bluuebunny/crossref_metadata_2025 huggingface dataset:
A randomized, open-label, multicentre, phase IV study evaluating palbociclib plus endocrine treatment versus a chemotherapy based treatment strategy in patients with hormone receptor positive/HER2-negative metastatic breast cancer in a real world setting.
Authors: Loibl Sibylle , Barinoff Jana , Seiler Sabine , Decker Thomas , Denkert Carsten , Luebbe Kristina , Furlanetto Jenny , Mueller Volkmar , Mundhenke Christoph , Schmidt Marcus , von Minckwitz Gunter , Uhlig Mathias , Burchardi Nicole , Thill Marc
Published: September 2018

TPS1115

Background: Although endocrine based therapy is recommended as first-line treatment in metastatic breast cancer (MBC) in patients with an HER2-/HR+ tumour up to 50% of the patients receive chemotherapy. Palbociclib (P) a CDK4/6 inhibitor improves PFS by 42% in endocrine sensitive and resistant HER2-/HR+ MBC when added to an endocrine therapy (ET). Patients included in clinical trials are often criticised not to be representative for real world breast cancer patients. Methods: Patients with first-line HER2-/HR+ MBC who are candidate for mono-chemotherapy will be eligible to be randomised 1:1 to receive either P plus ET per label or mono-chemotherapy per investigator´s choice with or without maintenance ET. In both study arms, treatment will be given until disease progression, unacceptable toxicity, withdrawal of consent of the patient or change of initial treatment plan (either planned six chemotherapy cycles followed by maintenance ET or chemotherapy until disease progression). Primary objective is to compare the time-to-treatment failure (TTF), defined as time from randomization to discontinuation of treatment for any reason, including disease progression, treatment toxicity and death. Secondary objectives are progression free survival, overall survival at 36 months, amongst other time to event endpoints; investigator assessed overall clinical response; toxicity and compliance; patient well-being and health care utilization by daily monitoring treatment impact. Aim: 360 patients will be accrued to show an improved TTF for P in combination with ET. Recruitment will start in QII/2017 and is planned for approximately 18 months in 100 sites in Germany, Spain, Poland, Italy, France, UK and Canada. Conclusions: The aim of the trial is to demonstrate that an endocrine based strategy consisting of ET plus P is superior to a chemotherapy based strategy as first-line therapy in women with HER2-/HR+ breast cancer in a real world setting.
CEA, CA15.3 and 18-FDG PET in the follow-up of early breast cancer (BC) patients (pts): A prospective, multicentric, randomized trial—KRONOS patient-oriented new surveillance study Italy.
Authors: Zamagni Claudio , Gion Massimo , Mariani Luigi , Stieber Petra , Rubino Daniela , Fanti Stefano , Baum Richard P. , Wirtz Ralph M , Hakim Rossella , Bernardi Alessandra , Cacciari Nicoletta , Quercia Sara , Fini Angela , Lenzi Manuela , Pizzirani Cinzia , Pagliaro Maria , Tomasini Sara , Toracchio Sonia , Carapelle Marianna , Barbieri Elena
Published: September 2018

TPS11627

Background: Current recommendations for breast cancer (BC) surveillance in asymptomatic patients (pts) include only mammography and physical examination and arise from two trials conducted in the 80’s. Since then new findings about BC biology, treatment and the introduction of cutting-edge diagnostic technologies such as 18-FDG PET have deeply modified our clinical scenarios. The aim of this prospective randomized trial is to verify if the serial measurement of CEA and CA15-3 followed by 18-FDG PET can anticipate the diagnosis of BC recurrence compared to control arm by estimation of the difference of restricted mean survival time (RMST) between the two arms. If the end-point will be met a subsequent extension trial will investigate the impact of the earlier diagnosis of distant metastases on survival. Methods: Pts diagnosed with stage I-III BC, who underwent adequate surgery are eligible. Special histologies and low-risk cases according to St. Gallen criteria are excluded. The study includes pts at the beginning of the follow-up after the conclusion of primary treatment (cohort 1), and pts that have concluded without relapse the first 5 years of follow-up (cohort 2). Eligible pts will be randomized in a 1:1 ratio to follow-up according to local practice (control arm) or to three-monthly serial dosing of CEA and CA15-3 and subsequent 18 FDG-PET only in case of an increase of CEA and/or CA 15.3 greater than a critical difference compared to baseline (experimental arm). The following stratification factors will be used: node negative vs positive, HER2 negative vs positive, ER positive vs negative. Eight-hundred pts will be enrolled over 3 years. For such a calculation, we made the assumption of a 20% baseline 5-year incidence of relapse. The target reduction of three months in RMST implies a median time of diagnostic anticipation, conditional on having BC recurrence, of 10 months. The follow-up will continue until 10 years from surgery. Since 23rd October 2014 573 pts have been enrolled. The present trial was approved by the Ethical Committee of each participating centre and is registered on Clinical trial information: NCT02261389.
A study of rovalpituzumab tesirine in frontline treatment of patients with DLL3 expressing extensive small cell lung cancer.
Authors: Hann Christine L. , Morgensztern Daniel , Dowlati Afshin , Burns Timothy Francis , Jotte Robert M. , Pennell Nathan A. , Richey Stephen Lane , Wolf Juergen , Sebastian Martin , Overbeck Tobias R. , Socinski Mark A. , Lally Satwant , Da Costa Daniel , Yalamanchili Sreeni , Camidge D. Ross
Published: September 2018

