bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II RCT of high-dose vitamin D supplementation for androgen deprivation therapy (ADT)-induced bone loss among older prostate cancer (PCa) patients.
Authors: Peppone Luke Joseph , Mustian Karen Michelle , Peoples Anita Roselyn , Kerns Sarah L. , Reschke Jennifer E , Cole Calvin , Janelsins Michelle Christine , Asare Matthew , Kamen Charles Stewart , Culakova Eva , Zhang Hong , Fung Chunkit , Lin Po-Ju , Mohile Supriya Gupta
Published: September 2018

10113

Background: ADT is the most commonly used systemic therapy for treating locally advanced and metastatic PCa. ADT use causes hypogonadism, which can result in accelerated bone loss and fragility fractures. Vitamin D (VITD) may protect against bone loss; however it remains unclear if the recommended daily allowance (RDA) of VITD is sufficient to reduce bone loss or whether higher doses are needed. The aim of this phase II RCT was to collect preliminary data on the effect of high-dose VITD on bone mineral density (BMD) in ADT-treated PCa patients compared to the RDA of VITD. Methods: Older PCa patients (≥60 years old) with VITD insufficiency ( < 32 ng/ml), within 6 months of starting ADT and with 6 more planned months of ADT were randomized 1:1 to high-dose VITD (hVITD; 600 IU/daily plus 50,000 IU/weekly) or RDA of VITD (rVITD; 600 IU/daily plus placebo weekly) for 24 weeks. All subjects received 100% of the RDA for calcium (1,000 mg/day). BMD was assessed at the total hip (TH) and lumbar spine (LS) via DXA at pre- and post-intervention. ANCOVA was used to test the change in BMD between groups. Results: 59 PCa patients were accrued (85% white; mean age = 67.6). Serum analyses confirmed high compliance in both groups (25-OH VITD change: hVITD = +32.0 ng/ml vs rVITD = +4.3 ng/ml; p < 0.01). The safety of hVITD was similar to rVITD (Grade I hypercalcemia: hVITD: n = 1 vs rVITD: n = 0). Bone loss was significantly reduced for the hVITD group compared to rVITD group for total hip (TH BMD% change: hVITD = −1.5% vs rVITD = −4.1%; p = 0.02), with a trend for the femoral neck (BMD% change: hVITD = −1.7% vs rVITD = −4.3%; p = 0.06) and trochanter (BMD% change: hVITD = −1.0% vs rVITD = −2.8%; p = 0.10). There was no difference between groups for LS bone loss (LS BMD% change: hVITD = −0.8% vs rVITD = −0.6%; p = 0.75). Conclusions: High-dose VITD supplementation produced significantly greater reductions in hip BMD loss among older PCa patients receiving ADT compared to rVITD. Clinically, higher doses of VITD may be necessary to effectively prevent ADT-induced bone loss. A definitive phase III RCT is needed to confirm these findings. Funding: NCI R21CA175793, K07CA168911 & UG1CA189961. Bio-Tech Pharmacal Inc. supplied all agents. Clinical trial information: NCT02064946.
Multimodal therapy for cancer related fatigue in patients with prostate cancer receiving radiotherapy and androgen deprivation therapy.
Authors: Yennu Sriram , Basen-Engquist Karen , Reed Valerie Klairisa , Carmack Cindy L. , Lee Andrew , Mahmood Usama , Choi Seungtaek , Hess Kenneth R. , Wu Jimin , Williams Janet L. , Lu Zhanni , Cella David , Kuban Deborah A. , Bruera Eduardo
Published: September 2018

10114

Background: There are limited studies to evaluate treatments that target causative mechanisms of Cancer-related-fatigue (CRF) using validated tools in a defined population. The objective is to determine the feasibility, and the preliminary estimates of the effects of various combinations of standardized exercise, cognitive behavioral therapy (CBT), and methylphenidate (multimodal therapy, or MMT) on CRF as measured by AUC of Functional Assessment of Chronic Illness Therapy- Fatigue (FACIT-F) subscale scores in Pts with prostate cancer receiving radiotherapy with androgen deprivation therapy. Methods: Prostate cancer Pts with CRF scheduled to receive radiotherapy with androgen deprivation therapy were eligible. Using a double blind (patient, investigators) randomized factorial study design, eligible Pts were randomized into 1 of the 8 arms, which included all possible combinations of the interventions (exercise, CBT, and methylphenidate) and/or their corresponding placebo treatments for a duration of 8 weeks. Results: 62/69 (89%) randomized Pts were evaluable. There were no differences in the demographics and baseline fatigue between groups. The adherence rates for pills, exercise and CBT were 96.5%, 67%, and 90% respectively. The study was feasible and there was no significant difference in adverse events by groups. Table 1 shows the comparison of AUC by treatment. For Pts receiving drug compared to placebo, the median FACIT-F AUC was 2328 vs 2095. The drug effect (estimate, 95% CI) in Pts who received Exercise was 596 (68.3, 1125); CBT was 354 (-121, 830); combined Exercise and CBT was -187 (-802,427); and control Exercise, control CBT was 294 (-192,781). Conclusions: Methylphenidate containing combinations were superior to no drug combinations. Methylphenidate + Exercise provided the best signal and should proceed to large randomized control trials. Clinical trial information: NCT01410942. [Table: see text]
Genomic alterations driving breast cancer (BC) metastases and their relationship with the subtype switch in the GEICAM ConvertHER study.
Authors: Albanell Joan , Gonzalez Abel , Gonzalez-Angulo Ana M. , Eterovic Agda Karina , Martinez-De Duenas Eduardo , Zheng Xiaofeng , Guerrero Angel , Liu Shuying , Pérez-Carrión Ramon , Chen Ken , Chacon Jose Ignacio , Mills Gordon B. , Antolín Novoa Silvia , Blancas Isabel , Sanchez-Arago Maria , Carrasco Eva Maria , Caballero Rosalia , Rojo Federico , Meric-Bernstam Funda , Lluch Hernandez Ana
Published: September 2018

