bluuebunny/crossref_metadata_2025 huggingface dataset:
Four versus five chemotherapy courses in patients with low risk acute myeloid leukemia: A Children’s Oncology Group report.
Authors: Getz Kelly D. , Alonzo Todd Allen , Sung Lillian , Meshinchi Soheil , Gerbing Robert B , Raimondi Susana , Hirsch Betsy A , Kahwash Samir B , Choi John , Kolb E. Anders , Gamis Alan S. , Aplenc Richard
Published: September 2018

10515

Background: For pediatric patients with low risk (LR) acute myeloid leukemia (AML), the Children’s Oncology Group (COG) trial AAML1031 used a 4-course chemotherapy backbone consisting of two induction courses of cytarabine/daunorubicin/etoposide, a third course of cytarabine/etoposide and a fourth course of cytarabine/mitoxantrone. The prior COG trial, AAML0531, included the same four courses plus a fifth course of high dose cytarabine. Removal of course 5 from AAML1031 was based in part on prior studies that suggested no benefit from a fifth course. Methods: We compared overall survival (OS), disease free survival (DFS), and relapse risk (RR) for LR patients receiving four versus five chemotherapy courses in a pooled analysis of comparable patients treated on AAML0531 and AAML1031. LR was defined as the presence of inv(16)/t(16;16) or t(8;21) cytogenetic features, NPM1 or CEBPA mutations, or MRD < 0.1% post-Induction I in those with no high risk features. AAML0531 patients assigned to gemotuzumab were excluded. Follow-up for outcomes began at the start of course 4. Cox (OS and EFS) and risk (RR) regressions were used to estimate unadjusted hazard ratios (HR) comparing outcomes for patients who received only four versus five chemotherapy courses. Start of a fifth chemotherapy course was assessed as a time-varying exposure in all analyses to avoid exposure misclassification. Results: A total of 921 LR patients (225 from AAML0531, 696 from AAML1031) were included; 191 (21%) received a fifth course. There were no significant differences in distributions of sex, age, race, or ethnicity between patients treated with four or five courses. Median times to absolute neutrophil count and platelet count recovery after course 4 were also comparable. Patients who received only four courses had significantly lower OS (HR = 1.83, 95% CI: 1.22-2.74, p = 0.003), DSF (HR = 1.49, 95% CI: 1.13-1.97, p = 0.005), and higher RR (HR = 1.42, 95% CI: 1.08-1.88, p = 0.013) compared to those who received five courses. Conclusions: Removal of a fifth cytarabine-containing course appears to result in worse OS, DFS, and RR in pediatric patients with LR AML. Multivariable analyses to further refine the estimates are ongoing.
Long-term incidence of venous thromboembolism (VTE) among survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Madenci Arin L , Weil Brent , Liu Qi , Gibson Todd M. , Yasui Yutaka , Leisenring Wendy M. , Howell Rebecca M. , Tinkle Christopher , Nekhlyudov Larissa , Diller Lisa , Armstrong Gregory T. , Oeffinger Kevin C. , Weldon Christopher Bertero
Published: September 2018

10562

Background: This study aimed to estimate the incidence of late-occurring VTE among survivors of childhood cancer, and to identify associated demographic and clinical factors that define high-risk subgroups for potential screening and prevention. Methods: Using data from CCSS, a multi-institutional, longitudinal cohort of 5-year survivors of childhood cancer (diagnosed 1970-1999) and their siblings, the primary endpoint of self-reported late VTE (occurring ≥5 years after diagnosis) was estimated using multivariable piecewise exponential models adjusted for age, sex, and race. Generalized estimating equations accounted for potential within-family correlation where applicable. Results: Among 23,601 survivors and 5051 siblings, the incidence of VTE was 1.15 and 0.48 events per 1000 person-years, respectively. For survivors, median age at last follow-up was 28.6 years (range 5.6-58.3) and median follow-up time from diagnosis was 21.2 years (range 5.0-39.3). The adjusted rate ratio (RR) for survivors compared to siblings was 2.2 (95% confidence interval [CI] = 1.7-2.8, P< 0.01). Among survivors, risk factors for VTE included BMI≥30kg/m2 (ref. BMI 18.5-24.5; RR = 1.5, CI = 1.2-2.0, P< 0.01), increasing number of severe or life-threatening (i.e. CTCAE grades 3 or 4) non-VTE chronic conditions (ref. 0 conditions; 1-2 conditions: RR = 2.5, CI = 2.0-3.1, P< 0.01 ; ≥3 conditions: RR = 3.5, CI = 2.5-4.9, P< 0.01), and cancer recurrence or second malignant neoplasm (RR = 3.5, CI = 2.7-4.6, P< 0.01). Incidence of late VTE was associated with increased subsequent mortality, independent of non-VTE chronic conditions (RR 2.2, 95% CI = 1.7-2.8, P< 0.01). Conclusions: Survivors of childhood cancer remain at increased risk for VTE across their lifespan. While typically not causal, late VTE was associated with subsequent mortality. Care providers should be aware of this increased risk and consider interventions that target modifiable co-morbidities such as obesity. Surveillance and education should be directed toward high-risk survivors.
Choice of treatment and adherence to international ESO-ESMO (ABC) guidelines in HR+/HER2-ve metastatic breast cancer (MBC) patients (pts).
Authors: Cazzaniga Marina Elena , Mustacchi Giorgio , Romagnoli Emanuela , Montemurro Filippo , Caporello Paola , De Laurentiis Michele , Riccardi Ferdinando , Turletti Anna , De Angelis Claudia , Graziano Vincenzo , Livi Lorenzo , Del Mastro Lucia , Beano Alessandra , Garrone Ornella , Biganzoli Laura , Pronzato Paolo , De Placido Sabino ,   On Behalf of GIM 13-AMBRA Study Group
Published: September 2018

