tbuckley/cabot-search huggingface dataset:
Phase 1b study of avelumab in advanced previously treated mesothelioma: long-term follow-up from JAVELIN Solid Tumor.
Authors: Raffit Hassan, Anish Thomas, John J. Nemunaitis, Manish R. Patel, Jaafar Bennouna, Franklin Chen, Jean-Pierre Delord, Afshin Dowlati, Samith Thomas Kochuparambil, Matthew H Taylor, John D. Powderly, Ulka N. Vaishampayan, Claire F. Verschraegen, Hans Juergen Grote, Anja von Heydebreck, Kevin M. Chin, James L. Gulley
Journal: Journal of Clinical Oncology (2018)

8563 Background: Avelumab, a human anti-PD-L1 IgG1 antibody, is approved for treatment of metastatic Merkel cell carcinoma in various countries and advanced urothelial carcinoma progressed on platinum therapy in the US. We report updated results with avelumab in a phase 1b cohort of patients (pts) with mesothelioma. Methods: Pts with unresectable pleural or peritoneal mesothelioma progressed after platinum and pemetrexed therapy received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). A post-hoc landmark analysis was performed using a Cox regression model. Results: At data cutoff on Dec 31, 2016, 53 pts were treated and followed for a median of 24.8 mo (range 16.8–27.8). Pts had received a median of 2 prior lines of therapy (range 1–8). Confirmed ORR was 9.4% (95% CI 3.1–20.7) including complete response (CR) in 1.9% and partial response (PR) in 7.5%. Median duration of response was 15.2 mo (95% CI 11.1–not estimable). 26 pts (49.1%) had stable disease (SD) as best response and the disease control rate was 58.5%. Median PFS was 4.1 mo (95% CI 1.4–6.2) and the 6-mo PFS rate was 38.0% (95% CI 24.2–51.7). Median OS was 10.9 mo (95% CI 7.5–21.0) and the 12-mo OS rate was 45.9% (95% CI 31.9–58.8). In a landmark analysis of pts still on treatment at 3 mo, duration of OS beyond 3 mo was longer in patients who had achieved CR/PR (HR < 0.01; 95% CI 0–inf.) or SD (HR 0.43; 95% CI 0.20–0.89) vs other pts. In evaluable pts with PD-L1+ (n = 16) or PD-L1− (n = 27) tumors (≥5% tumor cell cutoff), ORR was 18.8% (95% CI 4.0–45.6) and 7.4% (95% CI 0.9–24.3), respectively. Treatment-related (TR)AEs occurred in 43 pts (81.1%), including infusion-related reaction (35.8%; all grade 1/2), chills (15.1%), fatigue (15.1%), and pyrexia (11.3%) in > 10%. 5 pts (9.4%) had a grade ≥3 TRAE. 12 pts (22.6%) had an immune-related TRAE, which was grade ≥3 in 3 pts (5.7%; pneumonitis, colitis, and type 1 diabetes mellitus). No treatment-related deaths occurred. Conclusions: Updated data confirm the clinical activity and acceptable safety of avelumab in pts with previously treated mesothelioma. Clinical trial information: NCT01772004.
ADVL1412: Initial results of a phase I/II study of nivolumab and ipilimumab in pediatric patients with relapsed/refractory solid tumors—A COG study.