1017

Background: To understand the mechanisms underlying the evolution of tumors in the process of metastasis, we studied 61 paired primary-relapse BC from the GEICAM ConvertHER study. While some of the metastases maintained the clinical (ER/PR and HER2 status) and/or intrinsic subtype (defined by expression arrays) of the original tumor (concordant), others exhibited a subtype shift (discordant). We aimed to identify the genomic alterations driving the metastases and, particularly, their relationship with the subtype switch. Methods: We detected the somatic variants (mutations and copy number alterations (CNAs)) affecting 202 genes across the 61 sample pairs via targeted sequencing. We employed the Cancer Genome Interpreter (cancergenomeinterpreter.org), a bioinformatics approach to identify the alterations most likely driving tumorigenesis, and subsequently identified those whose cancer cell fraction markedly changed in the metastases. We explored the clonal remodeling in metastasis comparing the cell fractions of driver mutations in both concordant and discordant tumors. Results: We found that 156 genes had 747 somatic mutations and 171 genes suffered 1042 somatic CNAs in the 61 studied tumor pairs. We identified a median of 11 and 9 mutations in primaries and metastases, respectively. Several frequent BC mutational drivers, such as TP53, PIK3CA, MLL3, MAP3K1, and NOTCH2 were amongst the more frequently changed their cancer cell fraction in metastases with respect to primaries. We found that driver mutations of discordant tumors exhibited a significantly higher increase of clonal cell fraction. Moreover, whether the clonal status of a driver mutation was conserved in the metastasis was significantly associated to whether the tumor maintains its clinical subtype but not its intrinsic subtype. Conclusions: Our results suggest that a shift in the clinical subtype of BC undergoing metastasis is accompanied by more significant changes at the genomic level than those suffered by tumors that maintain their clinical subtype. This remodeling of the landscape of drivers could open new therapeutic opportunities to specifically target discordant BC.
A mouse-human phase I co-clinical trial of taselisib in combination with TDM1 in advanced HER2-positive breast cancer (MBC).
Authors: Metzger Filho Otto , Goel Shom , Barry William Thomas , Hamilton Erika Paige , Tolaney Sara M. , Yardley Denise A. , Rees Rebecca , Demeo Michelle , Mills Caitlin , Hafner Marc , Winer Eric P. , Zhao Jean , Krop Ian E.
Published: September 2018

1030

Background: PI3K blockade has the potential to revert resistance to anti-HER2 therapies. Methods: Pre-clinical experiments were conducted in parallel to a phase Ib study with the PI3-kinase inhibitor Taselisib + T-DM1 in HER2+ MBC. Results: Pre-clinically, HER2+ cell lines (HCC1954, MDA-MB-361, MDA-MB453) treated with T-DM1 until resistance had decreased HER2 expression. Tx with Taselisib restored HER2 levels in T-DM1 resistant cells. In vivo, the combination of T-DM1 + Taselisib was superior to either agent alone in transgenic mammary carcinomas driven by HER2 with or without a PIK3CA H1047R transgene. The phase Ib study enrolled 26 pts with HER2+ MBC. Median age was 57 (38-95), ER+ (58%), ER- (42%). PIK3CA wild type (35%) mutant (23%) pending results (42%). Pts had a median of 2 lines of prior tx for MBC. Prior T-DM1 was given to 38.5% of pts. Median duration of tx among 18 pts was 4 cycles (2-19). 8 pts remain on tx. No DLTs were observed in the 2 dose levels explored: T-DM1 (3.6mg/Kg) q3 wk with either Taselisib 2mg QD or Taselisib 4mg QD. 20 patients were included in the expansion phase. Most common G3 G4 AEs were thrombocytopenia (19.2%), diarrhea (15.4%), vomiting (7.7%), lipase increase (7.7%) and hyperglycemia (7.7%). Pneumonitis was reported in 4 cases (3 G1, 1 G2); further evaluation revealed elevated beta-glucan in 3 of the 4 cases raising suspicion for pneumocystis pneumonia (PJP). 24/26 pts were evaluable for confirmed response: (4% CR, 29% PR, 50% SD). Confirmed PR/CR according to prior TMD1 (yes 30% no 36%) and PIK3CA mut status (40% mut, 22% wild type; 9/23 PIK3CA results pending). Median PFS was 7.6 mos (95% CI 2.9 to NR). Conclusions: The combination of Taselisib + T-DM1 is superior to either agent alone in mouse models of HER2+ BC. In the phase Ib study, T-DM1 + Taselisib had an acceptable safety profile although PJP prophylaxis should be considered for this regimen. Thrombocytopenia was reversible with no bleeding events. Preliminary evidence of efficacy was observed regardless of PIK3CA status or prior tx with T-DM1. This co-clinical trial allowed for the rapid translation of lab observations to the clinical setting and provided data to facilitate interpretation of the clinical results. Clinical trial information: NCT02390427.
A phase Ib dose escalation study of combined inhibition of IDO1 (GDC-0919) and PD-L1 (atezolizumab) in patients (pts) with locally advanced or metastatic solid tumors.
Authors: Burris Howard A. , Gordon Michael S. , Hellmann Matthew David , LoRusso Patricia , Emens Leisha A. , Hodi F. Stephen , Lieu Christopher Hanyoung , Infante Jeffrey R. , Tsai Frank Yung-Chin , Eder Joseph Paul , Cleary James M. , Jelovac Danijela , Tsuhako Amy L. , Mueller Lars , Lin Ray , Morrissey Kari , Mahrus Sami , Morley Roland , Pirzkall Andrea , Davis Sarah Lindsey
Published: September 2018

