CONSORT diagram for patient disposition and availability of biomarker for analyses.

CTC enumeration patterns in all population CTCs by best overall response rate.

Representative pre- and post-olaratumab monotherapy biopsies from the same patient, stained with IHC for PDGFRα (A, B) and PDGFRβ (C, D) and displayed at 200x total magnification. Pre-olaratumab images are A and C; post-treatment images are B and D.

Treatment-emergent adverse events reported in {greater than or equal to}10% patients.

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m 2 , d1 and d8) and D (75 mg/m 2 , d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

Abstract This phase Ib study enumerated whole blood circulating tumor cells (CTC) and evaluated biomarkers in patients with potentially resectable soft-tissue sarcoma (STS) treated with olaratumab monotherapy (20 mg/kg) for one cycle followed by up to six cycles of olaratumab (20 mg/kg, cycles 1–2; 15 mg/kg, cycles 3–7) plus doxorubicin (75 mg/m2 on day 1). CTCs, platelet-derived growth factor receptors (PDGFR), and PDGF ligand expression in tumor tissue pre- and post-olaratumab monotherapy were evaluated. Antitumor activity, safety, pharmacokinetics, and PET/biomarker association with clinical outcome were assessed. Of 51 treated patients, 35, 43, and 37 were evaluable for CTC enumeration, PDGFRs, and PDGF ligand expression, respectively. An increase in CTCs at cycle 1 day 8 was observed, followed by a significant reduction by cycle 3 day 1 or 30-day follow-up. Decrease in CTC counts after olaratumab monotherapy was higher in patients with disease control than without disease control (57.9% vs. 31.2%). Baseline IHC expression was positive in most patients for PDGFRα [n = 31 (72.1%)] and PDGFRβ [n = 36 (83.7%)]. Similar rates were observed post-olaratumab monotherapy [PDGFRα, n = 30 (69.8%); PDGFRβ, n = 33 (76.7%)]. Eleven patients (29.7%) showed a 30% reduction by RT-PCR in PDGFRα at cycle 2. PDGFR expression and PET response showed no correlation with clinical outcome. Safety and pharmacokinetic profiles were consistent with previous reports. This study, the first to use a validated method for CTC detection, confirms that CTC enumeration in STS is feasible. However, no correlation was observed between PDGFRα expression and clinical outcome.

Olaratumab is a monoclonal antibody that specifically binds to platelet‐derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21‐day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high‐dose ifosfamide by investigator choice for subsequent 21‐day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A‐C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose‐limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma‐glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment‐emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.

e14097 Background: Patient attrition during study follow up is a concern in all clinical trials, although its impact on study results has rarely been assessed. In oncology, in particular, where studies are lengthier and may be extended into longitudinal studies, there is an increased likelihood of loss to follow up (LTFU) (Gill et al., 2018). This creates a heightened need to understand how it affects the trial’s validity. The loss of data from patients who have been LTFU can reduce a study’s precision and power. This imprecision not only impacts the results of the current study but can also affect future research as well as future patient treatment options. Studies have found that participant characteristics differ in individuals LTFU as compared to those who remain in follow up (Childs et al., 2011; Geng et al., 2008; Hochheimer et al., 2016). This further emphasizes how attrition can skew study results and their interpretation and supports the need to minimize patient attrition during follow up in order to reduce bias and generate robust study estimates. Methods: This study assessed the impact of LTFU rates on the study estimates through simulations using SAS software. While all endpoints can be affected by LTFU, this study assessed time-to-event endpoints. Exponential distribution was assumed with varying rates of LTFU. In addition, the work covered suggestions for reducing LTFU. Results: Even for low rates of LTFU, biases are introduced in time-to event endpoints. Conclusions: Researchers should make every effort to minimize the extent of LTFU in the design and of and conduct of their trials.