1057

Background: ESO/ESMO recently developed consensus guidelines for MBC treatment, potentially applicable worldwide. Aim of the present analysis is to verify the adherence to ABC recommendations for HR+ve MBC in the context of the AMBRA study. Methods: AMBRA is a longitudinal cohort study, aiming to describe the choice of first and subsequent lines of treatment in HER2-ve MBC pts receiving at least one Chemotherapy (CHT) (SABCS 2016, P5-15-07 & P5-14-09). For the present analysis, we selected 6 statements from the ABC1 & ABC2 Conferences, comparing them with the clinical choices of 1st-line therapy in all evaluable cases. Results: So far, 791/1500 pts have been registered into the study, 673 of them (85%) with HR+ MBC. Main characteristics are: N+=422 (62.2%), adjuvant chemotherapy=288 (42.4%), median DFI=70 months. 26 pts were excluded due to change into HR-ve (26; 3.8%). Endocrine Therapy (ET) was the 1st-line of treatment in 187/647 (27.8%), CHT in 310 (47.9%) and CHT followed by ET in 135 (20.8%). Viscera was the main site of disease in 328 pts (48.7%): 56 (17%) received ET, 209 (63.7%) CHT alone, the remaining CHT followed by ET. Median DFI was similar in all the 3 groups. Selected recommendations and percentages of adherence are reported in the table below. Conclusions: The adherence to clinical recommendation about the use of ET as 1st-line treatment in HR+ pts is very low; a potential bias could be due to the selection of the study population. Visceral disease appears to be often a key factor for selecting CHT as 1st-line treatment. In pts receiving ET, the recommendation to use AIs, TAM or F is transposed in almost all the cases. [Table: see text]
Treat ER+ight: Canadian prospective observational study in post-menopausal HR+HER2- advanced breast cancer women—First interim analysis (IA).
Authors: Ferrario Cristiano , Califaretti Nadia , Doyle Catherine , Dent Susan Faye , Roy Josee-Anne , Perri Sabrina R. , Chia Stephen K. L.
Published: September 2018

1067

Background: Treat ER+ight is the first Canadian real-world study enrolling patients (pts) previously exposed to NSAI therapy and currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (ET+TT). Methods: This first planned IA describes baseline parameters and adverse event (AE) prevention strategies adopted by 16 centers since Feb 2016 upon enrolling pts initiating ET or ET+TT. Results: See Table.Conclusions: This IA suggests that pts initiating ET+TT are younger, have a better ECOG status, mostly visceral disease and receive more prophylactic/proactive AE prevention therapies. Insights into real-world dosing and sequence will be presented. Clinical trial information: NCT02753686. [Table: see text]
Immune microenvironment in brain metastases of breast cancer.
Authors: Ogiya Rin , Niikura Naoki , Kumaki Nobue , Yasojima Hiroyuki , Iwasa Tsutomu , Kanbayashi Chizuko , Oshitanai Risa , Tsuneizumi Michiko , Watanabe Ken-ichi , Matsui Akira , Fujisawa Tomomi , Saji Shigehira , Tokuda Yutaka , Masuda Norikazu , Iwata Hiroji
Published: September 2018

1081

Background: In patients with brain metastasis (BM) of melanoma or lung cancer, significant activity of immune checkpoint inhibitors has been reported. However, details of the immune microenvironment in BM has not been unveiled. In this study, we used immunohistochemistry (IHC) to compare primary breast tumors and BM tumor samples with respect to tumor infiltrating lymphocytes (TILs) and tumor characteristics related to the immune system. Methods: We retrospectively identified 107 patients with breast cancer, diagnosed with BM, who had undergone surgery between 2001 and 2012 at 8 institutions. We collected 191 samples which included both BM samples alone and pair-matched samples (primary and BM). Hematoxylin and eosin (H&E) stained slides were evaluated for stromal TILs in 10% increments (0–1%, > 1– < 10%, 10%–100%). IHC was performed using the following primary antibodies: CD4, CD8, Foxp3, PD-L1, PD-L2 and HLA class I. The cells positive for each antibody signal were counted automatically using ImageJ (NIH). The expression of PD-L1, PD-L2, and HLA on the tumor cells was scored as 0 (negative), 1 (weak or focal), or 2 (strong). Results: The median category of TILs of BM tumors was > 1– < 10% (range: 1–30%). Forty-six pair-matched samples were analyzed and the percentage of TILs in the primary breast tumor was significantly higher than that in BM samples (paired t-test, P < 0.01). The number of CD4/CD8/Foxp3 positive cells in primary breast tumor was also significantly higher than in BM samples (paired t-test, P < 0.05 for all categories). The negative/positive conversion occurred with the expression of HLA/PD-L2 on tumor cells (paired t-test, P = 0.03/0.06, respectively). No significant difference was observed in the overall survival (OS) of patients, from initial BM, based on high or low TILs (log-rank test, P = 0.131). However, triple negative breast cancer patients with low TILs had significantly shorter OS compared with patients with high TILs (log-rank test, P = 0.04). Conclusions: We demonstrated that TILs in BM tumors was significantly lower as compared to primary breast tumors. The expression of immune related molecules on tumor cells was converted in BM tumors.
Phase 2 study of pembrolizumab as first-line therapy for PD-L1–positive metastatic triple-negative breast cancer (mTNBC): Preliminary data from KEYNOTE-086 cohort B.
Authors: Adams Sylvia , Loi Sherene , Toppmeyer Deborah , Cescon David W. , De Laurentiis Michele , Nanda Rita , Winer Eric P. , Mukai Hirofumi , Tamura Kenji , Armstrong Anne , Liu Minetta C. , Iwata Hiroji , Ryvo Larisa , Wimberger Pauline , Card Deborah , Ding Yu , Karantza Vassiliki , Schmid Peter
Published: September 2018