Authors: Kara L. Davis, Elizabeth Fox, Joel M. Reid, Xiaowei Liu, Charles G. Minard, Brenda Weigel, Crystal Mackall
Journal: Journal of Clinical Oncology (2017)

10526 Background: Checkpoint inhibitors have produced impressive responses in cancer. We report results of a Phase 1 study of nivolumab (nivo) alone and in combination with ipilumumab (ipi) in children with relapsed/refractory solid tumors and activity of nivo in patients with osteosarcoma (OS) and Ewing sarcoma (EWS) treated with the RP2D. Methods: Children with relapsed/refractory solid tumors (excluding CNS tumors or metastases) were eligible for Phase I Cohorts A and C. Using a rolling 6 design, Cohort A tested nivo at the adult RP2D, 3mg/kg Q14d (cycle = 28d). Cohort C tested nivo + ipi at 2 dose levels (DLs): DL1 nivo 1mg/kg + ipi 1mg/kg and DL2 nivo 3mg/kg + ipi 1mg/kg Q21d x 4 then nivo alone Q14d. At the RP2Ds, 6 additional patients were enrolled in each cohort for pharmacokinetics (PK). Phase II expansion cohorts enrolled patients with measurable OS (Cohort B2, n = 10) or EWS (Cohort B4, n = 10) respectively to assess activity of the RP2D of single agent nivo. Results: Twelve evaluable patients enrolled in Cohort A, none had DLTs. The pediatric RP2D of nivo alone was identified as 3 mg/kg Q14d. Five evaluable patients enrolled in Cohort C:DL1 without DLT, then 12 patients enrolled in Cohort C:DL2 with one DLT within the 21d reporting period (Gr 2 creatinine increase), defining the RP2D of nivo 3mg/kg + ipi 1mg/kg at the schedule above. In 39 patients treated in cohorts A, B2, B4 and C, pleural effusions occurred in 7 with variable attributions to drug, leading to a protocol amendment mandating supportive care and corticosteroids for pleural effusions on study. Common toxicities included anemia, elevated liver enzymes, rash, fatigue, and nausea, generally Grade 1. In Cohort A, nivo C max , t 1/2 and Cl p values were 63.2±15.7 mg/mL, 10.7±1.8 d and 0.196±0.075 ml/h/kg, respectively. In the Phase II expansion cohorts, no objective responses were observed in OS or EWS. Conclusions: Nivo alone or with ipi at the doses tested is safe in pediatric patients with relapsed/refractory solid tumors. The pediatric RP2D of nivo is 3mg/kg alone or in combination with ipi 1mg/kg. Single agent nivo did not have antitumor activity in OS or EWS. Enrollment to other expansion cohorts with nivo or nivo/ipi is ongoing. Clinical trial information: NCT02304458.
Mesenchymal stem cell directed baculoviral gene therapy of colon cancer.
Authors: Hakan Akbulut, Sedef H. Aktas, Ayse Eser Elcin, Mahmut Parmaksiz, Arzu Aktan Keskin, Arzu Coleri Cihan, Yasar Murat Elcin, Fikri Icli
Journal: Journal of Clinical Oncology (2016)

e14573 Background: Insufficient targeting of the therapeutic genes to tumor cells is one of the major reasons of failure in cancer gene therapy. Mesenchymal stem cells (MSC) can easily home to the tumor sites when administered intravenously because of the chronic inflammatory process induced by the tumor cells. Methods: In the current study, we constructed baculoviral vectors (BVs) carrying cytosine deaminase (CD) (BV-CD) or green fluorescence protein genes and tested the transduction efficiency of the vectors and in vivo efficacy of the bone marrow derived MSC (BM-MSC) loaded with BV-CD vector in a colon cancer model in BALB/c mice. Three groups of mice with 6 mice in each having approximately 50 mm3 of tumor nodules established by subcutaneous injection of CRL2638 colon cancer cells were used. The control group was given iv PBS, the second group iv injection of 1×105 BM-MSCs and the third group iv injection of 1×105 BM-MSCs loaded with 100 MOI of BV-CD. All the mice were given ip 500 mg/kg 5-FC in 0.5 ml of volume for 10 days. Results: While the transduction efficiency of the recombinant baculoviral vectors was almost 100% in Sf-9 insect cells at the dose of 100 MOI, it was approximately 70% in mouse tumor cells and BM-MSCs of the BALB/c mice. The BV-CD treatment caused a significant in vitro cytotoxicity when used with 5-fluorocytosine in various tumor cells. No toxicity was observed when the vector used alone in mammalian cells. The recombinant vector loaded BM-MSCs caused a significant delay in tumor growth (p < 0.01) and increased the median survival time of the tumor bearing mice approximately 40% when compared to either controls or unloaded MSCs (p < 0.05). Conclusions: Our results show that the recombinant BV-CD vector could be used either alone or loaded into BM-MSCs, in the treatment of colorectal cancer.