105

Background: GDC-0919, a small molecule inhibitor of indoleamine-2,3-dioxygenase 1 (IDO1), reduces tryptophan catabolism and kynurenine production within the tumor microenvironment that may promote normal effector T cell activity and an immunogenic state. IDO1 inhibition may complement targeting of PD-L1 with atezolizumab. Methods: A Phase Ib, open-label, study assessed safety, pharmacokinetics (PK), pharmacodynamics (PD), and anti-tumor activity (RECIST v1.1) of GDC-0919 and atezolizumab in pts with locally advanced or metastatic solid tumors. Pts were given escalating doses of GDC-0919 (50-1000 mg orally twice daily, for 21 days) and atezolizumab (1200 mg IV, every 3 weeks) using a standard 3+3 design. Results: As of 14Dec2016, 52 pts were treated in 6 cohorts of GDC-0919 plus atezolizumab. The median number of prior systemic therapies was 3 (range 1-9); 2 pts received prior immunotherapy. Pts received a median of 4 cycles of GDC-0919 and atezolizumab (range 1-17). No MTD was identified. Across all dose levels, 1 DLT was observed (Grade [G] 3 sepsis syndrome at GDC-0919 200 mg); no G4/5 AEs were attributed to study treatment. G3+ AEs, regardless of causality were reported in 34 (65%) pts. Related G3 AEs were reported in 7 (13%) pts, included nausea, rash, sepsis syndrome, fatigue, and pneumonitis. Two pts (4%) had AEs leading to treatment discontinuation, related in 1/2 (G3 pneumonitis). Combination PK was consistent with single agent observations and supports BID dosing of GDC-0919. Peripheral PD showed dose-dependent decreases in plasma kynurenine, consistent with systemic modulation of IDO1. Preliminary efficacy data from 45 pts with ≥ 1 on-treatment tumor assessments included 4 patients (9%) with partial response and 11 (24%) pts with stable disease. Conclusions: The combination of GDC-0919 and atezolizumab was generally well-tolerated and demonstrated peripheral IDO1 modulation and preliminary efficacy in a heterogeneous patient population during dose escalation. The study is currently enrolling pts with select tumor types in expansion cohorts to assess tumor PD and combination efficacy. Clinical trial information: NCT02471846.
A high-risk genetic profile for premature menopause (PM) in childhood cancer survivors (CCS) exposed to gonadotoxic therapy: A report from the St. Jude Lifetime Cohort (SJLIFE) and Childhood Cancer Survivor Study (CCSS).
Authors: Brooke Russell J , Chemaitilly Wassim , Wilson Carmen Louise , Krasin Matthew J. , Li Zhenghong , Im Cindy , Morton Lindsay M. , Wu Gang , Wang Zhaoming , Chen Wenan , Howell Rebecca M. , Armstrong Gregory T. , Bhatia Smita , Chanock Stephen J. , Zhang Jinghui , Green Daniel M. , Sklar Charles A. , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka
Published: September 2018

10502

Background: CCS are at increased risk of therapy-related PM but contribution of genetic factors is unknown. Methods: Using Affymetrix 6.0 SNP array, treatment exposures [cumulative alkylating agents (AA), ovarian radiotherapy (RT) dose] and clinically-assessed PM status (menopause < 40 years), a genome-wide association analysis was conducted using logistic regression in SJLIFE. A cluster of most statistically significant SNPs on chr4 was further examined, stratifying by ovarian RT and AA. Replication was performed using self-reported PM in CCSS. Results: PM was diagnosed in 30 of 805 SJLIFE female survivors. A loci of 13 SNPs in 4 linkage disequilibrium blocks (mean r2 = 0.51) in the upstream regulatory region of Neuropeptide Receptor 2 ( NPY2R) was identified with a minimum p-value of 3.3x10-7 (all <10-5). ENCODE gene expression, motifs, and chromatin remodeling data suggest these SNPs alter transcription factor binding sites, potentially disrupting neuroendocrine events necessary for ovulation. Among CCS exposed to ovarian RT, homozygous carriers of a risk profile (RP) defined by 4 of the 13 SNPs, found in over half of the survivors with clinically-diagnosed PM and 1 in 7 in the general population, significantly increased PM risk (odds ratio (OR) 25.8, p=5.4x10-5) (Table). This finding was replicated using self-reported PM status of 1644 survivors in CCSS (OR 4.2, p=4.6x10-4). Prediction of clinically-diagnosed PM (in the SJLIFE discovery cohort) improved by adding the RP to the model with age and treatment (area under ROC curve 0.84 vs. 0.93, p=0.011). Conclusions: The common RP is associated with PM risk in pediatric cancer survivors and may have potential for clinical application. [Table: see text]
Temporal trends in late-onset morbidity and mortality after medulloblastoma diagnosed across three decades: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Salloum Ralph , Chen Yan , Yasui Yutaka , Packer Roger , Leisenring Wendy M. , Wells Elizabeth M. , King Allison A. , Howell Rebecca M. , Gibson Todd M. , Krull Kevin R. , Robison Leslie L. , Oeffinger Kevin C. , Fouladi Maryam , Armstrong Gregory T.
Published: September 2018

10516

Background: Therapy for medulloblastoma and primitive neuroectodermal tumor has evolved from surgery and adjuvant radiotherapy to risk-adapted multimodal regimens. The impact of these changes in treatment on long-term outcomes remains unknown. Methods: Cumulative incidence of late mortality ( > 5 years from diagnosis), subsequent malignant neoplasms (SMN), chronic health conditions and psychosocial functioning were evaluated among 5-year survivors in CCSS diagnosed between 1970 and 1999. Survivors were stratified according to treatment decade (1970s, 1980s, 1990s) and treatment exposure (surgery + craniospinal irradiation [CSI] ≥30 Gy, no chemotherapy; surgery + CSI ≥30 Gy + chemotherapy [high-risk therapy], surgery + CSI ˂30 Gy + chemotherapy [standard-risk therapy]). Rate ratios (RRs), odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for long-term outcomes among treatment eras and exposure groups using multivariable piecewise-exponential models. Results: Among 1,380 eligible survivors (median [range] age 29 [6-20] years; 21.4 [5-44] years from diagnosis), the 15-year cumulative incidence of all-cause (21.9% 1970s vs. 12.8% 1990s; p = 0.003) and recurrence-related (16.2% vs 9.6%, p = 0.03) late mortality decreased with no reduction in mortality attributable to late effects of therapy including SMN. Among 959 participants, the incidence of SMN did not decrease by era or by treatment group. However, survivors treated in the 1990s had an increased cumulative incidence of severe, life-threatening and fatal health conditions (16.9% 1970s vs 25.4% 1990s; p = 0.03), and were more likely to develop multiple severe or life-threatening health conditions, RR = 2.98 (95% CI, 1.10-8.07). Survivors of standard-risk therapy were less likely to use special education services than high-risk therapy patients, OR = 0.51 (95% CI, 0.33-0.78). Conclusions: Historical changes in therapy have improved 5-year survival, reduced risk of late mortality due to disease recurrence, and reduced special education utilization, at the cost of increased risk for multiple, severe and life-threatening chronic health conditions.
Longitudinal analysis of quality of life outcomes in children during treatment for acute lymphoblastic leukemia: A report from the Children’s Oncology Group (COG) AALL0932.
Authors: Zheng Daniel , Lu Xiaomin , Ross Wilhelmenia L. , Angiolillo Anne L. , Schore Reuven , Balsamo Lyn M. , Devidas Meenakshi , Whitley Moira K. , Kadan-Lottick Nina S.
Published: September 2018

