Chow, Warren

Background. This single-arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable, pulmonary metastatic osteosarcoma. Patients and Methods. Patients with pulmonary metastatic osteosarcoma unresponsive to chemotherapy were eligible. Patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28-day cycles. Tumor responses were evaluated by local radiology assessment 1 month prior to and after initiation of treatment to calculate tumor doubling time and after every even numbered cycle. The primary endpoints were progression-free survival at 4 months, concomitant with a demonstrated 30% increase in tumor doubling time relative to the pretreatment growth rate. Results. 12 patients (7 female) were enrolled. The study was terminated prematurely due to withdrawal of financial support by the sponsor. 8 subjects were eligible for the primary analysis, whereas 4 patients were in a predefined exploratory “slow-growing” cohort. In the “fast-growing” cohort, 3 of the 8 patients (37.5%) eligible for first-stage analysis were deemed “success” by the preplanned criteria, adequate to proceed to second-stage accrual. In addition, 1 of the 4 patients in the “slow-growing” cohort experienced a partial remission. Grade 1-2 diarrhea was the most common adverse event, and grade 3 events were infrequent. Conclusion. This study illustrates a novel method of demonstrating positive drug activity in osteosarcoma by increasing tumor doubling time, and this is further supported by a partial response in a patient with “slow-growing” disease. This trial is registered with NCT01759303.

TPS11582 Background: Letetresgene autoleucel (lete-cel; GSK3377794) is an autologous T-cell product using a genetically modified T-cell receptor to target cancer cells expressing the cancer testis antigen New-York esophageal squamous cell carcinoma 1 (NY-ESO-1). Lete-cel is currently being investigated alone and in combination in multiple tumor types [1,2]. NY-ESO-1 is expressed in 70‒80% of synovial sarcoma (SS) and 80‒90% of myxoid/round cell liposarcoma (MRCLS) tumors [3,4], suggesting these tumors may be prime lete-cel targets. This master protocol design (IGNYTE-ESO; NCT03967223) enables evaluation of multiple cell therapies in multiple tumor types and treatment stages in separate substudies, beginning with lete-cel in Substudies 1 and 2 for SS and MRCLS. Methods: Substudy 1 is a single-arm study assessing lete-cel in treatment-naïve patients (pts; ie, anthracycline therapy-naïve for metastatic disease) with advanced (metastatic/unresectable) NY-ESO-1+ SS or MRCLS as a first line of therapy (n=10 planned). Substudy 2 is a pivotal, single-arm study assessing lete-cel in pts with NY-ESO-1+ SS or MRCLS who progressed after anthracycline therapy (n=70 planned). Key eligibility criteria are age ≥10 y and NY-ESO-1 and HLA-A*02 positivity. Exclusion criteria include prior NY-ESO-1–specific/gene therapy, allogeneic stem cell transplant, and central nervous system metastases. Screened pts undergo leukapheresis for lete-cel manufacture, lymphodepletion, lete-cel infusion, and follow-up (FU). Long-term FU (15 y) may be done under a separate protocol. The Substudy 2 primary endpoint is overall response rate (ORR) per RECIST v1.1 assessed by central independent review. Substudy 1 is not testing any formal hypotheses; statistical analysis will be descriptive. Substudy 2 is comparing ORR with the historical control assuming at least 90% power with 0.025 one-sided type I error. Secondary endpoints include efficacy (time to/duration of response, disease control rate, progression-free survival), safety (adverse event [AE] frequency/severity, serious AEs, AEs of special interest), and pharmacokinetic (maximum transgene expansion [Cmax], time to Cmax, area under the time curve from zero to time t as data permit). Enrollment began in December 2019. References: 1. Reckamp KL, et al. Ann Oncol 2019;30(Suppl_5):v602–v660. 2. Rapoport A, et al. J Clin Oncol 2020 38:15_suppl, TPS8555. 3. D’Angelo SP, et al. Cancer Discov 2018;8(8):944–957. 4. D’Angelo SP, et al. J Clin Oncol 2018 36:15_suppl, 3005. Funding: GSK. Editorial support was provided by Eithne Maguire, PhD, of Fishawack Indicia, part of Fishawack Health, and funded by GSK. Previously presented at BSG 2021 (P914542). Clinical trial information: NCT03967223.

