Recurrent Solid Tumors Research Articles

Phase 1/2a trial of intravenous BAL101553, a novel controller of the spindle assembly checkpoint, in advanced solid tumours

BackgroundBAL101553 (lisavanbulin), the lysine prodrug of BAL27862 (avanbulin), exhibits broad anti-proliferative activity in human cancer models refractory to clinically relevant microtubule-targeting agents.MethodsThis two-part, open-label, phase 1/2a study aimed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of 2-h infusion of BAL101553 in adults with advanced or recurrent solid tumours. The MTD was determined using a modified accelerated titration design in phase I. Patients received BAL101553 at the MTD and at lower doses in the phase 2a expansion to characterise safety and efficacy and to determine the recommended phase 2 dose (RP2D).ResultsSeventy-three patients received BAL101553 at doses of 15–80 mg/m2 (phase 1, n = 24; phase 2a, n = 49). The MTD was 60 mg/m2; DLTs observed at doses ≥60 mg/m2 were reversible Grade 2–3 gait disturbance with Grade 2 peripheral sensory neuropathy. In phase 2a, asymptomatic myocardial injury was observed at doses ≥45 mg/m2. The RP2D for 2-h intravenous infusion was 30 mg/m2. The overall disease control rate was 26.3% in the efficacy population.ConclusionsThe RP2D for 2-h infusion of BAL101553 was well tolerated. Dose-limiting neurological and myocardial side effects were consistent with the agent’s vascular-disrupting properties.Clinical trial registrationEudraCT: 2010-024237-23.

Abstract A59: Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients

Abstract Introduction: Molecular techniques have been incorporated into the diagnostic algorithms for many specific tumors, but the diagnostic role of next-generation sequencing has not been described at a population level. We report diagnostically relevant alterations identified by large-scale sequencing in a prospective cohort of pediatric solid tumors. Methods and Objectives: Patients are eligible for the GAIN / iCat2 study if they have a high-risk, recurrent, or refractory extracranial solid tumor diagnosed at age 30 or less and have an adequate sample for sequencing available. After informed consent, tumor was sequenced using a next-generation sequencing assay that evaluates 447 genes and includes data about sequence variants, copy number alterations, and, in selected genes, translocations. Some cases received additional sequencing via RNASeq or targeted RNA sequencing for further evaluation of fusions. Diagnostic relevance was determined according to AMP/ASCO/CAP standards and guidelines for the reporting of sequence variants in cancer. Results: 349 patients were enrolled as of December 31, 2018, and had tumor tissue successfully sequenced. These patients represent 60 unique diagnoses according to the WHO ICD-O classification. The most common single diagnoses were osteosarcoma (n=64), Ewing sarcoma (n=44), and alveolar rhabdomyosarcoma (n=32). For 349 patients, 184 (53%) had one or more genetic alterations that were diagnostically relevant, of which 159 (86%) were structural variants, 16 (8%) were sequence variants, and 9 (5%) were copy number variations. Alterations of high diagnostic relevance include CIC-DUX4 fusions in sarcoma (n=8), TP53 intron 1 rearrangements in osteosarcoma (n=26), DICER1 sequence variants in various tumors (n=7), and BCOR internal tandem duplications in clear-cell sarcoma of kidney and primitive myxoid mesenchymal tumor of infancy (n=3). Conclusions: Diagnostically relevant alterations were identified in over half of pediatric solid tumor patients evaluated. Gene fusions are particularly prevalent. These results support a role for sequencing that includes robust fusion assessment to inform diagnosis in patients with pediatric solid tumors. Citation Format: Alanna J. Church, Laura B. Corson, Alma Imamovic-Tuco, Gianna R. Strand, Dierdre Reidy, Duong Doan, Robert S. Pinches, Mark A. Applebaum, Rochelle Bagatell, Brian D. Crompton, Steven G. DuBois, Julia L. Glade Bender, Theodore W. Laetsch, Lobin A. Lee, Neal I. Lindeman, Marian H. Harris, Margaret E. Macy, Luke Maese, Navin Pinto, Amit J. Sabnis, Eliezer M. Van Allen, Susan I. Vear, Daniel A. Weiser, Catherine M. Clinton, Katherine A. Janeway. Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A59.

Abstract B67: EGFR as a target in pediatric solid tumors

Abstract The epidermal growth factor receptor (EGFR or HER1) is a cell surface tyrosine kinase receptor that is expressed in a diverse group of epithelial and nonepithelial tissues and broadly associated with cell proliferation and differentiation. Expression of wild-type EGFR and activating mutations are described in many malignancies, including a variety of pediatric solid tumors. In the setting of malignancy, EGFR has been associated with aggressive disease, chemotherapy resistance, and increased metastatic potential. Employment of anti-EGFR agents has yielded some promising results, but they are not always effective against all cancer-associated aberrant EGFR expression and are frequently associated with notable off-tumor toxicities due to the expression of EGFR in normal tissue. The unique EGFR monoclonal antibody (mAb) 806 selectively binds to an epitope on the extracellular portion of human EGFR expressed on the surface of tumor cells. This antibody recognizes the deletion mutant EGFRvIII commonly present in glioblastomas and some other solid tumors as well as wild-type EGFR. We designed a phase I trial for pediatric and young adult patients with recurrent or refractory solid tumors expressing epidermal growth factor (EGFR) to examine the safety and feasibility of administering autologous, peripheral blood-derived T cells that have been genetically modified to express a second-generation (2G) EGFR806-specific chimeric antigen receptor (CAR). Literature review and evaluation of EGFR immunohistochemistry (IHC) performed on several tissue microarrays were used to estimate the percentage of EGFR positivity among common subtypes of pediatric cancer. Using these tools, we hypothesized that 15-40% of otherwise eligible patients would meet the eligibility criteria of EGFR positivity. The trial opened in August of 2018. To date, a total of 33 patient tumors have undergone EGFR IHC to determine eligibility for the trial. 9/33 (27.3%) have been EGFR+. EGFR+ histologies include BCOR fusion sarcoma (3), germ cell tumor (2), osteosarcoma, Ewing sarcoma, desmoplastic small round cell tumor, and synovial sarcoma. Our eligibility testing thus far demonstrates EGFR expression by IHC in a variety of histologies. Two rare diseases, recurrent BCOR fusion sarcoma and refractory germ cell tumors, have demonstrated a significantly higher rate of EGFR IHC positivity, (3/3)100% and (2/3) 66.7%, respectively. These early results indicate that this trial and other anti-EGFR therapies may be most effectively targeted to certain subgroups of pediatric cancer patients. Citation Format: Catherine M. Albert, Navin R. Pinto, Erin R. Rudzinski, Julie R. Park. EGFR as a target in pediatric solid tumors [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B67.

