tbuckley/cabot-search huggingface dataset:
Phase 1/2 intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia.
Authors: Cornelis Martinus van Tilburg, Till Milde, Ruth Witt, Jonas Ecker, Angelika Seitz, Jens-Peter Schenk, Michael Fruehwald, Arnulf Pekrun, Claudia Rössig, Regina Wieland, Christian Flotho, Uwe Kordes, Bernd Gruhn, Thorsten Simon, Christin Linderkamp, Lenka Taylor, Juergen Burhenne, Stefan M. Pfister, Irini Karapanagiotou-Schenkel, Olaf Witt
Journal: Journal of Clinical Oncology (2018)

10535 Background: In preclinical pediatric cancer models, the HDAC inhibitor vorinostat showed significant activity only at higher concentrations compared with those achieved with currently recommended dosing regimens. The aim of this trial was to intra-individually dose escalate to an individual maximum tolerated dose (MTD) in order to increase the likelihood of response whilst keeping toxicity acceptable. Methods: Children 3 – 18 years old with relapsed or therapy-refractory solid tumor, lymphoma or leukemia were eligible. In phase 1 an intra-patient dose (de)escalation was performed until the MTD was reached. After identification of MTD, patients did continue treatment in phase 2 at their individual MTD until progression. Results: Fifty-two patients were enrolled and 50 received treatment. 27/50 patients completed the intra-patient (de)escalation phase 1 part and entered phase 2. A safe starting dose of 130mg/m2/day with weekly increments of 50mg/m2 was determined (maximum: 580mg/m2/day). 46/50 (92%) patients experienced treatment related AEs, in 44 patients (88%) ≥ CTCAE grade 3. Of the patients who reached phase 2, 24/27 patients (89%) experienced treatment related AEs, in 17 patients (63%) ≥ grade 3. Most of the grade 3-4 AEs were reversible hematologic toxicity (mostly thrombocytopenia), fatigue, nutrition and gastrointestinal disorders and weight loss. The median MTD was 280mg/m2/day (range 130 - 580mg/m2/day). Overall response rate (CR + PR + SD) in the phase 2 was 6/27 (22%). 5 patients stayed on treatment for > 12 months receiving doses of 280 – 580mg/m2/day. 3 patients with histological high grade glioma and one with metastasized SETTLE tumor showed PR, one with a medulloblastoma showed prolonged SD. 1 patient was on drug for > 4 years. Conclusions: A safe starting dose of 130mg/m2/day for individual dose escalation with weekly increments of 50mg/m2 was identified. This resulted in higher drug exposure associated with responses and long-term disease stabilization confirming that activity can only be expected at doses higher than currently recommended. The toxicity profile was compatible with published adult and pediatric safety data. PK, PD and biomarker analysis are ongoing. Clinical trial information: NCT01422499.
Demographic profile and treatment results of non metastatic young rectal cancer patients from a teritiary cancer care centre in India.