The FDA Amendments Act of 2007 — Assessing Its Effects a Decade Later
Authors: Jerry Avorn, Aaron Kesselheim, Ameet Sarpatwari
Journal: New England Journal of Medicine (2018)

The FDA Amendments Act of 2007 With more than a decade of experience accumulated, it is clear that the FDAAA introduced important improvements in the FDA’s capacity to track medication effects and mitigate risk. But challenges persist.
Adjuvant chemotherapy outcome in unselected single-center non-small cell lung cancer (NSCLC) population.
Authors: Marie Florescu, Normand Blais, Mustapha Ali Tehfe, Mathieu Gravel
Journal: Journal of Clinical Oncology (2017)

e20089 Background: Adjuvant chemotherapy with Cisplatinum/Vinorelbine is an established regimen since a decade in selected resected NSCLC population in order to improve DFS and overall survival. However, the outcome of patients treated outside the research protocols is not as good as in clinical trials. Methods: We retrospectively reviewed 209pts resected stage I to III NSCLC patients using our SARDO database, treated in our University hospital between 2006 and 2015 with a median follow-up of 13mos. Any adjuvant chemotherapy was recorded. Results: Amongst 209 resected NSCLC patients, 185pts (89%) had negative margins and 24pts (11%) have positive margins resection. The observation group and the chemotherapy group in both settings were well-balanced in terms of demographic, co-morbidities and tumor characteristics. As expected, the median overall survival (mOS) in negative margins was significantly better than in positive margins patients (43mos vs 24mos p = 0.029). In negative margins patients, no survival benefit was seen in stage I (A and B) (57 mos for chemo group vs 77 mos for observation group p = 0,217) and stage III (A and B) (39mos mOS for chemo group vs 40mos for observation group, p = 0.37), but a trend for improved mOS was seen in stage II (52 mos for chemo group vs 38 mos for observation group, p = 0.114), also consistent with mPFS results for each group. However, for the small number of patients with positive margins, a significant improvement in survival was seen in chemotherapy arm (mOS 37mos) compared to observational arm (mOS 11mos p = 0,039). No significant difference in survival was seen between Carbo/Taxol regimen and Cisplatinum/Vinorelbine regimen (43 mos vs 38 mos p = 0,658). Conclusions: In our unselected population, adjuvant chemotherapy did not show the improvement in survival expected with margin negative resected NSCLC. In positive resected NSCLC, adjuvant chemotherapy benefit was statistically significant, emphasizing need to treatment to these patients.
Treatment focused genetic testing (TFGT) for ovarian cancer (OC) patients: The Catalan Institute of Oncology (ICO) network experience.