The Efficacy and Safety of Apatinib in Refractory/Relapse Advanced Pediatric Solid Tumor: A Retrospective Study.

BackgroundThe prognosis of recurrent or refractory advanced childhood solid tumor patients is very poor and new therapeutic strategies are in urgent need. This study aimed to determine the efficacy and safety of apatinib in pediatric refractory/relapse advanced solid tumor patients.Patients and MethodsThe study retrospectively reviewed recurrent or refractory advanced pediatric solid tumor patients who were treated with apatinib, an oral small-molecule tyrosine kinase inhibitor (TKI) that targets vascular endothelial growth factor receptor-2 (VEGFR2), at the Sun Yat-sen University Cancer Center (China) from January 2016 to March 2019.ResultsFifty-six patients were included in the safety evaluation and 49 patients were included in the efficacy evaluation. The objective responses rate (ORR) was 26.5% (95% CI 15–41): 0 CR (complete response) and 13 PR (partial response). Disease control rate (DCR) (CR+PR+SD) was 79.6% (95% CI 65–90). The median progression-free survival (PFS) was 4.0 months (95% CI 2.6–5.4). There was no significant difference for ORR or PFS between the A (apatinib monotherapy), A+MT (apatinib combined with oral metronomic therapy) and A+SC (apatinib combined with salvage combination chemotherapy) group (p>0.05). The most common grade 3 or 4 adverse events were neutropenia (9[16.1%]), thrombocytopenia (8[14.3%]), hand-foot syndrome (3[5.4%]), hypertension (3[5.4%]), anaemia (3[5.4%]) and mucositis (2[3.6%]). Hypertension was the most serious adverse event and one death that occurred was considered as drug-related.ConclusionApatinib showed promising clinical activity in heavily treated recurrent or refractory advanced childhood solid tumor patients. However, it is necessary to pay special attention to monitoring blood pressure when using apatinib in children. Prospective randomized controlled clinical trial is warranted.

Risk Factors for Tumor Recurrence Following Primary Intravenous Chemotherapy (Chemoreduction) for Retinoblastoma in 869 Eyes of 551 Patients.

To identify risk factors for retinoblastoma recurrence following chemoreduction. This was a retrospective review of patients with retinoblastoma treated from 1994 to 2019 using chemoreduction with analysis for recurrence using Kaplan-Meier, Cox regression, and logistic regression. There were 869 eyes of 551 patients with retinoblastoma treated with chemoreduction. Follow-up in 556 eyes revealed main solid tumor recurrence (n = 355, 64%), subretinal seed recurrence (n = 244, 44%), vitreous seed recurrence (n = 162, 29%), and/or new tumor (n = 118, 21%) requiring management with focal therapy (transpupillary thermotherapy, cryotherapy) (n = 294, 53%), intra-arterial chemotherapy (n = 125, 22%), intravitreal chemotherapy (n = 36, 6%), plaque radiotherapy (n = 120, 22%), external beam radiotherapy (n = 57, 10%), and/or enucleation (n = 49, 9%). Of all recurrences, 62% were detected by 1 year, 86% by 2 years, 94% by 3 years, 98% by 5 years, 99% by 10 years, and 100% by 15 years. Risk factors for recurrence on multivariate analysis included younger patient age at presentation (odds ratio [OR] = 1.02 [1.00 to 1.04] per 1 month decrease, P = .02), greater International Classification of Retinoblastoma group (OR = 1.24 [1.05 to 1.47] per 1 more advanced group, P = .01), shorter tumor distance to optic disc (OR = 1.11 [1.01 to 1.21] per 1 mm decrease, P = .03), and presence of subretinal seeds (OR = 1.66 [1.09 to 2.53], P = .02). Retinoblastoma recurrence after chemoreduction is usually detected within the first 3 years following treatment. Younger patients with more advanced, posteriorly located tumors and subretinal seeds at presentation are at increased risk, but recurrence can often be managed with globe-sparing therapy. [J Pediatr Ophthalmol Strabismus. 2020;57(4):224-234.].

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network

BackgroundThe phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. Patients and methodsPaediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. ResultsForty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. ConclusionsIn this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. Trial registrationNCT01962103 and EudraCT 2013-000144-26.

A phase I/II study of lenvatinib (LEN) plus everolimus (EVE) in recurrent and refractory pediatric solid tumors, including CNS tumors.

