tbuckley/cabot-search huggingface dataset:
Predictive value of phase I trials for safety and final approved dose in later trials: Analysis of 33,845 patients.
Authors: Denis Leonardo Fontes Jardim, Kenneth R. Hess, Patricia LoRusso, Razelle Kurzrock, David S. Hong
Journal: Journal of Clinical Oncology (2013)

2509 Background: Phase I trials (Ph1) use data efficiently from a small number of patients (pts) to define a maximum tolerated dose (MTD) and the safety profile of new agents. It is unclear how well these trials perform in predicting the future approved dose of agents and in assuring the safety of pts in later trials. Here we compared data obtained from Ph1 and registration trials of the respective agents. Methods: We searched the US Food and Drug Administration (FDA) website for drugs approved in non-pediatric cancers between Jan. 1990 and Oct. 2012. Recommended phase II dose (R2PD), dose-limiting toxicities (DLTs) and grade (G) 3 and 4 adverse events from Ph1 were compared with doses and safety in later trials listed on updated package inserts. Proportions from independent groups were compared using the chi-squared test. Multiple logistic regression analysis adjusted these comparisons for potentially confounding factors. Results: A total of 78 Ph1 (3,499 pts) and 88 later trials (33,845 pts) were included. In 60% (n=50) of 84 matched trials in the dose comparison analysis, the dose from the later trial was the RP2D (often derived from the MTD) from a Ph1. In a multivariable analysis, Ph1 of oral drugs were more predictive of the final approved dose (78% adopting the RP2D oral vs. 43% IV drugs, p=0.011). Other Ph1 characteristics (number of pts, dose levels and tumor type) had no influence on the odds of adopting the RP2D. 55% of phase I DLTs were among the 4 most frequent high-grade events in later trials, with a higher frequency for DLTs of cytotoxic agents (p=0.061). Of the 525 clinically significant toxicities in later trials, 70% (n=369) were described in Ph1. There was a clear relationship (p=0.0032) between increasing the number of pts in the Ph1 (up to 60) and the ability to describe future clinically relevant side effects. Among 28,597 pts in later trials with available data the death rate that was possibly related to drug was 1.48%. Conclusions: Dosing based on Ph1 was associated with a low toxicity-related death rate on later trials. The ability to predict clinically significant toxicities correlates with the number of pts on the initial Ph1. However, the final dose in later trials was the exact RP2D of the Ph1 in only 60% of cases.
GAIN-(L): Efficacy and biomarker findings of RG7160 (GA201), a novel, dual-acting monoclonal antibody (mAb) designed to enhance antibody-dependent cellular cytotoxicity (ADCC), in combination with first-line cisplatin and pemetrexed in metastatic nonsquamous NSCLC.
Authors: James F. Spicer, Enriqueta Felip, Lionel Bosquée, Vanesa Gregorc, Iker Lopez Calderero, Pablo Martinez, Ana Montes, Cristina Sorlini, Marion Gabriele Ott, Sophie Golding, Luisa Mariconti, Maria Longauer Banholzer, Alexandre Passioukov, David Carlile, Luigi Manenti, Luis Paz-Ares
Journal: Journal of Clinical Oncology (2012)