Authors: Haresh Kunhiparambath, Subhash Gupta, Supriya Mallick, Rony Benson, Dayanand Sharma, Pramod Kumar Julka, Goura Kishor Rath
Journal: Journal of Clinical Oncology (2016)

e15151 Background: Young rectum presents a peculiar situation with patients presenting with adverse histologies and more advanced stage when compared to older rectal cancer patients. Methods: We evaluated patient records of young carcinoma rectum[less than 35 years] treated radically in our unit in the department of Radiotherapy from 2007 to 2013.Patients with early stage disease were taken up for upfront surgery, Patients with locally advanced disease underwent surgery after short course of radiation(25 Gray in 5 fractions)or after the long course radio-chemotherapy(45 Gray in 25 fractions with concurrent capecitabine.Adjuvant chemotherapy(capecitabine plus oxalliplatin*6 cycles) after preoperative radio or radio-chemotherapy was planned was planned for patients with high risk feature (T4 primary, node positive, margin positive).Progression free survival (PFS) was calculated from the time to progression or death. Kaplan Meier method was used for survival analysis. Results: A total of 38 patients of young rectal cancer were registered during this period. Family history of cancer was present in 2 patients. Median age at presentation was 27 years [range 16-34]. Male to female ratio was 1.23:1. The median karnofsky performance status was 70[range 30-100]. 29 [76.3%] patients presented in advanced stage of the disease (stage III and IV). Mucinous, signet, and other poor risk histology was seen in 19 [50%] patients. Median CEA was 12.6 [range 0.9-200]. 34(89.5%) patients recieved radiotherapy(24 patients preop and 10 patients postop) and 24 patients recieved adjuvant radiotherapy. Median follow-up was 10 months. 9 patients had progression of disease. Distant metastasis was the most common type of failure seen in 7 [77.7%] patients. The 1 yearand 3 year progression free survival [PFS] was 74.1 % and 57.1% respectively. Conclusions: There is a higher proportion of poor histology subtypes among young rectal cancer patients when compared to adult patients. The high incidence of poor histological subtypesconfer poor prognosis these patients.
A meta-analysis exploring the role of PET and PET-CT in the management of potentially resectable colorectal cancer liver metastasis.
Authors: Julian Daza Vargas, Natalie Solis, Sameer Parpia, Steven Gallinger, Carol-Anne Moulton, Pablo Emilio Serrano Aybar
Journal: Journal of Clinical Oncology (2018)

3547 Background: It has been proposed that PET alone or combined with CT imaging improves detection of extra-hepatic disease in colorectal cancer liver metastasis (CRCLM). The objective of this study was to determine whether PET/PET-CT has a role in the preoperative workup of patients with potentially resectable CRCLM. Methods: From 2000 to April 2017, MEDLINE, EMBASE, and CENTRAL were searched for randomized and non-randomized studies investigating the use of PET and/or PET-CT in CRCLM. Screening and data collection were performed in duplicate. The primary outcome was overall survival (OS). Secondary outcomes included disease-free survival (DFS), change in surgical management, and futile laparotomy. The quality of the evidence was assessed using GRADE. Random effect models were used to pool treatment effects. Moderate to high heterogeneity was explored via subgroup analyses established a priori. Results: Of 4034 reviewed articles, 22 were included for subsequent analysis. PET/PET-CT did not improve OS (HR 0.94, 95% CI 0.69 – 1.26, I2 = 0%) or DFS (HR 1.01, 95% CI 0.82 – 1.26, I2 = 0%) when used preoperatively to determine surgical candidacy. In subgroup analyses, PET/PET-CT changed surgical management in 8% of cases (95% CI 5 – 11%, I2= 0), and did not reduce futile laparotomies (RR 0.59, 95% CI 0.24 – 1.47, I2= 47%) in randomized studies. In contrast, PET/PET-CT changed surgical management in 20% of cases (95% CI 17 – 22%, I2 = 0) and resulted in fewer futile laparotomies (OR 0.51, 95% CI 0.32 – 0.81, I2 = 0%) in non-randomized studies. Conclusions: The use of pre-operative PET/PET-CT does not improve OS or DFS in CRCLM. In addition, there is moderate to high quality evidence demonstrating it has a minimal impact on planning surgical management, and does not prevent unnecessary surgeries.
Phase I trial of z-endoxifen with estrogen receptor imaging in adults with advanced hormone receptor–positive solid tumors including desmoid and gynecologic tumors.