10527 Background: Proangiogenic signaling pathways cooperate with mTOR-mediated regulation of cell growth and maintenance to drive development of many pediatric cancers. We report results of the phase 1 dose escalation for LEN + EVE in pediatric patients (pts) with recurrent solid and CNS tumors conducted by Children’s Oncology Group. Methods: Dose escalation was conducted using a rolling-6 design. Pts received LEN + EVE orally once daily in continuous 28-day cycles. Dose determination was based on toxicity (CTCAE v4.03) during cycle 1. Pharmacokinetics (PK) of plasma LEN and EVE were monitored. Results: 17 pts were enrolled (9 male; 8 female). Median (range) age was 10 (3–21) years; 8 pts had CNS tumors. 17 were evaluable for dose-limiting toxicity (DLT). Enrollment started at dose level 1 (DL 1; LEN 11 mg/m2 + EVE 3 mg/m2) and, after treatment of 3 pts, was initially de-escalated to DL –1 (LEN 8 mg/m2 + EVE 3 mg/m2) due to DLT of proteinuria in 1 pt and self-resolving headache in another who, on review, did not meet the definition of DLT. No pts enrolled at DL –1 (n = 5) experienced DLT. Overall, DLTs were observed in 2 of the first 6 patients enrolled at DL 1: the initial pt with proteinuria and 1 more pt with hypertriglyceridemia and hypercholesteremia. Because 2 pts had reversible DLT of different categories not related to Cmax or AUC, the DL 1 cohort was expanded to enroll an additional 6 pts, none of whom had DLT. Thus, 2/12 pts experienced DLT at DL 1. Overall, most common treatment-emergent adverse events (TEAEs; ≥ 50% of pts) were diarrhea, hypertension, hypertriglyceridemia, vomiting, abdominal pain, headache, and hypothyroidism. 47% of pts had ≥ 1 treatment-related TEAE grade ≥ 3; the most frequent was proteinuria (n = 2). On cycle 1 day 15, mean (SD) Cmax (ng/mL) for LEN at DL –1 and DL 1, respectively, was 314 (150) and 359 (270), and mean (SD) AUC0-8h (hr•ng/mL) for LEN was 1570 (935) and 1780 (1100). Taking all toxicities and PK into account, no further dose escalation was recommended. Best overall response in pts with measurable disease was 2/11 stable disease, 7/11 progressive disease, and 2/11 not evaluable. Conclusions: The recommended phase 2 dose of LEN + EVE in children with solid and CNS tumors was LEN 11 mg/m2 + EVE 3 mg/m2, with maximum daily doses capped at 18 mg and 5 mg, respectively. The toxicity profile was no more than additive to single-agent therapy. PK exposure was comparable with children on single-agent LEN and to adults receiving LEN + EVE. Enrollment to the phase 2 portion (Ewing sarcoma, high-grade glioma, and rhabdomyosarcoma strata) is ongoing. Clinical trial information: NCT03245151.

Evidence of intratumoral localization, activation, and immunomodulatory effect of CX-072, a probody therapeutic targeting PD-L1, in a phase I/II trial.

3108 Background: PROBODY therapeutics (Pb-Tx) are masked antibodies designed to be selectively activated in the tumor microenvironment by tumor-associated proteases and to remain largely inactive in normal tissue. CX-072, a Pb-Tx directed against PD-L1, is designed to reduce the potential for immune-associated adverse events in normal tissues while maintaining anti-tumor activity. CX-072 is being investigated in PROCLAIM-CX-072 (NCT03013491), a first-in-human phase 1/2 trial. CX-072 is administered as monotherapy or in combination with ipilimumab to patients with metastatic or recurrent solid tumors or lymphomas for which approved PD-1/-L1–based therapy is not available. We present the updated results of a tissue-based biomarker program designed to assess activation, localization, and mechanism of action of CX-072 in patient tumors. Methods: Tumor biopsies were collected during the screening phase, and also 3–5 days after the first or third dose of 0.3–30 mg/kg CX-072. Tumor-associated protease activity was measured by tissue zymography. Intratumoral CX-072 activation was measured using capillary immunoelectrophoresis, and PD-L1 levels were measured by an ultrasensitive ELISA. Intratumoral CD8 expression was analyzed using immunohistochemistry. Intact and total CX-072 in plasma were measured by LC-MS/MS. Results: Twenty-six of 30 (87%) evaluable predose biopsies had detectable levels of relevant protease activity. Intratumoral activation of CX-072 was quantifiable in 3 of 8 (38%) biopsies from patients treated with CX-072 at 3 mg/kg and in 12 of 12 (100%) biopsies from patients treated with ≥10 mg/kg. In contrast, CX-072 remained predominantly in the intact form in circulation. The molar ratio of activated intratumoral CX-072 to total intratumoral PD-L1 ranged from ~14x to > 100x in patients dosed at 10 mg/kg, and the calculated tumor receptor occupancy for these patients was ≥99%, congruent with quantitative systems pharmacology model predictions. An increase in CD8+ T cells and elevation of cytotoxic T-cell markers was observed in the tumors of 11 of 18 (61%) CX-072 monotherapy patients, consistent with inhibition of the PD-L1 pathway. Conclusions: These results demonstrate that the Pb-Tx CX-072 behaves as designed in patients. Clinical trial information: NCT03013491 .

Phase I study of regorafenib in combination with vincristine and irinotecan in pediatric patients with recurrent or refractory solid tumors.

