tbuckley/cabot-search huggingface dataset:
Expanded cohort results from CheckMate 016: A phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC).
Authors: Hans J. Hammers, Elizabeth R. Plimack, Jeffrey R. Infante, Brian I. Rini, David F. McDermott, Marc Ernstoff, Martin Henner Voss, Padmanee Sharma, Sumanta Kumar Pal, Albiruni R. A. Razak, Christian K. Kollmannsberger, Daniel Yick Chin Heng, Jennifer L. Spratlin, Yun Shen, Paul Gagnier, Asim Amin
Journal: Journal of Clinical Oncology (2015)

4516 Background: Nivolumab (N), a fully human IgG4 immune checkpoint inhibitor antibody, has shown durable response and encouraging overall survival (OS) in mRCC. Previously in CheckMate 016, N + ipilimumab (I) demonstrated manageable safety and promising antitumor activity in mRCC. Here, we report results from expansion cohorts in this study (NCT01472081). Methods: Patients (pts) with mRCC were randomized to N 3 mg/kg + I 1 mg/kg (N3 + I1), N 1 mg/kg + I 3 mg/kg (N1 + I3) or N 3 mg/kg + I 3 mg/kg (N3 + I3) IV Q3W for 4 doses, then N 3 mg/kg IV Q2W until progression or toxicity. Primary endpoint: safety. Other endpoints: objective response rate (ORR), duration of response (DOR), OS. DOR and OS were assessed by Kaplan-Meier method. Results: Pts randomized to N3 + I1 and N1 + I3 cohorts were expanded to 47 pts per arm; N3 + I3 (n = 6) arm showed early toxicity and did not proceed to expansion. 53% and 47% of pts were treatment naive and previously treated in N3 + I1; 45% and 55% were in N1 + I3. Median (range) follow-up was 34.3 (15.4 – 80.1) wks in N3 + I1 and 31.3 (4.6 – 79.9) wks in N1 + I3. Treatment-related AEs were seen in 88% of pts. Discontinuations for any grade AE occurred in 16% of pts. Grade 3-4 treatment-related AEs occurred in 34% and 64% of pts in N3 + I1 and N1 + I3, respectively; most common: ↑ lipase (13% and 26%), ↑ ALT (4% and 19%), diarrhea (2% and 15%), colitis (0 and 13%), ↑ AST (4% and 9%), and ↑ amylase (4% and 9%). Most common grade 3-4 select AEs were GI and hepatic (N3 + I1, N1 + I3); GI: 2%, 23%; hepatic: 4%, 21%. Efficacy is summarized in the table below. Conclusions: Updated results from expanded cohorts in CheckMate 016 confirm initial safety findings and promising antitumor activity for N + I in pts with mRCC. OS results for N + I in mRCC appear encouraging and support further development of this combination in the first-line setting. Clinical trial information: NCT01472081. N3 + I1 n = 47 N1 + I3 n = 47 OS, mos (range) NR (3.5 – 18.4+) NR (1.1 – 18.4+) Overall ORRa, n (%) 18 (38) 20 (43) Stable disease, n (%) 19 (40) 18 (38) Median DORb, wks (range) NR (4.1+ – 67.1+) 53.9 (6.1+ – 66.0+) Median PFS, wks (range) 30.3 (4.7+ – 72.6+) 36.0 (4.1+ – 77.9+) PFS, 24 wks, % (95% CI) 53 (37 – 67) 64 (47 – 77) aConfirmed response + unconfirmed response; bConfirmed response. NR, not reached.
PARPi in PCa results in decreased availability of DNA repair factors.