1088

Background: Standard first-line treatment for mTNBC is chemotherapy. However, outcomes are poor, and new treatment options are needed. Cohort B of KEYNOTE-086 (NCT02447003) assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients (pts) with PD-L1–positive mTNBC. Methods: Men and women with centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, ECOG PS 0-1, and a tumor PD-L1 combined positive score (CPS) ≥1% received pembrolizumab 200 mg Q3W for 24 mo or until disease progression, intolerable toxicity, or investigator or pt decision. Tumor imaging was performed Q9W for 12 mo and Q12W thereafter. Clinically stable pts with PD could remain on pembrolizumab until PD was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, DOR, and PFS (RECIST v1.1, central review). Planned enrollment was 80 pts. This analysis included all pts who had ≥18 wk of follow-up as of Nov 10, 2016. Results: 79 of the first 137 pts with PD-L1–evaluable tumors (58%) had PD-L1 CPS ≥1%. Of the first 52 pts enrolled, 100% were women, median age was 53 y, 40% had elevated LDH, 69% had visceral metastases, and 87% received prior (neo)adjuvant therapy. After a median follow-up of 7.0 mo (range 4.4-12.5), 15 (29%) pts remained on pembrolizumab. Treatment-related AEs occurred in 37 (71%) pts, most commonly fatigue (31%), nausea (15%), and diarrhea (13%). 4 (8%) pts experienced 5 grade 3-4 treatment-related AEs: back pain, fatigue, hyponatremia, hypotension, and migraine (n = 1 each). No pts died or discontinued pembrolizumab due to an AE. ORR was 23% (95% CI 14%-36%). Best overall response was CR in 4%, PR in 19%, SD in 17%, PD in 58%, and not assessed in 2%. Median time to response was 8.7 wk (range 8.1-17.7). Median DOR was 8.4 mo (range, 2.1+ to 8.4), with 8 (67%) responses ongoing at cutoff. Median PFS was 2.1 mo (95% CI, 2.0-3.9); estimated 6-mo PFS rate was 29%. Conclusions: Data from the first 52 pts enrolled in KEYNOTE-086 cohort B suggest that pembrolizumab monotherapy has a manageable safety profile and promising antitumor activity as first-line therapy for PD-L1–positive mTNBC. Clinical trial information: NCT02447003.
Overall survival (OS) in patients (Pts) with diagnostic positive (Dx+) breast cancer: Subgroup analysis from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in AR+ triple-negative breast cancer (TNBC) treated with 0-1 prior lines of therapy.
Authors: Traina Tiffany A. , Yardley Denise A. , Schwartzberg Lee Steven , O'Shaughnessy Joyce , Cortes Javier , Awada Ahmad , Kelly Catherine Margaret , Trudeau Maureen E. , Schmid Peter , Gianni Luca , Gucalp Ayca , Garcia-Estevez Laura , Nanda Rita , Ademuyiwa Foluso Olabisi , Chan Stephen , Steinberg Joyce Leta , Blaney Martha Elizabeth , Tudor Iulia Cristina , Uppal Hirdesh , Miller Kathy
Published: September 2018

1089

Background: The AR may be a novel therapeutic target for pts with AR-driven TNBC. ENZA, a potent AR inhibitor approved in men with metastatic prostate cancer, was evaluated in this phase 2 study of pts with AR+ TNBC. A genomic signature associated with AR-driven biology was identified; updated OS results in pts treated with 0-1 prior lines of therapy are presented. Methods: This is an open-label, Simon two-stage study (NCT01889238) of ENZA monotherapy in advanced AR+ TNBC (AR > 0% by IHC). Bone-only disease and unlimited prior regimens were allowed; CNS metastases or seizure history were exclusionary. The primary endpoint was clinical benefit rate at 16 weeks (CBR16) in evaluable pts (AR > 10% and ≥1 postbaseline assessment). OS was an exploratory endpoint. Results in intent-to-treat (ITT) and evaluable pts were presented previously (Traina TA et al. J Clin Oncol. 2015;33:1003). Results: 118 pts were enrolled (ITT). CBR16 in 78 evaluable pts was 33.3%. Of the 118 ITT pts, 56 were Dx+ and 62 were Dx–; ≥50% received 0-1 prior lines of therapy (28 Dx+, 37 Dx–). As of 26 Nov 2016 there were 83 deaths (median follow-up 28 mo); median OS (mOS) was 13 mo (95% CI; 8-18). In the Dx+ subgroup there were 32 deaths (mOS 20 mo [95% CI; 13-29]) vs 51 deaths in the Dx– subgroup (mOS 8 mo [95% CI; 5-11]). In pts with 0-1 prior lines of therapy, there were 13 deaths in the Dx+ subgroup (mOS 29 mo [95% CI; 19-not reached] vs 28 in the Dx– subgroup (mOS 10 mo [95% CI; 7-15]). The most common adverse events (AEs) were fatigue and nausea; fatigue was the only grade 3 related AE in > 5% of pts. A multi-covariate Cox analysis identified Dx status (+ vs –) and line of therapy (0-1 vs ≥2) as the only variables significantly associated with OS. Conclusions: In this study, the mOS of pts with Dx+ TNBC who received 0-1 prior lines of therapy appears longer than that of unselected historic controls. ENZA may represent a therapeutic option in pts with AR+ TNBC who would otherwise receive cytotoxic chemotherapy and is currently being evaluated in ENDEAR, a phase 3 study in pts with Dx+ advanced TNBC and 0-1 prior lines of therapy. Clinical trial information: NCT01889238.
Multicenter phase II study of pembrolizumab (P) in advanced soft tissue (STS) and bone sarcomas (BS): Final results of SARC028 and biomarker analyses.
Authors: Burgess Melissa Amber , Bolejack Vanessa , Van Tine Brian Andrew , Schuetze Scott , Hu James , D'Angelo Sandra P. , Attia Steven , Priebat Dennis A. , Okuno Scott H. , Riedel Richard F. , Davis Lara Emily , Movva Sujana , Reed Damon R. , Butterfield Lisa Helene , Roszik Jason , Reinke Denise K. , Baker Laurence H. , Maki Robert G. , Patel Shreyaskumar , Tawbi Hussein Abdul-Hassan
Published: September 2018