10507 Background: In pediatric patients with solid tumors, regorafenib demonstrated acceptable tolerability and preliminary anti-tumor activity. This phase 1 study evaluated regorafenib in combination with vincristine/irinotecan in pediatric patients with rhabdomyosarcoma (RMS) and other solid tumors. Methods: Patients with relapsed/refractory tumors received intravenous vincristine (1.5 mg/m2, Days 1 and 8) and irinotecan (50 mg/m2/day, Days 1–5) plus once-daily oral regorafenib (patients 6– < 24 months: 60 mg/m2 escalating to 65 mg/m2; patients 2– < 18 years: 72 mg/m2 escalating to 82 mg/m2) on either Days 1–14 (concomitant dosing) or Days 8–21 (sequential dosing) during each 21-day cycle. As per protocol, at least 50% of patients were required to have RMS. Results: At the time of the cut-off, of 21 treated patients (RMS, n = 12; Ewing sarcoma, n = 5; neuroblastoma, n = 3; Wilms tumor, n = 1), two had concomitant (72 mg/m2) and 19 had sequential (72 mg/m2, n = 6; 82 mg/m2, n = 13) dosing. Median age was 10 years (1.5–17.0). Patients received a median of 3 cycles (1–17); dose reductions of irinotecan occurred in 62% of patients. Grade 3 dose-limiting toxicities were reported in both patients receiving concomitant dosing (peripheral neuropathy and liver injury; pain, vomiting, febrile aplasia) and one patient each in the sequential groups (rash and elevated AST; thrombocytopenia). Concomitant dosing was discontinued. The maximum tolerated dose and recommended phase 2 dose (RP2D) of regorafenib in the sequential combination was 82 mg/m2. The most common grade ≥3 treatment-emergent adverse events were neutropenia (71%), thrombocytopenia (33%), leukopenia (29%), anemia (24%), and ALT increased (24%). The response rate was 38%, including 1 complete (RMS) and 7 partial responders (5 RMS, 2 Ewing sarcoma); 3 of whom had prior irinotecan. Six (4 with alveolar subtype) of 12 patients with RMS had a response. Nine patients (43%) had stable disease (maximum duration 17 cycles). After the cut-off, partial response was reported for two additional patients (1 RMS, 1 Ewing sarcoma). Conclusions: Regorafenib can be combined at its single agent RP2D of 82 mg/m2 with standard-dose vincristine/irinotecan (with appropriate dose modifications) in pediatric patients with refractory/relapsed solid tumors in a sequential dosing schedule. Clinical activity was observed in patients with sarcoma. Clinical trial information: NCT02085148.

A phase I study of APL-501, an anti-PD-1 antibody, in patients with recurrent or advanced solid tumors.

e15125 Background: APL-501 is a humanized monoclonal antibody targeting programmed cell death-1 (PD-1). APL-501 is being evaluated in patients (pts) with advanced recurrent and relapsed solid tumors who had not been previously treated with an immune checkpoint inhibitor in an ongoing 3-part Phase 1 trial (NCT03053466). Herein, we present the emerging pharmacokinetic (PK) and receptor occupancy (RO), safety and preliminary efficacy. Methods: Weight-based dose escalation (1, 3, and 10 mg/kg, Part 1) and Extension (Part 2) has been completed and the study is currently enrolling specific tumor types (MSI-H/dMMR and Carcinoma of Unknown Primary [CUP]) into the Expansion Cohorts (Part 3). Relapsed/refractory solid tumor pts were enrolled in Part 1 and Part 2. Key exclusion criteria included prior therapy targeting PD-1/PD-L1 and uncontrolled CNS metastases. APL-501 was administered IV over 1 hour every 14 days. Serum and PBMCs were collected for PK and RO analysis, respectively. RO was assessed using different T-cell markers measured by flow cytometry of PBMC. Anti-tumor activity was assessed by investigators using RECIST and irRECIST. Safety was assessed using CTCAE, v4.03. Results: As of 31 Dec 2019, 22 pts were enrolled with a mean age of 62.1 (SD: 12.2) years. ECOG PS 0/1 reported at 10/12 pts, respectively. Pts had a median number of 3 prior lines of therapy (range, 1 – 9) and median time to treatment from initial diagnosis was 30.1 months (range, 6.7 – 184.8). Across doses evaluated, APL-501 demonstrated dose proportional PK. One hundred percent (100%) RO was observed across all doses evaluated. No dose limiting toxicities were reported. Fifteen pts (68.2%) had related AEs; two pts (9.1%) had Grade ≥ 3 related AEs to APL-501. Eight pts had stable disease and two pts had partial response by RECIST (esophageal adenocarcinoma and CUP). Seven pts remained on therapy for ≥ 24 weeks. The recommended phase 2 dose (RP2D) has been determined to be 400 mg IV every 14 days (non-weight-based) based on safety and PK modeling. Conclusions: Preliminary results indicate clinical activity of APL-501 in relapsed/refractory malignant disease with a generally tolerable safety profile. The PK and RO profile, across all doses evaluated, appears comparable to marketed PD-1 inhibitors. Continued exploration of APL-501 with the RP2D in CUP and MSI-H/dMMR tumors is being planned. Clinical trial information: NCT03053466 .

The first report of pediatric patients with solid tumors treated with venetoclax.

10524 Background: Dependence on the prosurvival protein B-cell lymphoma 2 (BCL-2) occurs in certain pediatric solid tumors, resulting in tumorigenesis and resistance to therapies. Venetoclax (VEN), an orally administered BCL-2-selective inhibitor, has preclinical anticancer activity in human-derived neuroblastoma models. Reported here are preliminary results from pediatric patients (pts) with recurrent or refractory (R/R) solid tumors treated with VEN monotherapy or VEN with cyclophosphamide and topotecan (Cy-Topo). Methods: This phase 1 open-label, 2-part study (NCT03236857) enrolled pts < 25 yr old with R/R malignancies; we report only on pts with solid tumors. Following a dose ramp-up, pts received 800 mg VEN (age/weight-adjusted adult equivalent) once daily for the first 8 wk; Cy-Topo was added optionally after wk 8. Dose-limiting toxicities (DLTs) were assessed during the first 21 days of VEN therapy or cycle 1 of VEN-Cy-Topo. Objectives included safety, toxicity, and preliminary efficacy. Results: As of Dec 17, 2019, 11 solid tumor pts were enrolled: neuroblastoma (n = 6), rhabdomyosarcoma (n = 2), Wilms’ tumor, Carney-Stratakis syndrome, and low-grade fibromyxoid sarcoma (n = 1 each). Median age was 11 yr (range 3–22); median time on study was 6.9 mo (range 1.2–17.8). All pts experienced ≥1 treatment-emergent adverse event (TEAE); vomiting (72%; all grades) was most common. Grade ≥3 TEAEs were reported in 82% of pts; febrile neutropenia (64%), decreased blood cell count, and neutropenia (36% each) were the most common. Seven pts received 800-mg monotherapy for 8 wk; 3 of these pts did not receive Cy-Topo after monotherapy. Of the 7 pts who received VEN-Cy-Topo, 3 pts received 400 mg VEN with Cy-Topo. DLTs of grade 4 neutropenia/thrombocytopenia with delayed count recovery occurred in 2 pts on 800 mg VEN-Cy-Topo, necessitating a dose de-escalation (to 400 mg VEN). Grade 4 neutropenia occurred in 2 pts on 400 mg VEN with Cy-Topo, leading to the addition of myeloid growth factor to the therapy regimen. The best response after 8 wk of VEN monotherapy was stable disease (SD). Six pts were evaluable for tumor response with VEN-Cy-Topo; 1 neuroblastoma pt had a complete response after 5 cycles of 400 mg VEN, 4 pts had SD (3 on 800 mg and 1 on 400 mg VEN) and 1 (800 mg VEN) had progressive disease as best response. Conclusions: Continuous dosing of VEN with Cy-Topo was not tolerated due to cytopenias in 4/7 pts with solid tumors. Discontinuous dosing of VEN with Cy-Topo is being explored. Clinical trial information: NCT03236857.