TPS2598

Background: Treatment and survival of SCLC patients (pts) has remained mostly unchanged over past decades with high response rates to initial therapy (cisplatin/carboplatin + etoposide), but relapse is near universal with median survival < 1 year in extensive disease. Delta-like protein 3 (DLL3) is an inhibitory ligand of the Notch receptor family identified as a novel target in high-grade neuroendocrine tumors, and is highly expressed in SCLC but not in normal tissue. Rovalpituzumab tesirine (Rova-T™) is an antibody-drug conjugate targeting DLL3. A Phase I study of Rova-T monotherapy in 2nd and 3rd line SCLC pts demonstrated encouraging antitumor activity with an ORR of 18% in all pts, and an ORR of 38% in DLL3-high pts (Rudin et al., Lancet Oncol, 2016.). Methods: This is a Phase I, open-label, multicenter study (NCT02819999; no pts enrolled as of 7 February 2017).In Phase Ia (escalation), 15-34 previously untreated DLL3-high pts will be enrolled and randomized to 1 of 4 cohorts. The primary objective of the Phase Ia portion is assessment of safety and dose-limiting toxicities (DLTs). Phase Ib (expansion) will enroll up to 2 cohorts of 30 pts each, and its primary objective is to characterize antitumor activity of the selected cohort(s). Secondary objectives (Phase Ia/b) include assessment of pharmacokinetics and anti-therapeutic antibodies against Rova-T, and characterization of antitumor activity (Phase Ia). Eligible pts: adults with histologically or cytologically confirmed extensive DLL3-high SCLC based on immunohistochemistry; ECOG 0-1; and life expectancy ≥ 12 weeks. Clinical trial information: NCT02819999. [Table: see text]
Phase IB study to evaluate the safety of selinexor in combination with multiple standard chemotherapy agents in patients with advanced malignancies.
Authors: Naing Aung , Fu Siqing , Tsimberidou Apostolia Maria , Pant Shubham , Piha-Paul Sarina Anne , Janku Filip , Hong David S. , Colen Rivka R. , Carter Brett W. , Evans Elizabeth , Tawbi Hussein Abdul-Hassan , Karp Daniel D. , Subbiah Vivek , Dev Rony , Hess Kenneth R. , Ueno Naoto T. , Simon George R. , Overman Michael J. , Coleman Robert L. , Meric-Bernstam Funda
Published: September 2018

TPS2603

Background: Selinexor is a first-in-class, slowly reversible, Selective Inhibitor of Nuclear Export (SINE) compound that specifically blocks XPO1. Inhibition of XPO1 results in nuclear localization, accumulation, and reactivation of tumor suppressor proteins, therefore selectively inducing apoptosis in cancer cells, while largely sparing normal cells. This unique property of XPO1 inhibition has been deployed as a novel therapeutic strategy with success in several solid tumors and hematologic malignancy clinical trials. Preclinical studies have shown that SINE compounds behave synergistically to enhance cancer cell death with combined with different therapeutic agents. This Phase I trial is based on such preclinical evidence. The primary objective of the study is to establish the safety and tolerability of selinexor when given in combination with thirteen standard chemotherapy regimens. The secondary objectives are to determine disease control and progression-free survival of patients receiving selinexor administered with standard chemotherapy treatments in specific tumor subsets. Methods: Adult patients ≥ 18 years of age are eligible if they have histologically confirmed neoplasms (excluding hematological malignancies and brain tumors) that are refractory to established therapy known to provide clinical benefit for their condition. Patients are required to have either measurable disease (RECIST 1.1) or evaluable disease, and an ECOG performance status of 0-1. Enrollment is ongoing for dose escalation with the plan for dose expansion as follows: Clinical trial information: NCT02419495. [Table: see text]
GCT1021-01, a first-in-human, open-label, dose-escalation trial with expansion cohorts to evaluate safety of Axl-specific antibody-drug conjugate (HuMax-Axl-ADC) in patients with solid tumors (NCT02988817).
Authors: Lassen Ulrik Niels , Ramalingam Suresh S. , Lopez Juanita Suzanne , Harvey R Donald , Ameratunga Malaka , de Hoon Jan , Losic Nedjad , Lisby Steen , Forssmann Ulf , Vergote Ignace
Published: September 2018

TPS2605

Background: HuMax-AXL-ADC is an antibody-drug conjugate (ADC) composed of an Axl-specific human monoclonal immunoglobulin G1 (IgG1κ) conjugated via a protease-cleavable valine-citrulline linker to the microtubule disrupting agent monomethyl auristatin E (MMAE). In vivo, HuMax-AXL-ADC demonstrated therapeutic anti-tumor efficacy in patient-derived xenograft models representing a variety of solid cancers, including pancreas, thyroid, lung, esophageal, cervical cancers and malignant melanoma. The non-clinical safety profile and pharmacokinetics (PK) of a once every 3 weeks (1Q3W) dosing schedule were established in cynomolgus monkeys. Methods: The primary objective of this trial is to determine the MTD and to establish the safety profile of HuMax-AXL-ADC in a mixed population of patients with specified solid tumors: ovarian, cervical, endometrial, thyroid cancer, NSCLC, and malignant melanoma. The trial consists of two parts, a phase I dose escalation part and a phase IIa expansion part. The dose escalation part explores two different dosing regimens: the first investigates doses from 0.3 up to 2.8 mg/kg to be administered 1Q3W. The second investigates doses in the range of 0.45 to 1.4 mg/kg to be administered weekly for 3 weeks followed by one treatment-free week (3Q4W dosing schedule). The second arm has a delayed start to inform a safe starting dose: when at least 8 patients have been evaluated for dose limiting toxicities, the 1.5 mg/kg cohort of the 1Q3W arm has been declared safe, and the predicted PK parameters of the starting dose in the 3Q4W arm are below pre-defined limits, the 3Q4W arm will be initiated. The 1Q3W arm follows a modified Bayesian Continuous Reassessment Method including escalation with overdose control in up to 41 patients on up to 7 main and 4 intermediate dose levels while the 3Q4W arm is run as a standard 3+3 trial design on up to 5-6 dose levels. In the phase IIa expansion part, further safety and biological activity data will be generated in selected indications using cohorts of 22 patients (11+11 patients in each cohort applying the Simon’s two-stage design). Clinical trial information: NCT 02988817.
An open-label, phase II study of tipifarnib for the treatment of HRAS mutant solid tumors, including squamous cell carcinomas of the head and neck.
Authors: Ho Alan Loh , Chau Nicole Grace , Wong Deborah Jean Lee , Cabanillas Maria E. , Bauman Jessica Ruth , Bible Keith Christopher , Brose Marcia S. , Calvo Emiliano , Boni Valentina , Burrows Francis , Melvin Carrie L. , Scholz Catherine Rose , Gualberto Antonio
Published: September 2018