10522

Background: 5-year event-free survival for average-risk acute lymphoblastic leukemia (AR-ALL) in children is ~95%. However, therapy involves multi-agent chemotherapy, frequent hospital visits (duration of therapy is 26 months for girls and 38 months for boys) and painful procedures that can adversely affect quality of life (QOL). Methods: AR-ALL patients enrolled on COG AALL0932 were offered participation if ≥4 years old at diagnosis with an English-speaking parent. At ~2, 8, 17, 26, and 38 (boys only) months after diagnosis, parents completed the PedsQL4.0 and the Family Assessment Device instruments for QOL (assessing physical and emotional functioning) and family functioning, respectively. The proportions of individuals scoring in the impaired range (i.e. 2 SD below population mean) were calculated at each timepoint. Patterns of impairment over time and potential predictors were examined. Results: 594 participants with AR-ALL (48% female, 68% white) were diagnosed at a median age of 5.6 (IQR: 4.6–7.1) years. At 2 months, a significant percentage of participants had impaired scores compared to population norms for physical (36.5 vs. 2.3; 95% CI 32.3-40.8) and emotional functioning (26.2 vs. 2.3; 95% CI 22.5-30.2). Although scores improved over time, elevations persisted at 26 months for physical (11.9 vs. 2.3; 95% CI 8.4-16.1) and emotional (9.8 vs. 2.3; 95% CI 2.0-6.7) functioning. In repeated measures analysis with multivariate modeling, emotional impairment at 2 months (OR 3.7; 95% CI 1.5-7.7) and abnormal family functioning (OR 1.5; 95% CI 1.1-2.1) significantly predicted emotional impairment. QOL outcomes were similar for girls at 26 months and boys at 38 months. Conclusions: Many children with AR-ALL experience severe impairment in both physical and emotional functioning that begins early in treatment and persists. Family functioning is a modifiable risk factor that may be targeted for early screening and intervention.
A phase I/II study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors (iMATRIX-Atezolizumab).
Authors: Geoerger Birgit , Karski Erin E. , Zwaan Michel , Casanova Michela , Marshall Lynley V. , DuBois Steven G. , Kowgier Matthew , Tagen Michael , Kwan Antonia , Das-Thakur Meghna , Trippett Tanya Maria
Published: September 2018

10524

Background: Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anticancer T-cell response. The iMATRIX-Atezolizumab study (phase I/II, multicenter, open-label; NCT02541604) assessed the safety, pharmacokinetics (PK) and preliminary activity of atezolizumab in pediatric/young adult patients with refractory/relapsed solid tumors. Methods: Patients aged < 30 years with refractory/relapsed non-central nervous system solid tumors received atezolizumab every 3 weeks until loss of clinical benefit ( < 18 years old, 15mg/kg [maximum dose 1200mg]; ≥18 years old, 1200mg). Safety/PK were assessed across tumor types and initial response was assessed by tumor-type cohorts after approximately 10 patients in each cohort had been treated. Results: As of July 19 2016, 74 patients (median age 14 years; range 2–29) were enrolled: osteosarcoma, n = 12; Ewing sarcoma, n = 11; neuroblastoma, n = 11; rhabdomyosarcoma (RMS), n = 10; non-RMS soft tissue sarcoma, n = 10; Wilms tumor, n = 6; Hodgkin lymphoma (HL), n = 5; non-HL, n = 1; other tumor types, n = 8. PK data (n = 48) were similar to that in adults (geometric mean Cmin, µg/mL [cycle 2, day 1, pre-dose]: 53.6 [2– < 6 years old]; 54.1 [6– < 12 years old]; 62.0 [12– < 18 years old]; 68.0 [adult]). Most tumors, except HL, had < 1% (score 0) tumor cell [TC]/tumor-infiltrating immune cell (IC) PD-L1 expression with overall TC/IC-positive expression rates (≥1%, score 1–3) of 7% and 10%, respectively. All available HL samples had ≥5% (score 2–3) TC/IC PD-L1 expression. 67/71 patients who received atezolizumab (median cycles 2; range 1–10) had ≥1 adverse event (AE; mainly immune-related grade 1–2); 17 patients (24%) had treatment-related grade 3–4 AEs. One AE (grade 3 transaminase increase) led to study drug discontinuation. Common AEs were pyrexia (37%), fatigue (34%) and constipation (32%). 2/5 patients with HL had a partial response (PR); the only patient with atypical rhabdoid tumor (RT) had an unconfirmed PR. Conclusions: The PK and safety profile of atezolizumab in pediatric and young adult patients is similar to that in adults. Preliminary antitumor activity was seen in HL and RT; new cohorts are planned in RT and atypical teratoid RT. Clinical trial information: NCT02541604.
ADVL1412: Initial results of a phase I/II study of nivolumab and ipilimumab in pediatric patients with relapsed/refractory solid tumors—A COG study.
Authors: Davis Kara L. , Fox Elizabeth , Reid Joel M. , Liu Xiaowei , Minard Charles G. , Weigel Brenda , Mackall Crystal
Published: September 2018