Updated entrectinib data in children and adolescents with recurrent or refractory solid tumors, including primary CNS tumors.

107 Background: The phase 1/2 STARTRK-NG trial (NCT02650401) is evaluating entrectinib, a CNS-penetrant oral inhibitor of TRK, ROS1 and ALK tyrosine kinases, in children and adolescents < 21 years old with recurrent/refractory solid tumors, including primary CNS tumors. Methods: After determining the recommended dose as 550mg/m2/day in all-comers, expansion cohorts with gene-fusion-positive CNS/solid tumors ( NTRK1/2/3 and ROS1) are being enrolled. Results: As of 1 July 2019 (data cut-off), 34 patients (4.9 months to 20 years old; median age 7 years) have been evaluated for response to treatment with entrectinib. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) using RANO for CNS tumors, RECISTv1.1 for solid tumors, or Curie score for neuroblastomas. Responses in fusion-positive patients were assessed by blinded independent central review (BICR), and occurred at doses ≥400mg/m2. Best responses in patients with fusion-positive CNS tumors (n = 8) were four CR ( ETV6-NTRK3, EML1-NTRK2, GOPC-ROS1, and TPR-NTRK1), two PR ( KANK1-NTRK2 and EEF1G-ROS1), and two PD ( EML4-ALK and PARP6-NTRK3). In patients with fusion-positive solid tumors (n = 6) best responses were three CR ( DCTN1-ALK, ETV6-NTRK3, and ETV6-NTRK3), and three PR ( TFG-ROS1, EML4-NTRK3, and KIF5B-ALK). Responses (Investigator-assessed) in patients with non-fusion tumors (n = 20) were one CR ( ALK F1174L mutation), four SD, ten PD, and five patients were unevaluable or had no data. The objective response rate (defined as the total number of CR and PR) in fusion-positive patients was 86% (12/14) versus 5% (1/20) in non-fusion patients. Similarly, PFS was 17.5 months (95% CI 7.4–NE) in fusion-positive patients versus 1.9 months (1.8–5.7; p = 0.0002) in non-fusion patients. Most commonly reported treatment-related adverse events included weight gain (n = 14 [5 Grade 3/4]), elevated creatinine (n = 13), anemia (n = 13), nausea (n = 11), increased ALT (n = 10 [1 Grade 3/4]), increased AST (n = 10 [1 Grade 3/4]), decreased neutrophils (n = 9 [6 Grade 3/4]), and bone fractures (n = 7, of which 4 were treatment related). Conclusions: In children and adolescents < 21 years old, entrectinib has produced striking, rapid, and durable responses in solid tumors with target gene fusions, especially in high-grade CNS neoplasms. Clinical trial information: NCT02650401.

Variety of clinical trial enrollment by actionable tumor suppressor genotype.

e15674 Background: In the last decade, genomics has been increasingly used for therapeutic management of cancer. In precision oncology, genes that can be directly or indirectly targeted with therapeutic agents are considered “actionable”. However, not all alterations affect gene function and alterations in tumor suppressor genes are especially challenging to interpret. The objective of this study was to determine frequency of trial enrollment in patients with “actionable” tumor suppressor alterations and determine whether this varied by genotype and tumor type. Methods: A single-institution retrospective review was performed on patients with metastatic, advanced, or recurrent solid tumors perceived to likely benefit from genomic profiling. Between 1/2015 and 1/2020, the top 5 tumor suppressor alterations CDKN2A, BRCA1/2, PTEN, ATM and NF1 were considered most common “actionable” tumor suppressor genes among patients reviewed by MD Anderson Precision Oncology Decision Support system. Once literature-based or inferred actionability of the tumor-suppressor alteration was determined, a clinical record review was performed to assess an institution-specific annotation detailing trial availability. This annotation matches somatic genomic alteration based on therapeutic significance and availability of matched investigative therapy based on available literature at the time. From here, patient demographics and trial enrollment was extracted from the electronic medical record. Results: 424 patients were categorized as having actionable alterations that had a trial available for enrollment based on genomic characteristics. Of these, 61 patients (14%) enrolled in a matched trial. Primary reasons for non-enrollment for a specific alteration were: enrollment in non-targeted therapeutic trial (39%), treatment with another stand of care therapy (32%), or enrollment in another genomically matched trial targeting another genomic alteration (14%). There was variability in enrollment by disease type approaching statistical significance (p = 0.073). CDKN2A alterations were the most common while BRCA1/2 had the highest rate of matched enrollment (39.5%). Conclusions: In this cohort of patients, the presence of an actionable tumor-suppressor alteration was associated with trial enrollment varying by genotype. Further work is needed to determine the impact of decision support on trial enrollment as well as strategies to increase actionability by building genomically-driven combination therapy trials.