e14078 Background: Traditional methods such as the 3+3 design developed in the 1940s continue to be used in the majority of early phase oncology studies. Researchers have found that the traditional methods identify the appropriate dose level only 30% of the time. Patients are also exposed to sub-therapeutic doses due to the conservative methods. With these limitations on traditional design options, innovative methods need to be developed, adopted and assessed. Methods: This quantitative study assessed the association of the design methods (adaptive versus traditional) used for early phase oncology studies (adaptive versus traditional) and the outcome of late stage clinical trials. Differences by cancer type and by drug classification were also assessed. A sample of studies for this analysis was extracted from the National Institute of Health Clinical registry and results database. The data used for the analysis was extracted by the Clinical Trials Transformation Initiative (CTTI) Aggregate Analysis of ClinicalTrials.gov (AACT). Results: When assessing study design and outcome, there were lower odds of a positive outcome when adaptive methods were used though this association was not statistically significant (OR [95% highest posterior density (HPD)]:0.66 [0.20, 1.21]). Among the different drug types, using adaptive compared to traditional methods was associated with significantly higher odds of a positive outcome for taxanes, OR: 2.75, 95% HPD: 1.01, 5.16) and other, OR: 3.23, 95% HPD: 1.58, 5.46) but no association among studies of monoclonal antibodies or protein kinase inhibitors. There were no significant associations between early phase study design and outcome in late phase studies by cancer type (lung, breast, other). Conclusions: While results associated with the use of adaptive methods were not significant, further research should be conducted using all completed oncology clinical trials in the database to more precisely determine the relationship between adaptive study design in early phase oncology studies and outcomes in late stage studies. In addition, improvements in traditional versus adaptive design capture in the ClinicalTrials.gov database needs to be considered.

10541 Background: Olaratumab (O), a PDGFRα antagonist, is a targeted human IgG1 monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, -BB, and -CC binding and receptor activation, and has improved survival outcomes in adults with advanced sarcoma. Methods: This ongoing Phase 1, multicenter, dose-escalation study (NCT02677116) enrolled patients (pts) aged < 18 years, with a diagnosis of relapsed or refractory solid tumors, to 2 dose levels (Parts A and B) of O combined with fixed doses of standard chemotherapy with doxorubicin (D), vincristine/irinotecan (VI), or high-dose ifosfamide (I). Pts in Part A received 1 cycle (21 days) of O monotherapy at 15mg/kg IV on Days 1 and 8 followed by O + (D, VI, or I) for subsequent 21-day cycles. Each combination arm was complete when 6 pts received 2 full cycles. The primary objective of Part A was to determine the safety and tolerability of O 15mg/kg + (D, VI, or I) based on any dose-limiting toxicity (DLT) and O serum exposure matching between adult and pediatric pts. Results: Pts enrolled by O + chemotherapy regimen (n) were D (11), VI (10), and I (9). One pt (3.3%) experienced a DLT during the DLT period (Cycles 1 and 2), which consisted of grade (G) 4 elevated ALT while on O monotherapy. No ≥G3 infusion- or cardiac-related treatment emergent adverse events (AEs) occurred. Treatment-related AEs (TRAEs) ≥G3 reported in ≥2 pts are presented (Table). Serum concentrations of O in pediatric pts were within expected ranges based on adult exposure. Conclusions: Based on Part A results,O 15mg/kg as monotherapy or in combination with D, VI, or I is tolerable in pediatric pts with relapsed or refractory solid tumors. Part B of this trial is currently enrolling. Clinical trial information: NCT02677116.TRAE, n (%) O + D O + VI O + I G3 G4 G3 G4 G3 G4 ALT increased 0 0 1 (10.0) 0 0 1 (11.1) Anemia 1 (9.1) 0 1 (10.0) 1 (10.0) 3 (33.3) 0 Leukopenia 0 2 (18.2) 0 1 (10.0) 0 3 (33.3) Lymphopenia 0 1 (9.1) 1 (10.0) 0 1 (11.1) 4 (44.4) Neutropenia 0 3 (27.3) 2 (20.0) 1 (10.0) 1 (11.1) 1 (11.1) Thrombocytopenia 0 1 (9.1) 0 1 (10.0) 3 (33.3) 1 (11.1) Vomiting 0 0 1 (10.0) 0 1 (11.1) 0

