bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.