7544 Background: GA201, a humanized, engineered IgG1 anti-Epidermal Growth Factor Receptor (EGFR) mAb designed to enhance ADCC, has shown promising clinical activity in phase I and in the neoadjuvant treatment of head and neck cancer. This phase Ib study (NCT01185847) aimed to determine the safety, pharmacokinetics (PK), activity and recommended phase II dose (RP2D) of GA201 in combination with chemotherapy in non-squamous NSCLC. Methods: Successive cohorts received GA201 1000 mg or 1400 mg (IV d1, d8 then 2-weekly (q2W)) in combination with chemotherapy at standard doses. Data cut off was 7 months after enrolling the last patient. Results: 14 patients (4 female) with performance status 0-1 were enrolled. No maximum tolerated dose was reached. Most common adverse events (AEs – all grades) included rash (100%), hypomagnesaemia (71%), infusion-related reactions (64%), mucosal inflammation (57%) and anemia (50%). AEs of ≥ grade 3 included rash (71%), skin fissure (21%), dry skin (14%), paronychia (14%), and asthenia (14%). Median timeto improvement of rash grade 3 was 11 days. AEs led to dose reduction for 4 patients and discontinuation for 1 patient. There were 6 confirmed partial responses (43%, 5 in 1400 mg cohort) and 7 patients (50%) with stable disease &gt;=9 weeks. Duration of response ranged between 5 and 42 weeks (3 patients still ongoing). Preliminary biomarker analysis shows a correlation between tumor-infiltrating CD16+ immune cells and target lesion shrinkage at first tumor assessment [R(spear)=-0.65 (p=0.02)]; no apparent correlation between EGFR H-score and response was found. PK data supports 1400 mg as the RP2D (d1, d8 then q2W). Conclusions: The RP2D of GA201 in combination with chemotherapy was established to be 1400 mg. The incidence of EGFR associated rash was high and guidelines to reduce its severity were implemented with a noted improvement in tolerability. Promising antitumor activity was observed. Biomarker data support the mode of action of GA201 via ADCC. A randomized phase II trial of this combination is ongoing and fully recruited.
An exploratory study of radium-223 and vascular endothelial growth factor targeted therapy (VEGF TT) in patients (pts) with metastatic renal cell carcinoma (mRCC) and bone metastases (BM).
Authors: Rana R. McKay, Kathryn P. Gray, Laura Polacek, Mark M Pomerantz, Katherine M. Krajewski, Heather Jacene, Joaquim Bellmunt, Dror Michaelson, Lauren Christine Harshman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2017)

466 Background: BM frequently occur in pts with mRCC and are associated with worse survival. The primary aim was to investigate the effect of radium-223 with VEGF TT on bone turnover markers (BTMs) in mRCC pts with BM. Methods: Pts were stratified into cohort 1 (C1) if treatment (tx) naive (n=15) to receive pazopanib 800 mg daily or cohort 2 (C2) if previously treated (n=15) to receive sorafenib (SOR) 400 mg twice BID and could escalate to 600 mg BID at progression. All pts received radium-223 55 kBq/kg every 4 weeks x 6. A safety run-in was performed after 6 pts per cohort completed 2 cycles with criteria to halt enrollment if grade ≥3 tx-related adverse events (TRAEs) were observed in ≥80% of pts. Herein, we report the results of the safety run-in and early safety, biomarker, and imaging data for C2. Results: In the safety run-in, 5/12 (42%) pts experienced TRAEs including anemia, fatigue, liver test elevation, amylase elevation, rash, hand-foot-syndrome, and hypertension, and therefore enrollment continued. In C2, most pts had clear cell mRCC (n=10, 67%) and 47% (n=7) had liver metastases. 60% (n=9) received ≥3 prior txs. At the time of analysis, 8 (53%) pts discontinued tx with both agents for progression and 1 (7%) for toxicity. 5 pts (33%) received 6 doses of radium-223 and 2 (13%) remain on tx. 4 pts (27%) had SOR reductions and 4 (27%) had escalations. 5 pts (33%) had grade 3 TRAEs. Changes in BTM were assessed (Table). 33% of pts (n=5) had stable disease by RECIST, 27% (n=4) by Positron Emission Tomography Response Criteria in Solid Tumors, and 40% by MD Anderson Bone Response Criteria at first response assessment (FRA). Conclusions: Early data suggests that tx with radium-223 and SOR is safe and feasible. Tx resulted in early declines in BTM. Longer follow-up is needed to characterize the safety and effect on BTM. Clinical trial information: NCT02406521. [Table: see text]
Abstract 418: Mdm2 E3 Ligase-mediated Ubiquitination of Histone Deacetylase 1 in Vascular Calcification
Authors: Hyun Kook, Duk-Hwa Kwon, Gwang Hyeon Eom, Sera Shin, Hosouk Joung, Nakwon Choe, Yoon Seok Nam, Taewon Kook, Hyung Seok Kim, Yong Sook Kim, Jeong-Tae Koh, Nacksung Kim, Kwang Il Nam
Journal: Circulation Research (2015)

