bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II, multicenter, open-label, proof of concept study of tasquinimod in patients with advanced/metastatic hepatocellular (HCC), ovarian (OC), renal cell (RCC) and gastric (GC) carcinomas.
Authors: Escudier Bernard J. , Faivre Sandrine J. , Oza Amit M. , Van Cutsem Eric , Agnes Geniaux , Baton Frederique
Published: March 2020

TPS2622

Background: Treatment resistance and disease progression are common in HCC, OC, RCC and GC. Tasquinimod is an oral, quinoline-3-carboxamide derivative that binds to S100A9, resulting in immunomodulatory, anti-angiogenic and anti-metastatic effects involving downregulation of chemokine receptor type 4 and hypoxia-inducible factor. Tasquinimod significantly improves PFS (7.6 v 3.3 mo) in patients with metastatic hormone-resistant prostate cancer (Pili, R. et al. 2011. JCO 29:4022-8) and is in an ongoing phase III program. Its unique mode of action (MOA) makes tasquinimod attractive for other indications. The primary study objective is to determine the clinical activity of tasquinimod in advanced/metastatic HCC, OC, RCC and GC. Tasquinimod has been shown to delay disease progression with limited tumor shrinkage, therefore an innovative design was proposed, with PFS rate as the main endpoint. Methods: Design: Phase II, multinational, exploratory proof of concept study to evaluate tasquinimod activity in 4 independent cohorts of patients (HCC, OC, RCC and GC) with progressive disease after standard therapy. An innovative design (Litwin S. 2007. Stat Med 26:4400-15) based on the proportion of patients who have not progressed nor died at predefined timepoints (PFS rate) will be used in each cohort independently. Patients: 110–200 patients (dependent on outcome of futility analyses) aged ≥18 yr, ECOG performance status 0 or 1 will be enrolled. Patients must have histologically confirmed and documented HCC, OC, RCC or GC and demonstrable disease progression on standard therapy. Recruitment is ongoing. Dosage: Tasquinimod will be administered as a starting dose of 0.5 mg/day, in each cohort. After 2 wks, the dose will be increased to 1 mg/day based on individual safety and tolerability. Primary endpoint: PFS rate, defined as the proportion of patients who have neither progressed nor died at 12 wks (GC), 16 wks (HCC, RCC) or 24 wks (OC). Secondary endpoints: Include OS, response rate, safety, pharmacokinetics, inflammatory and specific target biomarkers to explore comprehensively the MOA according to each disease type. Clinical trial information: NCT01743469.
Clinical and preclinical activity of SL-401, a targeted therapy directed to the interleukin-3 receptor on cancer stem cells and tumor bulk of hematologic malignancies, against blastic plasmacytoid dendritic cell neoplasm (BPDCN).
Authors: Frankel Arthur E. , Woo Jung Hee , Mauldin Jeremy Preston , Carraway Hetty Eileen , Frankfurt Olga , Forman Stephen J. , Brooks Christopher , Bergstein Ivan , Cirrito Thomas , Rowinsky Eric K.
Published: March 2020

TPS3105^

Background: Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), a rare and aggressive dendritic cell-derived hematologic malignancy that typically involves the skin and invariably progresses to a leukemic phase, has a dismal prognosis with a median survival of approximately 14 months. Since BPDCN cells express high levels of the interleukin-3 receptor (IL-3R), SL-401, a novel targeted therapy directed to IL-3R, is being developed to treat BPDCN and other IL-3R-expressing hematologic malignancies. SL-401 is a recombinant biologic comprised of IL-3 conjugated to a truncated diphtheria toxin, a potent inhibitor of protein synthesis (Frankel et al, Prot Eng 13, 575, 2000). SL-401 is cytotoxic in vitro to IL-3R-expressing leukemia blasts (Frankel et al, Leukemia 14, 576, 2000) and inhibits tumor growth in vivo (Black et al, Leukemia 17, 155, 2003). Recently, SL-401 demonstrated ultra-high anti-tumor potency against BPDCN cells in the femtomolar (10-15 M) range (Angelot-Delettre et al, Blood 118 Suppl 2588, 2011). Methods: In a Phase I/II trial of SL-401 in patients with IL-3R-expressing advanced hematologic malignancies, 4 patients with heavily pretreated BPDCN received a single cycle of SL-401 as a 15-minute infusion daily for 5 days. Results: All patients had CD4+/CD56+/CD123+ (IL-3Ralpha) expressing blasts and had failed previous combination chemotherapy regimens and allogeneic bone marrow transplantation. There were no serious adverse events. Three patients treated with SL-401 at 12.5 μg/kg/day (the planned pivotal Phase IIb trial dose) experienced complete responses (CRs). The CRs included disappearance of BPDCN in the skin, bone marrow, peripheral blood, spleen and lymph nodes. CR durations are 5, 3+, and 1+ months to date. Conclusions: Given these robust clinical responses, as well as the mechanistic rationale for SL-401 in BPDCN, additional BPDCN patients are being evaluated in the study and a pivotal Phase IIb multi-cycle trial in this ultra-orphan indication is being planned. Clinical trial information: NCT00397579.
A phase I study of the safety, tolerability, pharmacokinetics, and immunoregulatory activity of urelumab (BMS-663513) in subjects with advanced and/or metastatic solid tumors and relapsed/refractory B-cell non-Hodgkin’s lymphoma (B-NHL).
Authors: Melero Ignacio , Gangadhar Tara C. , Kohrt Holbrook Edwin , Segal Neil Howard , Logan Theodore , Urba Walter John , Hodi F. Stephen , Ott Patrick Alexander , Perez-Gracia Jose Luis , Wolchok Jedd D. , Shah Aadhar , Kurland John F. , Cohen Lewis J. , Levy Ronald , Wigginton Jon M. , Goldberg Stacie M.
Published: March 2020

