination products, with everolimus and pomalidomide, in pts with CLL or other B-cell lymphomas.
Authors: Gill Jennifer , He Wei , Schuster Stephen J. , Brander Danielle M. , Chatburn Elizabeth , Kennard Kaitlin , Anderson Barry Douglas , Nasta Sunita , Landsburg Daniel Jeffrey , Porter David L. , Napier Ellen , Latorre Tanya , Svoboda Jakub , Addis Victoria , Mato Anthony R. 
Published: September 2018

TPS7570 Background: Synthetic lethality (SL) relies on the chemical inhibition of two aberrant genes to selectively kill malignant cells. SL is now a clinical reality in an era of multiple targeted agents and advanced genetic testing. We investigated small molecule combinations for SL through in vitro and in vivo screening and optimization studies (Table, US patent 20160324878) and demonstrated the potential of SL through best-in-class combinations of targeted agents, immune modulation and low-dose combinations. We hypothesize that BTK and mTOR inhibition combined with an IMiD target multiple key signaling pathways, improve selective cell kill and address acquired drug-resistance. DTRM-555 is an optimized mechanism-based combination of the novel BTK inhibitor DTRM-12, with everolimus (E) and pomalidomide (P). In xenograft tumor models, DTRM-555 has shown superior efficacy over single agents at lower combined doses (1/18 of DTRM-12, 1/6 of E, and 1/6 of P). Methods: We are conducting a phase I, first-in-human multicenter trial exploring DTRM-555 in pts with CLL and B-cell NHL. Phase Ia consists of escalating DTRM-12 monotherapy doses. Phase Ib will explore doublet combination of DTRM-12 plus everolimus, and DTRM-555, the novel triplet combination. Safety is the primary study endpoint. Secondary endpoints include anti-tumor activity and pharmacokinetic studies. Eligible pts are > / = 18 years / ECOG < / = 1 with CLL or B-cell NHL with no available therapies. Treatment is administered for 21 consecutive days of a 28-day cycle, until disease progression or unacceptable toxicity. The trial commenced on 9/27/16. Phase 1a (single subject, 50/100mg respectively) has enrolled 5 pts without DLT and is currently at the 200 mg dose level. Up to 50 pts will be enrolled. Five additional sites are planned to open in the near future across the US. Clinical trial information: NCT02900716. [Table: see text]
B-MIND: MOR208 plus bendamustine (BEN) versus rituximab (RTX) plus BEN in patients with relapsed or refractory (R-R) diffuse large B-cell lymphoma (DLBCL): An open-label, randomized phase II/III trial.
Authors: Nowakowski Grzegorz S. , Belada David , Molina Lysianne , Kopeckova Katerina , Laribi Kamel , del Campo Garcia Raquel , Coiffier Bertrand , Jurczak Wojciech , Rummel Mathias J. , Hess Georg , Rosenwald Andreas , Winderlich Mark , Korolkiewicz Roman , Zinzani Pier Luigi 
Published: September 2018

TPS7571 Background: Patients ineligible for stem cell transplantation (SCT) or who relapse after SCT, and those who fail to respond to second-line or salvage chemotherapy, represent an unmet medical need for which new therapeutic strategies are required. MOR208 is a novel Fc-enhanced, humanized, monoclonal antibody directed against CD19. Significant single-agent activity of MOR208 in patients with R-R DLBCL (Jurczak et al., J Clin Oncol 34, 2016 [suppl; abstr 7545]) and enhancement of MOR208-mediated cytotoxicity by BEN in preclinical studies, provide a strong rationale to study MOR208 + BEN in patients with R-R DLBCL. Methods: B-MIND is a randomized (1:1), two-arm, multicenter, open-label, adaptive design, phase II/III study of MOR208 + BEN vs RTX + BEN in adult patients with histologically confirmed DLBCL who have relapsed after or are refractory to 1 to 3 prior lines of therapy and who are not candidates for high-dose chemotherapy and autologous SCT. At least 1 prior therapy line must have included a CD20-targeted therapy. Other key inclusion criteria: age ≥18 years; measurable disease; availability of tumor tissue for central pathology review; ECOG 0–2, and adequate major organ systems function. Key exclusion criteria: primary refractory DLBCL; central nervous system involvement, and known double/triple hit DLBCL genetics. The safety of the combination will be assessed in an initial phase II evaluation. Treatment will comprise 6 cycles of MOR208 (12 mg/kg IV) + BEN (90 mg/m2 IV) or RTX 375 mg/m2 IV + BEN. Patients achieving a response after cycle 6 will continue to receive antibody treatment for up to 18 additional cycles. Primary endpoint: progression-free survival (PFS); secondary endpoints include: best overall response, overall survival, safety, quality of life, immunogenicity and pharmacokinetics. Enrollment of 330 patients is anticipated in Europe, US and Asia-Pacific countries. Fourteen patients have been randomized to date. Clinical trial information: NCT02763319.
A multicenter, randomized, double-blind, placebo-controlled phase III study of the Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, in combination with rituximab versus placebo in combination with rituximab in patients with treatment-naive follicular lymphoma (PERSPECTIVE).
Authors: Fowler Nathan Hale , Flinn Ian , Rule Simon , Chen Robert W. , Kwei Long , Beaupre Darrin M. , Chu Alvina D. , Gordon Leo I. 
Published: September 2018