Vascular calcification (VC) often associates with many cardiovascular and metabolic diseases. Although VC is the cause of high morbidity and mortality, molecular mechanisms have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity enhanced VC in vivo and in vitro . HDAC1 protein was reduced in cell and animal calcification models and in human calcified coronary artery and this reduction preceded VC. Calcification stresses induced MDM2 E3 ligase, which resulted in HDAC1 K74 ubiquitination. Forced expression of MDM2 enhanced VC, whereas loss of MDM2 blunted it. A decoy peptide spanning HDAC1 K74 prevented VC. These results demonstrate a previously unknown ubiquitination pathway as well as the involvement of HDAC1 in VC. Our results suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.
<i>SOD2</i> rs4880 CT/CC genotype to predict poor survival for Chinese gastric cancer patients received platinum and fluorouracil based adjuvant chemotherapy.
Authors: Zhi Xu, Yi Chen, Nikki Lee, Meilin Wang, Jinfei Chen
Journal: Journal of Clinical Oncology (2015)

11037 Background: Adjuvant chemotherapy is a standard therapy for gastric cancer patients, however, treatment response is quite heterogeneous. Molecular biomarkers will be highly valuable to guide the therapy. The antioxidant enzymes superoxide dismutase 2 (SOD2) and glutathione S-transferase pi 1 (GSTP1) are involved in oxidative stress and drug detoxification, which modulate the efficacy of anticancer drugs. Here, we investigated the clinical associations of two single nucleotide polymorphisms of SOD2 and GSTP1 in stage II-III postoperative gastric cancer patients. Methods: SOD2 rs4880 and GSTP1 rs1695 were genotyped in 207 patients received postoperative platinum and fluorouracil based chemotherapy and 304 patients who did not. The genotyping were examined in DNA samples extracted from paraffin-embedded tumor tissue. Association of the 2 SNPs with each clinicopathologic feature was analyzed using the Pearson chi square test. Gastric cancer-specific overall survival was analyzed using Kaplan-Meier curves and log-rank tests. Multivariate Cox regression analyses of these SNPs also were performed. Results: SOD2 rs4880 CT/CC significantly associated with decreased median overall survival time of 23 months when compared to the TT genotype (mean overall survival time of 65.2 months, P= 0.002) only for patients received adjuvant chemotherapy. Stratification analysis showed SOD2 rs4880 CT/CC affected most significantly the clinical outcome for patients with tumor arising at gastric body (HR, 5.707, P= 0.002), well to moderately differentiated adenocarcinoma (HR, 4.900, P< 0.001), tumor of intestinal type (HR, 4.398, P< 0.001), or tumor size less or equal to 5 cm (HR, 2.490, P= 0.004); while GSTP1 rs1695 GA/GG was significant decreased overall survival time among patients with tumor arising at fundus or cardia (HR, 3.001, P= 0.004), or mucinous or signet-ring cell carcinoma (HR, 4.750, P= 0.042). Conclusions: The present study suggested the two polymorphisms would affect the adjuvant chemotherapy outcome in specific subtype of gastric cancer. SOD2 rs4880 could be used as a biomarker to predict the prognosis and response to therapy.
Curcumin for radiation dermatitis: A randomized, double-blind, placebo-controlled clinical trial of 30 breast cancer patients.
Authors: Julie L. Ryan, Charles E Heckler, Marilyn N Ling, Jacqueline P Williams, Alice P Pentland, Gary R. Morrow
Journal: Journal of Clinical Oncology (2012)

9027 Background: Radiation dermatitis occurs in approximately 95% of patients receiving radiation therapy for cancer and often leads to pain and treatment delays. There is no standard treatment with demonstrated effectiveness for the prevention of radiation dermatitis. We conducted a randomized, double-blind, placebo-control clinical trial to assess the efficacy of curcumin, a potent antioxidant and anti-inflammatory component of turmeric, to reduce radiation dermatitis in 30 breast cancer patients. Methods: Eligible patients included adult females with non-inflammatory breast cancer or carcinoma in situ prescribed radiation therapy without concurrent chemotherapy. After randomization, patients took four 500 mg capsules of curcumin or placebo three times daily throughout their course of radiation therapy (total daily dose = 6.0 g). Weekly assessments included Radiation Dermatitis Severity (RDS) Score, presence/absence of moist desquamation, erythema measure, and McGill Pain and Symptom Inventory (SI) questionnaires. Results: The 30 evaluable patients were white (90%; mean age = 58.1 years) with ER + PR + breast cancer (76.7%) who did not have total mastectomy (90%) or chemotherapy prior to start of radiation therapy (56.7%). No significant differences were observed between arms for demographics, compliance, erythema, pain, symptoms, or radiation skin dose. Standard pooled variances t-test showed that curcumin reduced RDS at end of treatment compared to placebo (mean RDS = 2.6 vs 3.4; p=0.008). Fisher’s exact test showed that curcumin significantly reduced the presence of moist desquamation at the end of radiation therapy (28.6% vs. 87.5 %; p=0.002). Repeated measures analysis confirmed divergence of RDS between curcumin and placebo arms at Week 5. Conclusions: Oral curcumin, 6.0 g daily during radiation therapy, reduced radiation dermatitis severity and moist desquamation in breast cancer patients. A multisite CCOP trial (N=700) is underway to confirm the effectiveness of curcumin to reduce radiation dermatitis severity during various radiation therapy regimens for breast cancer. Support: IND 75,444, Dermatology Foundation, KL2 RR024136, NCI PHS 1R25CA10618.
Integrating the patient (pt) voice with clinician reports to identify cancer-specific subsets of symptomatic adverse events (SymAE).
Authors: Jim Shaw, Rebecca Speck, William Lenderking, Caroleen Quach
Journal: Journal of Clinical Oncology (2017)