Authors: Matthew Joseph Schiewer, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2016)

301 Background: The first described roles for PARP-1 were in the repair of DNA damage and genomic maintenance, however, recent studies have identified PARP-1 as harboring critical context-dependent transcriptional regulatory functions in cancer, including regulating NFkB and HIF function. Our group recently discovered that PARP-1 enzymatic activity is a critical effector of AR function PCa, and assists in regulating AR-driven, PCa-associated phenotypes, including castrate-resistant AR function, tumor growth, and transition to CRPC. Additionally, recent clinical trial data of PARP inhibition as a single agent in advanced cancers has been promising. Given the preclinical and clinical data, pursuing a deeper understanding of the molecular underpinnings of PARP inhibitor action in PCa may yield markers of response and/or rationale for precision medicine. Methods: Hormone therapy-sensitive and CRPC models were transcriptionally profiled in response to PARP inhibition. Pathways were nominated for validation. Bioinformatics approaches were used to compare the PARP-1-sensitive transcritome with publicly available data sets. ChIP-qPCR was performed to examine the effect of PARPi on target genes of the nominated pathways. Patient specimen TMAs were utilized for PAR IHC. PARP inhibition reduced AR and E2F1 target gene expression, as well as significantly decreased expression of DNA repair genes. Both PARP enzymatic activity and the PARP-1-dependent transcriptional program are increased as a function of disease progression. Results: These data indicate that:(1) The PARPi-sensitive transcriptome holds major transcriptional regulatory events beyond AR signaling. (2) E2F1-regulated genes are sensitive to PARP-1 function. (3) The PARPi-sensitive E2F-regulated transcriptome is enriched for DNA repair factors. (4) PARP enzymatic and transcriptional functions are increased during disease progression. Conclusions: Taken together, this study demonstrates that the transcriptional roles of PARP-1 may contribute to the clinical response to PARP-1 inhibitors as single agents. This work was supported by a PCF YI award (to MJS).
Phase I study of amrubicin and cisplatin in previously untreated patients with advanced non-small-cell lung cancer
Authors: N. Yoshimura, S. Kudoh, T. Kimura, S. Mitsuoka, T. Yana, K. Hirata
Journal: Journal of Clinical Oncology (2008)

19119 Background: Amrubicin, a totally synthetic 9-aminoanthracycline, is one of the most active new agents for non- small-cell lung cancer (NSCLC). This is the first report of combination amrubicin with cisplatin in patients with advanced NSCLC. Methods: To determine the maximum-tolerated dose (MTD) and the recommended dose (RD) of amrubicin with a fixed dose of cisplatin, and to assess the toxicity and activity of this combination, we conducted a phase I trial in previously untreated patients with advanced NSCLC. In this study, patients with stage IIIB or IV NSCLC were eligible. Amrubicin, at a starting dose of 30 mg m-2 on days 1, 2, and 3, was combined with a fixed dose of cisplatin 80 mg m-2 on day 1. Chemotherapy was given in a 3-week cycle. Results: In this phase I study, 20 patients were enrolled. Dose-limiting toxicities (DLT) were neutropenia, febrile neutropenia, thrombocytopenia, and elevated creatinine levels. The MTD and RD were estimated to be 30 mg m-2. Overall response rate was 42.1% (95% CI 17.7% to 64.7%), the progression-free survival was 5.5 months (95% CI 4.7–5.7), the median survival time was 16.4 (95% CI 13.1–19.5) months, and 1-year survival rate was 65.2% (95% CI 52.4–78.0) in 17 patients treated at the RD, respectively. Conclusions: This regimen is tolerable and very active against advanced NSCLC in this phase I study, and its efficacy and toxicity should be confirmed in a phase II/III study. No significant financial relationships to disclose.
Bosutinib (BOS) and letrozole (LET) versus LET alone as first-line treatment in postmenopausal women with advanced breast cancer (ABC).