10526

Background: Checkpoint inhibitors have produced impressive responses in cancer. We report results of a Phase 1 study of nivolumab (nivo) alone and in combination with ipilumumab (ipi) in children with relapsed/refractory solid tumors and activity of nivo in patients with osteosarcoma (OS) and Ewing sarcoma (EWS) treated with the RP2D. Methods: Children with relapsed/refractory solid tumors (excluding CNS tumors or metastases) were eligible for Phase I Cohorts A and C. Using a rolling 6 design, Cohort A tested nivo at the adult RP2D, 3mg/kg Q14d (cycle = 28d). Cohort C tested nivo + ipi at 2 dose levels (DLs): DL1 nivo 1mg/kg + ipi 1mg/kg and DL2 nivo 3mg/kg + ipi 1mg/kg Q21d x 4 then nivo alone Q14d. At the RP2Ds, 6 additional patients were enrolled in each cohort for pharmacokinetics (PK). Phase II expansion cohorts enrolled patients with measurable OS (Cohort B2, n = 10) or EWS (Cohort B4, n = 10) respectively to assess activity of the RP2D of single agent nivo. Results: Twelve evaluable patients enrolled in Cohort A, none had DLTs. The pediatric RP2D of nivo alone was identified as 3 mg/kg Q14d. Five evaluable patients enrolled in Cohort C:DL1 without DLT, then 12 patients enrolled in Cohort C:DL2 with one DLT within the 21d reporting period (Gr 2 creatinine increase), defining the RP2D of nivo 3mg/kg + ipi 1mg/kg at the schedule above. In 39 patients treated in cohorts A, B2, B4 and C, pleural effusions occurred in 7 with variable attributions to drug, leading to a protocol amendment mandating supportive care and corticosteroids for pleural effusions on study. Common toxicities included anemia, elevated liver enzymes, rash, fatigue, and nausea, generally Grade 1. In Cohort A, nivo Cmax, t1/2 and Clpvalues were 63.2±15.7 mg/mL, 10.7±1.8 d and 0.196±0.075 ml/h/kg, respectively. In the Phase II expansion cohorts, no objective responses were observed in OS or EWS. Conclusions: Nivo alone or with ipi at the doses tested is safe in pediatric patients with relapsed/refractory solid tumors. The pediatric RP2D of nivo is 3mg/kg alone or in combination with ipi 1mg/kg. Single agent nivo did not have antitumor activity in OS or EWS. Enrollment to other expansion cohorts with nivo or nivo/ipi is ongoing. Clinical trial information: NCT02304458.
Outcomes of children with hereditary medullary thyroid carcinoma (MTC) treated with vandetanib.
Authors: Kraft Ira Lignugaris , Akshintala Srivandana , Derse-Anthony Claudia , Steinberg Seth M. , Venzon David J. , Dombi Eva , Waguespack Steven G. , Kapustina Oxana Borisovna , Fox Elizabeth , Balis Frank M. , Shern John Frederick , Glod John , Widemann Brigitte C.
Published: September 2018

10540

Background: Vandetanib is well tolerated and active in children with advanced or metastatic hereditary MTC (NCT00514046) [data cutoff 7/2011; Clin Cancer Res. 2013 Aug 1;19(15):4239-48]. We report outcomes as of 1/2017. Methods: We monitored toxicities, RECISTv1.0, carcinoembryonic antigen (CEA), and calcitonin (CT) response. Patients (pts) removed from the vandetanib trial were followed on a natural history study (NCT01660984). Results: Of 17 pts (8 male, age 13 years (9-17)*) enrolled, 1 was lost to follow-up. Of the 16 pts analyzed, 15 had a RET p.M918T germline mutation. The duration of vandetanib therapy was 5.6 years (0.1-9.2+) with treatment ongoing in 8 pts. Best response was partial response (PR) in 10, stable disease (SD) in 5, and progressive disease (PD) in 1 pt. Time to achieve PR (n = 10) was 0.6 years (0.4-2.4). Time to best response (n = 16) was 1.5 years (0.1-4.1). Duration of response was 5.1 years (1.3-8.6+) in pts with PR and 4.8 years (0.6-7.3+) in pts with SD. Seven of 8 pts with PD subsequently received sunitinib, sorafenib, and/or cabozantinib. Disease progression occurred as increase in target (n = 2), non-target/new lesions (n = 5), or CT/CEA (n = 1). Six pts died from disease 2.1 years (0.4-4.3) after stopping vandetanib. Progression free survival was 6.2 years (95% CI 3.0-na) and overall survival was 7.9 years (95% CI 5.9-na).Pts had no difference in enrollment age, baseline CT/CEA, or tumor size per response categories (n = 16). Rate of CEA/CT decrease during initial 4 months of treatment was not associated with PR/SD compared to PD (n = 16). While on vandetanib, 6 pts with PD had CEA or CT doubling time (DT) of < 2 years within 1 year prior to PD. All pts with ongoing PR/SD had CEA and CT DT > 2 years while on vandetanib. No pts came off treatment for toxicity. Dose reductions occurred in 8 pts for grade (gr) 2 weight loss (n = 2), palpitations (n = 1), arrhythmia (n = 1), elevated creatinine (n = 1), diarrhea (n = 2), and gr 3 constipation (n = 1). Conclusions: Many children with hereditary MTC sustained PR/SD on vandetanib. However, half ultimately developed PD and died from disease despite treatment with other targeted therapies. CEA/CT DT < 2 years within 1 year of progression on vandetanib may be associated with PD. *Median (range)
Single-agent dose-finding cohort of a phase 1/2 study of lenvatinib (LEN) in children and adolescents with refractory or relapsed solid tumors.
Authors: Gaspar Nathalie , Gallego Melcon Maria Soledad , Venkatramani Rajkumar , Bielack Stefan S. , Casanova Michela , Locatelli Franco , Thebaud Estelle , Rigaud Charlotte , Abbou Samuel , Gambart Marion , Morland Bruce , Aerts Isabelle , Kraljevic Silvija , Li Di , Maniar Hina , Hayato Seiichi , Dutcus Corina E , Campbell Hewson Quentin
Published: September 2018