155 Background: The Pt-Reported Outcomes Version of the Common Terminology Criteria for AE (PRO-CTCAE) was developed for pts to report on the frequency, severity, and interference of SymAE. A study was conducted to identify a hepatocellular carcinoma (HCC)-relevant subset of the PRO-CTCAE's 124 items to enhance evaluation of SymAE in HCC trials and long-term effects in survivorship. Methods: Qualitative and quantitative data were collected from medical oncologists specializing in HCC and pts diagnosed with HCC stratified by Child-Pugh class and treatment. Oncologists were asked about HCC diagnosis, treatment, and SymAE and provided ratings (ranging from 0 = unimportant to 10 = very important) of the following: 1) importance to pts of 34 prevalent SymAE from past HCC trials (all phases); 2) importance to pts of each PRO-CTCAE item; and 3) their own perceived importance of each PRO-CTCAE item with regard to tolerability. Pts were asked about their diagnosis, treatment, and experience of SymAE after which they completed the PRO-CTCAE and were debriefed on the importance of each item. Results: Four medical oncologists from Spain, Taiwan, Korea, and Hong Kong with ≥ 20 years of experience completed interviews. SymAE from prior trials rated highly important to pts (mean rating across oncologists ≥ 7) included hand-foot syndrome, diarrhea, fatigue, decreased appetite, rash, vomiting, and weight loss. PRO-CTCAE items rated highly important to pts included diarrhea, vomiting, shivering or shaking chills, hand-foot syndrome, rash, fatigue, difficulty swallowing, and loss of control of bowel movements. Items rated highly for tolerability included diarrhea, shivering or shaking chills, and hand-foot syndrome. Pt interviews (planned up to 24) are ongoing. Conclusions: Oncologists identified 10 clinically relevant items from sponsor SymAE data and the PRO-CTCAE for use in HCC trials. Findings from pt interviews will compare provider and pt perspectives about SymAE and strengthen the set of selected items. Combining clinician and pt ratings with clinical trial data may be a promising method for identifying cancer-specific PRO-CTCAE item sets for use throughout the cancer care continuum.
Priorities for Public Health Spending—Reply
Authors: Ezekiel J. Emanuel
Journal: JAMA (2017)

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Crizotinib in patients with advanced ROS1-rearranged non-small cell lung cancer (NSCLC). Preliminary results of the ACSé phase II trial.
Authors: Denis Moro-Sibilot, Laura Faivre, Gerard Zalcman, Maurice Pérol, Fabrice Barlesi, Josiane Otto, Isabelle Monnet, Alexis B. Cortot, Marie Wislez, Hervé Lena, Julien Mazières, Xavier Durando, Sylvie Lantuejoul, Isabelle Rouquette, Anne McLeer Florin, Gilbert Ferretti, Natalie Hoog Labouret, Frederique Nowak, Marta Jimenez, Gilles Vassal
Journal: Journal of Clinical Oncology (2015)