Authors: L. Chow, B. Xu, L. Y. Dirix, B. Moy, E. Leip, N. Bardy-Bouxin, L. Duvillie, T. Sarosiek
Journal: Journal of Clinical Oncology (2011)

614 Background: BOS (SKI-606) is an orally active, dual Src/Abl tyrosine kinase inhibitor. Elevations of Src activity occur in ~60% of breast tumors and correlate with tumor aggressiveness. A prior phase II study of single-agent BOS in patients (pts) with unselected heavily pretreated ABC revealed an overall response rate of 9.4% and 16-week progression-free survival (PFS) rate of 29.8%, with a median PFS of 9.9 weeks. As all responses were seen in pts with hormone receptor–positive (HR+) ABC and no prior hormonal therapy, BOS was combined with LET, a nonsteroidal aromatase inhibitor indicated for 1st- and 2nd-line treatment of postmenopausal women with HR+ ABC. Methods: This randomized, open-label, multicenter, 2-part, phase II, trial evaluated BOS and LET vs LET alone as 1st-line treatment in postmenopausal women with locally advanced or metastatic HR+ BC. Part 1 included a 28-day safety lead-in to confirm the dose for part 2; BOS 400 mg/LET 2.5 mg was administered orally once daily and pts were monitored for toxicity. Results: Sixteen pts participated in part 1 (safety lead-in phase). The most common treatment-emergent adverse events (any grade/grade ≥3) were diarrhea (81%/6%), vomiting (50%/6%), nausea (44%/0), rash (44%/13%), fatigue (25%/0), and dyspnea (25%/0). Grade 3/4 lab abnormalities (≥15% of pts) included increased alanine aminotransferase (ALT; 25%) and aspartate aminotransferase (AST; 19%). Four pts experienced dose-limiting toxicities, including grade 3/4 ALT and AST elevations (n = 2, with 1 case meeting the Hy's law criteria), grade 3 diarrhea and vomiting (n = 1), and grade 3 rash (n = 1); all events resolved upon treatment discontinuation. There was no overall determination of the study's efficacy, specifically PFS, due to early termination of the study. Conclusions: The combination of BOS plus LET was associated with a high rate of transaminase elevations, including 1 Hy's law case. Therefore, the study's risk/benefit was evaluated early in part 1 and subsequently led to early study termination due to an unfavorable risk/benefit ratio. However, given the prior evidence of efficacy of BOS monotherapy, alternative regimens with BOS should be explored for the treatment of ABC.
Whole-liver irradiation with hepatic arterial floxuridine/leucovorin/streptozotocin followed by hepatic arterial floxuridine/leucovorin and chemo-embolization with mitomycin C for patients with metastatic neuroendocrine tumors.
Authors: Mark Shilkrut, Sheela Hanasoge, Daniel Paul Normolle, Edgar Ben-Josef, William D. Ensminger, Theodore Steven Lawrence, Mary Uan-Sian Feng
Journal: Journal of Clinical Oncology (2012)

339 Background: Neuroendocrine tumors metastatic to liver are incurable with limited treatments. We conducted a phase I trial combining hepatic arterial (HA) chemotherapy, chemoembolization and dose-escalated whole liver radiotherapy (WLRT) to determine if the maximum safe dose of 32 Gy in 2 Gy fractions could be achieved. Methods: Patients (pts) with liver metastases from neuroendocrine tumors who failed somatostatin analog therapy were eligible. First, floxuridine (FUDR, 3 mg/m 2 /d) and leucovorin (LV, 300 mg/m 2 /d) were given by continuous hepatic artery infusion for 12 days; streptozotocin (500 mg/m 2 /d) was given over 3 h on days 5, 8 and 10. Concurrent WLRT was prescribed in 2 Gy/day with doses escalated from 24 Gy to 32 Gy using the time-to-event continual reassessment method for dose allocation with a target rate of dose-limiting grade (gr.) ≥ 3 radiation-induced liver disease (RILD) of 10%. 8 weeks later, for pts without RILD and other gr. ≥ 4 toxicities, continuous 72-h infusion with HA FUDR (3 mg/m 2 /d) and LV (300 mg/m 2 /d) was given, followed by chemoembolization with mitomycin C (20 mg) and polyvinyl alcohol foam. Results: 19 pts were enrolled in the trial. 8 pts received 24 Gy, 2 - 26 Gy, 1 - 28 Gy, 2 - 30 Gy and 6 - 32 Gy. 8 pts received only the first part of the treatment, 11 completed the entire protocol. No pts developed dose-limiting RILD; 5 - had gr. 3-4 increased liver function tests (LFT), 4 - had other gr. 4 toxicities after the first part of the treatment, primarily chemotherapy and embolization-related; 3 - had gr. 3 increased LFT, and 1 - had other gr. 4 toxicities after the second part of the treatment. 4 pts (21%) had partial response, 14 (74%) - stable disease and one pt (5%) receiving only part 1 had progressive disease. Median progression free survival for all pts was 20.6 (8.4-45.4) months (m); 15.4 (3.4-67.8) m for pts who received the first part of the treatment only, and 27.9 (8.4 – infinite) m for pts who received both parts of treatment. Conclusions: This study showed that chemotherapy can be safely combined with a full dose of WLRT and subsequent chemoembolization without producing RILD.