330 Background: Increased platelet-derived growth factor receptor alpha (PDGFRα) expression is linked to epithelial-mesenchymal transition in pancreatic cancer. Olaratumab (O) is a fully human monoclonal antibody against PDGFRα previously approved for the treatment of advanced soft tissue sarcoma. Here, we report the initial safety and antitumor activity data of O in combination with nab-paclitaxel + gemcitabine (nPG) in first-line metastatic pancreatic cancer patients (pts). Methods: In this 3+3 dose escalation study, pts with stage IV pancreatic cancer received intravenous 15 mg/kg (cohort 1) or 20 mg/kg (cohort 2) O + nPG (125 mg/m2/1000 mg/m2) on D1, 8, and 15 of a 28-day cycle. Following dose escalation, additional pts were enrolled in an expansion phase to confirm safety. Primary objective was to determine a dose of O that can be safely combined with nPG. Results: As of September 2018, 10 pts were treated in dose escalation (cohort 1: 3 pts; cohort 2: 7 pts) with no dose-limiting toxicities (DLTs) observed. Safety of 20 mg/kg O + nPG was confirmed in the expansion cohort; 1 of 12 pts (8.3%) experienced a DLT of grade 4 neutropenia. Most frequent adverse events (AEs) (≥ 25%) reported across all cohorts included fatigue (50%); neutropenia (50%); nausea (46%); thrombocytopenia (41%); and constipation (32%). Related grade ≥ 3 AEs reported in > 2 pts were neutropenia (N = 7; 32%), infusion-related reaction, and neuropathy (both N = 3; 14%). There were no deaths related to study drugs. Among pts evaluable for response, 2 of 15 pts had a partial response and 11 pts had stable disease as best response for an objective response rate of 13%. Notably, 2 of 3 pts in cohort 1 continue on treatment for more than 12 months as of the data cut-off. Updated data will be presented at the meeting. Conclusions: Both dose levels were tolerated. Safety profile was similar to nPG chemotherapy with most toxicity manageable through dose adjustments of nPG. Clinical trial information: NCT03086369.

TPS2599 Background: Olaratumab (LY3012207, IMC-3G3), a PDGFRα antagonist, is a targeted human IgG1 monoclonal antibody that specifically binds PDGFRα, blocking PDGF-AA, -BB, and -CC binding and receptor activation. Preclinical studies of olaratumab with or without chemotherapy have demonstrated antitumor activity in human sarcoma xenograft models. Positive survival outcomes were observed in adult patients with advanced soft tissue sarcoma when they were treated with olaratumab + doxorubicin vs doxorubicin alone in a randomized phase 2 trial. Methods: This multicenter clinical trial (NCT02677116) includes patients < 18 years of age with a diagnosis of relapsed or refractory solid tumors not amenable to curative treatment, for whom chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide is deemed appropriate. The primary objective is to determine a recommended dose of olaratumab + ≥1 chemotherapy regimen(s) in pediatric patients based on any dose-limiting toxicity, and olaratumab serum exposure-matching between adult and pediatric patients. Secondary objectives include assessment of antitumor activity of each combination, immunogenicity, and pharmacokinetics. At least 12 pediatric patients will be treated with 1 cycle (21 days) of olaratumab monotherapy (dose level 1 [Part A] and dose level 2 [Part B]) on Days 1 and 8. If the patient does not experience a dose-limiting toxicity in the first cycle of monotherapy, the patient will then receive olaratumab plus either doxorubicin, vincristine/irinotecan, or high-dose ifosfamide per investigator discretion. Dose-limiting toxicity criteria will also be evaluated for the respective combinations in cycle 2. Treatment will continue until disease progression or other discontinuation criteria are met. Dose level 2 will be initiated after acceptable safety results from dose level 1 monotherapy (a minimum of 6 evaluable patients, and the pharmacokinetic profile). As of December 2016, enrollment is currently occurring in dose level 1. Clinical trial information: NCT02677116.