TPS2618

Background: Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase (FT). FT catalyzes the post-translational attachment of farnesyl groups to signaling proteins that are requisite for localization to the inner cell membrane. While all RAS isoforms (KRAS/NRAS/HRAS) are FT substrates, only HRAS is exclusively dependent upon farnesylation for membrane localization and signaling activation, making HRAS mutant tumors uniquely susceptible to tipifarnib mediated inhibition of FT. Tipifarnib has demonstrated robust activity in HRAS mutant head and neck squamous cell carcinoma (HNSCC) and HRAS mutant squamous non-small cell lung cancer (NSCLC) patient derived xenograft (PDX) models resistant to standard therapies. Methods: This is a multi-institutional, open-label Phase II trial evaluating the efficacy and safety of tipifarnib for pts with HRAS mutant solid tumors. Pts must have either unresectable, locally advanced or metastatic non-hematological malignancies that harbor a missense HRAS mutation. The primary endpoint of the study is overall response rate. Secondary endpoints include safety and tolerability, PFS, duration of response. Two cohorts (N = 18 each) are enrolling, each being evaluated with a Simon two-stage design. Cohort 1 is for patients with malignant thyroid tumors of any histology. Cohort 2 was originally designated for pts with any other solid tumor. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this group, enrollment to the second stage of Cohort 2 has been limited to HRAS mutant HNSCC since August 2016. Enrolled patients are treated with tipifarnib 900 mg administered orally twice daily on days 1-7 and 15-21 of 28-day treatment cycles until progression of disease or unacceptable toxicity. Clinical trial information: NCT02383927.
A phase 1b/2 study of CD30-specific chimeric antigen receptor T-cell (CAR-T) therapy in combination with bendamustine in patients with CD30+ Hodgkin and non-Hodgkin lymphoma.
Authors: Park Steven I. , Serody Jonathan Stuart , Shea Thomas C. , Grover Natalie Sophia , Ivanova Anastasia , Morrison Kaitlin , Eldridge Paul , Mckay Katie , Cheng Catherine J , Covington Deborah , Wehner Kimberly , Dotti Gianpietro , Savoldo Barbara
Published: September 2018

TPS3095

Background: CAR-T therapy has emerged as one of the most promising therapeutic approaches for lymphoma. CD30 antigen is expressed on virtually all Hodgkin (HL) and various subtypes of non-Hodgkin lymphoma (NHL). HL and NHL are both sensitive to the cellular immune response and antibody-directed therapy, which makes CD30 an excellent target for CAR-Ts. In the “first-in-human” clinical trial of CD30.CAR-Ts, the dose of 2 × 108 CD30.CAR-Ts/m2 was found to be safe; however, no conditioning therapy was given prior to CD30.CAR-T infusion and the expansion of CAR-Ts was thus limited. In the current study, we have further developed the CD30.CAR-T-based therapy by combining it with bendamustine. We hypothesized that bendamustine may improve therapeutic efficacy of CD30.CAR-Ts by causing sufficient depletion of endogenous immune cells to facilitate the expansion and persistence of CAR-Ts in vivo. Methods: In this phase 1b/2 clinical study, patients with CD30+ HL or NHL receive bendamustine followed by CD30.CAR-Ts (NCT02690545). The primary objective is to establish the safety of CD30.CAR-Ts in combination with bendamustine. Secondary objectives include estimation of 2-year overall and progression-free survival rates. Patients receive bendamustine (90 mg/m2 on days 1 and 2) followed by CD30.CAR-Ts within 1 to 4 days of lymphodepletion. The maximal tolerated dose is determined based on 3 + 3 design for dose escalation starting at 1 × 108 CD30.CAR-Ts/m2. If the first 3 enrolled subjects do not experience a DLT within 6 weeks of the cell infusion, the number of cells for the infusion is increased to 2 x 108/m2. Once the number of cells for infusion is established, up to 25 subjects will be enrolled in the Phase 2 portion of the study to further establish the safety and efficacy of this treatment regimen. Response will be assessed at 6 weeks after CD30.CAR-Ts infusion, and a second CD30.CAR-Ts infusion equal to or lower than the dose may be administered to patients with partial response or stable disease. Patient’s peripheral blood samples will be evaluated at various time points to monitor safety, function, and persistence of transduced T-cells. Clinical trial information: NCT02690545.
Nivolumab in combination with daratumumab, with or without pomalidomide and dexamethasone, for relapsed/refractory multiple myeloma: 2 cohorts of the phase 1 CheckMate 039 safety study.
Authors: Lesokhin Alexander M. , Kumar Shaji , Popa McKiver Mihaela A. , Zhu Lili , Farsaci Benedetto , Borrello Ivan
Published: September 2018