Retrospective evaluation of tyrosine kinase inhibitor (TKI)-everolimus (eve) and/or TKI-eve-TKI sequences in metastatic renal cell carcinoma (mRCC): A French survey—The sector study.
Authors: Stephane Oudard, Florence Joly, Lionnel Geoffrois, Brigitte Laguerre, Nadine Houede, Philippe Barthelemy, Marine Gross-Goupil, Vano Yann-Alexandre, Olivier Lucidarme, François Bidault, Nadia Kelkouli, Bernard Escudier
Journal: Journal of Clinical Oncology (2014)

509 Background: In the RECORD-1 study, only 22% of the mRCC patients (pts) received eve in pure 2 nd line. Thus more data in real world are needed. A retrospective French survey, on a large patient population, was designed to evaluate efficacy for the sequence TKI-eve and/or TKI-eve-TKI in mRCC. Methods: Between 10/08 and 10/12, 164 mRCC pts from 26 french centers, who progressed on initial TKI and received eve as 2 nd line were recorded. In these pts, 3 rd line TKI was recorded. Primary endpoint was Duration of Treatment (DT) of each sequence. Secondary endpoints were best radiological response for eve evaluated by 2 independent radiologists, tolerability, dose reduction, overall survival from the start of first TKI (OS). Patients characteristics: Amongst 164 pts, 144 pts with follow-up &gt; 4 months since initiation of eve were evaluated, 59/144 pts received TKI-eve-TKI. Before eve initiation: median age was 65 yrs, most pts were male (70.3%), had clear cell histology (92.3%), had received sunitinib as first TKI (94.4%). Main comorbidities were: hypertension (43.8%), diabetes (15.3%), and hypercholesterolemia (19.4%). At the time of eve initiation, MSKCC classification was good (24.4%), intermediate (61.5%) or poor (14.1%). Results: median DT of eve was 4 months and 21% pts were treated &gt;9 months with 2.9% PR and 67.6% SD by central review. Correlation between response to first TKI and eve was observed. Dose reduction of eve for toxicity was 23.2%. The most common toxicities (all grades) were: stomatitis (25.3%), PNI (13%), fatigue (40.7%), hyperglycemia (9.3%), hypercholesterolemia (17.3%) and hypertriglyceridemia (22.8%). Median duration of TKI-eve sequence was 18 months (IC95%: 15-20), and OS was 36 months (IC95%: 27-56). For TKI-eve-TKI sequence (59 pts), sorafenib was mostly used (76.3%) with dose reduction and clinical benefit rate of 26.7% and 42.2% respectively. Median DT and OS were 24 and 41 months (IC95%: 19-29; 25-57) respectively. Conclusions: In real world experience, for mRCC pts receiving TKI-eve sequence, median DT of eve is 4 months with OS of 36 months which compares favorably with RECORD1 and RECORD 3 trials respectively.
Intensity-modulated radiation therapy (IMRT) with concurrent chemotherapy for anal cancer: A large single-institution experience.