Authors: Maria Pilar Barretina-Ginesta, Hanan Ahmed-Ouahid, Beatriz Pardo, Marta Gil-Martin, Margarita Romeo, Alicia Garcia-Arias, Nuria Sala, Lidia Feliubadalo, Esther Darder, Ares Solanes, Monica Salinas, Angela Velasco, Alexandre Teule, Gabriel Capella, Conxi Lazaro, Joan Brunet
Journal: Journal of Clinical Oncology (2016)

e17071 Background: Since the approval of the PARP inhibitor olaparib, the TFGT indications for OC have dramatically increased. Furthermore, several guidelines include genetic testing for all non-mucinous OC patients irrespectively of age and family history. Methods: The ICO network comprises 4 Medical Oncology Departments, 3 Cancer Genetic Counselling Units (CGCU) and 2 Cancer Family Units (CFU) being all of them referral centres for a total of 25 hospitals that cover a population of 3.5 m inhabitants. In December 2014, the Gyne Oncologists Team in collaboration with the CGCU members and the Molecular Diagnosis Laboratory (MDL) of the ICO network established a consensus protocol on indications for risk assessment (RA) and TFGT. All new pts diagnosed with epithelial non-mucinous OC or platinum sensitive relapse were referred to CGCU. An express track for RA at CGCU (0-10 days) and test results delivery ( < 35 days) was defined for OC patients whose germline BRCA1/2 test results were needed to tailor their treatment. Results: Between January 1st and November 30th, 115 new OC patients were refered to the CGCU. 27 (23 %) followed the express track. Median time from the referral date to test results for standard GC was 77 days (36-98) and 27 days (18-65) for express GC. Median age was 59 (23-80) and 63% had not family history of cancer. Serous carcinoma was the most frequent histology (96 %). BRCA1/2 results were available for 100 patients. Deleterious mutations were identified in 22% of patients (15% in the group without family history of cancer). Variants of uncertain significance were found in 9% of cases. Conclusions: After an initial 11 months experience review, our protocol warrants adequate RA for all patients tested for BRCA1/2 mutations as well as quick results when needed to establish a therapeutic strategy. Time to first appointment for RA and test results was optimal for patients with olaparib indication. The relatively high frequency of germline BRCA1/2 mutations could be explained by the bias selection of patients with platinum sensitive relapse. We continue to implement the protocol to end up testing all patients at diagnosis after having the results for all prevalent cases.
A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck.
Authors: Matthew H. Taylor, Drew W. Rasco, Marcia S. Brose, Nicholas J. Vogelzang, Stephen Lane Richey, Allen Lee Cohn, Donald A. Richards, Daniel E. Stepan, Corina E. Dutcus, Matthew Guo, Robert Charles Shumaker, Emmett V. Schmidt, Lori J. Wirth
Journal: Journal of Clinical Oncology (2018)

6016 Background: Lenvatinib (LEN) is a multikinase inhibitor of vascular endothelial growth factor receptor 1−3, fibroblast growth factor receptor 1−4, platelet-derived growth factor receptor α, RET, and KIT. Pembrolizumab (PEM) is an anti-PD-1 antibody approved for the second-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) based on durable responses and an objective response rate (ORR) of 16% (Bauml J et al, J Clin Oncol 2017). We report initial results of the SCCHN cohort from a phase 1b/2 trial of the LEN + PEM combination (NCT02501096). Methods: In this multicenter, open-label study, patients (pts) with measurable, confirmed metastatic SCCHN and ECOG performance status ≤1 received LEN (20 mg/day orally) + PEM (200 mg Q3W, IV). Pts were not preselected based on PD-L1 status. Tumor assessments were performed by study investigators using immune-related RECIST (irRECIST). The phase 2 primary endpoint was ORR at 24 weeks (ORRWK24). Secondary endpoints included ORR, progression-free survival (PFS), and duration of response (DOR), which is calculated for pts with complete or partial responses. Results: At data cutoff of August 1, 2017, 22 pts with SCCHN (regardless of PD-L1 status) were enrolled. 86% of pts had ≥1 prior anticancer therapy. Median follow-up for PFS was 7.6 months (95% confidence interval [CI], 4.2–12.6) per irRECIST. Efficacy outcomes are summarized in the table. Grade 3 or 4 AEs occurred in 91% of pts (grade 4 AEs in 14%). However, 4 (18%) discontinued study treatment due to AEs. The most common AEs were fatigue (55%), decreased appetite (41%), hypertension (41%), diarrhea (36%), and nausea (36%). Updated data will be presented. Conclusions: LEN + PEM demonstrated promising clinical activity and manageable toxicities, supporting further evaluation of the LEN + PEM combination in pts with SCCHN. Clinical trial information: NCT02501096.Outcome irRECIST (N = 22) ORRWK24, n (%)* 8 (36.4) 95% CI 17.2–59.3 ORR, n (%)† 8 (36.4) 95% CI 17.2–59.3 Median DOR, months (95% CI)‡ 8.2 (2.2–not estimable) Median PFS, months (95% CI) 8.2 (4.3–not estimable) PFS rate at 12 months, % (95% CI) 37.2 (12.8–62.2) *8 partial responses (PR). †7 PRs, 1 complete response. ‡4 of the 8 (50%) responders achieved a DOR of > 6 months.