11008

Background: SARC028 is the first multicenter Phase II study of P monotherapy in patients (pts) with STS and BS. Designed to detect clinical efficacy signals in multiple histologies, the study collected blood & tissue samples on all pts. We report extended clinical follow-up and in-depth biomarker correlates of response. Methods: The primary endpoint was objective response rate (ORR) by RECIST 1.1. Secondary endpoints were safety, 12 wk progression-free survival (PFS), and overall survival (OS). The STS arm had 10 pts in each of 4 cohorts: undifferentiated pleomorphic sarcoma (UPS), dedifferentiated liposarcoma (DDLPS), synovial sarcoma (SS) and leiomyosarcoma (LMS). The BS arm included 40 pts with osteosarcoma (OS), Ewing sarcoma (ES) or dedifferentiated chondrosarcoma (CS). Pre- and on-P biopsies were required as well as blood at multiple time points. Tumor was assessed for PD-L1 expression (clone 22C3) and immune infiltrates by multi-color IHC (Vectra). Ongoing analyses include circulating cytokine and checkpoint levels and exome (DNA), transcriptome (RNA), and T-cell receptor (TCR) sequencing. Results: 86 pts were enrolled, 80 were evaluable for response. For STS, median follow-up was 14.5 months. The ORR in the overall STS cohort was 18% and the 12-wk PFS 55% [95% CI, 42-71]). Clinical activity was variable by histologic subtype with 40% ORR in UPS (1 CR and 3PR out of 10 evaluable pts), 2 PR/10 were seen in DDLPS, 1PR/10 in SS and 0/10 in LMS. For BS, median follow-up was 12.3 months (ORR 5%; 12-wk PFS 28% [95% CI, 14-41]), with 1PR/22 OS, 1PR/5 CS and 0/13 ES. 70 pre-P tissues were analyzed (11 excluded for insufficiency), with PD-L1+ in 3/70 (4%); all 3 were UPS. Of the 2 evaluable pts, 1 had CR and 1 PR. 2 OS were PD-L1+ on multi-color IHC, 1 had PR. All PD-L1+ samples had CD8+ T-cell infiltration. There were no post-P PD-L1+ samples. Conclusions: P has clinical activity in UPS and LPS, and expansion cohorts in those subtypes are planned. Pre-treatment PD-L1 expression was infrequent, but correlated with T-cell infiltration and response in UPS & OS. Ongoing biomarker analyses that may guide combination strategies are ongoing and will be presented at the meeting. Clinical trial information: NCT02301039.
Prospective development of a patient reported outcomes (PRO) tool in desmoid tumors: A novel clinical trial endpoint.
Authors: Paty Jean , Maddux Leanne , Gounder Mrinal M.
Published: September 2018

11022

Background: Desmoid tumors (DT) are locally aggressive and cause significant morbidity. Clinical trials in DT typically utilize response rates and progression free survival as primary endpoints. However, these endpoints do not capture improvements in clinical symptoms. To date, there are no validated PRO tools in DT to capture the patient experience and efficacy of a drug. Methods: A review of the published literature and interviews with sarcoma clinicians were used to formulate a list of signs and symptoms and impact on patients (pts). These were collected to build a conceptual model. DT pts (n = 31) with a range of anatomical locations and presentations were interviewed, initially in an open-ended fashion, followed by interrogating the conceptual model. For the concepts that pts reported, they were asked to rate how disturbing each was on a 0-10 scale (0 being not at all, and 10 being as bad as they can imagine). The pts interview data was then used to refine the conceptual model and generate two new PRO instruments Results: Pt interviews demonstrated that across tumor locations, the most frequent and disturbing symptoms were: ‘muscle’ pain (65% pts, median disturbance (MD) of 6.8), ‘nerve’ pain (73%, MD 6.0), and fatigue (65%, MD 5.0). Some symptoms were specific to tumor locations, especially abdominal tumors. Restricted range of motion (68%, MD 4.0), fear (84%, MD 6.5), sleep disturbance (77%, MD 7.5) , disfigurement (81%, MD 6.8), and impact on daily activities (65%, MD 6.8) were the most frequent and disturbing impact on pts lives. These concepts were then used to develop two new PRO instruments: the sign and symptom PRO includes 11 items; the impact on pts lives instrument includes 17 items. The instruments vary in asking pts about the last 24 hours, or the last week. Conclusions: This is the first validated PRO tool in DT. This tool adequately captures symptoms central to the DT pts experience and its impacts on their lives. The instruments are ready for implementation in a DT clinical trial for further evaluation of their measurement properties.
Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study.
Authors: Spira Alexander I. , Hamid Omid , Bauer Todd Michael , Borges Virginia F. , Wasser Jeffrey S. , Smith David C. , Clark Amy Sanders , Schmidt Emmett V. , Zhao Yufan , Maleski Janet E. , Gangadhar Tara C.
Published: September 2018