Phase I expansion cohort to evaluate the combination of bevacizumab, sorafenib and low-dose cyclophosphamide in children and young adults with refractory or recurrent solid tumours

BackgroundAngiogenesis is critical for tumour growth and metastasis. Dual inhibition of vascular endothelial growth factors and platelet-derived growth factor receptors suppresses angiogenesis. This expansion cohort of a phase I study targeted angiogenesis with sorafenib, bevacizumab and low-dose cyclophosphamide in children and young adults with recurrent solid tumours. MethodsAn expansion cohort including patients with refractory or recurrent solid tumours was enrolled and received bevacizumab (15 mg/kg IV, day 1), sorafenib (90 mg/m2 po twice daily, days 1–21) and low-dose cyclophosphamide (50 mg/m2 po daily, days 1–21). Each course was 21 days. Toxicities were assessed using Common Terminology Criteria for Adverse Events, v3.0, and responses were evaluated by Response Evaluation Criteria in Solid Tumors criteria. Serial bevacizumab pharmacokinetic (PK) studies were performed during course 1. ResultsTwenty-four patients (15 males; median age 14.5 yrs; range 1–22 yr) received a median of 6 courses (range 1–18). Twelve patients had a bone or soft tissue sarcoma. The most common grade III/IV non-haematologic toxicities were hypertension (N = 4), hand/foot rash (N = 3) and elevated lipase (N = 3). The most common grade III/IV haematologic toxicities were neutropenia (N = 7) and lymphopenia (N = 17). Three patients (2 synovial sarcoma, 1 rhabdoid tumour) achieved a partial response and 18 had stable disease. The progression-free survival at 3 and 6 months were 78.1% (95% confidence interval [CI] 60.6–95.6%) and 54% (95% CI 30.2–78.2%), respectively. Bevacizumab PKs in 15 patients was similar to published adult PK results. ConclusionsIntravenous bevacizumab combined with oral sorafenib and low-dose cyclophosphamide was tolerated and demonstrated promising activity in a subset of childhood solid tumours.

First-in-Human, Multicenter, Phase I Dose-Escalation and Expansion Study of Anti-Mesothelin Antibody–Drug Conjugate Anetumab Ravtansine in Advanced or Metastatic Solid Tumors

PURPOSEThis phase I study, which to our knowledge is the first-in-human study of this kind, investigates the safety, tolerability, pharmacokinetics, and clinical activity of anetumab ravtansine, an antibody–drug conjugate of anti-mesothelin antibody linked to maytansinoid DM4, in patients with advanced, metastatic, or recurrent solid tumors known to express the tumor-differentiation antigen mesothelin.PATIENTS AND METHODSThis phase I, open-label, multicenter, dose-escalation and dose-expansion study of anetumab ravtansine enrolled 148 adult patients with multiple solid tumor types. Ten dose-escalation cohorts of patients with advanced or metastatic solid tumors (0.15-7.5 mg/kg) received anetumab ravtansine once every 3 weeks, and 6 expansion cohorts of patients with advanced, recurrent ovarian cancer or malignant mesothelioma received anetumab ravtansine at the maximum tolerated dose once every 3 weeks, 1.8 mg/kg once per week, and 2.2 mg/kg once per week.RESULTSForty-five patients were enrolled across the 10 dose-escalation cohorts. The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg once every 3 weeks or 2.2 mg/kg once per week. Thirty-two patients were enrolled in the 6.5 mg/kg once-every-3-weeks, 35 in the 1.8 mg/kg once-per-week, and 36 in the 2.2 mg/kg once-per-week expansion cohorts. The most common drug-related adverse events were fatigue, nausea, diarrhea, anorexia, vomiting, peripheral sensory neuropathy, and keratitis/keratopathy. There were no drug-related deaths. Anetumab ravtansine pharmacokinetics were dose proportional; the average half-life was 5.5 days. Among 148 patients with mesothelioma or ovarian, pancreatic, non–small-cell lung, and breast cancers, 1 had a complete response, 11 had partial responses, and 66 had stable disease. High levels of tumor mesothelin expression were detected in patients with clinical activity.CONCLUSIONAnetumab ravtansine exhibited a manageable safety and favorable pharmacokinetic profile with encouraging preliminary antitumor activity in heavily pretreated patients with mesothelin-expressing solid tumors. The results allowed for the determination of recommended doses, schedules, and patient populations for anetumab ravtansine in phase II studies.

Extracellular vesicles from human liver stem cells inhibit renal cancer stem cell-derived tumor growth in vitro and in vivo.

Cancer stem cells (CSCs) are considered as responsible for initiation, maintenance and recurrence of solid tumors, thus representing the key for tumor eradication. The antitumor activity of extracellular vesicles (EVs) derived from different stem cell sources has been investigated with conflicting results. In our study, we evaluated, both in vitro and in vivo, the effect of EVs derived from human bone marrow mesenchymal stromal cells (MSCs) and from a population of human liver stem cells (HLSCs) of mesenchymal origin on renal CSCs. In vitro, both EV sources displayed pro‐apoptotic, anti‐proliferative and anti‐invasive effects on renal CSCs, but not on differentiated tumor cells. Pre‐treatment of renal CSCs with EVs, before subcutaneous injection in SCID mice, delayed tumor onset. We subsequently investigated the in vivo effect of MSC‐ and HLSC‐EVs systemic administration on progression of CSC‐generated renal tumors. Tumor bio‐distribution analysis identified intravenous treatment as best route of administration. HLSC‐EVs, but not MSC‐EVs, significantly impaired subcutaneous tumor growth by reducing tumor vascularization and inducing tumor cell apoptosis. Moreover, intravenous treatment with HLSC‐EVs improved metastasis‐free survival. In EV treated tumor explants, we observed both the transfer and the induction of miR‐145 and of miR‐200 family members. In transfected CSCs, the same miRNAs affected cell growth, invasion and survival. In conclusion, our results showed a specific antitumor effect of HLSC‐EVs on CSC‐derived renal tumors in vivo, possibly ascribed to the transfer and induction of specific antitumor miRNAs. Our study provides further evidence for a possible clinical application of stem cell‐EVs in tumor treatment.