8065 Background: Molecular alterations of crizotinib (crz) targets (ALK, MET, ROS1) are found in a wide range of malignancies. To avoid uncontrolled off-label use and allow for a nationwide safe access to crz for patients (pts) with an ALK, MET or ROS1 positive (+) tumor, the French National Cancer Institute (INCa) launched the AcSé program, funding both access to tumor molecular diagnosis and an exploratory multi-tumor 2-stage design phase II trial. We report the preliminary results of the ROS1+ NSCLC cohort. Methods: ROS1 status was determined in 28 regional INCa molecular genetic centers by break-apart FISH assays. Patients with ROS1 rearrangements, progressing after at least one standard treatment (including a platinum-based doublet, unless pts were considered as unfit for chemotherapy) were proposed to receive crz 250 mg BID. Responses were centrally assessed using RECIST v1.1. The objective response rate (ORR) and disease control rate (DCR) were assessed every 8 weeks. Results: From Aug. 5, 2013 to Dec. 12, 2014, 34 pts with ROS1+ NSCLC were enrolled out of 37 expected pts. 32 pts had received crz, including 3 recently enrolled pts, leading to 29 pts with clinical information. Median age: 62 years (range 33–81), 69% females, 93% non-squamous histology, and 93% metastatic disease at study entry. Median number of prior treatments: 2 (range 1 –12). Twenty one pts were still on treatment at the cut-off date, 8 have stopped crz (5 PD, 2 adverse events (AEs), 1 death). Among the 24 pts evaluable for response at 8 weeks, we observed 1 CR, 14 PR, 6 SD and 3 PD, leading to ORR = 63% [95% CI:41-81], and DCR = 88% [68-97]. DCR at 6 months was 53% and disease control was achieved in 8/15 evaluable pts. Crz was well tolerated with only 9 grade ≥ 3 AEs or SAE. Most common AEs, mainly grade 1, were visual disorders (62% of pts), peripheral edema (55%), diarrhea (51%), nausea (41%), and elevated transaminases (51%). Conclusions: Crz was well tolerated and achieved a robust treatment response rate in ROS1+ NSCLC. These results underline the interest of integrating ROS1 in biomarkers routine screening. Survival data and duration of response will be presented. Clinical trial information: NCT02034981.
Clinical characteristics of <i>KRAS</i> mutations in NSCLC and their impact on outcomes to first-line chemotherapy.
Authors: Mohit Butaney, Jennifer Porter, Neal Ian Lindeman, Pasi A. Janne, Michael S. Rabin, J Paul Marcoux, Bruce E. Johnson, David Michael Jackman
Journal: Journal of Clinical Oncology (2012)

7588 Background: KRAS is one of the most commonly mutated oncogenes in non-small cell lung cancer (NSCLC). While the impact of EGFR mutations and EML4-alk translocations has been well-described, there is limited information about the impact of these somatic mutations on response to chemotherapy. Methods: We retrospectively reviewed the demographics and clinical outcomes of patients with KRAS mutations and compared these to patients who were KRAS wild-type (WT). Eligible pts received 1st-line IV chemo for stage IV NSCLC at DFCI and had known information about both KRAS and EGFR status. Since the biology and impact of EGFR mutations on response to chemo is well-described, we excluded such pts from the analysis. The primary endpoint was progression-free survival (PFS) with first-line chemo; secondary endpoints included radiographic response rate (RR) and overall survival (OS). Results: Between 2/05 and 8/11, there were 63 eligible KRAS pts and 97 eligible WT pts. The groups were similar in age (median 65yrs in both groups), % female (K 62, WT 54) race (K 89% white/6% black, 5% other; WT 86% white,/6% black/8% other), histology (K 90%adeno/8% NSCLC NOS; WT 86% adeno/9%NSCLC NOS), and % of pts receiving 1/2/3 agents in 1 st line (K 11/56/33; WT 18/53/30). KRAS pts were less likely to be never or light smokers (4% vs 33% for WT). Nonsmokers were more likely to harbor KRAS transition rather than transversion mutations (3 transition, 1 transversion), while the converse held for smokers (51 transversions, 8 transitions). Median PFS was similar for KRAS vs WT (K .65 vs WT 4.8 months, p=0.81). RR (29% for both groups), disease control rates (K 73% vs WT 78%), and median OS (K 13.5 vs WT 12.1 months, p=.525) were also similar. Outcomes of KRAS pts to 2 nd line chemotherapy (PFS 2.2, OS 8.6) are similar to those seen for WT patients in this setting. There was no significant difference in outcomes based on gender, smoking status, drug received (pemetrexed-based vs taxane based), or specific KRAS genotype. Conclusions: Pts with KRAS mutations experience similar outcomes to standard chemotherapy as those who are wild-type for EGFR and KRAS. Going forward, these data can serve as a reference for control arms of KRAS-specific randomized trials.