TPS3102

Background: Multiple myeloma (MM) is largely incurable despite available therapies, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and monoclonal antibodies (mAbs). As most MM patients (pts) eventually have relapsed/refractory (RR) disease, there is an unmet need. Myeloma cells upregulate PD-L1 [Liu et al, 2007]. Nivolumab (nivo), an immuno-oncology mAb, binds PD-1 on T cells and natural killer cells and inhibits signaling by PD-L1–expressing tumor cells, thus augmenting antitumor immunity. Nivo monotherapy has shown acceptable safety and modest clinical activity in RRMM [Lesokhin et al 2016]. Daratumumab (dara) is a cytolytic mAb that targets CD38+ myeloma cells, inducing antibody‐dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, and apoptosis, and may have an immunomodulatory role via depletion of CD38+ immune-suppressor cells [Dimopoulos et al 2016]. Dara is approved as monotherapy (US: after ≥3 prior lines of therapy; EU: after a prior PI and IMiD and progression on last therapy), and with lenalidomide/dexamethasone (dex) or bortezomib/dex (US: after ≥1 prior line of therapy for both combinations). Combining PD-1 and CD38 mAbs, immunotherapies with different mechanisms of action, may overcome resistance and improve outcomes. This phase 1 safety study (NCT01592370) includes multiple cohorts of nivo as monotherapy or in combination regimens across RR hematologic malignancies; 2 MM cohorts will evaluate nivo plus dara, with or without pomalidomide and dex. Methods: Eligible pts are aged ≥18 y, with RRMM after ≥2 prior therapies. Pts are RR to their last regimen, RR to prior IMiD and PI therapy, and agreed to bone marrow aspiration. Primary outcome of safety/tolerability will be measured by incidence of drug-related adverse events (AEs), serious AEs, and laboratory test abnormalities. Secondary endpoints include minimal residual disease, overall response rates and duration of response, and progression-free survival. Study funding: BMS. Writing support: C Tomas, Caudex, funded by BMS. Clinical trial information: NCT01592370.
A phase I trial of ALKS 4230, an engineered cytokine activator of NK and effector T cells, in patients with advanced solid tumors.
Authors: Vaishampayan Ulka N. , Ernstoff Marc S. , Velcheti Vamsidhar , Hoimes Christopher J. , Fishman Mayer N. , Cho Daniel C. , McDermott David F. , Kurman Michael R. , Alvarez Juan , Sun Lei , Slichenmyer William , Rossi Sean
Published: September 2018

TPS3111

Background: ALKS 4230 is an engineered fusion protein comprised of a circularly permuted interleukin-2 (IL-2) and IL-2 Receptor (IL-2R) α designed to selectively activate the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γc. The iaIL-2R is expressed predominantly on effector lymphocytes, which play an important role in driving antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of haIL-2R-expressing cell types including immunosuppressive CD4+ regulatory T (Treg) cells at concentrations below those at which iaIL-2R bearing effector cells are activated. Also, the haIL-2R is expressed on endothelial cells and may contribute to IL-2 mediated toxicity via capillary leak syndrome. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to provide enhanced tumor killing as well as improved tolerability. Methods: ALKS 4230 is being studied in a phase 1 first-in-human trial in patients with advanced solid tumors. Key study objectives are to determine a recommended phase 2 dose and characterize the safety profile, pharmacokinetics (PK), pharmacodynamics (PD) and evidence of antitumor activity. A dose-escalation phase in patients with refractory solid tumors (Part A) will be followed by expansion cohorts in defined populations (Part B). ALKS 4230 is administered as a 30-minute intravenous infusion once daily for five days each cycle. Eligibility requires age 18, ECOG PS 0-1 and adequate bone marrow, liver and kidney function. The dose will be escalated until reaching MTD or an Optimal Biologic Dose. The first two dose cohorts will use a 3+3 design. Subsequent cohorts in Part A will enroll a minimum of 6 subjects. In Part B up to 21 patients will be enrolled into each of four tumor-specific cohorts. Peripheral blood samples will be collected for PK, immunogenicity and PD assessments. The primary PD endpoint is change-from-baseline in CD8+ T, NK and Treg cell counts. Other PD measures include serum concentrations of multiple proinflammatory cytokines and immunohistochemical assessment of markers of immune activation in tumor tissue from selected patients. Recruitment for Part A is ongoing. Clinical trial information: NCT02799095.
CanStem303C trial: A phase III study of napabucasin (BBI-608) in combination with 5-fluorouracil (5-FU), leucovorin, irinotecan (FOLFIRI) in adult patients with previously treated metastatic colorectal cancer (mCRC).
Authors: Grothey Axel , Shah Manish A. , Yoshino Takayuki , Van Cutsem Eric , Taieb Julien , Xu Ruihua , Tebbutt Niall C. , Falcone Alfredo , Cervantes Andres , Borodyansky Laura , Li Chiang
Published: September 2018