10544

Background: LEN is an inhibitor of vascular endothelial growth factor (VEGF) receptors 1‒3, fibroblast growth factor receptors 1‒4, platelet-derived growth factor receptor α, RET, and KIT. LEN is approved in adults for radioiodine-refractory differentiated thyroid cancer (DTC) and in combination with everolimus in patients (pts) with advanced renal cell carcinoma. We show results from the single-agent LEN dose-finding part of a phase 1/2 study in children and adolescents with solid tumors. Methods: Pts had any relapsed or refractory solid tumor, evaluable or measurable disease, were aged 2 to ≤18 years, had < 2 prior VEGF-targeted therapies, and adequate organ function. A starting dose of LEN 11 mg/m2was escalated with a time-to-event continual reassessment method. The primary endpoint was to determine the LEN recommended dose (RD). Secondary objectives included best overall response (BOR), objective response rate, safety, and pharmacokinetics (PK). Results: 23 pts enrolled (11 mg/m2: n = 5, 14 mg/m2: n = 11, 17 mg/m2: n = 7). The most common tumors were rhabdomyosarcoma (n = 5), Ewing sarcoma (n = 4), and neuroblastoma (n = 3). 3 Dose-limiting toxicities occurred in cycle 1 at 14 mg/m2 (increased alanine aminotransferase: 1; hypertension: 2). All pts had any-grade treatment-emergent adverse events (TEAEs; grade 3/4: 65%). Most common any-grade TEAEs were vomiting (52%), abdominal pain (48%), decreased appetite (48%), diarrhea (44%), and hypothyroidism (44%). 1 Pt discontinued LEN due to a LEN-related TEAE (hypertension). BOR was stable disease (n = 10). Effect of age on oral clearance and central volume of distribution was not significant. Exposure was similar to that in adults. LEN 14 mg/m2/day was therefore identified as the RD. Updated cohort 1 data will be shown. Conclusions: The LEN RD in children and adolescents was similar to the adult dose and showed a reasonable safety profile. PK in these pts did not differ significantly from that in adults. The phase 1b dose-finding study of LEN in combination with chemotherapy in osteosarcoma (OS) and phase 2 LEN monotherapy (RD 14 mg/m2) parts in DTC and OS are ongoing. Clinical trial information: NCT02432274.
Relationship between the cumulative burden (CB) of chronic health conditions (CHC) and health-related quality of life (HRQoL) among childhood cancer survivors (CCS): The St. Jude Lifetime (SJLIFE) cohort.
Authors: Bhakta Nickhill , Liu Qi , Ehrhardt Matthew J. , Ness Kirsten K. , Krull Kevin R. , Srivastava Deo Kumar , Ganz Patricia A. , Yasui Yutaka , Hudson Melissa M. , Robison Leslie L. , Huang I-Chan
Published: September 2018

10560

Background: Adult CCS experience an excess burden of CHC. The association between disease burden (estimated using CB) and HRQoL has not been extensively assessed. Methods: 2878 CCS (mean [range] age 32.1 [18.3-66.2] years; time from diagnosis 25.0 [10.2-51.0] years) were enrolled in SJLIFE (eligibility: survived >10 years and >18 years of age) and clinically evaluated for 168 graded CHC using the St. Jude modified Common Terminology Criteria for Adverse Events. HRQoL was assessed using the Short Form 36 survey and categorized into Low (< -0.5 SDs), Average (-0.5 to 0.5 SDs), and High (> 0.5 SDs) subgroups from the Physical and Mental Component Summary (PCS, MCS) and Vitality Scale using cohort age- and sex-specific values. CB (average number of grade 3-4 [severe/life-threatening] CHC/survivor) for each CHC was calculated and summed for each HRQoL subgroup. Results: Survivors with low PCS had, on average, more CHC CB compared to those with High and Average PCS. Higher CHC CB was also associated with poorer Vitality and MCS, but the differences in effect size were smaller than PCS. When CB for each of the 3 HRQoL scores were compared by subgroups across 12 organ systems and subsequent neoplasms, CB at age 50 differed significantly (p<0.05) across PCS, MCS, and Vitality in 9, 3 and 7 of the 13 systems, respectively. Conclusions: Survivors with lower HRQoL scores have more CHC, but the patterns of this association vary in PCS, MCS and Vitality by CHC organ systems, suggesting adult CCS adjust better to certain types of CHC than others. Future research will focus on CHC with greatest impact on functioning. [Table: see text]
Endothelial dysfunction in adult survivors of childhood cancer: A report from the St. Jude Lifetime Cohort study.
Authors: Mulrooney Daniel A. , Ness Kirsten K. , Huang Sujuan , Santucci Aimee , Hebbel Robert P. , Solovey Anna S. , Duprez Daniel , Ehrhardt Matthew J. , Green Daniel M. , Srivastava Deokumar , Robison Leslie L. , Hudson Melissa M.
Published: September 2018

10564

Background: Endothelial dysfunction, as an indicator of vascular disease in childhood cancer survivors (CCS) has not been widely studied. Methods: Markers of vascular inflammation (high sensitivity C-reactive protein [hsCRP]), hemostasis (fibrinogen), activation (endothelial cell expression of vascular cell adhesion molecule [VCAM-1]) and functional testing (large/small artery elasticity [L/SAE], pulse wave velocity [PWV]) were assessed in 200 CCS, ≥10 years from diagnosis, and 192 age/gender matched healthy controls. Exclusion criteria included: inflammatory processes, use of anti-inflammatory or cardiovascular medications, or pregnancy. Differences were assessed by adjusted multivariable linear regression. Results: CCS (53% male) of leukemia/lymphoma (59%), central nervous system tumors (6%), sarcomas (11.5%), embryonal tumors (22.5%), and other (1%) had a mean age at diagnosis 7.3 years (SD ±5.7). CCS and controls did not differ in current age (mean 34.1 ±9.2 vs. 33.5 years ±9.8), body mass index, smoking, mean systolic (124 mm Hg ±11.7 vs. 123 ±11.9) or diastolic blood pressure (73 ±9.5 vs. 71 ±9.5). Fasting low- (110 mg/dl ±31 vs. 102 ±30) and high-density (52 ±16 vs. 56 ±18) cholesterol levels differed between survivors and controls (p<0.01). Endothelial expression of VCAM-1 and PWV were statistically significantly increased in CCS; arterial elasticity was significantly reduced (table). Therapeutic exposures (anthracyclines and radiation) were not significantly associated with endothelial dysfunction. Conclusions: Childhood cancer survivors have greater endothelial dysfunction, a sign of atherosclerosis, and preventive measures should be investigated. [Table: see text]
Intensity of end-of life-care in children with cancer: A population-based study.
Authors: Johnston Emily E. , Alvarez Elysia Marie , Saynina Olga , Sanders Lee , Bhatia Smita , Chamberlain Lisa J
Published: September 2018