TPS3107

Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses in T-cell directed therapy as well as in antibody-dependent cell-mediated cytotoxicity. Urelumab is an agonistic antibody targeting CD137 which has demonstrated antitumor activity against a variety of cancers in pre-clinical and clinical studies. We describe a phase I study to investigate the clinical and biologic effects of treatment with urelumab in patients with advanced solid tumors and B-cell non-Hodgkin’s lymphoma (B-NHL). Methods: This phase I study (n=70) will include dose escalation (Part 1) using a 6+9 design, cohort expansion (Part 2), and tumor-specific cohort expansion (Part 3). In Part 1, successive cohorts of pts with advanced solid tumors will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks). In Part 2, both cohorts (1 +2) will expand to 20 patients with advanced solid tumors. In Part 3, additional tumor-specific cohorts with B-NHL, colorectal cancer, and head and neck cancer (10 subjects each) will be enrolled at the highest tolerated dose. The primary objective of this study is to evaluate the safety and to define the MTD of the respective doses of 0.1 and 0.3 mg/kg administered every 3 weeks with special attention to hepatic toxicity. Secondary objectives include assessment of the preliminary antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity in peripheral blood and paired tumor biopsy specimens and associations with clinical outcome. Part 1 (dose escalation) has been completed without any DLTs. Clinical trial information: NCT01471210.
A phase Ib, open-label, multicenter study of urelumab (BMS-663513) in combination with rituximab in subjects with relapsed/refractory B-cell malignancies.
Authors: Kohrt Holbrook Edwin , Godwin John E. , Lossos Izidore S. , Williams Michael E. , Timmerman John , Link Brian K. , Goldberg Stacie M. , McGirr Analia , Kurland John F. , Wigginton Jon M. , Cohen Lewis J. , Levy Ronald
Published: March 2020

TPS3108

Background: CD137 (4-1BB) is a costimulatory molecule that belongs to the TNF superfamily. It is upregulated on activated lymphocytes, NK cells and dendritic cells and plays an important role in the potentiation of antigen-specific immune responses as well as in antibody-dependent cell-mediated cytotoxicity (ADCC). Urelumab is an agonistic antibody targeting the CD137 receptor. Preclinical evidence has shown that there is modulation of CD137 expression on NK cells after exposure to rituximab. Anti-CD137 agonist monoclonal antibody has been shown to have single-agent anti-lymphoma activity and to potentiate the anti-lymphoma activity of rituximab through enhancing ADCC. We hypothesized that upregulation of CD137 on NK cells by rituximab followed by urelumab could afford a mechanism-based approach to achieve enhanced biologic and/or clinical activity compared to either single agent alone. Here we describe a phase Ib study to investigate the clinical and biologic effects of combined treatment with urelumab and rituximab in patients with relapsed/refractory B-cell malignancies. Methods: This phase I study (n=100) will include dose escalation (Part 1) using a 3+3+3 design and cohort expansion (Part 2). In Part 1, successive cohorts of patients with relapsed/refractory B-NHL will be treated as follows: Cohort 1 (0.1 mg/kg q3weeks) and Cohort 2 (0.3 mg/kg q3weeks) with both cohorts in combination with rituximab 375 mg/m2 given weekly for the first 4 weeks of each 12 week cycle. In Part 2, cohorts of CLL (n=30), follicular lymphoma (FL) (n=30), and diffuse large B-cell lymphoma (DLBCL) (n=20) will be treated at the dose level found to be safe for the urelumab/rituximab combination. The primary objective of the study is to evaluate the safety and define a safe and effective dose of the urelumab/rituximab combination. Secondary objectives include assessment of the antitumor activity, pharmacokinetics, and immunogenicity. Exploratory objectives include investigation of the immunoregulatory activity of this combination in peripheral blood and paired tumor biopsy specimens and the association of these effects with clinical response/toxicity. Clinical trial information: NCT01775631.
Chimeric antigen receptor (CAR+) modified T cells targeting prostate specific membrane antigen (PSMA) in patients (pts) with castrate metastatic prostate cancer (CMPC).
Authors: Slovin Susan F. , Wang Xiuyan , Hullings Melanie , Arauz Gabrielle , Bartido Shirley , Lewis Jason Stuart , Schöder Heiko , Zanzonico Pat , Scher Howard I. , Riviere Isabelle
Published: March 2020