TPS7576 Background: Follicular lymphoma (FL) is the most common subtype of indolent non-Hodgkin lymphoma. A limited number of chemotherapy-free options exist for patients with treatment-naïve (TN) FL who are older or who have comorbidities. Single-agent rituximab is considered a treatment option for elderly or infirm patients. In a phase 2 study, frontline treatment with ibrutinib in combination with rituximab for 4 weekly doses without maintenance resulted in an ORR of 85% (CR, 35%) with a median follow-up of 22 months and an 18-month PFS rate of 87% (Fowler Blood 2016). The phase 2 study serves as the basis for the randomized, double-blind, placebo-controlled phase 3 PERSPECTIVE (PCYC-1141-CA) trial. PERSPECTIVE will be conducted in two parts and will uniquely test (1) whether frontline treatment with ibrutinib in combination with rituximab results in prolongation of PFS compared to rituximab alone, and (2) whether continuous versus finite treatment with ibrutinib affects PFS outcomes. Methods: In the ongoing PERSPECTIVE trial, approximately 440 patients with TN FL meeting at least one Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion will be randomized if they also meet one of the following criteria: age ≥70 years or age 60 to 69 with one or more comorbidities (creatinine clearance 30-59 mL/min or ECOG performance status of 2). Patients will be randomized to receive either ibrutinib or oral placebo once daily. All patients will be given rituximab for 4 weekly doses followed by maintenance. After at least 2 years of treatment in Part 1, patients randomized to ibrutinib who still remain on ibrutinib will be re-randomized in Part 2 to continue ibrutinib or switch to placebo. Key exclusion criteria include any prior treatment for FL, evidence of CNS involvement, or transformation. Analyses will be conducted in two distinct parts, both with a primary endpoint of PFS. The study is open for enrollment with sites planned in the US, EU, and Asia Pacific. Clinical trial information: NCT02947347.
Phase 1 study of the safety and efficacy of INCB050465 combined with obinutuzumab and bendamustine for relapsed or refractory (R/R) follicular lymphoma (FL) (CITADEL-102).
Authors: Coleman Morton , Salar Antonio , Munoz Javier , Galanina Natalie , Faivre Thea , Zinzani Pier Luigi 
Published: September 2018