TPS3619

Background: Cancer stem cells are considered to be fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinically, napabucasin sensitizes cancer cells to chemotherapeutics, including 5-FU and irinotecan. Encouraging anticancer activity in advanced CRC was observed in a phase Ib/II (Bendell et al, GI ASCO 2017) study of 63 pts with disease control rate (DCR) of 93% (28/30) and overall response rate (ORR) of 33% (10/30) in FOLFIRI-naïve pts who have had an on-study RECIST evaluation. On the basis of these data, a phase III trial is being conducted in North America, Europe, Australia, and Asia. Methods: This study (ClinicalTrials.gov NCT02753127) will assess the efficacy of napabucasin+FOLFIRI vs FOLFIRI in pts with mCRC (n = 1250). Addition of bevacizumab (bev) is permissible per investigator choice. Pts must have failed 1 prior line of therapy with oxaliplatin and a fluoropyrimidine +/- bev for metastatic disease. Pts are randomized 1:1 to receive napabucasin 240 mg PO BID plus FOLFIRI bi-weekly, or FOLFIRI bi-weekly (bev may be added to FOLFIRI by investigator choice) and stratified by geography, time to progression on 1st-line therapy, RAS mutation status, bev as part of study treatment and primary tumor location. Treatment will continue until disease progression, or another discontinuation criterion. Primary endpoint is overall survival (OS) in the general study population (ITT) (HR 0.80 for OS improvement from 12.54 to 15.68 months); secondary endpoints include OS in the biomarker positive (biomarker+) population, progression free survival (PFS) in the ITT population, PFS in biomarker+ population, ORR and DCR in the ITT and in biomarker+ populations, safety and quality of life. Also, blood and tumor archival tissue will be assessed for PK and biomarker analyses. Global enrollment is underway. Clinical trial information: NCT02753127.
Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): The phase II AVETUX-CRC trial (AIO KRK 0216).
Authors: Stein Alexander , Binder Mascha , Bokemeyer Carsten , Al Batran Salah Eddin , Hinke Axel , Hegewisch-Becker Susanna
Published: September 2018

TPS3620

Background: Inhibition of the PD-1/L1 axis has shown to improve survival as single agent in a variety of tumor types. The efficacy of single agent PD-1/L1 inhibition in patients with treatment refractory MCRC seems to be limited to hypermutated tumors characterized by mismatch repair deficiency. 1st line chemotherapy (e.g. FOLFOX) with cetuximab for patients with RAS/BRAF wildtype MCRC result in objective response rates of about 60%, thus substantial antigen release will likely occur triggering immune control. Furthermore, the induction of immunogenic cell death has been recently shown for cetuximab-based regimen. Thus, the evaluation of FOLFOX and cetuximab in combination with avelumab in 1st line MCRC is of particular interest. Methods: AVETUX is a single arm exploratory phase II investigator initiated trial. Patients with RAS/BRAF wildtype MCRC will be included independent of mismatch repair status to receive mFOLFOX6 and cetuximab in combination with avelumab (10mg/kg from day 1 of cycle 2 onwards). Treatment with avelumab is limited to a maximum of 18 months. Primary endpoint is 12month progression-free survival rate, which should be increased from 40% to 57%, with type I error of 10% and 80% power, leading to a sample size of 43 patients. An early stopping rule will be applied in case of an increase in toxicity after the first 15 patients received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics (RAS/EGFR). Recruitment will start in 11 German sites early 2017. Clinical trial information: EudraCT No 2016-004434-26. Conclusion: The AVETUX trial will determine the feasibility and early efficacy of FOLFOX and cetuximab combined with avelumab in 1st line MCRC. The translational research program will shed light on the potential mode of action of this novel combination. Clinical trial information: 2016-004434-26.
A phase II, open label study of tucatinib (ONT-380) combined with trastuzumab in patients with HER2+ metastatic colorectal cancer (mCRC)(MOUNTAINEER).
Authors: Strickler John H. , Niedzwiecki Donna , Zemla Tyler , Cercek Andrea , Fakih Marwan , Ng Kimmie , Sanchez Federico Augusto , Wu Christina Sing-Ying , Peterson Scott , Bandel Lorelei , Grothey Axel , Bekaii-Saab Tanios S.
Published: September 2018

TPS3624

Background: To improve survival for patients with mCRC, efforts are needed to identify and treat actionable genomic alterations. HER2 is amplified in approximately 5-8% of patients with KRAS and NRAS (RAS) wild-type mCRC. HER2 functions as an oncogenic driver and a mediator of EGFR antibody (Ab) resistance. Although prior studies have shown that anti-HER2 therapies are active in patients with HER2+ (HER2 IHC 3+ or HER2 amplified) mCRC, there are no HER2-directed therapies approved for these patients. Tucatinib is a potent and highly selective oral small molecule tyrosine kinase inhibitor of HER2, currently being developed to treat metastatic breast cancer. In HER2+ CRC patient derived xenograft models, tucatinib has substantial anti-tumor activity. The addition of the anti-HER2 monoclonal Ab trastuzumab augments tumor growth inhibition. Methods: This single-arm phase II study will test the combination of tucatinib and trastuzumab in patients with HER2+ mCRC. Eligible patients include those with RAS wild-type mCRC who have been previously treated with 5-FU, oxaliplatin, irinotecan, and an anti-VEGF monoclonal Ab. Patients must have HER2+ disease by IHC, FISH, or NGS. Prior treatment with anti-HER2 targeting therapy is excluded. The primary objective is to assess the objective response rate for the combination. Secondary objectives are to evaluate the efficacy (PFS, OS, clinical benefit rate), safety, and tolerability of the combination. Correlation between tissue and blood-based biomarkers and clinical outcomes will be explored. Blood will be collected at baseline and each restaging to determine if the combination eliminates HER2 amplified circulating tumor DNA. Subjects will receive tucatinib at a dose of 300mg by mouth daily, and trastuzumab will be administered every 3 weeks (8 mg/kg IV day 1 of cycle 1, then 6 mg/kg IV Q3 weeks). Response will be assessed every 3 cycles (9 weeks) per RECIST version 1.1. Both agents will be provided by the study. This study was initiated in February 2017. Recruitment is ongoing at 8 sites in the Academic and Community Cancer Research United (ACCRU) network. Clinical trial information: NCT03043313.
LUNA: A randomized phase II trial of liver resection plus chemotherapy or chemotherapy alone in patients with unresectable lung and resectable liver metastases from colorectal adenocarcinoma.
Authors: Chun Yun Shin , Mehran Reza J. , Tzeng Ching-Wei David , Kee Bryan K. , Dasari A. , Sepesi Boris , Conrad Claudius , Aloia Thomas A. , Kopetz Scott , Vauthey Jean-Nicolas
Published: September 2018

