tbuckley/cabot-search huggingface dataset:
Pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) in patients (pts) with advanced, EGFR wild-type (wt) Non-Small Cell Lung Cancer (NSCLC): A randomized phase II trial.
Authors: Tianhong Li, Bilal Piperdi, William Vincent Walsh, Mimi Kim, Laurel A. Beckett, Huiyu Wen, Kaili Zhou, Rasim A. Gucalp, Missak Haigentz, Venu Gopal Bathini, Srikanth Gajavelli, Meera Sreedhara, Primo Lara, David R. Gandara, Roman Perez-Soler
Journal: Journal of Clinical Oncology (2015)

8044 Background: We previously reported that PDS of Pem and Erl (Pem 500 mg/m2 IV on day 1 and Erl 150 mg po QD on days 2-17 of a 21-day cycle) as 2nd-line therapy has promising clinical activity over Pem alone in 75 unselected pts with advanced non-squamous NSCLC (NCT00950365; Li et al., ASCO 2013). Given pts with EGFR mutant NSCLC usually have better clinical response to Pem or Erl monotherapy, we updated the efficacy analysis restricted to those pts with confirmed EGFR wt NSCLC. Methods: EGFR genotype status was determined by the Clinical Laboratory Improvement Amendments-certified RT-PCR, direct sequencing, and/or Sequenom multiplex genotype tests using archival formalin fixed, paraffin embedded tumor specimens or plasma circulating tumor DNA from study pts. For those pts with only blood samples, a repeat or alternative test was used to confirm the status of EGFR wt genotype. The parent study was designed to detect an increase in median progression-free survival (mPFS) by 50%, i.e., a hazard ratio (HR) of ≤ 0.67. Results: 59 (79%) of 75 eligible pts had confirmed EGFR wt (N=52) or EGFR-mutant (N=7) genotype. The results are summarized in Table 1. Longer PFS was observed in pts with EGFR WT NSCLC treated with the combination (Arm B). Conclusions: PDS of Pem and Erl as 2nd-line therapy appears to have promising clinical activity in pts with advanced, EGFR wt non-squamous NSCLC, which comprises of 85% of non-Asian NSCLC pts, and warrants further confirmation. (UL1 RR024146, P30CA093373, Astellas, Eli Lilly). Clinical trial information: NCT00950365.Clinical efficacy in pts with EGFR wt NSCLC. Treatment Arm (Pt No) Median Age Female Smoking hx (< 15 PY) mPFS: mo (95% CI) Median OS: mo (95% CI) ORR: % (95% CI) DCR 3mo: % (95% CI) DCR 6mo: % (95% CI) DCR 12mo: % (95% CI) A: Pem (N = 21) 64 57.1% 23.8% 3.5 (1.6-5.5) 9.2 (3.3-11.8) 10% (0-22%) 52% (31%-74%) 29% (9%-48%) 10% (0-22%) B: Pem + Erl (N = 31) 62 54.8% 25.8% 5.3 (3.6-7.6) 9.9 (6.6-20.0) 29% (13%-45%) 71% (55%-87%) 45% (28%-63%) 23% (8%-37%) p value 0.23$ 0.87& 0.87& 0.11* 0.44* 0.17# 0.24# 0.26# 0.28# HR (95% CI) 0.63 (0.4-1.1) 0.77 (0.4-1.4) $t-test; &chi-square; *Log-rank test; #Fisher’s exact test.
Multitargeted antiangiogenic tyrosine kinase inhibitors in advanced non-small cell lung cancer: A meta-analysis of randomized controlled trials.