1103

Background: Epacadostat is an oral, potent, and selective inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophan-catabolizing enzyme that induces immune tolerance via T-cell suppression and is associated with poor patient (pt) survival when overexpressed in some cancers. The ongoing, open-label, phase 1/2 (P1/2) ECHO-202/KEYNOTE-037 study is evaluating the efficacy, safety, and tolerability of epacadostat plus PD-1 inhibitor pembrolizumab (E + P) in pts with advanced/recurrent cancers. We report P1/2 study outcomes for triple-negative breast cancer (TNBC) pts and P2 outcomes for ovarian cancer (OVC; no P1) pts as of a 29OCT2016 data cutoff. Methods: Eligible pts were ≥18 years old with no prior checkpoint inhibitor treatment (tx); prior platinum/taxane tx was required for OVC pts. As part of P1 dose escalation, TNBC pts received E (300 mg BID) + P (200 mg Q3W). In P2, TNBC and OVC pts received E (100 mg BID) + P (200 mg Q3W). Response (RECIST v1.1) was assessed in evaluable pts. Safety and tolerability were assessed in pts with ≥1 dose of E + P. Results: A total of 39 pts with TNBC and 37 with OVC were enrolled. The majority of TNBC pts (56%, n = 22) and OVC pts (78%, n = 29) received ≥3 prior lines of tx. For TNBC pts, ORR (CR+PR) was 10% (n = 4; all PR) and DCR (CR+PR+SD) was 36% (n = 14; 10 SD); ORR and DCR for pts with ≤2 prior tx were 12% (n = 2) and 29% (n = 5), respectively, and for ≥3 prior tx were 9% (n = 2) and 41% (n = 9). For OVC pts, ORR was 8% (n = 3; all PR) and DCR was 35% (n = 13; 10 SD); ORR and DCR for pts with ≤2 prior tx were 13% (n = 1) and 25% (n = 2), and for ≥3 prior tx were 7% (n = 2) and 38% (n = 11). The most common TRAEs (≥15% of pts) were rash (18%), fatigue (15%), and nausea (15%) in the 39 TNBC pts, and fatigue (19%) in the 37 OVC pts. Grade ≥3 TRAEs occurred in 13% of TNBC pts (n = 5; none in > 1 pt) and 19% of OVC pts (n = 7; only rash occurred in > 1 pt [n = 3]). TRAEs led to discontinuation in 1 TNBC pt (grade 3 ascites) and 1 OVC pt (grade 2 arthralgia). Conclusions: E + P tx was generally well tolerated and showed antitumor activity consistent with previously reported P monotherapy in pts with advanced TNBC or OVC. Biomarker analysis is ongoing to characterize pt populations enrolled in this study. Clinical trial information: NCT02178722.
Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).
Authors: Lee Chee Khoon , Scott Clare L. , Lindeman Geoffrey John , Gibbs Emma , Badger Heath D. , Paterson Robin John , Macnab Lauren , Kwan Edmond Michael , Boyle Frances M. , Friedlander Michael ,   On Behalf of the Australia and New Zealand Breast Cancer Trials Group
Published: September 2018

1104

Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.
Administration of aldoxorubicin and 14 days continuous infusion of ifosfamide/mesna in metastatic or locally advanced sarcomas.
Authors: Eilber Frederick C. , Sankhala Kamalesh Kumar , Chawla Sant P. , Chua-Alcala Victoria S. , Gordon Erlinda Maria , Quon Doris , Kim Katherine , Chawla Shanta , Wu Nancy , Wieland Scott , Levitt Daniel J.
Published: September 2018

11051

Background: Aldoxorubicin (A) has demonstrated superior anti-tumor efficacy and lack of cumulative cardiac toxicity in multiple studies. A is doxorubicin (D) with a linker which rapidly binds in vivo to albumin after iv. We studied the combination of A administered on Day 1 with continuous infusion (CI) of ifosfamide/Mesna (I-M) days 1-14, as first line therapy or second line therapy in patients with soft tissue sarcomas (STS) to evaluate efficacy and toxicity. Methods: 27 patients have entered the study at 250 mg/m2 ( 185 mg/m2 D equiv) administered on Day 1. I-M (1 g/m2 of each per day) was given up to 14 days as a CI via an out-patient portable pump. Chemotherapy cycles were repeated at 28 day interval. I-M was limited to a maximum of 6 cycles to avoid cumulative marrow toxicity, but A was continued per investigator decision in responding or SD patients for clinical benefit. Subjects were followed for tumor response (RECIST 1.1) by CT scans and echocardiogram/ECG for cardiac toxicity every 8 weeks along with standard labs. Enrollment continues up to 50 patients. Results: Demographics: Leiomyosarc. = 20%, liposarc. = 20%, synovial sarc. = 20%, rhabdosarc. = 8%, others = 32%. Caucasian, 11% Asian, 4% Black; 67% no prior tx, 26% 1 prior tx, 7% > 1 prior tx; Median cum. A = 1000 mg/m2 (740 mg/m2 D eq.; 185-4070 mg/m2 D eq.); I = 6.9 g/m2 (2.1-12.6 g/m2). Best response: 42% PR, 58% SD. Median PFS not reached. 10 subjects with either PR or SD had surgery to remove accesible tumors. Range of tumor necrosis = 70 to > 95%. Grade 3/4 AEs: neutropenia = 78%, febrile neutropenia = 9%, thrombocytopenia = 22%, anemia = 65%, nausea = 4%. Related SAEs = 4 (febrile neutropenia (2), pyrexia, stomatitis). No tx related deaths. No clinically significant cardiac AEs, no decrease in LVEF > 20% Conclusions: A can be administered for prolonged periods and safely with CI ifosfamide/mesna and achieves high ORR and SD with substantial tumor necrosis. Clinical trial information: NCT02235701.
Phase 2 multicenter study of the EZH2 inhibitor tazemetostat in adults with INI1 negative epithelioid sarcoma (NCT02601950).
Authors: Gounder Mrinal M. , Stacchiotti Silvia , Schöffski Patrick , Attia Steven , Italiano Antoine , Jones Robin , Demetri George D. , Blakemore Stephen , Clawson Alicia , Daigle Scott , Ribich Scott , Roche Maria , Rodstrom Jill , Ho Peter T.C. , Cote Gregory Michael
Published: September 2018