10574

Background: There is growing evidence that adult oncology patients who know they are dying choose less intense care. Further, high intensity care is associated with worse caregiver outcomes. Little is known about pediatric oncology end-of-life care intensity. Methods: Using the California Office of Statewide Health Planning and Development administrative database linked to death certificates, we performed a retrospective population based analysis of cancer patients aged 0-21 who died between 2000 and 2011. The frequency of previously defined end-of-life intensity markers (hospital death, intense medical interventions, IV chemotherapy, and gastrostomy and tracheostomy tube placement) were calculated and multivariable logistic regression was used to determine clinical and sociodemographic factors associated with > 2 intensity markers (as above), intense medical intervention (cardiopulmonary resuscitation, intubation, ICU admission, or hemodialysis), and hospital death. Results: The 3,732 pediatric cancer decedents were 34% non-Hispanic whites and 45% Hispanic; 41% had hematologic malignancies and 59% solid tumors. The most prevalent intensity markers included: hospital death (63%) and ICU admission (20%). 65% had > 1 intensity marker, 23% > 2, and 22% > 1 intense medical intervention. There was a bimodal association between age and intensity: the youngest patients (age < 5) and adolescent patients (age 15-21) were more likely to receive intense care: < 5y (intense medical intervention: OR = 1.42; 95% CI, 1.1-1.9; hospital death: OR = 1.72; 95% CI, 1.4-2.2; > 2 markers: OR = 1.37, 95% CI 1.1-1.8); 15-21y (intense medical: OR = 1.48; 95% CI, 1.2-1.9; hospital death: OR = 1.39; 95% CI, 1.1-1.7; > 2 markers: OR = 1.35, 1.1-1.7) (references: 5-9y). Other factors associated with intensity included, hematologic malignancies, minority status, and death between 2008 and 2011 vs. < 2008. Conclusions: Nearly two-thirds of the pediatric cancer decedents had ≥1 marker of intense care and disparities exist. Patients < 5 and adolescents were more likely to receive intense end-of-life care. Further research needs to determine if these rates and variation are consistent with patient goals and factors associated with goal concurrent care.
Safety and tolerability of the dual PI3K/mTOR inhibitor LY3023414 in combination with fulvestrant in treatment refractory advanced breast cancer patients.
Authors: Varghese Anna M. , Moore Kathleen N. , Hamilton Erika Paige , Hyman David Michael , Jhaveri Komal L. , Wang Xuejing Aimee , Callies Sophie , Fink Aaron Alan , Wacheck Volker , Bendell Johanna C.
Published: September 2018

1064

Background: Thephosphatidylinositol 3-kinase (PI3K) /mammalian target of rapamycin (mTOR) pathway is frequently activated in breast cancer. LY3023414 (LY) is an oral ATP- competitive inhibitor that selectively and potently inhibits class I PI3K isoforms, mTOR, and DNA-PK. The recommended phase 2 dose (RP2D) of LY monotherapy was previously established to be 200 mg twice daily (BID). Here we present the safety and preliminary activity data of LY in combination with fulvestrant (F) for breast cancer patients (pts) as part of a multi-cohort Phase 1 study. Methods: Pts with advanced HR+, HER2- breast cancer refractory to standard treatment received 200 mg LY BID + 500 mg F (day 1 and 15, then once monthly). Eligible pts had measurable disease and baseline tumor tissue available. Primary objective was to determine a RP2D. Other objectives included assessment of pharmacokinetics (PK), antitumor activity, and biomarker analysis. Results: 9 pts received LY + F in the breast cancer expansion cohort. All pts had multiple lines of prior systemic therapy (range 3-12), including chemotherapy. Dose limiting toxicity was observed in one pt in the form of grade (Gr) 3 oral mucositis. Common possibly related adverse events included nausea (5 pts), vomiting (4 pts), oral mucositis (4 pts), decreased appetite (3 pts), fatigue (3 pts), mucosal inflammation (2 pts), and paresthesia (2 pts). No obvious impact of LY on F PK or of F on LY PK was observed. Median duration of treatment was 15 weeks (range 3-63). In the 6 pts evaluable for tumor response, there was 1 durable partial response according to RECIST (still on treatment for ≥11 months) and 4 further pts had a decrease in their target lesions for a disease control rate of 56%. The median progression-free survival for this cohort is 4.2 months (90% CI 1.8, NA). Of note, the partial response was observed in a pt harboring an activating PIK3CA mutation (H1047R). Further biomarker analysis is ongoing. Conclusions: The RP2D of LY in combination with F is 200mg BID and may cause tumor regression or stabilization in breast cancer pts. Clinical trial information: NCT01655225.
A phase II study of glembatumumab vedotin (GV), an antibody-drug conjugate (ADC) targeting gpNMB, in advanced melanoma.
Authors: Ott Patrick Alexander , Pavlick Anna C. , Johnson Douglas Buckner , Hart Lowell L. , Infante Jeffrey R. , Luke Jason John , Lutzky Jose , Rothschild Neal Evan , Spitler Lynn E. , Cowey Charles Lance , Alizadeh Aaron , Salama April K. , Yin Xiaoyan , Bagley Rebecca G. , Wang Ying , Hamid Omid
Published: September 2018

109

Background: gpNMB is an internalizable transmembrane glycoprotein expressed in melanoma and multiple other tumor types. The ADC GV (CDX-011) delivers the potent cytotoxin MMAE to gpNMB+ cells. GV has shown promising activity in advanced melanoma and breast cancer. Methods: This Phase II study (CDX011-05) assessed the efficacy and safety of GV monotherapy (1.9 mg/kg q3w) for patients (pts) with advanced melanoma progressive after ≤1 chemotherapy, ≥1 checkpoint inhibitor (CPI) and if BRAFV600mutated, ≥1 BRAF/MEK inhibitor. Central IHC determined gpNMB expression in archival and/or pre-treatment tumor. Primary endpoint was objective response rate (ORR) (RECIST 1.1) with ≥6 responders out of 52 evaluable pts as threshold for antitumor activity. Additional endpoints: progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK/PD and correlation of tumor gpNMB expression with efficacy. Results: 62 pts enrolled (all evaluable) had median age of 67 years; 55% male; 21% BRAFV600mutated; 63% with ≥3 lines prior therapy; 100% had prior CPI; 100% Stage IV; 89% M1c. One confirmed complete response (CR) and 6 confirmed partial responses (PR, including 1 unconfirmed CR) were seen (confirmed ORR = 11%, p = 0.035 comparing to reference ORR 5%); 33 pts had stable disease including 3 unconfirmed PR. Median DOR = 6.0 (range: 4.1, 14+) months (mos), median PFS = 4.3 mos and median OS = 9.8 mos; 26 pts continue to be followed for survival. All pts with available tissue (60/60) had gpNMB+ tumors; 47/60 had 100% gpNMB+ epithelial cells; no clear correlation with outcome was seen in this population with consistent high expression. Toxicities included alopecia, neuropathy, rash, fatigue and neutropenia. Treatment-related rash in cycle 1 was associated with improved ORR (rash = 22%; no rash = 7%), PFS (p = 0.007) and OS (p = 0.035). Conclusions: GV has promising activity (primary endpoint of ORR was met) with a manageable safety profile in heavily pre-treated melanoma pts. Additional cohorts evaluating GV with either varlilumab, an activating anti-CD27 monoclonal antibody, or PD-1 inhibitors are open to accrual to provide further insights into the synergy of ADC and immunotherapy. Clinical trial information: NCT02302339.
Dynamic relationship between cycling kinetics of triple-negative breast cancer and tumor infiltrating immune cells.
Authors: Choudhary Ishita , Klimov Sergey , Rida Padmashree C.G. , Ogden Angela , Green Andrew R. , Aleskandarany Mohammed A. , Rakha Emad A. , Ellis Ian O. , Biganzoli Elia , Sarkar Surojit , Kalia Vandana , Aneja Ritu
Published: September 2018