Authors: Wenhua Liang, Li Zhang
Journal: Journal of Clinical Oncology (2013)

8089 Background: Novel multitargeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have showed promising advantages in combination with chemotherapy or as monotherapy in treatments of advanced non-small cell lung cancer (NSCLC). Since the efficacy and safety of these small molecules have been evaluated by several phase II/III randomized controlled trials (RCTs), we seek to summarize the current evidences by performing a meta-analysis. Methods: PubMed, EMBASE, the Cochrane Library as well as the ASCO and ESMO databases were searched for eligible literatures. We defined the experimental arm as MATKI-containing group while the control arm as MATKI-free group. The endpoints being evaluated included overall survival (OS), progression free survival (PFS), objective response rate (ORR) and disease control rate (DCR), as well as adverse events (AEs). Pooled hazard ratios (HRs) for survival outcomes and odds ratio (ORs) for dichotomous data, with 95% confidence intervals (CI) were calculated using REVMAN 5.0. Subgroup analysis was conducted according to each agent respectively. Results: Five agents (vandetanib, sunitinib, cediranib, sorafenib, motesanib) with comparable data could be analyzed. Fifteen phase II/III RCTs that involved a total of 8854 participants were included. Compared to MATKI-free group, MATKI-containing group was associated with significant longer PFS (HR 0.824, 95% CI 0.759 to 0.895, P&lt;0.001), superior ORR (OR 1.27, 95% CI 1.13 to 1.42, P&lt;0.0001) and DCR (OR 1.14, 95% CI 1.04 to 1.25, P=0.006). However, although some improvement in OS was observed, the benefit did not reach statistical significance (HR 0.962, 95% CI 0.912 to 1.015, P=0.157). In terms of subgroup results, sorafinib was revealed to yield no improvement in all endpoints. The specific AEs in patients who received these agents were rash, diarrhea and hypertension. Conclusions: Regimens consisting of multitargeted antiangiogenic TKIs were superior to those without these agents in terms of tumor response and PFS in patients with advanced NSCLC. However, no significant benefits in OS were observed. In addition, sorafinib seemed to has no substantial efficacy for NSCLC patients.
Relationship between tumor location and oncogenes mutations (<i>RAS</i>, <i>BRAF</i>, and <i>PIK3CA</i>) in colorectal cancer.
Authors: Daisuke Inagaki, Manabu Shiozawa, Tetta Satoyoshi, Yousuke Atsumi, Masaaki Murakawa, Keisuke Kazama, Toru Aoyama, Akio Higuchi, Soichiro Morinaga, Yasushi Rino, Munetaka Masuda, Yohei Miyagi
Journal: Journal of Clinical Oncology (2017)

580 Background: Several studies have reported that right-sided colon cancers (RCC) and left-sided colon cancers (LCC) differ in several factors including genetic features. We investigated the difference in clinicopathological characteristics and oncogenic mutation status between patients with RCC and LCC in all stages. Methods: This study was a prospective, observational study. Patients were recruited from December 2014 to February 2016. Formalin-fixed paraffin-embedded tissue blocks were collected and DNA wes extracted from tissue sections from 158 cases. Mutations in KRAS, NRAS, HRAS, BRAF and PIK3CAwere detected by next-generation DNA sequencer. Tumors from cecum to transverse colon were defined as RCC, and tumors from descending colon to rectsigmoid were defined as LCC. Results: RCC was 66 patients and LCC was 92 patients. Poorly differentiated adenocarcinoma or mutinous adenocarcinoma were significantly more frequent in RCC compared to LCC (P = 0.047). KRAS mutations were detected in 35 patients with RCC (53.0%) and in 32 patients with LCC (34.8%). NRAS mutations were detected in 2 patients with RCC (3.0%) and in 3 patients with LCC (3.3%). There was no HRAS mutation in all patients. BRAF mutations were detected in 7 patient with RCC (10.6%) and in 2 patients with LCC (2.2%). PIK3CA mutations were detected in 8 patients with RCC (12.1%) and in 10 patients with LCC (10.9%). KRAS and BRAF mutation in RCC were significantly more frequent than in LCC (P = 0.022 and P = 0.024, respectively). These mutations were not significantly different according to tumor stage. In this study, both KRAS and BRAFmutations were exclusive. Conclusions: KRAS and BRAF mutation were more frequent in the patients with RCC compared to those with LCC in all stages. This study suggested that it was important to evaluate BRAF mutation in addition to KRAS in order to select more effective treatments, especially in RCC.