Providers’ adherence to surveillance recommendations for colon and rectal cancer survivors.
Authors: Guadalupe R. Palos, Paula A. Lewis-Patterson, Katherine Ramsey Gilmore, Patricia Chapman, Weiqi Bi, Maria Alma Rodriguez
Journal: Journal of Clinical Oncology (2016)

e21571 Background: Surveillance for patients of colon (CC) and rectal cancer (RC) is a core dimension of quality survivorship care. Minimum standards of care (MSoCs) were embedded in clinical algorithms developed by our academic cancer center. MSoC included yearly 1) carcinoembryonic antigen (CEA) testing only if CEAs were previously elevated, 2) colonoscopy, 3) computed tomography (CT) for chest and CT or MRI for abdomen/pelvis at various times, and 4) yearly digital rectal exam (DRE’s) in RC survivors. In this longitudinal analysis, we evaluated providers’ adherence rates for surveillance of MSoCs. Methods: A retrospective chart review was conducted to identify eligible patients scheduled in the CRC Survivorship Clinic between 09/01/2011 and 08/31/2014. A total of 117 cases were identified with 19 excluded for various reasons. Demographic/clinical characteristics, dates/results of surveillance, abnormal findings, and recurrence outcomes for 98 cases were reviewed for each clinic visit. Adherence (ARs) were calculated for the percentage of visits compliant for each MSoC. Data were collected from electronic medical records and summary care plans. Descriptive statistics summarized rates and demographic/clinical characteristics. Results: Of 98 CRC survivors, 58% were diagnosed with CC and 42% with RC, 64% were Caucasian, 52% were male, 54% ages 65-89 years, and 68% were 5-9 years post-treatment. 57% of RC survivors were Stage I-IIB and 52% of CC were Stage IIIA-C or IV. ARs for CEA testing were higher for RC survivors (60%) compared to CC rates (39%). The weighted AR averages of both sites were: colonoscopies (98%), CT chest (59%), and CT/MRI abdomen and pelvis (61%). ARs for DREs in RC survivors were 89%. Abnormal findings included presentation of 3 diverticula cases and 18 cases of polyps (with 100% removed). There were no reports of recurrent or new cancers in this cohort of survivors. Conclusions: Our results demonstrate high providers’ adherence rates for some recommendations of surveillance in colon and rectal survivors but surprisingly not for the simpler CEA laboratory test. Further longitudinal follow-up is warranted to determine whether intense surveillance contributes to improved outcomes among cancer survivors.
Tetanus toxoid pre-conditioning in recurrent glioblastoma treated with dendritic cell immunotherapy is associated to CD8+ T cell response.