1100

Background: Recent studies show strong correlation between tumor infiltrating lymphocytes (TILs) and triple-negative breast cancer (TNBC) patient survival. CD8+ T cells serve as a favorable prognostic marker for TNBC. In addition, other cells such as CD4+ T cells, macrophages, B cells, and Tregs also infiltrate tumors. In this study, we delineate a strong relationship between the cycling kinetics of proliferating cells in TNBCs and antitumor immune response. Methods: A multi-institutional study performed by our group has previously shown that KAMS (Ki67-Adjusted Mitotic Score) provides a measure of the cycling kinetics of proliferating tumor cells and robustly stratifies TNBC patients into slow cycling (low KAMS) cyclophosphamide-methotrexate-fluorouracil (CMF)-responsive and fast cycling (high KAMS) CMF-resistant subgroups. In this study, we reviewed clinical data from 124 CMF-treated TNBC patients from Nottingham Hospital and sought correlations between cycling kinetics (High/Low KAMS) and tumor infiltrating immune cells. Results: We found that slow cycling TNBCs had higher mean expression of tumor infiltrating immune cells than fast cycling TNBCs. Intratumoral CD68 (p = 0.003), CD3 (p = 0.006), CD20 (p = 0.01), FOXP3 (p = 0.01), and total numbers of intratumoral and stromal CD68 (p = 0.01) and CD3 (p = 0.03) expressing cells were found to be significantly higher in low KAMS tumors than in high KAMS tumors. Of these biomarkers, CD68 was significantly associated with patients’ breast cancer-specific survival (BCSS): (a) low KAMS, high CD68 TNBCs had better BCSS than low KAMS, low CD68 (p = 0.01) TNBCs, and (b) high KAMS, low CD68 cases had better BCSS than high KAMS, high CD68 cases. Conclusions: Our observation that there are more TILs in slow cycling TNBCs suggests that there may be a dynamic cross-regulation between cycling kinetics and antitumor immune response. From our surprising observation that CD68 exerts polar roles in low/high KAMS subgroups, we propose that distinctions in M1 and M2 macrophage subsets in slow and fast cycling TNBCs may correlate with distinct outcomes. In addition, metabolic competition between tumor and immune cells may determine the level and function of TILs.
Phase III study of aldoxorubicin vs investigators' choice as treatment for relapsed/refractory soft tissue sarcomas.
Authors: Chawla Sant P. , Ganjoo Kristen N. , Schuetze Scott , Papai Zsuzsanna , Van Tine Brian Andrew , Choy Edwin , Liebner David A. , Agulnik Mark , Chawla Shanta , Wieland Scott , Levitt Daniel J.
Published: September 2018

11000

Background: Aldoxorubicin (A) is a novel drug that binds covalently to albumin in the circulation, accumulates in tumors and releases doxorubicin in the acidic tumor environment. It has demonstrated enhanced antitumor activity in several murine models and in a phase IIb STS study when compared with doxorubicin. Trial Design: Phase III open-label study evaluating efficacy and safety of A compared to investigators' choice (IC) of treatment in subjects with soft tissue sarcomas (STS) who have relapsed or were refractory to prior chemotherapy. Objectives: (1) Primary: Efficacy of A vs IC: progression-free survival (PFS); (2) Secondary: Efficacy of A vs IC: tumor response (ORR), disease control rate (DCR; CR+PR+SD > 4 months), overall survival (OS) and safety. Methods: A: 350 mg/m2 (260 mg/m2dox. equiv.) iv q3 wks. IC drugs: dacarbazine, doxorubicin, pazopanib, ifosfamide, gemcitabine/docetaxel administered per package insert or study site's standard practice; provided, with G-CSF, by the sponsor. AEs, serum chemistries, CBCs, EKG and ECHOs obtained frequently. CT scans every 6 weeks for 30 weeks, then every 12 weeks; analyzed using RECIST 1.1 by Blinded Independent Central Review. Results: Randomized 433 subjects; 79 countries; 313 (72%) in North America (NA) and 121 (28%) in Rest of World (ROW). Leiomyosarcoma 42.5%, liposarcoma 15%, synovial sarcoma 9%, others 33.5%, L-sarcomas (lipo+leiomyo) 57.5%. Median PFS Total Pop. (months): A= 4.06; IC= 2.96; p = 0.12; HR = 0.82 (0.64-1.06). Median PFS NA (months): A= 4.21; IC= 2.96; p = 0.027; HR = 0.71 (0.53-0.97). Median PFS L-sarcomas (months): A= 5.32; IC= 2.96; p = 0.007; HR = 0.62 (0.44-0.88). DCR Total Pop.(%): A= 30.3; IC= 20.9; p = 0.028; DCR NA (%): A= 32.9; IC= 19.2; p = 0.007; DCR L-Sarcomas (%): A= 37.5; IC= 23.0; p = 0.018. ORR and OS will be reported. TEAEs gr 3 or 4 (%): A= 61.0; IC= 46.4. Trtmt Rel. SAEs (%): A= 27.0; IC= 14.0. TEAEs leading to Drug Discontinue (%): A= 4.2; IC= 6.3. Trtmt Related Deaths (#); A= 3; IC= 0; LVEF < 50% expected (%): A= 2.8%;Dox = 12.8%. Conclusions: Aldox is an active, well-tolerated drug for treating relapsed or refractory STS and is significantly better than standard treatments for patients with L-sarcomas. Clinical trial information: NCT02049905.