A phase II multicentric study of sunitinib administered as upfront therapy in glioblastoma: A study by the GEINO group.
Authors: Carmen Balana, Miguel J. Gil Gil, Gaspar Reynes, Jaume Capellades, Teresa Ribalta, Oscar Gallego, Pedro Pérez Segura, Eugenia Verger
Journal: Journal of Clinical Oncology (2012)

2045 Background: Sunitinib is a multitargeted tyrosine kinase inhibitor that has direct antitumor and antiangiogenesis activity through targeting VEGFR 1-2, PDGFR α-β, c-kit, bFGF, (CSF-1), FLT3 and RET. Experimental studies in GB mice showed angiogenic activity, prolonged survival and synergy with irradiation Methods: Eligible pts were ≤75 years with GB not amenable to resection, PS≥2, MMS ≥25. Treatment was sunitinib 37.5mg daily for 8 w before radiotherapy, during radiotherapy (60Gy, 6 w) and after radiotherapy until disease progression. Primary endpoint was overall response (OR) (RANO criteria) after 8 w of sunitinib treatment before radiotherapy. Secondary endpoints were % pts free of neurological deterioration before radiotherapy, % pts who completed radiotherapy, PFS, OS and 1-year survival. We used a Simon 2-stage design (12 →20) based on OR to calculate the number of patients needed to detect at least 10% of responses with α error of 0.05 and β error of 0.10. Twelve patients were included in the first phase and one response was needed to continue study accrual. Results: 12 pts were enrolled: 7 males, median age 65 years, PS≥1: 8pts, median MMS 26.5. Neurological deficit: 5pts, DXM treatment 10/12, non-EIDS 3/12. Treatment: 5 pts completed 8 w of therapy, 2pts completed 7 w, 4 pts ≤ 6w. Toxicity G3 and 4: diarrhea (1pt), asthenia (2pts), skin and EDDPP (2), mucositis (2), fatal CNS hemorrhage (1), hypercholesterolemia and hypertriglycemia (1). OR was 1/12 SD, 11/12 P; radiological response was SD in 5 pts but 4 pts progressed neurologically. Only 2 pts completed radiotherapy plus sunitinib. The only SD received treatment for 18 w. Median PFS was 7.5w (CI 95% 5.8-9.2), OS 16w (CI 95% 0.5-23.7), 1year OS: 0%. Conclusions: the trial was closed after the first stage due to lack of response. Sunitinib is an inactive agent in glioblastoma.
Tumortropic adipose-derived stem cells carrying smart nanotherapeutics for targeted delivery and dual-modality therapy of orthotopic glioblastoma
Authors: Wen-Chia Huang, I.-Lin Lu, Wen-Hsuan Chiang, Yi-Wen Lin, Yuan-Chung Tsai, Hsin-Hung Chen, Chien-Wen Chang, Chi-Shiun Chiang, Hsin-Cheng Chiu
Journal: Journal of Controlled Release (2017)
Study to explore the willingness of patients (pts) to undergo biopsy at the time of breast cancer (BC) recurrence.