TPS3115

Background: A phase I dose-escalating study to assess safety, dose and targeting efficiency of genetically modified autologous human T cells targeted to PSMA was initiated. Preclinical models demonstrated anti-tumor activity and accumulation, migration, and persistence of these cells to tumor. The autologous PSMA-targeted T cells utilizes the P28z second generation chimeric antigen receptor following iv cyclophosphamide (Cy). For safety, the herpes simplex virus-1 thymidine kinase (hsvtk) gene is co-expressed with the P28z receptor, rendering T cells sensitive to ganciclovir for immediate T cell elimination. The expression of hsvtk enables PET imaging using radiolabeled FIAU to localize these T cells Methods: Autologous T cells are activated from a leukapheresis product using anti-CD3/CD28 Dynabeads. Release criteria include mean vector copy number by Q-PCR and vector identity by Southern blot, absence of Replication Competent Retrovirus and residual Dynabeads. Pts were dosed from 107 to 3 x 107 CAR+ T cells/kg.All 7 pts received 300mg/m2 of Cy one day before infusion. Baseline and post treatment imaging included FDG, FDHT and 18F-FIAU PET scans. Results: Three pts in cohort 1 received 1 x 107 CAR+ T cells/kg safely. A fourth pt received the same dose with a modified vector with higher copy number. One pt had stable disease for > 6 months; a second pt has stable scans for > 20 months; the third and fourth patients progressed. Of 3 pts in cohort 2, one received 1.5 x 107 CAR+ T cells/kg and 2 received 3 x 107 CAR+ cell/kg. All 3 had intermittent fever spikes up to 39oC associated with increased levels of IL-4, IL-8, IP-10, sIL-2ra and IL-6 suggesting T cell activation. CAR+ cells persisted in the circulation for up to 2 weeks. Scans with 18F-FIAU labeling suggests that imaging may be cell dose dependent. Conclusions: We have shown that pts can be safely treated with an ex vivo transduction, expansion and therapeutic protocol for the generation of PSMA targeted T cells. Cytokine production suggests in vivo activation and persistence of T cells in blood for up to 2 weeks. Ongoing imaging with 18F may be suboptimal; a second cohort of pts will be studied with 124I-FIAU. Clinical trial information: NCTO1140373.
Intergroup ALFA/GOELAMS randomized phase II trial of lirilumab anti-KIR monoclonal antibody (IPH2102/BMS986015) as maintenance treatment in elderly patients with acute myeloid leukemia (EFFIKIR trial).
Authors: Vey Norbert , Dombret Hervé , Ifrah Norbert , Pigneux Arnaud , Gardin Claude , Buyse Marc E. , Andre Pascale , Tirouvanziam-Martin Anne , Zerbib Robert Albert , Buffet Renaud , Rozencweig Marcel
Published: March 2020

TPS3117^

Background: Inhibitory killer immunoglobulin-like receptors (KIR) negatively regulate natural killer (NK) cell–mediated killing of HLA class I–expressing tumors. Lack of KIR-HLA class I interactions has been associated with potent NK cell-mediated antitumor efficacy and increased survival in patients with acute myeloid leukemia (AML) upon haploidentical stem cell transplantation from KIR-mismatched donors(Ruggeri, Blood 2007). Anti-KIR antibody treatment resulted in long-term survival in SCID mice inoculated with lethal autologous AML cells (Romagne, Blood 2009). Lirilumab is a second generation fully human monoclonal antibody targeting the major inhibitory KIR on NK cells. The objectives of this study are to determine if maintenance therapy with lirilumab can improve leukemia-free survival (LFS) of elderly patients in first complete remission (CR1) of AML and to assess two dose schedules leading to either intermittent or continuous KIR occupancy. Methods: EFFIKIR is a randomized double-blind 3-arm placebo controlled trial of lirilumab in elderly patients in CR1 of AML. Patients aged 60 to 80 in CR1 of AML following standard induction and consolidation programs are randomly allocated to receive placebo or lirilumab given at either 0.1 mg/kg q 12 weeks or 1 mg/kg q 4 weeks according to a minimization algorithm adjusting for center, primary vs. secondary AML, no. of consolidation cycles (1 vs. 2) and cytogenetics (intermediate vs. high risk). Patients are to receive up to 2 yrs of therapy. ECOG performance status of 0-1, adequate hematologic, liver and renal function, and recovery from toxicities of prior chemotherapies are required. Patients are excluded if they are eligible for bone marrow transplantation and if the time interval since last consolidation exceeds 3 mos. The primary endpoint is LFS based on independent central review. The trial will accrue 50 patients in each arm and is powered (80%) to detect an improvement in LFS with a hazard ratio of 0.60 and a one-sided alpha of 0.05. Each dose schedule will be compared to placebo using a Hochberg procedure. The first patient was randomized on 12/11/2012. Clinical trial information: NCT01687387.
Sequential ipilimumab (Ipi) versus best supportive care (BSC) following first-line chemotherapy (Ctx) in patients (pts) with unresectable locally advanced or metastatic gastric or gastro-esophageal junction (GEJ) cancer: A randomized, open-label, two-arm, phase II trial (CA184-162) of immunotherapy as a maintenance concept.
Authors: Moehler Markus Hermann , Kim Yeul Hong , Tan Iain B. , Balogh Agnes , Sanchez Teresa Kong , Bang Yung-Jue
Published: March 2020

TPS4151

Background: First-line systemic CTX is standard-of-care for advanced gastric cancer. However, most pts relapse or have severe adverse events (AEs), creating a need for new therapies with better benefit/risk and toxicity profiles. Endogenous immune activity against tumor cells has been demonstrated in the human gastric cancer tumor microenvironment, supporting a role for immunotherapy. As a new maintenance concept, sequential administration of immunotherapy may prolong clinical benefit of first-line CTX before disease progression (PD). Ipi, a fully human monoclonal antibody which binds CTLA-4, augments the antitumor immune response. Ipi improved overall survival (OS) in patients with advanced melanoma with AEs managed using product-specific treatment guidelines.This global (32 sites among 10 countries), multicenter, randomized, open-label, phase II trial (ClinicalTrials.gov identifier NCT01585987) will compare the efficacy of Ipi and BSC after first-line CTX. Methods: Pts with good performance status (0 or 1) and histologically confirmed, unresectable locally advanced or metastatic gastric or GEJ cancer without PD after first-line CTX with a fluoropyrimidine (F) and platinum (P) doublet will be eligible. Pts with radiological evidence of brain metastases, autoimmune/immune-mediated disease, inadequate hematologic, renal, and hepatic function, or are HER2+ will be ineligible. Pts will be randomized to Ipi (4 doses [10 mg/kg, IV Q3W], followed by Q12W) until confirmed immune-related PD or unacceptable toxicity, or to BSC (continuing F used in lead-in CTX or no active systemic therapy). The primary objective is to compare immune-related progression-free survival (PFS): immune-related response criteria were derived from World Health Organization (WHO) criteria to better capture Ipi response patterns. Secondary objectives are to compare PFS per mWHO criteria and OS, and estimate immune-related best overall response rate. The study is planned to randomize 114 pts. Clinical trial information: NCT01585987.
Metiv-HCC: A phase III clinical trial evaluating tivantinib (ARQ 197), a MET inhibitor, versus placebo as second-line in patients (pts) with MET-high inoperable hepatocellular carcinoma (HCC).
Authors: Santoro Armando , Porta Camillo , Rimassa Lorenza , Borbath Ivan , Daniele Bruno , Finn Richard S. , Raoul Jean-Luc , Schwartz Lawrence H. , He Aiwu Ruth , Trojan Jorg , Peck-Radosavljevic Markus , Abbadessa Giovanni , Goldberg Terri Robin , Bruix Jordi
Published: March 2020