TPS3625

Background: Liver resection for metastatic colorectal cancer is associated with 5-year overall survival (OS) of 58% and accepted as standard of care. However, the role of liver resection with unresectable low-volume lung metastases is unknown. A recent retrospective study showed that resection of liver metastases was associated with statistically improved OS compared to a matched group of patients treated with systemic therapy alone for lung and liver metastases (3-year OS 43% vs. 14%; Mise Y, Ann Surg Oncol 2015). LUNA is a single-institution phase 2 randomized trial designed to determine the overall survival benefit of liver resection in patients with unresectable lung metastases and to integrate biological surrogates to risk stratify patients and optimize patient selection for hepatectomy. Methods: Eligibility criteria include resectable liver metastases, defined as sufficient liver remnant volume, adequate vascular inflow and outflow, and preservation of 2 contiguous liver segments. Low-volume lung metastases are defined as solid pulmonary nodules < 2 cm in size and < 15 in number. Chest computed tomography is reviewed by an attending thoracic surgeon, and lung metastases are deemed unresectable due to anatomic location, distribution, or patients’ comorbidities. Previous treatment with systemic chemotherapy and/or biologic agents is permitted. After stratification by KRAS status and primary tumor location in the colon vs. rectum, patients are randomized 1:1 to liver resection plus chemotherapy or no liver resection with chemotherapy at the discretion of the treating oncologist as routine standard of care. Patients are restaged every 3‒6 months until 3 years after randomization or death. The primary endpoint is OS. Secondary endpoints include quality of life and identification of biological surrogates in blood and resected liver tissue associated with response to chemotherapy, time to tumor progression, and survival. Targeting an effect size of extending median OS from 17 to 34 months will provide 80% power with 0.05 one-sided alpha with a sample size of 80 patients. Clinical trial information: NCT02738606.
Tivo-3: A phase 3, randomized, controlled, multi-center, open-label study to compare tivozanib hydrochloride to sorafenib in subjects with refractory advanced renal cell carcinoma (RCC).
Authors: Rini Brian I. , Atkins Michael B. , Escudier Bernard J. , Hutson Thomas E. , Koralewski Piotr , McDermott David F. , Pal Sumanta K. , Needle Michael N. , Porta Camillo
Published: September 2018

TPS4600

Background: Tivozanib is a biochemically potent and selective VEGF tyrosine kinase inhibitor in clinical development in RCC. Other agents used for treatment of RCC inhibit multiple tyrosine kinases in addition to the VEGF receptor tyrosine kinase, leading to off-target toxicities such as fatigue, hand-foot syndrome, stomatitis, and neutropenia. The adverse event (AE) profile of tivozanib demonstrates minimal off-target toxicities. TIVO-1 (AV-951-09-301) was an open-label, randomized, controlled, multi-national, multi-center, parallel-arm trial comparing tivozanib to sorafenib in patients with advanced RCC. The blinded independent radiological assessment showed the median progression free survival (mPFS) in the tivozanib arm to be 11.9 months (95% confidence interval (CI) [9.3, 14.7]), compared with 9.1 months (95% CI [7.3, 9.5]) in the sorafenib arm (p = 0.042, HR = 0.797). Overall survival had a negative trend, most likely due to a one-way crossover for patients randomized to sorafenib. This study is designed, in part, to demonstrate that the negative trend in OS was an artifact. Methods: Subjects with metastatic RCC who have failed 2 or 3 prior systemic regimens, one of which includes a VEGFR TKI other than sorafenib or tivozanib, will be randomized in a 1:1 ratio stratified by the IMDC risk category (favorable; intermediate; poor) and prior therapy (two VEGFR TKIs; a prior checkpoint inhibitor plus a prior VEGFR TKI; a prior VEGFR TKI plus any other systemic agent). The primary objective is to compare the progression-free survival (PFS) of subjects randomized to tivozanib with those randomized to sorafenib as assessed by blinded independent radiological review (IRR). Secondary endpoints are overall survival, objective response rate, and duration of response. Clinical trial information: NCT02627963.
A phase 1/1b multicenter, open-label, dose escalation and dose expansion study to evaluate the safety, pharmacokinetics, immunogenicity, and antitumor activity of MEDI3726 in patients with metastatic, castration-resistant prostate cancer who have received prior treatment with abiraterone or enzalutamide.
Authors: Fleming Mark T. , Cathomas Richard , Petrylak Daniel Peter , Wang Judy Sing-Zan , Bander Neil Harrison , Zammarchi Francesca , van Berkel Patrick H. , Cho Song Hye , Elgeioushi Nairouz , Bothos John , Scheuber Anita , de Bono Johann
Published: September 2018