Topological properties of crystals and quasicrystals is a subject of recent and growing interest. This Letter reports an experiment where, for certain quasicrystals, these properties can be directly retrieved from diffraction. We directly observe, using an interferometric approach, all of the topological invariants of finite-length Fibonacci chains in their diffraction pattern. We also quantitatively demonstrate the stability of these topological invariants with respect to structural disorder.

We present a general and useful method to predict the existence, frequency, and spatial properties of gap states in photonic (and other) structures with a gapped spectrum. This method is established using the scattering approach. It offers a viewpoint based on a geometrical Fabry-Perot model. We demonstrate the capabilities of this model by predicting the behaviour of topological edge states in quasi-periodic structures.

We report on a study of topological properties of Fibonacci quasicrystals. Chern numbers which label the dense set of spectral gaps, are shown to be related to the underlying palindromic symmetry. Topological and spectral features are related to the two independent phases of the scattering matrix: the total phase shift describing the frequency spectrum and the chiral phase sensitive to topological features. Conveniently designed gap modes with spectral properties directly related to the Chern numbers allow to scan these phases. An effective topological Fabry-Perot cavity is presented.

Purpose: In men with extracapsular disease or positive surgical margins after radical prostatectomy immediate adjuvant therapy decreases the risk of biochemical recurrence at the cost of increased toxicity. We further stratified these men into a low risk group in which watchful waiting after surgery may be preferred and a high risk cohort in which adjuvant therapy may be preferred.Materials and Methods: We performed a retrospective analysis of the records of 902 men treated with radical prostatectomy in the Shared Equal-Access Regional Cancer Hospital (SEARCH) database between 1988 and 2007 with positive surgical margins and/or extracapsular disease without seminal vesicle invasion or lymph node metastasis. The significant independent predictors of biochemical recurrence were determined using a multivariate Cox proportional hazards model. Based on the recurrence risk generated from the multivariate Cox proportional hazards regression model we generated tables to estimate the risk of recurrence-free survival 1, 3 and 5 years after surgery.Results: At a median of 3 years of followup, 346 patients (39%) had biochemical recurrence. On multivariate analysis the significant predictors of biochemical recurrence were age more than 60 years, prostate specific antigen more than 10 ng/ml, Gleason score 4 + 3 and 8-10, 2 or more sites of positive surgical margins and prostate specimen weight 30 gm or less. As determined by the concordance index, the overall predictive accuracy of the model was 0.67, while it was 0.60 for the postoperative Kattan nomogram in this patient population.Conclusions: We have developed a simple instrument that, once validated, may aid in the postoperative decision making process for men at intermediate risk for recurrence after prostatectomy.

The Dana-Farber Cancer Institute (DFCI) Childhood ALL Consortium Protocol 95-01 was designed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy. Patients participated in randomized comparisons of (1) doxorubicin given with or without dexrazoxane, a cardioprotectant (high-risk patients), (2) intensive intrathecal chemotherapy and cranial radiation (standard-risk patients), and (3) Erwinia and Escherichia coli asparaginase (all patients). Between 1996 and 2000, 491 patients (aged 0-18 years) were enrolled (272 standard risk and 219 high risk). With a median of 5.7 years of follow-up, the estimated 5-year event-free survival (EFS) for all patients was 82%+/-2%. Dexrazoxane did not have a significant impact on the 5-year EFS of high-risk patients (P=.99), and there was no significant difference in outcome of standard-risk patients based on type of central nervous system (CNS) treatment (P=.26). Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78%+/-4% versus 89%+/-3%, P=.01). We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious.