TPS4159

Background: Tivantinibis a selective, non-ATP competitive, oral inhibitor of MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF). MET over-expression is associated with poor prognosis in HCC patients. A phase Ib study (Santoro et al, Br J Cancer, 2013) with tivantinib 360mg BID revealed no worsening of liver function in cirrhotic HCC pts. A randomized, placebo-controlled phase 2 study identified HCC patients with high tumor MET expression at immunohistochemistry (IHC) as the target population for tivantinib in second line (overall survival: 7.2 months on tivantinib, 3.8 months on placebo, HR: 0.38, p=0.01), and selected 240mg BID as the appropriate dose for HCC patients (Santoro et al, Lancet Oncol, 2013). Methods: Enrollment forthis phase III clinical trial (ARQ 197-A-U303, NCT01755767) has begun.Eligible pts must present with Child Pugh A; ECOG performance score <1; inoperable RECIST 1.1 measurable disease; adequate bone marrow, liver and kidney functions; no prior liver transplant. Pts must have progressed after or not tolerated one prior line of systemic therapy including sorafenib and their tumor samples must be deemed MET-High by IHC at a central laboratory to be eligible. Approximately 303 pts are randomized 2:1 to receive tivantinib 240mg PO twice daily or placebo. Pts are stratified by vascular invasion, metastases, and alphafetoprotein level, and they are evaluated by CT or MRI scan at 8-week intervals. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival and safety. Treatment continues until confirmed disease progression or unacceptable toxicity. Pts discontinued from study treatment will be followed for survival. Participating centers are located in Europe, Australia, New Zealand, and the Americas. This trial is expected to complete enrollment by mid-2015, and an interim analysis is planned when approximately 60% of OS events are reached. Clinical trial information: NCT01755767.
A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Amin Asim , Ernstoff Marc S. , Infante Jeffrey R. , Heng Daniel Yick Chin , Rini Brian I. , Plimack Elizabeth R. , McDermott David F. , Kollmannsberger Christian K. , Reaume Martin Neil , Spratlin Jennifer L. , Knox Jennifer J. , Voss Martin Henner , Pal Sumanta Kumar , Shen Yun , Dhar Arindam , Hammers Hans J.
Published: March 2020

TPS4593

Background: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors are established therapies for mRCC. However, sunitinib and pazopanib rarely elicit durable responses. Programmed death-1 receptor (PD-1) is an immune checkpoint modulator that suppresses T-cell activation by interacting with its ligands (PD-L1/2) on antigen presenting cells and some tumor cells. Nivolumab, a PD-1 receptor blocking antibody, has shown durable responses in previously treated pts with mRCC in Phase 1 and 2 trials. Ipilimumab is an immune checkpoint inhibitor (anti-CTLA-4 antibody) already approved for the treatment of advanced melanoma. We describe an ongoing Phase 1 dose-escalation and expansion study evaluating combination of nivolumab with sunitinib, pazopanib or ipilimumab in pts with mRCC. Methods: Patients with histologically confirmed mRCC are treated on 4 parallel arms: nivolumab 2.0 or 5.0 mg/kg + sunitinib standard dosing (Arm S), nivolumab 2.0 or 5.0 mg/kg + pazopanib standard dosing (Arm P), nivolumab 3 mg/kg + ipilimumab 1 mg/kg as induction (Arm I-1), and nivolumab 1 mg/kg + ipilimumab 3 mg/kg as induction (Arm I-3) with nivolumab 3 mg/kg maintenance for both arms. Arms S and P are being conducted in 2 phases: nivolumab dose-escalation phase for previously treated pts (≤18 pts/arm) and then dose-expansion phase for treatment-naïve pts (20 pts/arm) if the maximum tolerated dose is ≥5 mg/kg. Arms I-1 and I-3 are fixed-dose cohorts (20 pts/arm) including both treatment-naïve and previously treated pts. Most of the study population consists of pts with clear-cell histology; non-clear cell mRCC pts are allowed in the dose-escalation cohorts of Arms S and P. The primary objectives are to assess safety and tolerability, and to determine the recommended Phase 2 dose in pts with mRCC. The secondary objective is to assess preliminary antitumor activity (objective response rate and response duration per RECIST 1.1). Exploratory objectives are to evaluate overall survival, pharmacodynamics, and predictive biomarkers for the combinations, and pharmacokinetics and immunogenicity of nivolumab. Clinical trial information: NCT01472081.
A phase II multicenter study of the efficacy and safety of sunitinib given on an individualized schedule as first-line therapy for metastatic renal cell cancer.
Authors: Bjarnason Georg A. , Basappa Naveen S. , Knox Jennifer J. , Kollmannsberger Christian K. , Reaume M. Neil Neil , Zalewski Pawel , Macfarlane Robyn Jane , MacKenzie Mary J. , Hotte Sebastien J. , Heng Daniel Yick Chin , Soulieres Denis , Miller Jessie
Published: March 2020