Authors: Naoko Takebe, Geraldine Helen O'Sullivan Coyne, Shivaani Kummar, Joel M. Reid, Richard Piekarz, Lyndsay Harris, Lamin Juwara, Mary Flanagan Quinn, Nancy Moore, Peter L. Choyke, Esther Mena, Liza Lindenberg, Frank Lin, Matthew P. Goetz, Renee M. McGovern, Howard Streicher, Joseph M Covey, Jerry M. Collins, James H. Doroshow, Alice P. Chen
Journal: Journal of Clinical Oncology (2018)

2516 Background: Differential response to tamoxifen observed in patients (pts) with hormone receptor-positive cancer may be due to variations in tamoxifen metabolism from CYP2D6 genetic polymorphisms that limit exposure to the active metabolite, z-endoxifen (Z). We conducted a phase 1 clinical trial (3+3 design) with estrogen receptor imaging to determine the safety, MTD, and pharmacokinetics (PK) of oral Z. Methods: Adults with refractory gynecologic tumors, hormone-positive breast or other solid tumors, or desmoid tumors were eligible with ECOG performance status of 0-2 and adequate organ functions. Z was administered at 20, 40, 60, 100, 140, 200, 280, and 360 mg q day on a 28-day cycle. Estrogen receptor imaging with 16 alpha-[18F]-fluoro-17 beta-estradiol (FES)-PET was performed before dosing and, if positive, repeated during C1W1. Results: Median age of the 40 pts enrolled was 60 (range 21-80 yr) and 90% were female. MTD was not reached up to the targeted maximum dose of 360 mg/day. Of the 38 pts evaluable for response, 2 (fallopian tube and breast) had partial responses and 9 had 6+ cycles of stable disease. Pts stayed on study for 1-47+ cycles (average, 6 cycles; median, 2.5 cycles); two pts remain on treatment. Grade 3/4 adverse events occurring in ≥5% of pts were hypertension (13%), hyponatremia (8%), hypophosphatemia (8%), neutropenia (8%), dehydration (5%), and elevated ALT (5%). Mean Z plasma levels increased linearly with administered dose. Increases were seen in mean D1 Cmax (68.6 to 1309 ng/mL) and AUC0-24 (1084 to 20546 ng/mL∙hr) between doses of 20 and 360 mg/day. The elimination t½ was 30.6-55.9 hr, based on the AUC accumulation ratio of 2.4-3.9 over the 28-day dosing period. FES-PET from 9 pts with FES-positive lesions demonstrated a 2%-76% reduction in average FES standard uptake values following 2-5 days of Z. Conclusions: We established a targeted maximum dose of 360 mg/day Z and evidence of antitumor activity was observed. Oral Z administration produces Z plasma exposures well above those obtained after therapeutic doses of tamoxifen. Clinical Trial Information: NCT01273168. Supported in part by NCI Contracts CM52206 and HHSN261200800001E. Clinical trial information: 01273168.
Clinical outcomes of patients with lung cancer treated with radiotherapy and ANTI-PD-1 therapy: A multicenter retrospective analysis from GFPC Group.
Authors: Delphine Lerouge, Paul Lesueur, Alexandre Escande, Juliette Thariat, Alexis B. Cortot, Serge Danhier, Enora Vauléon, Isabelle Monnet, Christos Chouaid, Radj Gervais
Journal: Journal of Clinical Oncology (2018)

e21077 Background: Anti-PD-1 therapy with nivolumab has demonstrated improved overall survival (OS) in patients with non-small-cell-lung cancer (NSCLC). Indeed, since CheckMate 017 and 057 results, nivolumab is considered as the standard of care for second line treatment of recurrent/refractory NSCLC. In the setting of advanced/metastatic NSCLC, radiotherapy, whatever its modality, is routinely used, with curative or palliative intention. Many patients receive nivolumab and radiotherapy, concomitantly or not, during the course of their disease. A synergistic effect may occur. However data concerning this therapeutic association for NSCLC are rare. Pending the outcomes of prospective trials we report a large series of NSCLC patients who were treated with any radiotherapy and nivolumab in order to assess toxicity and efficacy. Methods: We retrospectively reviewed records from patients of three French centers, with metastatic or refractory NSCLC irradiated, concomitantly or from six months before to three months after nivolumab. Toxicities and outcomes were analysed. Results: We included 103 patients (144 cranial and extra-cranial irradiated targets). An adverse event (AE) was observed in 62 (60.2%) patients and grade 3-4 AE in 10% of patients. Among them, 9 patients reported 12 grade III-IV nivolumab related side effects,. Patients having received irradiation before nivolumab presented a higher risk of grade III-IV AE in comparison of with patients who received it during or after nivolumab (p = 0.001). One and 2years OS rates were 49.3% and 29.4% respectively whereas 1- and 2-years PFS were 18.8% and 10.2% respectively. Timing of irradiation delivery, before or after/during nivolumab administration was not associated to a better OS or PFS. Patients with nivolumab relative AE had statistically a better OS (p = 0.05) in comparison with patients without anti-PD1 toxicity. Conclusions: The combination of nivolumab with radiotherapy in patients with NSCLC was not associated with an increased risk of severe or unexpected toxicities. This study provides reassuring elements, to propose this association in clinical practice, when palliative irradiation is necessary.