Identification of biomarkers of immune checkpoint blockade efficacy in recurrent or refractory solid tumor malignancies.

Patients with advanced solid malignancies recurrent or resistant to standard therapy have limited treatment options. The role of molecular biomarkers for predicting immune checkpoint blockade (ICB) efficacy are not well characterized in these patients. Tumor mutational profiles of 490 patients with a variety of advanced solid tumors enrolled in a prospective protocol were analyzed to identify prognostic and predictive biomarkers. ICB therapy was defined as treatment with any CTLA-4, PD-1, and/or PD-L1 monoclonal antibody. ICB treatment was associated with significantly improved overall survival compared to non-ICB therapy. Multivariate regression analysis including the two variables of tumor mutation burden (TMB) and ICB, and their interaction term, showed favorable survival associated with ICB, unfavorable survival associated with TMB without ICB treatment, and improved outcome with increasing TMB in ICB treated patients. Tumor TP53 mutation was associated with worse survival, but these patients still benefitted from ICB. A more comprehensive multivariate analysis including cancer type, specific gene mutations, and TMB revealed that ICB treatment was an independent predictor of improved overall survival. Therefore, ICB-based therapeutic trials are beneficial in patients with advanced solid malignancies, but the most benefit may be restricted to patients with the right combination of TMB and specific tumor histology and genotype.

Abstract C002: Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors

Abstract Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) control the transition between G1 and S phases of the cell cycle and are dysregulated in a number of pediatric brain and solid tumors. Abemaciclib, a selective and potent small molecule CDK4/6 inhibitor that crosses the blood brain barrier, limits cell proliferation by suppressing phosphorylation of RB, leading to G1 arrest. Methods: We conducted a phase 1 trial of abemaciclib to determine the maximum tolerated dose (MTD), describe toxicities, and pharmacokinetic (PK) parameters of abemaciclib in pediatric patients with recurrent or refractory solid and CNS tumors. A stratum for newly diagnosed patients with diffuse midline glioma continues to enroll. A CDK mutation was not required, and patients with known RB1 mutations were excluded. Abemaciclib was administered orally twice daily on days 1-28 of a 28-day cycle. Four dose levels were planned (100, 130, 170, and 220 mg/m2/dose) and evaluated using a rolling-six design. Patients were enrolled to a dose expansion cohort at the MTD to ensure adequate PK sampling and safety. PK and pharmacodynamic (PD) analyses are ongoing. Results: The median age of 34 eligible patients was 13.8 years (range: 2.9 - 23.2). Seven (21%) patients had a solid tumor [osteosarcoma (N=2), neuroblastoma (N=1), rhabdomyosarcoma (N=1), desmoplastic small round cell tumor (N=1), clear cell sarcoma (N=1), and MRT of kidney (N=1)] and 27 (79%) patients had a malignant brain tumor [high-grade glioma (N=12), DIPG (N=5), ATRT (N=3), medulloblastoma (N=3), ependymoma (N=2), PNET (N=1), and CNS neuroblastoma (N=1)]. Twenty-three patients were evaluable for DLT. There were 2 cycle 1 DLTs, grade 4 thrombocytopenia and grade 3 vomiting and diarrhea, both occurring at dose level 3. The most common treatment-related cycle 1 adverse events were leukopenia (69%), neutropenia (53%), thrombocytopenia (44%), hypoalbuminemia (41%), anemia (38%), hypophosphatemia (34%) and diarrhea (34%). Conclusions: The pediatric MTD of abemaciclib was 130 mg/m2/dose administered orally twice daily on a 28-day cycle. Abemaciclib was well-tolerated with mainly hematologic toxicity. PK and PD will be used to further inform if 130 mg/m2/dose is the pediatric recommended phase 2 dose. Citation Format: Thomas Cash, Dolly Aguilera, Margaret E Macy, Lindsey Hoffman, Kathleen Dorris, Courtney McCracken, Bradley Hanberry, Robert Castellino, Tobey MacDonald, Cynthia Wetmore. Phase 1 study of abemaciclib in children with recurrent and refractory solid tumors including malignant brain tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C002. doi:10.1158/1535-7163.TARG-19-C002

Abstract A028: Clinical and analytic validation of FoundationOne CDx™ for NTRK fusion-positive solid tumors in patients treated with entrectinib