Authors: Melissa Pulfer Mitchell, Mirna Abboud, Christopher H. Crane, Cathy Eng, George J. Chang, Miguel A. Rodriguez-Bigas, John Michael Skibber, Y. Nancy You, Sam Beddar, Sunil Krishnan, Marc E. Delclos, Prajnan Das
Journal: Journal of Clinical Oncology (2012)

661 Background: IMRT for squamous cell anal carcinoma enables sparing of normal tissues potentially leading to decreased toxicity. We evaluated toxicity, local control and survival in anal cancer patients treated with IMRT and concurrent chemotherapy. Methods: Between March 2007 and January 2011, 65 patients were treated at our institution with IMRT and concurrent chemotherapy for newly diagnosed, localized squamous cell carcinoma of the anal canal. Radiotherapy was delivered with a simultaneous integrated boost technique, with dose based on the T stage. The median total dose to the primary tumor was 54 Gy (range 50 – 58.8 Gy) and the median dose to the pelvis was 45 Gy (range 40.5-50.4 Gy) delivered in 25-29 fractions. The concurrent chemotherapy regimens were 5-fluorouracil (5-FU) and cisplatin (75%), capecitabine and oxaliplatin (11%), 5-FU and mitomycin C (MMC) (5%), cisplatin and MMC (2%), capecitabine and cisplatin (2%), capecitabine and MMC (2%), and 5-FU given alone due to other co morbidities (5%). Results: Median age at diagnosis was 57 years (range 35-80). The patient population was 71% female. The percentage of patients with stage I, II, IIIA, and IIIB disease were 12%, 28%, 14% and 42%, respectively. Stage was Tx in 5%. 8% of patients were HIV positive. Grade 3 gastrointestinal toxicity occurred in 9% and moist desquamation beyond the perianal area occurred in 17%. 91% of patients completed treatment without a break. The median follow-up was 19 months (range 1 to 49 months). The 2-year local control was 93%. Four patients had a local recurrence, of which two underwent salvage APR, one refused surgery, and one patient, who also had metastatic disease, received chemotherapy. Four patients developed metastasis. The 2 year distant control was 93%. There were two deaths due to the development of metastatic disease. The 2-year overall and disease-free survival were 96% and 89%, respectively. Conclusions: Concurrent IMRT and chemotherapy was well tolerated with low rates of acute toxicity, and excellent local control, disease-free survival and overall survival. Our results compare favorably with other published data despite a higher proportion of patients with advanced disease.
Analgesic use and risk of renal cell cancer: Results from two prospective cohort studies.
Authors: Mark A Preston, Xuehong Zhang, Rebecca E Graff, Alejandro Sanchez, Steven L Chang, Meir J. Stampfer, Toni K. Choueiri, Kathryn M Wilson, Eunyoung Cho
Journal: Journal of Clinical Oncology (2016)

588 Background: The relationship between the widely used analgesics (i.e., aspirin, other nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen) and risk of total and lethal renal cell cancer remains unclear. Methods: We examined the associations between analgesic use and risk of renal cell cancer overall and by subtypes, in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS). We collected information on aspirin, other non-aspirin NSAIDs, and acetaminophen in 1990 in the NHS and in 1986 in the HPFS, and every 2 years thereafter. We used Cox proportional hazards models, controlling for other known and suspected risk factors, to examine the associations between baseline and duration of use of each analgesic and risk of total renal cell cancer, lethal renal cell cancer (resulted in death due to disease), as well as clear cell renal cell cancer. We pooled results using a random-effects model. Results: During follow-up of 22 years among 77,527 women and 26 years among 45,913 men, we documented 438 cases of renal cell cancer (230 in women and 208 in men), of which 106 were fatal (56 in women and 40 in men) and 300 were clear cell (165 in women and 135 in men). The pooled multivariable relative risks (RRs) for total renal cell cancer were 1.13 (95% CI: 0.91-1.39) for aspirin use, 1.34 (95% CI: 1.03-1.75) for non-aspirin NSAID use, and 1.07 (95% CI: 0.80-1.44) for acetaminophen use. Similar results were observed for lethal renal cell cancer and clear cell renal cell cancer. Importantly, longer duration of non-aspirin NSAID use was associated with an increased risk of renal cell cancer. The pooled (all p-heterogeneity &gt; 0.05) multivariable RRs for total renal cell cancer were 1.23 (95% CI: 0.94-1.62) for non-aspirin NSAID users of 4-10 years and 1.81 (95% CI: 1.21-2.72) for over 10 years. The corresponding RRs were 1.91 (95% CI: 1.04-3.49) and 3.97 (95% CI: 1.46-10.83) for lethal renal cell cancer, and 1.36 (95% CI: 0.99-1.88) and 1.58 (95% CI: 0.94-2.63) for clear cell renal cell cancer. Conclusions: Our findings support a significant positive association between non-aspirin NSAID use and risk of developing renal cell cancer, especially the lethal form.
Safety and feasibility of adjuvant chemotherapy with S-1 in Korean patients with curatively resected advanced gastric cancer.