TPS11578 Background: Conventional chondrosarcoma (cCS) accounts for ̃25% of primary bone cancers and is the second most common primary bone tumor after osteosarcoma. Surgical resection is the primary treatment for localized disease. No FDA approved therapy exists for advanced disease and chemotherapy has marginal efficacy with ORR < 12%. IDH1/2 mutation is seen in 50% of cases. Epigenetic dysregulation is central to oncogenesis in both IDH1/2 mutant and wild-type CS. Pre-clinical studies from our group show that combination treatment with HDAC and DNMT inhibitors is significantly more effective at suppressing the growth of CS models in vitro and in vivo compared to either therapy alone. The combination regimen mediates anti-tumor effects on CS by induction of apoptosis, induction of tumor suppressor genes (eg. E-cadherin), the induction of interferon responsive genes (eg. IRF7, OASL, ISG15, DDX58) and reversal of global hypomethylated state. Based on these findings we have designed a phase 2 clinical trial with an HDAC inhibitor (belinostat) and a DNMT inhibitor (guadecitabine) in patients with advanced cCS. Methods: NCI # 10330 is a single-arm, multi-center, Simon 2-stage, phase 2 clinical trial evaluating belinostat and guadecitabine in patients with advanced cCS. Eligible patients will have biopsy proven cCS which is measurable by RECIST v1.1 and amenable to biopsy, ECOG PS ≤ 2, any number of prior treatments (including none). Patients will receive guadecitabine 45 mg/m2 SC followed by belinostat 1000 mg/m2 IV once daily on days 1-5 of a 28-day cycle. A safety lead-in and continuous toxicity monitoring rule will be applied. The primary endpoint will be ORR. Since chemotherapy is associated with an ORR of 8-12% and targeted agents have shown an ORR of 0% in cCS, we will consider an ORR of 8% as inactive while an ORR of 28% will suggest promising activity. A Simon 2-stage design is employed. The design calls for 26 patients. If ≥ 2 responses are observed among 13 patients in stage I, the study will proceed to full accrual. If ≥ 5 responses are seen among 26 patients, the study treatment is considered promising. This design has 85% power with α of 0.054 to test for a response rate of 8% vs 28%. Secondary objectives include safety, tolerability and PFS. All patients will undergo pre-treatment and on-treatment tumor biopsies. Paired tissue will be used for correlative analysis including: 1) whole exome sequencing/RNAseq to evaluate changes in gene expression in response to treatment, 2) multiplex IHC to interrogate the effect of combination therapy on tumor immune microenvironment and 3) a global DNA methylation assay to better understand the changes in epigenetic landscape in response to treatment. This study is open throughout the ETCTN (NCT04340843). Six of the planned 26 patients in the safety lead-in have been enrolled without DLT. Further accrual is on hold pending completion of the safety lead-in. Clinical trial information: 04340843.

Abstract Trial Information Click here to access other published clinical trials. Lessons Learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92–3.67) months for regorafenib versus 2.07 (95% CI, 1.64–3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16–23.48) months for regorafenib and 4.89 (95% CI, 3.02–9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31–1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P < .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Abstract Lineage-specific growth factors mobilize peripheral blood progenitor cells (PBPC) and accelerate hematopoietic recovery after high-dose chemotherapy. Recombinant human thrombopoietin (rhTPO) may further increase the progenitor-cell content and regenerating potential of PBPC products. We evaluated the safety and activity of rhTPO as a PBPC mobilizer in combination with granulocyte colony-stimulating factor (G-CSF) in 29 breast cancer patients treated with high-dose chemotherapy followed by PBPC reinfusion. Initially, patients received escalating single doses of rhTPO intravenously (IV) at 0.6, 1.2, or 2.4 μg/kg, on day 1. Subsequent patients received rhTPO 0.6 or 0.3 μg/kg on days −3, −1, and 1, or 0.6 μg/kg on days −1 and 1. G-CSF, 5 μg/kg IV or subcutaneously (SC) twice daily, was started on day 3 and continued through aphereses. Twenty comparable, concurrently and identically treated patients (who were eligible and would have been treated on protocol but for the lack of study opening) mobilized with G-CSF alone served as comparisons. CD34+ cell yields were substantially higher with the first apheresis following rhTPO and G-CSF versus G-CSF alone: 4.1 × 106/kg (range, 1.3 to 17.6) versus 0.8 × 106/ kg (range, 0.3 to 4.2), P = .0003. The targeted minimum yield of 3 × 106CD34+ cells/kg was procured following a single apheresis procedure in 61% of the rhTPO and G-CSF–mobilized group versus 10% of G-CSF–mobilized patients (P = .001). In rhTPO and G-CSF mobilized patients, granulocyte (day 8 v 9, P= .0001) and platelet recovery (day 9 v 10, P= .07) were accelerated, and fewer erythrocyte (3 v 4,P = .02) and platelet (4 v 5, P = .02) transfusions were needed compared with G-CSF–mobilized patients. Peripheral blood platelet counts, following rhTPO and G-CSF, were increased by greater than 100% and the platelet content of PBPC products by 60% to 110% on the first and second days of aphereses (P &lt; .0001) with the greatest effect seen with repeated dosing of rhTPO at 0.6 μg/kg. rhTPO is safe and well tolerated as a mobilizing agent before PBPC collection. Mobilization with rhTPO and G-CSF, in comparison to a comparable, nonrandomized G-CSF–mobilized group of patients, decreases the number of apheresis procedures required, may accelerate hematopoietic recovery, and may reduce the number of transfusions required following high-dose chemotherapy for breast cancer.

Background This single‐arm, multicenter, phase 2 study evaluated the safety and antitumor activity of pazopanib in patients with unresectable or metastatic conventional chondrosarcoma. Methods Eligible patients had conventional chondrosarcoma of any grade with measurable tumors that were unresectable or metastatic. Patients with mesenchymal, dedifferentiated, and extraskeletal myxoid chondrosarcoma subtypes and patients who received prior tyrosine kinase inhibitor therapy were excluded. Pazopanib at 800 mg once daily was administered for 28‐day cycles. Tumor responses were evaluated by local radiology assessments every 2 cycles. The primary endpoint was the disease control rate (DCR) at week 16 (4 cycles). Results Forty‐seven patients were enrolled. The DCR at 16 weeks was 43% (95% confidence interval [CI], 28%‐58%), which was superior to the null hypothesis rate of 30%, but the 2‐sided P value (exact test) was .09 (1‐sided P = .045). One patient had a partial response. The median overall survival was 17.6 months (95% CI, 11.3‐35.0 months), and the median progression‐free survival was 7.9 months (95% CI, 3.7‐12.6 months). Grade 3 or higher adverse events were infrequent; hypertension (26%) and elevated alanine aminotransferase (9%) were most common. Conclusions This study provides evidence of positive drug activity for pazopanib in conventional chondrosarcoma.