TPS4594

Background: Retrospective reviews have shown poorer than expected response rate (RR), progression free survival (PFS) and overall survival (OS) in Sunitinib treated (Rx) Renal Cell Cancer (RCC) patients (pts) who experience minimal toxicity. This study is based on an individualized (individ) Rx strategy where dose/schedule modifications (DSM) were done to maximize dose and minimize time off Rx in 172 pts (Bjarnason ASCO-GU 2011). Pts started on 50mg 28 days (d) on/14d off. DSM were done to keep toxicity (fatigue, skin, GI, hematology) at ≤ grade-2. DSM-1 was 50mg 14d/7d with individ increases in d on Rx based on toxicity. DSM-2 was 50mg 7d/7d with individ increases in d on Rx. DSM-3 was 37.5mg continuously with individ 7d breaks. DSM-4 was 25mg continuously with individ 7d breaks.In pts with clear cell histology PFS was inferior (5.8 mo) on the standard 50mg 28d/14d schedule vs. DSM schedules (>14 months, p=0.0002) These data, confirmed in 185 pts at MD Anderson (Jonasch KCA 2012), suggest that pts with minimal toxicity after 28d on Rx may benefit from dose escalation. Methods: A prospective phase II study has opened in 11 centers in Canada. DSM are done as described above. Pts with minimal toxicity after 28d are escalated to 62.5 mg and then 75 mg on a 14d /7d schedule. We expect to dose escalate 25% of pts and maintain another 40% of pts on a 50 mg dose that would otherwise have been dose reduced. The primary objective is the PFS associated with this strategy. Secondary objectives include dose intensity, RR, OS, toxicity, and quality of life. Samples for Sunitinib pharmacokinetics are obtained during the first course and again when the ideal sunitinib schedule has been established. Samples for biomarker and DNA correlative studies are collected. Based on the standard arm of the EFFECT trial (identical eligibility criteria), we assume a median PFS of 8.5 months in pts Rx using standard dosing. We expect pts treated with the indiv dosing will have a median PFS of 14 months. With alpha=0.05, a two-sided, single-arm non-parametric survival test would have over 90% power to detect this difference with a total of 110 pts on study. Study enrollment began in July 2012 with 25 pts currently on study. Clinical trial information: NCT01499121.
A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).
Authors: Naumann R. Wendel , Gilbert Lucy , Miller Anthonette M. , Ma Hong , Ghamande Sharad A. , Vergote Ignace
Published: March 2020

TPS5613

Background: Folate receptor (FR) is expressed on the majority of epithelial ovarian cancers and FR expression appears to be a negative prognostic factor in this setting. Vintafolide (EC145) is a folate-conjugate designed to selectively deliver desacetylvinblastine monohydrazide (DAVLBH) to FR-expressing cells. 99mTc-Etarfolatide (EC20) is a technetium-labeled folate that identifies FR-expressing tumors. In a phase 2 study comparing vintafolide + PLD with PLD alone, the combination demonstrated a statistically and clinically significant delay in PFS (5.0 months) compared with PLD alone (2.7 months) in women with platinum-resistant ovarian cancer (Naumann et al, ASCO 2011). Data also indicated that 99mTc-etarfolatide may have utility for selecting patients most likely to benefit from vintafolide therapy. Methods: This is an international, randomized, double-blind, placebo-controlled phase 3 study of PLD ± vintafolide therapy compared in patients with primary or secondary platinum-resistant ovarian cancer (NCT01170650). Key eligibility criteria include: ≥18 years, pathology-confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, prior platinum-based chemotherapy, a RECIST v1.1 measureable lesion, and ECOG performance status 0 or 1. At baseline, patients undergo 99mTc-Etarfolatide imaging to identify FR-positive lesions and are subsequently randomized to the vintafolide ± PLD. PLD (50 mg/m2) adjusted for Ideal Body weight is administered on day 1 of a 4-week cycle and treatment continues until the maximum allowable cumulative dose (550 mg/m2) is reached or until disease progression or intolerable toxicity. Vintafolide (2.5 mg) or placebo is administered on days 1, 3, 5, 15, 17, and 19 of a 4-week cycle and treatment can continue for up to 20 cycles or until unacceptable toxicity or disease progression. The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in FR positive patients. Secondary objectives include OS, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing. Clinical trial information: NCT01170650.
Potentiation of cetuximab by inhibition of Tregs in metastatic squamous cell cancers of head and neck.
Authors: Jha Gautam Gopalji , Miller Jeffrey S
Published: March 2020