TPS5088

Background: Therapeutic advances have recently been achieved for patients with metastatic, castration-resistant prostate cancer (mCRPC) due to abiraterone acetate (ABI) and enzalutamide (ENZ). However, virtually all patients with mCRPC eventually progress in their disease, and further treatment options are limited. Prostate-specific membrane antigen (PSMA) is highly expressed in nearly all prostate cancers, and its expression is highest in mCRPC. MEDI3726 is an antibody-drug conjugate composed of anti-PSMA antibody derived from J591, site-specifically conjugated to the cytotoxic, DNA cross-linking, pyrrolobenzodiazepine dimer. MEDI3726 has demonstrated potent and specific in vitro and in vivo antitumor activity in human prostate cancer-derived preclinical models with different expression levels of PSMA. Methods: This is a first-in-human, phase 1/1b, multicenter, open-label, dose escalation and dose expansion study in patients who have received prior treatment with ABI or ENZ, with or without prior taxane-based chemotherapy in the mCRPC setting (NCT02991911). The primary objectives are to assess safety and tolerability, describe dose-limiting toxicities, and determine the maximum tolerated dose or maximum administered dose of MEDI3726. The secondary objectives are to evaluate MEDI3726 for its antitumor activity (based on a composite response according to RECIST Version 1.1, a reduction in prostate-specific antigen level of 50% or more compared to baseline, or a conversion in the circulating tumor cell count [defined as a reduction from ≥5 cells/7.5 mL blood to < 5 cells/7.5 mL blood]), safety and tolerability in combination with ENZ, pharmacokinetics alone and in combination with ENZ, and immunogenicity. Recruitment is ongoing for this study, which has an estimated total target enrollment of 224 patients. Clinical trial information: NCT02991911.
A randomized phase II study of chemoradiation (CRT) +/- nivolumab (Nivo) with sequential safety evaluations of Nivo +/- lirilumab (Liri) or ipilumumab (Ipi) concomitant with (C) RT in intermediate (IR) and high-risk (HR) head and neck squamous cell carcinoma (HNSCC) (RTOG 3504, NCT02764593).
Authors: Gillison Maura L. , Ferris Robert L. , Zhang Qiang , Colevas A. Dimitrios , Mell Loren K. , Kong Christina , Jordan Richard , Moore Kevin , Truong Minh Tam , Kirsch Claudia , Machtay Mitchell , Curran Walter John , Le Quynh-Thu
Published: September 2018

TPS6097

Background: Nivolumab (Nivo), a monoclonal antibody to the programmed death-1 (PD-1) immune checkpoint receptor, improved overall survival (OS) for patients (pts) with platinum-refractory, recurrent/metastatic HNSCC compared with standard therapy. A placebo controlled phase IIR trial was designed to investigate the hypothesis that Nivo added to platinum-based CRT will improve progression free survival (PFS) for pts with newly diagnosed IR/HR HNSCC. Methods: Eligibility includes IR HNSCC (p16+, oropharynx T1-2N2b-N3/T3-4N0-3, > 10 pack-years (pys) or T4N0-N3, T1-3N3 ≤ 10 pys) and HR HNSCC (oral cavity, larynx, hypopharynx, or p16(-) oropharynx, stage T1-2N2a-N3 or T3-4N0-3). After safety evaluation in 8 evaluable pts, 176 pts will be randomized (1:1) to cisplatin (40 mg/m2/week X 7) with radiation (IMRT, 70 Gy in 7 weeks) +/- Nivo/placebo (240 mgs q14 days X 5, then 480 mgs q28 X3). Primary endpoint is PFS. Secondary endpoints include OS, acute and chronic toxicity, quality of life and biomarkers (tumor PD-L1 expression; E6/7 seroreactivity and frequency of functional circulating and intraumoral T cells). Parallel with Phase IIR are sequential safety evaluations (see Table) in platinum eligible and ineligible ( > 70 years; ≥3 grade neuropathy; ≥2 hearing loss; or CrCl < 60 ml/min) cohorts (N = 10-20) of Nivo +/- Liri (anti-KIR) or Ipi (anti-CTLA4) concomitant with RT alone, cisplatin-RT or cetuximab-RT platforms followed by 3 months of adjuvant immunotherapy. The primary endpoint is safety and feasibility. With 8 evaluable pts, the probability of treatment assessed as toxic is > 78% when the true toxicity rate is > 45% and treatment assessed tolerable is > 80% if the true toxicity rate is < 20%. Clinical trial information: NCT02764593. [Table: see text]
Phase II trial of ribociclib and everolimus in p16 low anaplastic thyroid cancer (ATC).
Authors: Tawfik Bernard , Gerber David E. , Burtness Barbara , Hughes Randall S. , Myers Larry L. , Sumer Baran D. , Truelson John , Strom Tobin Joel , Kurian Pamela , Saleem Sehresh , Pearson Jean , Zhu Hong , Khan Saad A.
Published: September 2018