Authors: Mia Ivy Francl, Sophie Sun, Diego Villa, Karen A. Gelmon, Caroline A. Lohrisch
Journal: Journal of Clinical Oncology (2013)

1102 Background: Physicians (MDs) may not request a biopsy (BX) when metastatic (M1) diagnosis is certain, however, there is increasing awareness of the value of tissue for cancer discovery. In addition, biomarkers can change from initial BC to M1 in 20%, affecting treatment. With ethics approval we investigated under what conditions BC pts would agree to a BX of recurrent cancer, to guide MD practice. Methods: Consenting English speaking pts with M1, or at least 3 months post adjuvant therapy, were asked to complete a survey (at home or with research assistant) about willingness to undergo BX at M1. Demographic and disease information was collected. The BX scenarios increased in inconvenience/discomfort and decreased in direct benefit to pt. Results: Among 204 participants, mean age was 60 (29-92), 71% were caucasian, 73% completed more than high school, 84% lived within 1 hour of the cancer centre. 87 (43%) pts had no relapse (M0) and 116 (57%) had M1 (including 20 [17%] with local relapse only, 21 [18%] de novo M1). 82 (71%) of M1 pts reported having had a BX for M1. When it required only image guidance and minimal discomfort (eg ultrasound guided liver BX), 86% of M1 pts would have a BX to join a trial and 81% would for pure research; 69% and 76% of M0 pts would have a BX to join a trial, or for research only, respectively. The Table shows the responses for the most invasive BX. Conclusions: Two thirds of BC pts would undergo the most invasive/inconvenient BX to join a trial, and half would for pure research. This demonstrates a large degree of altruism in this BC population. Willingness increased as direct benefit increased and the pain/inconvenience decreased. This data suggests MDs should not be hesitant to ask BC pts for a BX at M1. This study was limited to English speaking pts and most were well educated, thus it may not reflect all cultural attitudes toward BX. [Table: see text]
Choice of starting dose for biopharmaceuticals in first-in-human phase I cancer clinical trials.
Authors: Aaron Richard Hansen, Natalie Cook, M Stacey Ricci, Albiruni R. A. Razak, Christophe Le Tourneau, Kathleen McKeever, Lorin Roskos, Rakesh Dixit, Lillian L. Siu, Mary Jane Hinrichs
Journal: Journal of Clinical Oncology (2014)

2596 Background: The conventional paradigm used to set a safe human starting dose (SD) in phase I trials with anti-cancer agents of low molecular weight is derived from 1/10th the severely toxic dose in 10% (STD10) of rodents or 1/6ththe highest nonseverely toxic dose (HNSTD) in nonrodents. There is no consensus on whether this paradigm can be safely applied to biotechnology derived products (BDP). Methods: A comprehensive search was conducted to identify all BDP (excluding immune checkpoint inhibitors and antibody drug conjugates) with sufficient nonclinical and clinical data to assess safety of hypothetical use of 1/6th HNSTD from a relevant species in a phase I trial. The HNSTD in nonrodents was compared to the maximum tolerated dose (MTD) or in the absence of the MTD, the maximum administered dose (MAD) in patients. In addition, 1/6thHNSTD was compared to the actual SD chosen for the first in human (FIH) trial, which employed a wide range of pharmacologic and toxicologic parameters to set the SD. Results: The search identified 23 BDP, of which 21 were monoclonal antibodies. The median ratio of MTD or MAD to the actual FIH SD was 36 (range 8 to 500). The majority of the BDP (21 of 23) were administered without reaching MTD in phase 1 trials. Hypothetical use of 1/6th HNSTD would not have exceeded MTD or MAD for all 23 BDP and would have reduced the median ratio of MTD or MAD to SD to 2.2 (range 1.2 to 10). While use of 1/6th HNSTD would have decreased the number of cohorts to reach MTD or MAD, hypothetical dose escalation of 1/6th HNSTD would have surpassed MTD or MAD for 10 of 23 (43%) BDP after 1 dose doubling. Only 7 of the 23 BDP included pharmacodynamic (PD) markers in animal models; however these markers were useful to determine the maximally biologic active dose in animals. Conclusions: Use of 1/6th HNSTD in nonrodents would not have resulted in unacceptable toxicities for the 23 BDP evaluated. Absence of MTD in animals and humans underscores the need to identify and utilize pharmacokinetic (PK) endpoints and PD biomarkers to guide SD selection for FIH phase I cancer trials. This approach could help reduce the number of dose-escalations needed to reach the optimum biological dose in phase 1 studies and limit unnecessary exposure to high drug levels in humans.