Authors: Marica Eoli, Cristina Corbetta, Valeria Cuccarini, Elena Anghileri, Simona Frigerio, Maria Tardini, Bianca Pollo, Carlo Antozzi, Maria Grazia Bruzzone, Serena Pellegatta, Gaetano Finocchiaro
Journal: Journal of Clinical Oncology (2018)

e14053 Background: Recurrent glioblastoma (GBM) are highly aggressive tumors allowing 6-8 month survival. Recent data suggested that tetanus/ diphtheria toxoid (Td) preconditioning could increase dendritic cells (DC) motility and efficacy of vaccination in newly diagnosed glioblastoma patients (Mitchell et al, 2015). Methods: Here we evaluated the possible benefits of immunotherapy with mature DC loaded with autologous tumor lysate in 8 patients with recurrent GBM, who received 24 hours before vaccination ipsilateral vaccine site pre-conditioning with tetanus Td. The primary endpoint was overall survival rate at 9 months after second surgery (OS-9). Patients were analysed for the effector response and the generation of CD8+ and CD4+ T effector and central memory and other relevant immunological parameters in peripheral blood before and after immunization Results: After a median follow-up of 9.6 months median OS was 9.3 (6.5-10.6) months and OS-9 62%. Based on OS > 9 months, five patients were defined, as responder and three asnot responder patients. Four responder patients showed CD8+ T cell activation evaluated as IFNG expression (evaluated by flow cytometry). Three of them also showed the generation of CD8+ T central memory. On the contrary, patients with recurrent GBM we had treated previously with DC vaccination in association with chemotherapy (temozolomide) and without preconditioning, failed to show immunological responses. Conclusions: The results suggest that preconditioning of the vaccine site and absence of temozolomide contribute to CD8+ responses to DC immunotherapy.
Randomized phase III study comparing an early PET driven treatment de-escalation to a not PET-monitored strategy in patients with advanced stages Hodgkin lymphoma: Final analysis of the AHL2011 LYSA study.
Authors: Olivier Casasnovas, Pauline Brice, Reda Bouabdallah, Gilles A. Salles, Aspasia Stamatoulas, Jehan Dupuis, Oumedaly Reman, Thomas Gastinne, Bertrand Joly, Kamal Bouabdallah, Emmanuelle Nicolas-Virelizier, Pierre Feugier, Franck Morschhauser, Richard Delarue, Alina Berriolo-Riedinger, Veronique Edeline, Alexandra Traverse-Glehen, Marc Andre, Nicolas Mounier, Michel Meignan
Journal: Journal of Clinical Oncology (2018)

7503 Background: Escalated BEACOPP (BEA) improves PFS but not OS in pts with advanced HL compared to ABVD and is associated to a higher risk of hematological toxicity, secondary leukemia and infertility. PET performed after 2 cycles of BEA (PET2) might identify a population with a better outcome suitable for de-escalation treatment without impairing the disease control. Methods: AHL 2011 (NCT01358747) was designed to evaluate in 16 to 60 y HL pts with stage III, IV or high risk IIB, a treatment strategy driven by PET after 2 BEA cycles, delivering 4 cycles of ABVD for PET2 negative pts and 4 cycles of BEA for PET2 positive pts. This PET driven strategy (arm B) was randomly compared to a standard treatment delivering 6 cycles of BEA (arm A). The allocation of treatment in the experimental arm was based on the central review of PET2 interpreted according to Deauville criteria. PFS was the primary endpoint with a hypothesis of non-inferiority of the PET driven arm compared to the standard arm. Results: 823 pts were registered including 413 and 410 pts in the arms A and B respectively. Pts characteristics were well balanced in both arms. PET2 positivity rate was similar in arms A (12%) and B (13%). Based on PET2 results, 346 (84%) pts received 4 cycles of ABVD and 51 (12%) 4 additional cycles of BEA in the experimental arm. The treatment toxicity was significantly higher in pts receiving 6 cycles of BEA compared to those who received 2 cycles of BEA + 4 cycles of ABVD with more frequent grade ≥3 AE (anemia (11% vs 2%), leukopenia (85% vs 74%), thrombocytopenia (44% vs 15%), and sepsis (7% vs 3%)) and SAE (45% vs 28% (p < 10-4). With a median follow up of 50 months, the 5y-PFS was similar in the standard (86.2%) and the PET driven arms (85.7%; p = 0.68). PET2 positivity was related to a significantly lower 5y-PFS compared to PET2 negative pts (70.7% vs 88.9%; p < 0.0001). OS was similar in both arms. Conclusions: PET performed after 2 cycles of BEA can be safely used to guide subsequent treatment and supports the response-adapted strategy delivering ABVD for pts with negative PET2 reducing the treatment-related immediate toxicity without impairing the disease control. Clinical trial information: NCT01358747.