TPS7578 Background: Aberrant PI3Kδ activation is implicated in B-cell non-Hodgkin lymphomas (NHL) including FL, the most common indolent subtype. INCB050465, a selective PI3Kδ inhibitor, is being evaluated in an ongoing phase 1/2 study as monotherapy for r/r B-cell NHL, including FL (ASH 2016; Abstract 4195). Obinutuzumab plus bendamustine is approved for patients (pts) with rituximab-refractory FL. This phase 1 cohort expansion study will assess the safety, efficacy, and pharmacokinetics of INCB050465 combined with obinutuzumab and bendamustine in pts with r/r FL (NCT03039114). Methods: Eligible adults will have documented CD20+ FL r/r to 1–4 prior treatments (must include rituximab), ≥1 measurable lesion ( > 1.5 cm in ≥1 dimension), ECOG PS ≤2, and adequate hematologic, hepatic and renal function. Exclusion criteria will include: transformation of FL to aggressive lymphoma or receipt of allogeneic stem cell transplant (SCT) ≤6 months (or having graft-versus-host-disease after allogeneic or autologous SCT ≤3 months) before study start; receipt of any PI3K inhibitor, obinutuzumab, or bendamustine ≤12 months, or rituximab ≤1 month prior to study. Part 1 (safety run-in) will use a 3+3 design. Pts will receive INCB050465 PO at a dose of 20 mg QD continuously for 2 cycles (1 cycle = 4 wks) followed by 20 mg QW. Up to 2 dose reductions will be allowed. Pts will receive obinutuzumab 1000 mg IV (cycle 1: days 1, 8, and 15; cycles 2–6: day 1) and bendamustine 90 mg/m2 IV (cycles 1–6: days 1 and 2). In part 2 (expansion), the safety and efficacy of INCB050465 (maximum tolerated dose) plus obinutuzumab and bendamustine will be evaluated in 30 pts, including pts treated in part 1 at the dose level deemed safe and tolerated. In both parts 1 and 2, pts not progressing after 6 cycles will be maintained on INCB050465 at the dose deemed safe and tolerated, and will continue on obinutuzumab 1000 mg IV administered on Day 1 of every second cycle for an additional 24 cycles or until disease progression. Response will be assessed using Lugano criteria (FDG-PET; CT/MRI) every 12 wks until cycle 12 and every 16 wks thereafter. The trial is open for enrollment. Clinical trial information: NCT03039114.
Novel phase 1a/1b dose-finding study design of CWP232291 (CWP291) in relapsed or refractory myeloma (MM).
Authors: Yoon Sung-Soo , Manasanch Elisabet Esteve , Min Chang Ki , Kim Jin Seok , Hauptschein Robert S , Choi Jeongeun , Chun Jae Kwang 
Published: September 2018

TPS8058 Background: CWP291, a novel peptidomimetic small molecule, has potent, selective inhibitory activity on a Wnt gene reporter, decreasing expression of β-catenin target genes, cyclin D1 and survivin. With broad anti-cancer efficacy in vitro, it significantly outperforms lenalidomide as a single agent combination in MM bone marrow engraftment models. Methods: This Phase 1a/1b study (NCT #02426723) was designed to define a well-tolerated dose of CWP291 as a single agent in subjects with R/R MM. CWP291 was administered IV over ≥30 minutes 2x weekly for 3 weeks out of a 4-week cycle, with standard 3+3 dose escalation design. But an important objective in terms of patient benefit and further clinical development was to explore activity of a combination regimen with lenalidomide. Thus, a novel study design allowed initiation of the Phase 1b as soon as CWP291 achieved a well-tolerated dose as a single agent. Combination therapy would start at one dose level lower. Enrollment of patients onto each arm was guided by Safety Review Committee assessments, including baseline laboratory values, performance status, extent of prior therapy, or prior adverse events related to lenalidomide. Results: Initiated September 2015, the starting dose was based on a prior Phase 1 study in AML, 198 mg/m2. There were 4 sites involved, and 11 patients enrolled over 12 months. Approval of the new design by regulatory authorities and IRBs was completed by November 2016. A well-tolerated single agent dose (297 mg/m2) was identified, allowing initiation of the Phase 1b at a dose of 198 mg/m2(one dose level lower) combined with lenalidomide. Four subjects were enrolled in ~2 months to the Phase 1b. Enrollment to both arms is continuing and the status of this study will be updated at presentation. Conclusions: The ability to consider combination therapy with a novel drug is clearly a motivation for patient participation in clinical trials; especially true in MM, as multiple new therapies are available. This trial design was approved and allowed based on assessment of individual patient safety and potential benefit. Rapid enrollment in the combination therapy arm may significantly foster development of novel agents with this study design. Clinical trial information: NCT #02426723.
Checkmate 816: A phase 3, randomized, open-label trial of nivolumab plus ipilimumab vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.
Authors: Forde Patrick M. , Chaft Jamie E. , Felip Enriqueta , Broderick Stephen , Girard Nicolas , Awad Mark M. , Kerr Keith , Blackwood-Chirchir Anne , Yang Rong , Geese William J. , Brahmer Julie R. 
Published: September 2018