A randomized phase II study of pelareorep (REO) plus docetaxel vs. docetaxel alone in patients with metastatic castration resistant prostate cancer (mCRPC): Canadian Cancer Trials Group study IND 209.
Authors: Bernhard J. Eigl, Eric Winquist, Dongsheng Tu, Sebastien J. Hotte, Christina M. Canil, Richard William Gregg, Muhammad Zulfiqar, Scott A. North, Susan Ellard, Joseph D. Ruether, Lyly H. Le, Ankineedu Saranya Kakumanu, Ashley Theis, Christopher M. Booth, Kylea R. Potvin, Kim N. Chi, Lesley Seymour
Journal: Journal of Clinical Oncology (2017)

5021 Background: Pelareorep (REO) is an oncolytic virus with in vitro and in vivo activity in many cancers, including prostate. It has in vitro synergism with microtubule targeted agents especially taxanes. We undertook a clinical trial to evaluate REO in mCRPC patients (pts) receiving docetaxel. Methods: In this randomized, open-label multicenter phase II study, pts received docetaxel 75mg/m2 on day 1 of a 21-day cycle in combination with REO given as 3x1010 TCID50 IV daily on days 1-5 (arm A), or alone (arm B). The primary endpoint was 12-week lack of disease progression (LPD) rate. Secondary endpoints included objective response rate; survival; circulating tumor cell (CTC) enumeration at 0, 6 and 12 weeks; PSA response rate and biomarkers. Results: Eighty-five pts were randomized. Median age was 69, ECOG performance status (PS) was 0/1/2 in 31%/66%/3% of pts. Bone/regional lymph node/liver metastases were present in 98%/24%/6% of pts. More pts in arm A had poor prognostic factors for survival at baseline (median prognostic index 1.44 vs. 1.29). The median number of cycles delivered for arms A/B was 7/9 (range 1-10 and 1-13). In arm A, 51%/68% of pts received ≥90% of planned dose intensity of docetaxel/REO respectively, vs. 76% of pts for docetaxel in arm B. Adverse events (AE) were as expected for docetaxel therapy but more prevalent in arm A (grade 3 or higher all AEs 80 vs. 74%). A higher rate of grade 4 febrile neutropenia was noted in arm A (7 vs. 0%) but may represent virus related fevers. The 12-week LPD rate was 61% and 52.4% in A/B respectively (p = 0.51). OS was worse in arm A vs. B (HR 1.95; 95% CI 0.94-4.06; p = 0.07 after adjusting for age, PS and baseline prognostic score). There was no difference between arms in CTC favourable status at any timepoint. No survival benefit of REO with D was found in any subset from the biomarker analysis. Conclusions: While the combination of REO with D for patients with mCRPC was tolerable and LPD rate was comparable in both arms, docetaxel dose intensity and survival were inferior and so this combination, as tested, does not merit further study. Clinical trial information: NCT01619813.
Differential expression of human cyclin G1 (CCNG1) in cancer: A novel biomarker in development for CCNG1 inhibitor therapy.