Phase I dose-finding study of the gamma secretase inhibitor PF-03084014 (PF-4014) in combination with docetaxel in patients (pts) with advanced triple-negative breast cancer (TNBC).
Authors: Giuseppe Curigliano, Philippe Georges Aftimos, Elizabeth Claire Dees, Patricia LoRusso, Mark D. Pegram, Ahmad Awada, Bo Huang, Rossano Cesari, Yuqiu Jiang, Mohammed Naveed Shaik, Kenneth Alan Kern, Marzia Adelia Locatelli
Journal: Journal of Clinical Oncology (2015)

1068 Background: Gamma secretase is a key component of the Notch signaling pathway, which is involved in cancer cell biology and survival in various tumor types including breast cancer. PF-4014 demonstrated synergistic anti-tumor activity with docetaxel in preclinical models, supporting clinical development of this combination. Methods: Pts received PF-4014 orally, twice daily (BID) in combination with docetaxel Q3W, following a matrix design with the modified toxicity probability interval method. The purpose was to estimate the maximum tolerated dose (MTD); the primary endpoint was first-cycle dose-limiting toxicity (DLT). The MTD was defined as the highest, tested dose with a first-cycle DLT rate < 0.33. Results: In all, 22 female pts received treatment; mean age 50 yrs (27-76 yrs). The most common treatment-related adverse events (AEs) were neutropenia (91%), fatigue (77%), leukopenia (68%), nausea (64%), alopecia (59%), diarrhea (59%), and anemia (50%), which were generally mild to moderate in severity. We also noted G3 leukopenia (41%), hypophosphatemia (14%), and pneumonia (14%); and G4 neutropenia (82%), leukopenia (23%) and febrile neutropenia (FN) (18%). One G5 treatment-related AE, septic shock, occurred. DLTs are listed in the table, by treatment cohort. One pt, previously treated with paclitaxel, had a confirmed partial response in first-line treatment for advanced TNBC. Six pts had stable disease. PK and pharmacodynamic evaluations of pathway modulation in surrogate (blood) and tumor tissues are ongoing. Co-administration with PF-4014 did not affect exposure to docetaxel. Conclusions: The MTD estimated for the combination in pts with advanced TNBC was PF-4014 100 mg BID/docetaxel 75 mg/m2. Antitumor activity will be assessed in an expansion cohort of pts with advanced TNBC (first-line setting). Clinical trial information: NCT01876251. Cohort PF-4014 100 mg BID/docetaxel 75 mg/m2 PF-4014 150 mg BID/docetaxel 75 mg/m2 PF-4014 100 mg BID/docetaxel 100 mg/m2 Evaluable pts, n 8 11 3 DLT events, n (%) 1 (13) G3 diarrhea 4 (36) G3 dehydration, G3 nausea, G4 FN, G5 septic shock 1 (33) G3 diarrhea and G4 FN
A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN).