TPS8577 Background: At initial diagnosis, 20% of patients (pts) with NSCLC present with early-stage disease. The 5-year overall survival (OS) rate after surgery for stage IB–IIIA NSCLC is 25%–60%. Addition of adjuvant chemotherapy to surgery only provides a 5% absolute OS benefit at 5 years. Neoadjuvant treatment with immune checkpoint inhibitors may extend OS in early-stage NSCLC by enhancing systemic immunity and eradicating micrometastatic disease. In contrast to the adjuvant setting, the neoadjuvant setting is associated with a higher tumor burden, the presence of abundant tumor antigens, and the consequent potential for tumor-associated neoantigen presentation to the immune system. In an ongoing feasibility trial in pts with stage IB–IIIA NSCLC, nivolumab (nivo; a fully human PD-1 immune checkpoint inhibitor antibody) given alone as neoadjuvant treatment induced a major pathological response (MPR; < 10% residual viable tumor cells) rate of 39% (7/18), did not delay or interfere with surgery, and was not associated with new safety signals. In a phase 1 study in pts with stage IIIB/IV NSCLC, first-line nivo + ipilimumab (ipi; a CTLA-4 immune checkpoint inhibitor antibody) showed a greater radiologic objective response rate than nivo alone (39% vs 23%). These data provided the rationale for Checkmate 816 (NCT02998528), a phase 3 study evaluating nivo + ipi vs platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC. Methods: Approximately 326 pts aged ≥18 years with resectable stage IB/II/IIIA NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, and Asia. Pts are ineligible if they have autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Pts will be randomized to receive nivo + ipi or platinum-doublet chemotherapy. The primary endpoint is MPR rate. Secondary endpoints include event-free survival, OS, and complete pathological response. Start date is January 2017. The estimated primary completion date is July 2019. Clinical trial information: NCT02998528.
eXalt3: A phase III study of ensartinib (X-396) in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
Authors: Horn Leora , Wu Yi-Long , Reck Martin , Liang Chris , Tan Fenlai , Harrow Kimberly , Oertel Vance , Dukart Gary , Mok Tony 
Published: September 2018

TPS8578 Background: Ensartinib is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Ensartinib has demonstrated activity in ALK treatment naïve and previously treated patients and has a generally well tolerated safety profile. Methods: eXalt3 (NCT02767804) is a global, randomized, open-label phase III study comparing the efficacy and safety of ensartinib to crizotinib in ALK- positive TKI naïve non-small cell lung cancer (NSCLC) patients. It is being conducted in > 100 sites in North America, South America, Europe, and the Asia/Pacific region. Enrollment began in 2016. The primary efficacy endpoint is progression free survival (PFS) assessed by independent radiology review. Secondary efficacy endpoints include overall survival, response rates (overall and central nervous system [CNS]), PFS by investigator assessment, time to response, duration of response, and time to CNS progression. Approximately 270 patients with ALK+ NSCLC who have received no prior ALK TKI and up to one prior chemotherapy regimen will be randomized 1:1 to ensartinib 225 mg QD, or crizotinib 250 mg BID, with stratification based on prior chemotherapy, ECOG performance status (PS), CNS metastases and geographic region. Eligibility includes patients ≥ 18 years of age, stage IIIB or IV ALK+ NSCLC. Patients are required to have measurable disease per RECIST 1.1, adequate organ function, and an ECOG PS of ≤2. Adequate tumor tissue (archival or fresh biopsy) must be available for central testing. The study has > 80% power to detect a superior effect of ensartinib over crizotinib in PFS at a 2-sided alpha level of 0.05. Clinical trial information: NCT02767804.
Checkmate 743: A phase 3, randomized, open-label trial of nivolumab (nivo) plus ipilimumab (ipi) vs pemetrexed plus cisplatin or carboplatin as first-line therapy in unresectable pleural mesothelioma.
Authors: Zalcman Gerard , Peters Solange , Mansfield Aaron Scott , Jahan Thierry Marie , Popat Sanjay , Scherpereel Arnaud , Hu Wenhua , Selvaggi Giovanni , Baas Paul 
Published: September 2018