TPS6101

Background: There are few effective treatment options for patients with metastatic squamous cell cancers of head and neck (HNSCC). The only significant advance in the last few decades has been approval of cetuximab, a monoclonal antibody directed against the overexpressed epidermal growth factor receptor (EGFR). Despite its high specificity for EGFR, cetuximab as single-agent has resulted in response rates of only 13% and PFS of less than 2 months. Recent evidence suggests that cetuximab may induce tumor cell killing through an immune-mediated ADCC and not through blockade of EGFR signaling. Cetuximab binds EGFR on tumor cells making them targets for natural killer (NK) cell-mediated lysis. The effectiveness of cetuximab is limited by the tumor mediated immune-suppression that inhibits NK and other effector cells. This local and possibly generalized immune suppression is primarily mediated by regulatory T cells (Tregs) which inhibit NK cells and other effector cells. HNSCC tumors are highly immunosuppressive and characterized by marked and persistent elevation of inhibitory Tregs. The myelosuppression and immunosuppression caused by cyclophosphamide is dose dependent, and at lower doses cyclophosphamide has been shown to selectively deplete Tregs, restore NK cell activity and paradoxically induce auto-immunity. Objectives: To assess potentiation of clinical response by tracking PFS, OS and HRQOL and immune augmentation in tumor biopsies and blood samples. Methods: The current pilot study (n=15) will assess the hypothesis that Tregs, which are elevated in HNSCC, can be suppressed with cyclophosphamide and that this suppression can lead to improved anti-tumor responses mediated by cetuximab. Eligibility: Metastatic HNSCC progressed on initial chemotherapy or not a candidate for platinum Treatment: Daily oral cyclophosphamide 50 mg bid and weekly cetuximab (SOC). Patients will have blood collected for immune monitoring at weeks 0, 3, 6, 12 and pre and post treatment biopsies at week 0, 6. T cell subsets, NK cell function, Tregs, MDSC will be assessed at tumor site and in blood for immune response. Restaging CT scans will be done pretreatment and at weeks 6, 12. Clinical trial information: NCT01581970.
N-SAS BC06: A phase III study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole (LET): The New Primary Endocrine-Therapy Origination Study (NEOS).
Authors: Iwata Hiroji , Ohtani Shoichiro , Fujisawa Tomomi , Taira Naruto , Masuda Norikazu , Kashiwaba Masahiro , Yamamoto Yutaka , Toyama Tatsuya , Yamaguchi Takuhiro
Published: March 2020

TPS654

Background: It is uncertain whether adjuvant chemotherapy is required in the treatment of postmenopausal women with hormone-responsive and intermediate risk breast cancer. The TAILORx and MINDACT trials are ongoing and utilize gene expression profiling in order to answer this question. We have initiated a new study to address this matter by using response to initial neoadjuvant endocrine therapy. The primary aim of this phase III study is to evaluate the necessity of using adjuvant chemotherapy for the treatment of postmenopausal breast cancer patients with node-negative, ER-positive and HER2-negative tumors who responded to neoadjuvant LET. Methods: Inclusion criteria are T1c-T2N0M0, ER-positive by IHC (<10%), HER2-negative, postmenopausal women under 75 years old and written informed consent. Lymph node positive patients as assessed by SLNB are excluded. Neoadjuvant LET is administered for 24-28 weeks before surgery. CR, PR or SD patients are then randomized into two arms receiving either chemotherapy plus LET for 4.5-5 years or LET alone for 4.5-5 years after surgery. If the primary tumor response is defined as PD before surgery, the treatment will be changed at the investigator's discretion (surgery, chemotherapy or other endocrine therapy, but these patients will be followed up). The primary endpoint is disease-free survival (DFS), and secondary endpoints are overall survival (OS), response rate of LET, pathological response, breast conserving surgery rate, DFS/OS by response rate of LET, safety, QOL and cost-effectiveness. This study utilizes a randomized selection design. The objective of this design is to select the arm with the better outcome. We also conduct an additional translational research and central pathological review of ER, PgR, HER2, and Ki67.Patient recruitment commenced in May 2008 and 803 patients were enrolled at the end of 2012. A total of 850 patients will be enrolled at the end of May 2013. This study is supported by Public Health Research Foundation. Clinical trial information: UMIN000001090.
PIKHER2: A phase Ib/II study evaluating safety and efficacy of oral BKM120 in combination with lapatinib in HER2-positive, PI3K-activated, trastuzumab-resistant advanced breast cancer.
Authors: Goncalves Anthony , Isambert Nicolas , Campone Mario , Dieras Veronique , Boher Jean Marie , Boyer-Chamard Agnes , Esterni Benjamin , Provansal Magali , Extra Jean-Marc , Viens Patrice
Published: March 2020

TPS663

Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. BKM120 is an oral pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 study will evaluate safety and efficacy of oral, daily lapatinib-BKM120 combination in HER2-positive, trastuzumab-resistant advanced breast cancer (ABC) with activated PI3K/AKT/mTOR pathway. Methods: This open label, single arm, multi-center study includes a phase Ib dose-escalation part and a phase II expansion part at the recommended dose (RP2D). Primary objectives include determination of the maximum-tolerated dose (MTD) of BKM120 in combination with lapatinib in trastumuzab-resistant HER2-positive ABC (phase Ib part) and evaluation of the activity of BKM120-lapatinib combination at RP2D as measured by objective response rate (ORR) in patients with activated PI3K/AKT/mTOR pathway, as defined by PTEN-negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or overexpression of phospho-AKT by IHC (phase II part). Secondary objectives include safety and tolerability of the combination, clinical benefit and progression-free survival, pharmacokinetic profiles, biological and pharmacodynamic correlates. Main eligibility criteria are PS ≤ 1, HER2-positive ABC resistant to trastuzumab, documented activated PI3K/AKT/mTOR pathway (phase II part only). A modified CRM using an adaptive Bayesian model guides the dose escalation of both agents with a maximum of 24 patients planned to be enrolled in phase Ib part. Efficacy will be tested according to a standard 2-stage Simon design under the following unacceptable and desirable hypotheses: H0, ORR <= 10% (unacceptable rate) vs. H1, ORR >=30% (desirable rate). A maximum of 35 patients with activated PI3K/AKT/mTOR pathway is planned to be enrolled in phase II part with an interim look after 18 evaluable patients will have been recruited. Clinical trial information: NCT01589861.
NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+ DCIS resected by lumpectomy (Lx).
Authors: Cobleigh Melody A. , Anderson Stewart J. , Julian Thomas B. , Siziopikou Kalliopi P. , Arthur Douglas W. , Rabinovitch Rachel , Zheng Ping , Mamounas Eleftherios P. , Wolmark Norman
Published: March 2020