11058

Background: Epithelioid sarcoma (ES) is a rare soft tissue sarcoma (STS) typically seen in young adults accounting for < 1% of all STS. While local disease may be indolent, ES can rapidly spread and patients (pts) with distant metastasis are often resistant to systemic treatment with 1 year survival of < 50%. The defining molecular feature of ES is the absence of tumor expression of INI1, a SWI/SNF subunit member involved in chromatin remodeling. Tazemetostat, a potent and selective EZH2 inhibitor, has demonstrated tumor regressions in INI1 negative preclinical malignant rhabdoid tumors (MRT) models and phase 1 clinical activity in MRT and ES pts. The proposed mechanism of tazemetostat sensitivity is INI1 loss inducing compromised SWI/SNF activity and tumor dependence on PRC2 activity (of which EZH2 is the catalytic subunit). Preliminary phase 2 safety and efficacy of tazemetostat in ES pts is reported here. Methods: This is a phase 2 multicenter open-label single arm study of tazemetostat (800 mg po BID) in adult pts with ES whose tumors harbor evidence of INI1 loss. Pts enroll into 1 of 5 cohorts of different tumor types with INI1 loss/reduction, up to 30 pts each, using a 2-stage Green-Dahlberg design. For the ES cohort, primary endpoint is disease control rate (DCR) defined as objective response of any duration or stable disease (SD) lasting ≥32 wks. Success at stage 2 required DCR in ≥5/30 treated pts. Key secondary endpoints include safety/tolerability, ORR, PFS, OS, PK and response biomarkers e.g. H3K27me3. Results: In 31 ES pts with a median of 1 prior systemic therapy, stage 2 DCR criteria was surpassed with a RECIST confirmed PR (4 pts) and SD ≥32 wks (2 pts) observed to date. 13 pts are still on treatment therefore DCR and ORR will be updated. Tazemetostat was well tolerated with grade 1/2 fatigue (39%), nausea (26%) and vomiting (19%) as the most frequently reported AEs regardless of attribution. Conclusions: In the largest prospective clinical trial of ES to date, tazemetostat monotherapy shows promising antitumor activity, including confirmed responses and long-term SD, with favorable safety/tolerability in ES. Enrollment has been expanded to 60 ES pts given the clinical activity described here. Clinical trial information: NCT02601950.
Discordance of histo-pathological diagnosis of patients with soft tissue sarcoma referred to tertiary care center.
Authors: Rastogi Sameer , Aggarwal Aditi , Soti Kamal Raj , Vanidassane Ilavarasi , Sharma Mehar C , Yadav Ajay , Sharma Aparna , Kataria Babita , Deo S. V. S.
Published: September 2018

11064

Background: Reaching to the correct histo-pathological diagnosis of soft tissue sarcomas (STS) is a great challenge and is cornerstone for treatment planning. Need of expertise for diagnosis is limited by lack of expert pathologists and dedicated sarcoma oncologists in India. Through this study we highlight the pattern of pathological diagnosis and accuracy outside specialist centre. Methods: We did retrospective analysis of all patients referred to us with diagnosis of STS in the last 12 months (January 2016 to 2017). According to protocol, all patients had pathology review from our institute. If blocks were available then they were reviewed and if necessary, fresh biopsy was performed. Besides, pathological diagnosis was reviewed in joint clinic, giving clinico-radiological inputs to sarcoma pathologists. For patients diagnosed outside and had discordant report, we divided them into major discrepancy (including change of diagnosis of sarcoma to benign or other histological entity that could potentially change the treatment plan) or minor discrepancy (like mild change in grade or histopathological diagnosis not affecting the treatment plan). Results: There were 149 patients registered with median age of 36 years (14-77 years) and 93 patients (62.4%) were males. 85(57%) patients had localized disease. Most common subtypes were synovial sarcoma 16%, liposarcoma 9%, soft tissue ewings sarcoma 9%, MPNST 9%, leiomyosarcoma 8%, pleomorphic undifferentiated sarcoma 8% etc. Of 149 patients, 42 had not been worked up outside and thus comparison was not possible while 4 patients couldn’t retrieve blocks and repeat biopsy could not be performed. Of 97 patients (biopsy = 84, FNAC = 13) who had diagnosis from outside, 37% had major discrepancy and 24% had minor discrepancy compared with our biopsy review. Major discrepancy was more in non extremity than extremity STS (p = 0.003). Conclusions: Pathological diagnosis of more than half of patients referred from outside was discordant with respect to diagnosis of our centre with major implications on 37%. We believe this is due to lack of sarcoma pathology experts and virtually non-existent multidisciplinary clinics in set up outside tertiary care centres.
Correlation between a new growth modulation index (GMI)-based Geistra score and efficacy outcomes in patients (PTS) with advanced soft tissue sarcomas (ASTS) treated with trabectedin (T): A Spanish group for research on sarcomas (GEIS-38 study).
Authors: Martinez-Trufero Javier , Hindi Nadia , Cruz Josefina , Alvarez Alvarez Rosa Maria , Diaz Beveridge Roberto Pedro , Valverde Morales Claudia Maria , Gutierrez Antonio , Bernad Isabel Pajares , Lopez-Pousa Antonio , Vaz Salgado María Ángeles , Lavernia Javier , Cano Juana Maria , Sevilla Isabel , Rubió-Casadevall Jordi , De Juan Ana , Carrasco Juan Antonio , Hernandez Leon Nieves , Agra Pujol Carolina , Ferrando Lamana Lucia , Martin Broto Javier
Published: September 2018