Authors: Joshua Ravicz, Seiya Liu, Shiva Sreenath Andrali, Sandeep K. Reddy, Shankar Sellappan, Bryan Leong, Sant P. Chawla, Frederick L Hall, Erlinda Maria Gordon
Journal: Journal of Clinical Oncology (2018)

e24315 Background: CCNG1 inhibitor therapy, exemplified by DeltaRex-G, a tumor targeted gene vector bearing a cytocidal knock-out CCNG1 gene, has been shown to induce long term (9-12 years) survivorship in patients with metastatic solid tumors and hematologic malignancies. Purpose: To evaluate CCNG1 expression in tumors as a novel biomarker for identification of patients who are likely to benefit from CCNG1 inhibitor therapy. Methods: A qualified immunohistochemical staining protocol was used for enumeration of CCNG1 and Ki-67 nuclear staining cells in 17 tissue types across 15 organs. The significance of differences between the number of CCNG1 and Ki-67 nuclear staining cells in normal versus cancerous tissues were evaluated using paired Student’s t test. Pearson’s coefficient of correlation was used to evaluate the relationship between the number of Ki-67 versus CCNG1 nuclear staining cells. RNA sequence analysis was also used to compare CCNG1 expression in cancerous tissues versus normal tissues from 20 organ sites. Results: Significant differences were found when comparing CCNG1 nuclear staining percentages between analogous healthy and cancerous tissues (p = 0.002, df = 11). The nuclear staining percentages of CCNG1 and Ki-67 share a statistically significant, positive correlation (r = .936977, p < 0.00001). Gene expression, by RNA sequence analysis, of cancerous tissues versus normal tissues was not significantly different but no paired comparisons are currently available. Conclusions: Taken together, these data indicate that CCNG1 expression, obtained from a qualified IHC assay, is enhanced in cancerous tumors compared to their normal analogous counterparts and may be useful in predicting a favorable response to CCNG1 inhibitor therapy in patients with solid and hematologic malignancies. Studies are planned to confirm these results in a Phase 2 basket study of CCNG1 inhibitor therapy for CCNG1 expressing tumors. RNA sequence analysis utilizing paired comparisons of cancerous tumors with their normal counterparts are also proposed.
Margetuximab (M) plus pembrolizumab (P) in ERBB2-amplified PD-L1+ gastroesophageal adenocarcinoma (GEA) post trastuzumab (T).
Authors: Daniel V.T. Catenacci, Haeseong Park, Hope Elizabeth Uronis, Yoon-Koo Kang, Jill Lacy, Peter C. Enzinger, Se Hoon Park, Keun Wook Lee, Matthew C.H. Ng, Philip Jordan Gold, Jennifer Yen, Aleksandra Franovic, Ronan Joseph Kelly, Aisha Wynter-Horton, Daner Li, John Muth, Jan E. Baughman, Sam Hong, Jan Kenneth Davidson-Moncada, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2018)

4030 Background: T + chemo is standard 1st line therapy (tx) for HER2+ GEA patients (pts). However, pts typically progress within 6-8 months, with up to 30% demonstrating loss of HER2 positivity. No HER2 targeted agents have been shown effective in the post-T setting. We report the results of M, a novel anti-HER2 monoclonal antibody + P (anti-PD-1) in HER2+ GEA pts in 2nd line post T progression and describe a biomarker enrichment strategy that compensates for tumor heterogeneity. Methods: HER2+ (pre-T testing) PD-L1-unselected GEA pts were enrolled. Endpoints include safety, objective response rate (ORR) by RECIST, and progression free survival (PFS). Exploratory endpoints include ERBB2 amplification (amp) status pre-M+P tx circulating-tumor DNA (ctDNA) by NGS (Guardant360) and PD-L1 on archival tissue by IHC (22C3 pharmDx). Results: As of 1/10/18, 60 pts were dosed in cohort expansion; 30 in North America (NA), 30 in