TPS666

Background: A significant amount of DCIS is ER-negative and/or overexpresses HER2. This study will test HER2-targeted therapy in DCIS. Among T-treated HER2+ patients (pts) with DCIS treated with a single dose of T, T is found in ductal aspirates and antibody-dependent cell-mediated cytotoxicity activity for HER2 is increased. T boosts the effectiveness of RT in breast cancer xenograft models and cell lines. T given during whole breast irradiation (WBI) may improve results for HER2+ DCIS treated with lumpectomy (Lx). A trial to examine this question will enhance the understanding of breast tumor biology, the prevention of such tumors, and could possibly extend breast-conserving surgery benefits for women with DCIS. Methods: After Lx for pure DCIS, each pt’s DCIS lesion is centrally tested for HER2 using ASCO/CAP guidelines. HER2+ pts are randomly assigned to receive 2 doses of T, 3 weeks apart during WBI or to WBI alone. Women ≥18 yrs with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. ER and/or PR status must be known before random assignment. Primary aims are to determine if T decreases ipsilateral breast cancer (IBC) recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and/or overall survival can be improved with the use of T. 2000 pts will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 IBC events (7.5 - 8 yrs after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 IBC events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR-SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 1-1-13, 1,127 pts have been randomized into the study. Support: PHS NCI-U10-CA-69651, -12027, and -P30-CA-14599 from the US NCI, and Genentech, Inc. Clinical trial information: NCT00769379.
BATTLE-2 program: A biomarker-integrated targeted therapy study in previously treated patients with advanced non-small cell lung cancer (NSCLC).
Authors: Papadimitrakopoulou Vassiliki , Wistuba Ignacio Ivan , Lee J. Jack , Tsao Anne S. , Kalhor Neda , Fossella Frank V. , Heymach John , Alden Christine M , Gettinger Scott N. , Coombes Kevin R. , Saintigny Pierre , Tang Ximing , Duffield Emily , Boyer Julie , Davis Suzanne E , Powis Garth , Mauro David J. , Rubin Eric H. , Hong Waun Ki , Herbst Roy S.
Published: March 2020

TPS8118

Background: New strategies incorporating a personalized medicine approach for NSCLC treatment are increasingly explored and were pioneered in the prospective, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1) (Kim et al Cancer Discov 2011;1:44). Effective therapeutic strategies for mutant KRAS and other biomarkers of resistance in refractory NSCLC remain an unmet medical need. The BATTLE-2 clinical study is using EGFR, PI3K/AKT and MEK inhibitors and is designed to identify biomarkers for optimal patient selection for these therapies, with a long-term goal to significantly improve the survival of NCSLC patients (pts) (ClinicalTrials.gov NCT01248247). Methods: This is a four-arm, open-label, multi-center, biopsy-driven, adaptive randomization, phase II clinical trial in refractory NSCLC pts (failed at least 1 prior line of therapy). After a study-entry tumor biopsy, pts are adaptively randomized, based on KRAS status, to 4 trial arms: erlotinib, erlotinib plus the AKT inhibitor MK-2206, MK-2206 plus the MEK inhibitor selumetinib, and sorafenib. The primary objective is 8-week disease control rate (DCR). Baseline tumor testing includes KRAS and EGFR mutations and EML4/ALK translocation, the latter two being exclusion criteria. The trial is conducted in 2 stages. In Stage 1, 200 evaluable pts are adaptively randomized (AR) based on observed 8-week DCR and KRAS status while predictive biomarkers are being developed. In Stage 2, the AR model is refined to include the most predictive biomarkers tested in Stage 1, with subsequent Stage 2 AR based on the new algorithm, to a total of 400 evaluable pts. Selection of Stage 2 single and/or composite markers (“signatures”) follows a rigorous, internally and externally reviewed statistical analysis. All Stage 1 and 2 randomization biomarker assays are CLIA-certified. 219 pts have been enrolled and 124 pts randomized. 100 pts are evaluable for the 8-week DCR endpoint. Accrual updates, demographics, and further details will be presented at the meeting. Supported by NCI R01CA155196-01A1. Clinical trial information: NCT01248247.
Phase III trial of brentuximab vedotin and CHP versus CHOP in the frontline treatment of patients (pts) with CD30+ mature T-cell lymphomas (MTCL).
Authors: O'Connor Owen A. , Pro Barbara , Illidge Tim , Trumper Lorenz H. , Larsen Emily K. , Kennedy Dana A.
Published: March 2020

TPS8611

Background: MTCL including systemic anaplastic large cell lymphoma (sALCL) are aggressive neoplasms. Anthracycline-based multiagent chemotherapy regimens have demonstrated response rates ranging from 76 to 88%. Five-year overall survival rates range from 12 to 49% depending on the histologic subtype. Brentuximab vedotin is an antibody drug conjugate that has shown efficacy in a pivotal phase 2 study as a single agent in relapsed sALCL (Pro et al., J Clin Oncol, 2012) and evidence of clinical activity in combination with CHP in the frontline treatment of MTCL including sALCL in a phase 1 study (Fanale et al., ASH 2012). Methods: This randomized, double-blind, placebo-controlled, multicenter, phase 3 study (NCT01777152) is evaluating the safety and efficacy of 1.8 mg/kg brentuximab vedotin with CHP (A+CHP) vs CHOP for frontline treatment of CD30+ MTCL. Pts must have FDG-avid disease by PET and measureable disease of at least 1.5 cm by CT. Approximately 300 pts will be randomized 1:1 to receive A+CHP or CHOP for 6–8 cycles (q3wk). Randomization will be stratified by ALK+ sALCL vs other histologic subtypes and IPI score (0–1, 2–3, or 4–5). The target proportion of pts with a diagnosis of sALCL will be 75%. The primary objective is to compare progression-free survival (PFS) between the 2 treatment arms as determined by an independent review facility (IRF). Secondary objectives include comparisons of PFS per IRF in sALCL patients, safety, overall survival, and complete remission rate between the 2 arms. After completion of treatment, pts will be followed for disease progression, medical resource utilization, quality of life, and survival. Post-treatment stem cell transplant is permitted. Efficacy assessments will use the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). CT and PET scans will be performed at baseline, after Cycle 4, and after the completion of treatment. CT scans will also be performed at regular intervals during follow-up until disease progression, death, or analysis of the primary endpoint. Safety assessments will occur throughout the study until 30 days after last dose of study treatment. Enrollment for this global trial began in early 2013. Clinical trial information: NCT01777152.
A phase III study of ibrutinib in combination with bendamustine and rituximab (BR) in elderly patients with newly diagnosed mantle cell lymphoma (MCL).
Authors: Wang Michael , Gordon Leo I. , Rule Simon , Goy Andre , Hermine Olivier , Rizo Aleksandra , Zhuang Sen Hong , Dreyling Martin H.
Published: March 2020