TPS8581 Background: Malignant pleural mesothelioma (MPM) is an aggressive cancer with a 5-year overall survival (OS) rate of < 10%. At diagnosis, most patients (pts) have unresectable disease. Combination chemotherapy of cisplatin (or carboplatin as an alternative) + pemetrexed is the approved first-line standard of care. Phase 1 and 2 data suggest that targeting immune checkpoint pathways (eg, programmed death [PD]-1/PD-ligand 1 [PD-L1] and/or cytotoxic T-lymphocyte antigen-4 [CTLA-4]) may provide benefit with acceptable safety in MPM. In pts with previously treated, malignant mesothelioma, single-agent tremelimumab (a CTLA-4 inhibitor antibody) was active but did not improve OS vs placebo. In a phase 2 study of nivo (a fully human PD-1 immune checkpoint inhibitor antibody) in 34 pts with MPM that progressed after first-line platinum-based chemotherapy, 12-week disease control rate (DCR) was 50%, 5 pts had partial response, and 12 pts had stable disease. Given the data with single-agent CTLA-4 and PD-1 inhibitors and that CTLA-4 inhibition can induce PD-L1 expression, there is reason to anticipate synergy when combining CTLA-4 and PD-1 inhibitors in MPM. A phase 2 study assessing nivo alone and nivo + ipi (a CTLA-4 inhibitor antibody) in MPM is ongoing. CheckMate 743 (NCT02899299) is a phase 3 study that will evaluate the efficacy and safety of first-line nivo + ipi vs chemotherapy for MPM. Methods: Approximately 600 adult pts with unresectable MPM and ECOG performance status 0–1 will be randomized. Pts are ineligible if they have primary peritoneal, pericardial, or tunica vaginalis testis mesotheliomas; have active, untreated CNS metastases; or had received prior systemic therapy for pleural mesothelioma or a prior PD-1/PD-L1 or CTLA-4 checkpoint inhibitor antibody. Pts are randomized 1:1 to receive nivo + ipi or pemetrexed + cisplatin/carboplatin. Primary endpoints are OS and progression-free survival (PFS), assessed by blinded independent central review. Secondary endpoints are objective response rate (ORR), DCR, and correlation of PD-L1 expression level and efficacy (ORR, PFS, and OS). Clinical trial information: NCT02899299.
A phase 3, randomized study of first-line durvalumab (D) ± tremelimumab (T) + platinum-based chemotherapy (CT) vs CT alone in extensive disease small-cell lung cancer (ED-SCLC): Caspian.
Authors: Paz-Ares Luis G. , Jiang Haiyi , Huang Yifan , Dennis Phillip A. 
Published: September 2018

TPS8586 Background: SCLC accounts for ~13% of all lung cancers and is characterized by rapid growth and early metastases development. Standard of care CT for pts presenting with ED-SCLC is associated with the development of resistance, leading to poor treatment outcomes. As such, new therapies are needed. The high mutation burden associated with SCLC provides a rationale for investigating immune checkpoint blockade in this tumor type. D is a selective, high-affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. T is a selective human IgG2 mAb against CTLA-4. D alone and in combination with T has demonstrated a manageable safety profile and encouraging antitumor activity in non-small cell lung cancer (NSCLC). D ± T in combination with CT has also shown acceptable tolerability and preliminary signs of clinical activity in advanced NSCLC and thus may provide benefit in SCLC. Methods: CASPIAN (NCT03043872) is a Phase 3, randomized, multicenter, open-label, global study to determine the efficacy of CT in combination with D ± T as first-line treatment in ED-SCLC (Stage IV). Treatment-naïve pts (N = ~795; WHO/ECOG PS 0 or 1) will be randomized 1:1:1 to receive D (1500 mg) + T (75 mg) i.v. every 3 weeks (q3w) + CT (Arm 1); D (75 mg) i.v. q3w + CT (Arm 2); or CT alone (Arm 3). D ± T will be concurrently administered with CT in Arms 1 and 2 and will continue post-CT (1 further dose for T; until confirmed progressive disease for D). CT (etoposide [80–100 mg/m2] i.v. on Days 1–3 q3w + carboplatin [AUC 5–6] i.v. on Day 1 q3w or cisplatin [75–80 mg/m2] i.v. on Day 1 q3w) will be given for up to 4 cycles in Arms 1 and 2 and up to 6 cycles in Arm 3. The co-primary endpoints are overall survival (OS) and progression-free survival (PFS) using blinded independent central review (RECIST v1.1), for Arm 1 vs Arm 3. Secondary endpoints include OS and PFS for Arm 2 vs Arm 3 and Arm 1 vs Arm 2, ORR, OS at 18 months, proportion of patients alive and progression free at 6 and 12 months, PK, immunogenicity, HRQoL, and safety and tolerability. Exploratory endpoints include PFS after subsequent anticancer therapy and correlation of biomarkers with response to treatment. Recruitment is ongoing. Clinical trial information: NCT03043872.