Asia (A). Tx was well tolerated, with 13% of pts having TRAE ≥ grade 3, 3 drug-related SAEs, and 2 cases of autoimmune hepatitis and 1 pneumonitis. ERBB2 amp was detected by ctDNA in 61% of pts tested, mainly distal gastric cancer (GC) over proximal GEJ pts, and was inversely correlated with acquired driver mutations. PD-L1 was positive in 34% of pts tested, and was independent of clinical metrics but was enriched in ctDNA ERRB2+ pts (41% vs. 33%). Of 57 evaluable pts to date in expansion (30 NA and 27 A), best ORR was 16% and disease control rate (DCR) was 54%. Both ctDNA ERBB2 amp and PD-L1 positivity predicted response (24% vs. 0% [p = .0655] and 36% vs. 5% [p = .0367], respectively). In ctDNA ERBB2+/PD-L1+ pts, which were all GC, the ORR was 57% and DCR 86%. Conclusions: M+P is a well-tolerated regimen with antitumor activity in 2nd line HER2+ GEA. Consistent with prior tissue-based reports, many GEA pts progressing on T have lost ERBB2amp. ERBB2 status by ctDNA NGS post-T could predict response to M+P, particularly in PD-L1+ pts. Our results suggest that M+P has encouraging preliminary activity in patients with advanced GC, and that biomarker selection based on ctDNA ERBB2 and PD-L1 could enrich for the responding population. Clinical trial information: NCT02689284.
Weekly nab-paclitaxel plus carboplatin as neoadjuvant therapy for IIIA-N2 lung squamous cell carcinoma: A prospective phase II study.
Authors: Jian- Quan Zhu, Yu Zhang, Dongsheng Yue, Xiaoliang Zhao, Qiang Zhang, Hui Chen, Changli Wang
Journal: Journal of Clinical Oncology (2018)

e20501 Background: To evaluate the safety and antitumor activity of weekly nab-paclitaxel combined with carboplatin in patients with advanced stage IIIA-N2 NSCLC patients with squamous histology Methods: From April 2015 to August 2017, 36 treatment-naive, pathologically diagnosed IIIA-N2 lung squamous cell carcinoma patients were enrolled and given two cycles of weekly nab-paclitaxel (100mg/m2, day1,8,15 of a 21-day cycle) plus Carboplatin (AUC = 5 at day 1, q3w) as neoadjuvant therapy. Then resectability was assessed and surgery was performed for resectable lesions. Post-operative adjuvant chemotherapy regimens is the combination of Nab-paclitaxel (100mg/m2, qw×6) and carboplatin (AUC 5, Q3W×2); for patients with PD, adjuvant chemotherapy regimen will be changed. The primary objective is the safety and efficacy, and the secondary objectives are quality of life and the role of prognostic biomarker SPARC. Results: Of 36 patients, 3 stopped treatment due to patient decision. 33 were finally evaluated and 1 is still on treatment. Significant tumor volume shrinkage was seen in some patients after the neoadjuvant therapy. 66.7% patients achieved partial response (PR), 21.2% patients achieved stable disease (SD). Disease control (PR +SD) rate was 87.9%. Finally, 23 patients underwent surgical resection, the resectablity rate was 69.7%. 12.1% occurred disease progress and failed to achieve resection, including 3 with local progress and 1 with pulmonary metastatic nodule; Among 22 PR pts, 4 failed to achieve resection, in which 1 was due to heart function, the other 3 due to personal unwillingness. 2 of 7 with stable disease failed to achieve resection; the pathological improvement in T stage and N stage before and after treatment was 81.8% (18/22) and 50% (11/22) respectively. The major adverse event was neutropenia (grade I and II) and no serious AE was found. Conclusions: Nab-paclitaxel in combination with Carboplatin showed promising ORR rate and resection rate in of IIIA-N2 lung squamous cell carcinoma. The regimen could be a new chemo option as the neoadjuvant treatment. PFS and OS data will be reported after follow up completing.