7005 Background: Temsirolimus (CCI-779), an ester of sirolimus, is an inhibitor of mTOR, shown to inhibit tumor cell proliferation in non-clinical models. Standard chemotherapy typically results in a 9 month median survival in extensive stage small cell lung cancer (SCLC-ES). A Phase II study was initiated in patients (pts) with SCLC-ES in remission (CR, PR, SD) following 4–6 cycles of carboplatin or cisplatin+etoposide or irinotecan, to determine the effects of temsirolimus on progression-free and overall survival. Methods: Between January 2002 and December 2003, 87 pts were randomized to 2 dose levels of temsirolimus (86 pts are eligible for this analysis): 44 pts to 25 mg (Arm A); 42 pts to 250 mg (Arm B), both given IV over 30 minutes weekly until progression. Pts were entered 4–8 weeks after completing induction therapy.Their characteristics are: male 42 (49%), female 44(51%); PS0: 38(44%), 1: 41(48%), 2: 4(5%); brain metastases 5(6%). Median follow up time is 33.8 months. Results: Toxicity: There were no treatment related grade (G) 5 toxicities on either arm. Worst G3/4 degree reported: 21 pts on Arm A and 26 pts in Arm B. G3/4 neutropenia: 4 in each arm; thrombocytopenia: 3 in Arm A, 9 in Arm B; hypercholesterolemia/triglyceridemia: 1/1 in Arm A, 3/3 in Arm B; hypophosphatemia: 2 in Arm A, 6 in Arm B. G3 allergic reaction: 1 in each arm; urticaria: 2 in Arm B. Survival: 8/44 pts (18%) are alive on Arm A, and 16/42 (38%) are alive on Arm B at the time of analysis. The median survival for all pts is 19.8 months (95% CI: 16.3 -22.9 months): Arms A 16.5 months and Arm B, 22.9 months. The median progression free survival for all pts is 5.5 months (95% CI: 4.4 - 7.7 months): Arm A 4.7 months and Arm B, 6.3 months. By comparison, the post randomization median survival was 8.9 months in 242 pts with CR, PR, SD following cisplatin+etoposide induction in ECOG phase III study E7593 (JCO 19:2114,2001). Conclusion: Temsirolimus appears to have significant activity in extensive stage small cell lung cancer and should be studied further in this setting. No significant financial relationships to disclose.

8505 Background: Myocardial injury echo monitoring is recommended during DOX. We examined the relationship between echo-determined left ventricular (LV) function & structure & serum cardiac troponin T (cTnT), a sensitive & specific measure of myocardial injury during DOX and continuation therapy for ALL. Methods: 206 high-risk ALL pts were randomized on DFCI protocol 95–001 to receive DOX alone (30 mg/m2/dose, n=101 pts, 300 mg/m2 cumulative dose), or dexrazoxane (DEX) (300 mg/m2) followed by DOX (n=105 pts). cTnT was assayed before, during, & after DOX in 76 DOX-only pts & 82 DEX-DOX pts with 2377 samples (mean-15.1 samples/pt). Pts with cTnT had 462 echos (median-2.5 echos/pt) while receiving (n=162) or at 198 days (median) after DOX (n=164, during continuation). Echo z-scores (standard deviations ± the predicted value) of LV function (fractional shortening [FS] & contractility) & structure (end-diastolic diameter) were determined. In this substudy the echo & cTnT results were compared. Results: Elevations of cTnT (>0.01 ng/mL) occurred in 35% (55/158) of pts. Pts treated with DOX alone were significantly more likely to have elevated cTnT samples (50 vs 21%; P<0.001). Echos prior to DOX showed normal LV FS (n=84, mean z-score, 0.19, P=0.51) & contractility (n=22, mean z-score, -0.02, P=0.96); but slight LV dilation (n=79, dimension z-score, 0.28, P=0.03). After DOX, FS (n=91, mean z-score, -1.06, P<0.0001) & contractility (n=29, mean z-score, −0.82, P=0.02) were depressed & dimension was normal (n=89, mean z-score, 0.01, P=0.92). However, there were no significant differences between the DOX-alone & DEX-DOX pts for mean LV dimension, FS, or contractility before, during, or after DOX. FS was significantly depressed in both treatment groups during & after DOX. Conclusion: Echo-determined LV structure & function during therapy for ALL may not accurately assess myocardial injury measured by cTnT. The role of echo monitoring during therapy requires further study. Transient confounders (e.g., cytokine-mediated myocardial depressant substances) may misrepresent DOX-associated myocardial injury. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chiron NCI; Pharmacia-Upjohn, Inc.; Roche Diagnostocs Corp.