Abstract Introduction: Patients whose tumors harbor NTRK gene fusions represent an extremely small proportion of the overall cancer population (i.e., ~0.32-1%). While adult and pediatric cancer patients with NTRK fusion-positive solid tumors are rare, they comprise a patient population with a targetable alteration for whom there is currently no accepted standard of care. Comprehensive genomic profiling assays are a critical component in the identification of this sub-population, and herein we describe the clinical validation and analytic performance of FoundationOne CDx™ (F1CDx) as the companion diagnostic for entrectinib, a potent inhibitor of ROS1 and TRK A/B/C kinases. F1CDx and entrectinib were approved in Japan for the respective diagnosis and treatment of adult and pediatric patients with NTRK fusion-positive advanced recurrent solid tumors. Methods: Analytical concordance was determined by comparing F1CDx to a validated RNA NGS fusion panel using 28 NTRK fusion-positive and 53 NTRK fusion-negative samples. Concordance was defined as the overall percent agreement (OPA) between the two assays. Positive and negative percent agreement (PPA, NPA) were calculated using the RNA assay as the reference. Analytical sensitivity was calculated from representative gene fusions based on the 95% probability of detection, and intermediate precision was assessed from NTRK-positive samples run at and slightly above the platform limit of detection. Clinical validation for F1CDx as a companion diagnostic for entrectinib in Japan was estimated based upon patients in the primary efficacy population who had samples remaining for F1CDx testing using multiple imputation and sensitivity analysis of the concordance of F1CDx to the various enrollment assays. Results: OPA between F1CDx and an orthogonally validated RNA NGS fusion panel was 92.6% (95% CI: 84.6-97.2%). PPA and NPA values were 85.7% (95% CI: 67.3-96.0%) and 96.2% (95% CI: 87.0-99.5%), respectively. Platform sensitivity for rearrangements was between 6.4-11.3% tumor purity. Repeatability for NTRK fusions was 100% (95% CI: 73.5-100.0%) and reproducibility was 100% (95% CI: 90.3-100.0%). OPA, PPA and NPA values comparing F1CDx to the multiple enrollment assays utilized for the STARTRK-2 trial were 95.7% (95% CI: 87.8-99.1%), 84.2% (95% CI: 60.4-96.6%), and 100.0% (95% CI: 92.9-100.0%), respectively. The previously reported overall response rate (ORR) for the primary efficacy population in the STARTRK-2 trial was 57.4% (95% CI: 42.3-70.7%)1. Bridging analysis estimated that the ORR for the F1CDx NTRK-positive population was 50.0% (95% CI: 24.7-75.4%), with acceptable balance between co-variates in the F1CDx evaluable and non-evaluable populations. Conclusions: The DNA-based F1CDx assay demonstrated strong concordance compared to an externally validated RNA NGS fusion panel (92.6% OPA) for the detection of NTRK fusions. Furthermore, an analysis of the clinical efficacy demonstrated comparable results between F1CDx NTRK-positive patients (ORR of 50%; 95% CI: 24.7-75.4%) and the overall NTRK fusion-positive population (ORR of 57%; 95% CI: 42.3-70.7%) from the STARTRK-2 clinical trial evaluating entrectinib in patients with solid tumors. 1. ESMO [https://www.esmo.org/Oncology-News/Entrectinib-NTRK-Fusion-Positive-Tumours-Demetri] Citation Format: David Fabrizio, Coren Milbury, Wai-Ki Yip, Bahar Yilmazel, Xiaobo Bai, Juan Liao, David Smith, Christine Burns, Christine Vietz. Clinical and analytic validation of FoundationOne CDx™ for NTRK fusion-positive solid tumors in patients treated with entrectinib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A028. doi:10.1158/1535-7163.TARG-19-A028

68P - A novel anti-EGFR antibody HLX07 for potential treatment of squamous cell carcinoma of the head and neck

BackgroundHLX07 is a fully-humanised anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) with re-engineered Fab rendering its less immunogenic and better binding affinity than cetuximab. In-vivo studies of HLX07 demonstrated either equal or superior efficacy to cetuximab at the same dose level. Here, we present the data from the phase 1 study of HLX07 in advanced solid tumours. MethodsWe conducted an open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), PK and clinical response of HLX07 in subjects with recurrent or metastatic solid tumours unamendable to standard therapy. Subjects received once weekly intravenous infusion of HLX07 at doses of 50, 100, 200, 400, 600 and 800 mg until disease progression, withdrawal of consent or development of toxicities. Dose-limiting toxicities (DLTs) were evaluated within 28 days after the first dose and CT/MRI scans were evaluated every 8 weeks after the first infusion for treatment response. Safety, immunogenicity, PK and clinical response evaluations were performed throughout the study period. ResultsHLX07 was first approved to initiate clinical trial by the Taiwan and US FDAs; subject recruitment began in late 2016. As of 13-June-2019, 19 subjects received HLX07 in the study with the longest follow-up period of over 224 days. Among the 16 subjects who had been evaluated for efficacy, 1 subject with advanced colon cancer in 600 mg cohort achieved partial response and 5 subjects in different cohorts achieved stable disease status. Particularly at the 400 mg dose level, 30% of patients were in stable disease status at week 16 evaluation. Possibly related to HLX07 AEs with grade >2 severity included skin rashes (10.6%), hypophosphatemia (5.3%), hypomagnesemia (5.3%) and hypocalcemia (5.3%). No novel safety signal was identified; no DLT was noted up to 800 mg cohort. The PK data up to 600 mg was described in the following table.Table68P PK parameter of HLX07 at 50, 100, 200, 400 and 600 mg dose levelsTableDose (mg)Cmax (×μg/mL)AUC0-t (×h*μg/mL)t1/2 (MEAN CV%)(h)-1st dose4th dose1st dose4th dose1st dose4th dose5015.01535131131.08 (14.12%)23.11(32.61%)10043.2412067311039.70 (37.61%)55.87 (11.98%)20076.1995793954174.61 (12.49%)154.56 (38.73%)400119216908523274106.60 (19.68%)131.28 (57.48%)6001583111427869567138.64 (10.49%)210.27 (26.59%) ConclusionsHLX07 is generally well tolerated without reaching the MTD up to 800 mg weekly cohort and exhibits antitumour activity with durable objective responses at various doses. These findings support the initiation of a phase 1b/2 study of HLX07 plus chemotherapy in advanced solid tumours with the longest follow-up time of over 275 days as of 20-June-2019. Additionally, HLX07 is currently under safety and efficacy investigation combined with anti-PD-1 antibody, HLX10, in squamous cell carcinoma of head and neck. Clinical trial identificationHLX07-001 Phase 1 study (NCT02648490); HLX07-002 Phase 1b/2 study (NCT03577704). Legal entity responsible for the studyShanghai Henlius Biotech, Inc.; Taiwan Henlix Biotech Co., Ltd. FundingShanghai Henlius Biotech, Inc. DisclosureM.M. Hou: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. C.L. Ho: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. H.Y. Lin: Research grant / Funding (institution): Taiwan Henlix Biotech Co., Ltd. W. Jiang: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S. Liu: Full / Part-time employment: Shanghai Henlius Biotech,Inc. Y. Hong: Full / Part-time employment: Shanghai Henlius Biotech, Inc. A. LUK: Full / Part-time employment: Shanghai Henlius Biotech, Inc. S.F. Lin: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd. T.C. Hsieh: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd. E. Liu: Full / Part-time employment: Taiwan Henlix Biotech Co., Ltd.