Authors: Jae Ho Jeong, Min-Hee Ryu, Sung Sook Lee, Baek-Yeol Ryoo, Sang Hong Lee, Kab Choong Kim, Jeong Hwan Yook, Sung Tae Oh, Byung Sik Kim, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2012)

121 Background: Adjuvant chemotherapy with S-1 has been proven effective for patients with curatively resected advanced gastric cancer with D2 lymph node dissection in Japan. We assessed the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients with stage II, III or IV(M0) gastric cancer. Methods: A total of 305 patients with stage II, III or IV(M0) gastric cancer received adjuvant S-1 chemotherapy following curative gastrectomy with D2 lymph node dissection in Asan Medical Center between October 2007 and December 2009. Adjuvant chemotherapy with S-1 was started 3-6 weeks after surgery and it was administered orally twice daily at the dose of 40 mg/m 2 for 4 weeks followed by 2 weeks of rest, every 6 weeks 8 times for 1 year. We retrospectively reviewed the medical records of the patients and evaluated the safety and feasibility of adjuvant S-1 chemotherapy in Korean patients. Results: Among the 305 patients, 248 (81.3%) and 198 (64.9%) patients completed 4 and 8 cycles of adjuvant chemotherapy, respectively. The most common reasons for discontinuation of treatment were adverse event (43.9%) and recurrence (26.2%). Among the 305 patients, 75 (24.6%) patients required dose reduction because of toxicities. The most common grade 3/4 toxicities were neutropenia (12.8%), diarrhea (5.3%), abdominal pain (3.8%), and anemia (3.3%). Multivariate analysis showed that total gastrectomy (H.R. 2.50; 95% C.I. 1.32-4.72, p=0.005) and female gender (H.R. 1.95; 95% C.I. 1.03-3.66, p=0.039) were independent risk factors for grade 3/4 hematologic toxicities, and old age (&gt;65 years) (H.R. 2.92; 95% C.I. 1.50-5.69, p=0.002) was an independent risk factor for grade 3 non-hematologic toxicities. Conclusions: Adjuvant chemotherapy with S-1 for 1 year was safe and feasible in Korean patients. Old age, female gender, and total gastrectomy were independent risk factors for severe toxicities of adjuvant S-1 chemotherapy.
Perceptions of caregivers on the participation of cancer patients into clinical trials.
Authors: A. T. Lera, M. C. Miranda, P. Santi, G. Brito, P. Prestes, M. Oliveira, A. Del Giglio, R. P. Riechelmann
Journal: Journal of Clinical Oncology (2011)

6040 Background: The accrual rate of patients into cancer clinical trials has been consistently low. Among the barriers to trial enrolment, the influence of caregivers on patients’ decision to participate has been scantily evaluated. We aimed to understand the perceptions of caregivers on patient enrollment into clinical trials. Methods: Caregivers of three groups of cancer patients (40 cancer survivors, 40 metastatic patients under chemotherapy treatment and 40 patients who were receiving supportive care exclusively) completed a questionnaire about demographic data, their relationship with the patient under their care, their knowledge about clinical trials and how they perceived clinical trial participation by such patients. A visual analogue scale (VAS; zero= no influence, 10=maximum influence) was also completed by caregivers to self-measure their influence on the participation of cancer patients into clinical trials. Summary statistics were used to report the results. Results: 120 caregivers took part in this cross-sectional survey: 75% were female, more than half did not have an educational degree, they were either married to (41%) or children (27%) of patients, and spent a median of 6.2 days per week with the patient. 91(76%) were unaware of clinical trials and only 16 (13%) patients had participated in a clinical trial. 85 (71%) caregivers were favorable of patients participating in clinical trials; although, this number dropped to 66 (55%) when the trial was placebo-controlled. Sixty percent of caregivers self-reported moderate to strong influence on patient decision to clinical trial enrollment (scored at least 7 points in VAS). While no difference among the patient groups was seen regarding the influence of caregiver on trial participatation, caregivers of cancer survivors were less likely to accept trial participation than other groups (p=0.06). Conclusions: Caregivers of cancer patients have a favorable opinion toward clinical trial participation and have a strong influence on patients’ decisions. Educational actions focused on caregivers could improve patient enrollment into cancer clinical trials.