TPS8613^

Background: MCL is a distinct subtype of B-cell non-Hodgkin lymphoma (NHL) accounting for approximately 6% of NHL diagnoses. Current immunochemotherapy followed by rituximab maintenance results in a prolonged duration of remission, but a constant relapse pattern is still observed. Ibrutinib, an oral Bruton's tyrosine kinase(BTK) inhibitor, demonstrated promising single-agent activity in 115 patients with relapsed or refractory MCL who were enrolled in the phase II study PCYC-1104. The overall response rate (ORR) was 68%, with 46% of patients achieving partial response (PR) and 22% achieving complete remission (CR) (Wang ASH 2012). Blum et al (ASH 2012) demonstrated that ibrutinib can be safely combined with BR in a phase I combination study in relapsed or refractory NHL and that it enhanced BR’s clinical activity with an ORR in 5 evaluable MCL patients of 100% (80% CR, 20% PR). These data suggest that combining ibrutinib with BR will improve the outcome of these patients. Methods: The SHINE study, PCI-32765MCL3002, is a phase III double-blind study of ibrutinib in combination with BR versus BR for the treatment of patients with newly diagnosed MCL. The study aims to enroll 520 patients (approximately 260 patients per arm). All patients will receive BR therapy for 6 cycles; those patients achieving a CR or PR will receive R maintenance for 2 years. In addition to BR and R, all patients will receive an oral daily dose of 560 mg ibrutinib or placebo concomitant with the chemotherapy and ongoing as a single agent until disease progression or unacceptable toxicity. The primary objective is to evaluate if the addition of ibrutinib to BR will result in prolongation of progression-free survival, with secondary objectives of ORR (CR+PR), CR rate, duration of response, safety, and overall survival. The study will enroll patients aged 65 years or older who are not suitable for high-dose chemotherapy. Key exclusion criteria include diagnosis or treatment for malignancy other than MCL, requirement for treatment with warfarin or equivalent vitamin K antagonists, and treatment with strong CYP3A4/5 inhibitors. Approximately 200 sites globally will enroll patients. Enrollment began in Q1 of 2013. Clinical trial information: NCT01776840.
A randomized, multicenter, open-label, phase III study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients (pts) with relapsed or refractory (RR) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): RESONATE.
Authors: Byrd John C. , Barrientos Jacqueline Claudia , Devereux Stephen , Brown Jennifer R. , Kay Neil E. , Reddy Nishitha M. , O'Brien Susan Mary , Kipps Thomas J. , Furman Richard R. , Schuster Stephen J. , Bloor Adrian , Gill Devinder Singh , Thornton Patrick , Dearden Claire E. , Jäger Ulrich , Barker Christine , Lin Jennifer , Kunkel Lori A. , James Danelle Frances , Hillmen Peter
Published: March 2020

TPS8619

Background: Chemoimmunotherapy (CIT) treatment approaches such as FCR have markedly improved outcomes for CLL pts when administered as initial or second-line therapy. Despite this progress, virtually all pts relapse and effective salvage regimens that induce durable remissions or can be administered safely to elderly pts or those with comorbidities are lacking. BTK, an essential mediator of B-cell receptor signaling, is a novel target in CLL. Ibrutinib, a first-in class inhibitor of BTK, promotes apoptosis and inhibits proliferation, migration and adhesion in CLL cells. Phase II data of ibrutinib monotherapy in RR CLL demonstrated an estimated PFS and OS of 75% and 83% respectively at 26 months (Byrd Abst #189 ASH 2012). These findings confirmed BTK as an important target in CLL and supported initiation of a pivotal phase III study in pts with RR CLL/SLL. Methods: PCYC-1112-CA is an ongoing international Phase 3 randomized controlled study of ibrutinib versus ofatumumab for treatment of pts with RR CLL/SLL. The study is enrolling 350 planned pts in 9 countries. Pts are randomized 1:1 to receive ibrutinib 420 mg orally once daily or ofatumumab per the package insert at 300 mg for the first dose, then 2000 mg for a total of 12 doses over 24 weeks. Pts are stratified based on del 17p and disease refractory to purine analogs. Key inclusion criteria include RR CLL/SLL with >= 1 prior line of therapy including pts who experienced a short remission duration to purine analog based CIT, pts who are older or have comorbidities, and pts with del 17p. Pts must have active disease meeting criterion for requiring therapy and measurable nodal disease by CT. Key exclusion criteria include Richter’s transformation, stem cell transplantation within 6 months, GVHD or immunosuppression, platelet count <30,000 cells/ul or use of warfarin The primary objective of the study is PFS evaluated by an IRC. Other outcomes include ORR, OS, hematologic improvement, and safety. An independent DMC is monitoring the study. Clinical trial information: NCT01744691.