11070

Background: The GMI is a marker of drug activity and represents an intra-patient comparison of successive time to progression (TTP), defined as the TTP ratio between the second (or later) line (TTPn) of therapy divided by the prior line (TTPn−1). Defining a clinical profile of pts with GMI >1.33 could help to identify pts who can gain greater benefit from T. Methods: We retrospectively evaluated the concordance between the GMI and the efficacy outcomes and clinical profiles of 198 pts with ASTS treated with trabectedin 1.5 mg/m² (24-h infusion q3w) as a 2nd or further-line treatment from Jan 2007 to Jun 2016. Results: After a median follow-up of 58 months (m; range: 18-172) median overall survival from ASTS diagnosis (MOS) and from T (MT-OS) were 27.5 m (23-32.1) and 10.8 m (8.9-12.7), respectively, while median TTP from T (MT-TTP) and T-1 were 3.4 m (2.8-4) and 3.5 m (2.8-4.2). Overall, 106 pts (53%) had a GMI <1; 22 (11%) a GMI=1-1.33 and 70 pts (35%) a GMI >1.33. A high GMI (<1.33 vs >1.33) correlated with favorable efficacy outcomes: MT-OS: 23 vs 36 m (p<0.001), MT-TTP 2.3 vs 8.2 m (p<0.001) and clinical benefit (objective response + stable disease) 23% vs 68% (p=0.001). The multivariate analysis identified L-type sarcoma (Odds ratio: 1.99, 95% CI 1.06-3.71), metastatic free interval (MFI) from initial diagnosis > 8.1 m (2.24, 95%CI 1.19-4.18) and Karnofsky >80 (2.3, 95%CI 1.00-5.28) as factors independently associated to GMI> 1.33. Based on these 3 variables we defined a new GEISTRA score assigning 1 point for each adversely affected variable: non L-Sarcoma, MFI<8.1m or Karnofsky <80. This score showed a strong correlation with MT-TTP (p<0.001) and MT-OS (p<0.001). Conclusions: Based on the high GMI we defined a new GEISTRA score, which is strongly associated with favorable efficacy outcomes in pts with ASTS treated with T. Thus, GEISTRA score could be a potentially useful predictable clinical tool for T benefit. [Table: see text]
Prognostic value of microscopic evaluation of organ infiltration and visceral resection margins (VRM) in patients with retroperitoneal sarcomas (RPS).
Authors: Renne Salvatore Lorenzo , Tagliabue Marta , Pasquali Sandro , Collini Paola , Barisella Marta , Callegaro Dario , Colombo Chiara , Gronchi Alessandro , Fiore Marco
Published: September 2018

11074

Background: Surgery with gross margin clearance (R0 and R1) is the standard treatment for RPS and visceral resection has been proposed even in the absence of macroscopic visceral infiltration. Formal definition and margin sampling procedures for pathological evaluation are lacking for RPS. This study investigated VRM as well as viscera infiltration and their association with patient survival. Methods: Consecutive patients operated on for primary RPS (2009-2014) were extracted from a prospectively maintained database. VRM were sampled for each resected organ and classified as negative and positive. Also, tumor infiltration of resected organs was classified as follow: absence of infiltration, infiltration of perivisceral fat, early infiltration (i.e., renal/adrenal capsule, muscular fascia, contact with muscular tunica of hollow viscera), and infiltration of the viscera. Results: In 207 patients VRM were negative in 182 (88%) and positive 25 (12%). Organ infiltration was absent, perivisceral, early, and visceral in 37 (18%), 13 (6%), 17 (8%), and 140 (68%), respectively. Overall survival analysis showed that patients with negative VRM plus organ infiltration (HR = 3.56; 95%CI 1.15-11.00, P = 0.028) and those with positive VRM irrespective of organ infiltration (HR = 7.76; 95%CI 2.18-27.65, P = 0.002) did worse that patients with negative VRM plus no organ infiltration, after adjustment from known prognostic features. Conclusions: After liberal multivisceral resection for primary RPS, up to 80% of patients have infiltrated organs at some extent, while VRM are positive in up to 10% of cases. Visceral resection is justified even in the absence of macroscopic infiltration. Systematic evaluation of microscopic involvement of adjacent viscera may stratify prognosis.
A phase I/II dose escalation and expansion study of cabiralizumab (cabira; FPA-008), an anti-CSF1R antibody, in tenosynovial giant cell tumor (TGCT, diffuse pigmented villonodular synovitis D-PVNS).
Authors: Sankhala Kamalesh Kumar , Blay Jean-Yves , Ganjoo Kristen N. , Italiano Antoine , Hassan Andrew Bassim , Kim Tae Min , Ravi Vinod , Cassier Philippe Alexandre , Rutkowski Piotr , Sankar Neil , Qazi Ibrahim , Sikorski Robert S. , Collins Helen , Zhang Charlie , Shocron Ellyn , Gelderblom Hans
Published: September 2018

11078

Background: TGCTis a proliferative, neoplastic joint disease that presents as single nodule (local) or multiple nodules (diffuse D-TGCT). Localized overexpression of colony stimulating factor 1 (CSF1) leads to recruitment of cells expressing the CSF1 receptor (CSF1R), formation of a tumor and inflammation of joints and tendons. Cabira is a monoclonal antibody that inhibits the interaction of the CSF1 and IL-34 ligands with their shared receptor CSF1R. Methods: This Ph 1/2 study is evaluating the safety and efficacy of cabira monotherapy administered IV Q 2wk for 6 mo in patients (pts) with D-TGCT. Eligible pts have inoperable D-TGCT or tumor for which resection would cause unacceptable morbidity. Response is evaluated by MRI, pt reported outcomes, and Ogilvie-Harris (O-H) score (which combines pain, synovitis, range of motion and functional capacity on a scale of 0-12). Results: As of 15 Dec 2016, 22 pts received ≥ 1 dose of cabira at 1, 2 or 4mg/kg. Dose-related exposure increase and significant reduction in target peripheral monocytes were observed. No dose limiting toxicity was identified. 4 mg/kg was chosen for Ph2 based on efficacy, tolerability, and PK. AEs ≥ Gr 2 ( > 10%) were CK elevation 46%, rash and other skin disorders 36%, fatigue 23%, and periorbital/peripheral/face edema 18% each. Gr 3 AEs in ≥ 2 pt were CK elevation (n = 8) and periorbital edema (n = 2). Four drug-related SAEs were reported in 3 pts; hypertension, fever, CRP elevation, and myocarditis. AEs of CK elevation were asymptomatic, improved to < 2X ULN after protocol mandated drug discontinuation and are a known on-target effect of CSF1R inhibition. An amendment was made during Phase 2 to allow dosing with higher CK levels Activity at 4 mg/kg was: 1PR and 1 CK discontinuation in 3 pts in Ph1; 4 PRs in 7 evaluable pts with 6 additional ongoing in Ph2. Positive functional status improvements by O-H score were noted in objective responders (from 2 to 7). Conclusions: The initial demonstration of objective and functional activity supports further development of cabiralizumab in pts with D-TGCT. Updated data from the ongoing Ph2 will be presented. NCT02471716 . Clinical trial information: NCT02471716.
Interferon-gamma (INFG), an important marker of response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) and melanoma patients.
Authors: Karachaliou Niki , Crespo Guillermo , Aldeguer Erika , Drozdowskyj Ana , Gimenez Capitan Ana , Teixido Cristina , Molina-Vila Miguel Angel , Viteri Ramirez Santiago , Morales-Espinosa Daniela , Gil Maria de los Llanos , Gonzalez-Cao Maria , Martin Algarra Salvador , Pérez-Ruiz Elisabeth , Marquez Rodas Ivan , Rodriguez-Abreu Delvys , Blanco Remei , Puertolas Teresa , Royo Maria Angeles , Rosell Rafael
Published: September 2018