Authors: Joaquim Bellmunt, Jan M. Kerst, Rafael Morales, Federico Vazquez Mazon, Enrique Grande, Ana Medina, Belen Gonzalez Gragera, Gustavo Rubio, Urbano Anido, Ovidio Fernandez Calvo, Enrique Gonzalez-Billalabeitia, Alfonsus Johannes Maria van den Eertwegh, Eduardo Pujol, Jose Luis Perez-Gracia, Jose-Luis Gonzalez-Larriba, Ricardo Collado, Maartje Los, Sonia Macia, Ronald De Wit
Journal: Journal of Clinical Oncology (2017)

285 Background: Despite the advent of immunotherapy in urothelial cancer, there is still a need to find effective cytotoxic agents beyond first line. Vinflunine is EMA approved and used in several European countries. Docetaxel is widely used in second line. Cabazitaxel is a taxane with clinical activity in docetaxel-refractory cancers. A randomised study was conducted to compare its efficacy vs vinflunine. Methods: This was a multicenter, randomised, open-label, phase II/III study, following a Simon’s optimal method with early stopping rules based on an interim futility analysis. The study (NCT01830231) was supported by a research grant from Sanofi. The trial was aiming at superiority of cabazitaxel compared to vinflunine in patients progressing to platinum. ECOG, anemia and liver metastases were stratification factors. The primary objective for the phase II study was overall response rate (ORR), and overall survival (OS) for the phase III. Secondary objectives included safety and progression free survival (PFS). Results: 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the two arms. Mean age 63 years; 56 (80%) were men. No statistically significant differences were detected between arms for ORR (p=0.26). Three patients (13%) obtained a partial response on cabazitazel (95% CI, 2.7–32.4) and six patients (30%) in the vinflunine arm (95% CI, 11.9–54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p=0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favouring vinflunine (median 7.6 versus 5.5 months). Grade 3-4 related adverse events were seen in 41% patients with no difference between arms. The most frequent toxicities associated with cabazitaxel were asthenia, diarrhea, anemia and febrile neutropenia. Conclusions: This phase II/III second line bladder trial comparing cabazitaxel with vinflunine was closed early when the phase II showed a lack of efficacy of the cabazitaxel arm. Vinflunine results were consistent with those observed in the phase III. Clinical trial information: NCT01830231.
Outcomes of PD-1/PD-L1 responders who discontinue therapy for immune-related adverse events (irAEs): Results of a cohort of patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Rana R. McKay, Dylan Martini, Raphael Brandao Moreira, Lana Hamieh, Craig Norton, Stephanie Anne Mullane, Meghara K. Walsh, Dror Michaelson, David F. McDermott, Eliezer VanAllen, Lauren Christine Harshman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

467 Background: Nivolumab, a monoclonal antibody against PD-1, has been shown to improve survival for pts with mRCC. The current standard of care is to administer treatment on a continuous basis until progression or toxicity. Outcomes of pts who experience a response to treatment and then discontinue therapy for irAEs have not been fully characterized. The purpose of this analysis was to evaluate outcomes of responders to PD-1/PD-L1 targeted therapy (TT) who discontinue treatment for irAEs. Methods: We identified pts with mRCC having experienced a response to PD-1/PD-L1 TT, which was subsequently discontinued for an irAE. Clinical characteristics, response, and survival data were collected. Results: We identified 9 mRCC pts who were treated with a PD-1/PD-L1 inhibitor, experienced a response to therapy, and subsequently discontinued treatment for an irAE. 8 had clear cell histology and 1 had translocation RCC. 7 pts were treatment naive. 2 pts had International mRCC Database Consortium favorable risk, 4 intermediate risk, and 3 poor risk disease. 44% (n = 4) of pts received PD-1/PD-L1 monotherapy and the overall median duration of therapy was 5 months (mos) (range 4-15). There was 1 complete response, 7 partial responses, and 1 stable disease (17% shrinkage). Treatment was discontinued for the following irAEs: arthritis, uveitis, arthropathy, hypophysitis, myositis, blepharitis, hepatitis, rash, pericarditis, and amylase and lipase elevations. After PD-1/PD-L1 treatment discontinuation, 4 (44%) pts remained progression free with a median time off therapy of 20 mos (range 10-44) and median time on therapy of 9 mos (range 4-15). 5 (56%) pts progressed within 6 mos (range 2-6) of treatment discontinuation and median time on therapy was 4 mos (range 3-10). Conclusions: We demonstrate that some pts can have persistent clinical benefit after discontinuation of PD-1/PD-L1 TT for irAEs. Larger studies are warranted to evaluate the need for continuous drug dosing in all pts, identify pts in which continuous dosing is not required, and evaluate long-term outcomes in this population.