TPS6098

Background: ATC is a rare thyroid cancer with a highly aggressive clinical course. Median OS is 3-4 months and 90% of patients die within 1 year of the diagnosis. There are no effective treatment options in metastatic disease. Targeted therapies to ALK and BRAF are occasionally associated with dramatic responses. Retinoblastoma (Rb) inhibits cell cycle progression and is inactivated by CDK 4/6, which is the target for ribociclib. Nearly all differentiated thyroid cancers are Rb negative, conversely nearly 100% of ATC expresses intact Rb which may be crucial for rapid cell cycle progression. Ribociclib is a CDK 4/6 inhibitors that slows cell cycle progression and DNA replication in tumors with functional Rb. The p16 protein similarly inhibits CDK4/6; if p16 levels are high Rb is phosphorylated and thus inactive. p16 is low in ATC, and from our comprehensive genomic analysis 30% of ATC lacks the p16 gene CDKN2a. Most ATC demonstrates PI3K/Akt/mTOR abnormalities, this pathway represents an attractive target in ATC. The mTOR inhibitor everolimus has shown promising efficacy in ATC cell lines, especially in those with TSC2 mutation whose wild type negatively regulates mTOR. Methods: The combination of everolimus and ribociclib targets mutations/abnormalities that are frequently seen in ATC, and is tolerable based on Phase I/II trial results in the latest arm of the biomarker/oncogene driven ATC Master Protocol . This open-label trial treats metastatic Rb+ ATC patients with p16-/ CDKN2a-. Treatment is ribociclib 400 mg + everolimus 5 mg QD. The primary endpoint is the overall response rate; secondary endpoints are PFS, OS, safety and toxicity. Exploratory objectives include if tissue biomarkers or mutations noted on Next Generation Sequencing correlate for enhanced/impaired response to combination therapy. Simon's two-stage design will be used with the null hypothesis that the true response rate is 5%, this will be tested against a one-sided alternative. In the first stage, 9 patients will be accrued. If no response in these 9 patients, the study will be stopped. Otherwise, 21 additional patients will be accrued for a total of 30. Clinical trial information: NCT02289144.
Biospecimen donors' views about biobank closure.
Authors: Pentz Rebecca D. , Dixon Margie D , Allen Samuel C
Published: September 2018

TPS6625

Background: The future of biobanks is often uncertain due to sporadic funding. A survey of 456 biobank administrators found that they consider the loss of funding to be either a "massive (40%)" or "moderate (31%)" concern. Only 26% of biobanks reported having a plan in the event of closure (Cadigan et al., Life Sciences, Society and Policy, 2013). Biospecimen donors’ views on how they want their tissue handled following biobank closure is unknown. Our study will be the first to determine how biospecimen donors want their data and biological materials handled if their biobanks were to close. We believe this report of 100 biospecimen donors’ views will be useful to researchers and tissue bank administrators in creating contingency tissue bank closure plans that incorporate biospecimen donors’ perspectives. Methods: We will complete accrual of 100 oncology biospecimen donors (current accrual is 65 patients) at one institution by interviewing them about their views of bank closure and preferences for the handling of their tissue post-closure. The interview asks participants if they have a preference for the handling of their tissue and information in the event of bank closure, and if so, if they prefer transfer of their materials to another tissue bank or destruction. Feelings about closure are captured in three categories: sad/disappointed, angry/frustrated, and other negative emotions. The effect of tissue bank closure upon trust in medical research is captured in three categories: decreases trust, does not decrease trust, and may decrease trust under certain circumstances. We ask the participants to rank the following options for transfer of their tissue and information: transfer to another local academic tissue bank, to a for-profit or pharmaceutical bank, to an international bank, or to a national bank. We also ask if any of these options are deemed absolutely unacceptable. Results: NA Conclusions: NA
Phase 3, randomized, double-blind, placebo-controlled study of venetoclax combined with azacitidine versus azacitidine in treatment-naïve patients with acute myeloid leukemia.
Authors: Potluri Jalaja , Xu Tu , Hong Wan-Jen , Mabry Mack H.
Published: September 2018

TPS7069

Background: Elderly acute myeloid leukemia (AML) is a biologically and clinically distinct disease with a diminished response to chemotherapy, low remission rates, and short disease-free and overall survival. Venetoclax (VEN) is a potent, selective small-molecular inhibitor of BCL-2. In preclinical models, venetoclax has been shown to kill AML cells as a single agent with demonstrated synergistic activity in combination with the DNA methyltransferase inhibitor azacitidine (AZA). Early clinical data from a phase 1b study (NCT02203773) showed that VEN plus AZA had an acceptable safety profile and promising efficacy in treatment-naïve elderly patients with AML. The current phase 3 study continues to evaluate the combination for this AML population. Methods: This phase 3, randomized, double-blind, placebo-controlled study (NCT02993523) is designed to assess VEN plus AZA compared with placebo plus AZA in treatment-naïve elderly and adult patients with AML who are not eligible for standard induction therapy due to age or comorbidities. Primary objectives of the study are to evaluate if VEN with AZA will improve overall survival (OS) and composite complete remission rate (CR+CRi) versus placebo with AZA. Secondary objectives include event-free survival, CR+CRi rate at the end of Cycle 1, and if combining VEN plus AZA reduces fatigue and improves global health status/quality of life based on patient reported outcomes versus placebo with AZA. Exploratory objectives are to evaluate biomarkers predictive of VEN activity including minimal residual disease negativity rate, and BCL-2 expression and outcome measures of overall survival and complete remission rate, as well as the impact of VEN on additional quality of life measures. Patients will be randomized 2:1 to VEN plus AZA (arm A) or placebo plus AZA (arm B). Patients on arm A will receive once daily 400 mg VEN orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days in a 28-day cycle. Patients on arm B will receive once daily placebo orally on days 1–28 plus daily 75 mg/m2 SC or IV AZA for 7 days on a 28-day cycle. Study recruitment began in February 2017, with target enrollment of 400 patients. Clinical trial information: NCT02993523.