11504

Background: PD-L1 can be induced by oncogenic signals or up-regulated via INFG in a STAT1- and NFκB-dependent manner. STAT3 opposes STAT1-mediated anti-tumor immune responses. I kappa B kinase epsilon (IKBKE) is an interferon signaling inducer. We explored whether INFG expression in pre-treatment tumors is associated with to the efficacy of ICB in NSCLC and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE and STAT1 was also examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1 and PD-L1 mRNA were examined. PD-L1 protein expression in tumor and immune cells was evaluated (Ventana SP142 assay). Progression free survival (PFS) and overall survival (OS) were estimated. Results: 17 previously treated NSCLC patients received nivolumab; 71% lung adenocarcinoma, 71% male, 53% smokers, 35% KRAS mutant, 88% EGFR wild-type (wt). 21 previously treated melanoma patients received pembrolizumab; 67% male, 67% BRAF wt. PFS to nivolumab was significantly longer in NSCLC patients with high vs. low INFG expression (5.12 vs. 2mo, p = 0.0124). PFS to pembrolizumab was significantly longer in melanoma patients with high vs. low INFG expression (4.99 vs. 1.86mo, p = 0.0099). Significantly longer OS was observed for melanoma patients with high vs. low INFG expression (not reached vs. 3.10mo p = 0.0183). There was a trend for longer OS for NSCLC patients with high vs. low INFG expression (10.15 vs. 4.86mo, p = 0.0687). The other gene levels and PD-L1 protein levels in tumor and immune cells did not affect the outcome to ICB. IKBKE was positively correlated with INFG and PD-L1 expression (NSCLC Spearman’s ρ = 0.58 and 0.65; melanoma Spearman’s ρ = 0.61 and 0.59), and STAT3 expression was loosely anticorrelated with PD-L1 expression (NSCLC Spearman’s ρ = −0.21; melanoma Pearson’s ρ = −0.01). Conclusions: INFG is an important marker for qRT-PCR mediated prediction of response to ICB in NSCLC and melanoma patients. Further research is warranted in order to validate that INFG is more accurate than PD-L1.
SHIVA: Randomized phase II trial comparing molecularly targeted therapy based on tumor molecular profiling versus conventional therapy in patients with refractory cancer—Overall survival (OS) analysis.
Authors: Dureau Sylvain , Ricci Francesco , Alt Marie , Loirat Delphine , Sablin Marie-Paule , Kamal Maud , Bieche Ivan , Armanet Sebastien , Delord Jean-Pierre , Goncalves Anthony , Gavoille Celine , Dubot Coraline , Isambert Nicolas , Campone Mario , Tredan Olivier , Marous Miguelle , Latouche Aurelien , Belin Lisa , Le Tourneau Christophe
Published: September 2018

11515

Background: The SHIVA trial is a multicentric randomized phase II trial comparing molecularly targeted therapy among 11 drugs based on tumor molecular profiling versus conventional therapy in patients with any type of cancer that is refractory to standard of care (NCT01771458). Only patients who had a druggable molecular alteration (DMA) identified on a mandatory tumor sample from a metastatic site using targeted sequencing, CGH and IHC were randomized. Cross-over was allowed at disease progression. The trial did not show any difference for its primary endpoint (PFS) [Le Tourneau et al., Lancet Oncol 2015]. We report here the OS of randomized and non-randomized patients. Methods: OS was estimated in the 4 following groups: 1) randomized patients, 2) patients for whom a DMA was identified but who were not subsequently randomized because they did not meet the randomization criteria (PS of 0 or 1, adequate organ function), 3) non-randomized patients because of the absence of DMA, and 4) non-randomized patients because no genomic analyses were performed. Since 70% of patients randomized into the standard arm eventually crossed over to the targeted therapy arm, all randomized patients were analyzed in group 1. The groups were compared in terms of patient characteristics using student and χ2 tests. OS was estimated using the Kaplan Meier method. Results: Among 741 patients included in SHIVA, 8 patients were included twice. Follow-up data were available for 680 out of the 733 patients. 197, 78, 222 and 183 patients belonged to groups 1 to 4, respectively. Median OS of the whole cohort was 7.9 months [95% CI: 7.0–9.1].As compared to non-randomized patients due to the absence of identified DMA, non-randomized patients with a DMA had a significantly worse prognosis: HR = 2.3 [95% CI: 1.7–3.0] (p > 0.0001) whereas randomized patients had a non-significant trend toward a better prognosis: HR = 0.85 [95% CI: 0.7–1.1] (p = 0.18). Conclusions: A statistically significant difference in OS was only observed in patients with a DMA who were not randomized. However, our analysis does not allow showing an intrinsic prognostic value of the DMA on OS.