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Purpose: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase II randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS. Patients and Methods: Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could cross over to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the two arms was also determined. Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial two treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the two treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of four or six cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates. See related commentary by Wilky and Maleddu, p. 1163

PTEN acts as a potent tumor suppressor within the PI3K/AKT/mTOR pathway. Germline mutations in the PTEN gene are a hallmark of PTEN hamartoma tumor syndrome, which includes Cowden syndrome, where they appear to elevate lifetime risk of cancer. Targeted AKT directed therapy has been proposed as an effective approach in cancer patients having germline PTEN mutations. The mechanism of action, safety and dosing regimen for the novel allosteric AKT inhibitor TAS-117 have been explored in a phase I study in Japan in which activity was observed against certain tumor types. Here we describe the study protocol of an international, two-part phase II study evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics and antitumor activity of TAS-117 in patients with advanced solid tumors harboring germline PTEN-inactivating mutations.

Supplementary Figure S1. Geometric mean plasma concentration-time profiles of BAY1436032 at dose levels of 150 mg to 1500 mg.

Purpose:BAY1436032, an inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), was active against multiple IDH1-R132X solid tumors in preclinical models. This first-in-human study was designed to determine the safety and pharmacokinetics of BAY1436032, and to evaluate its potential pharmacodynamics and antitumor effects.Patients and Methods:The study comprised of dose escalation and dose expansion cohorts. BAY1436032 tablets were orally administered twice daily on a continuous basis in subjects with mIDH1 solid tumors.Results:In dose escalation, 29 subjects with various tumor types were administered BAY1436032 across five doses (150–1,500 mg twice daily). BAY1432032 exhibited a relatively short half-life. Most evaluable subjects experienced target inhibition as indicated by a median maximal reduction of plasma R-2-hydroxyglutarate levels of 76%. BAY1436032 was well tolerated and an MTD was not identified. A dose of 1,500 mg twice daily was selected for dose expansion, where 52 subjects were treated in cohorts representing four different tumor types [lower grade glioma (LGG), glioblastoma, intrahepatic cholangiocarcinoma, and a basket cohort of other tumor types]. The best clinical outcomes were in subjects with LGG (n = 35), with an objective response rate of 11% (one complete response and three partial responses) and stable disease in 43%. As of August 2020, four of these subjects were in treatment for >2 years and still ongoing. Objective responses were observed only in LGG.Conclusions:BAY1436032 was well tolerated and showed evidence of target inhibition and durable objective responses in a small subset of subjects with LGG.

Supplementary Table S12. NGS analysis of select tumor-associated genes in archival tumor tissue obtained from a subset of subjects.

Supplementary Data from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors

Supplementary Table from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Supplementary Figure from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Supplementary Data from A Phase I Study of an MPS1 Inhibitor (BAY 1217389) in Combination with Paclitaxel Using a Novel Randomized Continual Reassessment Method for Dose Escalation

Supplementary Methods, Supplementary Results, Supplementary Tables S1-S11

Figure S1. shows total epirubicin concentrations (mean {plus minus} SD) at the end of infusion of 170 mg/m2 NC-6300 across cycles.

Table S1. shows progression Free Survival in individual subjects. Table S2. show exposures to epirubicinol in subjects who received infusion of NC-6300. Figure S1. shows total epirubicin concentrations (mean {plus minus} SD) at the end of infusion of 170 mg/m2 NC-6300 across cycles. Figure S2. shows mean Change in EORTC QLQ-C30 Score from Baseline.

Supplementary Figure from Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients With NTRK Fusion-Positive Solid Tumors

Purpose:Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination.Patients and Methods:Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination.Results:In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD.Conclusions:The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.

Purpose:NC-6300 is a novel nanoparticle formulation of epirubicin that has a pH-sensitive linker conjugated to epirubicin. It exhibits selective tumor accumulation owing to enhanced permeability and retention effect. We conducted a phase 1b trial to determine MTD and recommended phase II dose (RP2D) of NC-6300 monotherapy in advanced, metastatic, or unresectable solid tumors, including soft-tissue sarcomas.Patients and Methods:This phase 1b dose-escalation trial of NC-6300 monotherapy employed a Bayesian continuous reassessment method design. NC-6300 was administered on day 1 of every 21-day cycle, with epirubicin-equivalent dose increments from 125 to 215 mg/m2. Safety, efficacy, quality of life, and pharmacokinetic profile of NC-6300 monotherapy were evaluated.Results:Twenty-nine subjects (16 male) were enrolled: 17 with soft-tissue sarcoma, one with osteosarcoma, and 11 with other solid tumors. Observed dose-limiting toxicities included thrombocytopenia, stomatitis, lung infection, and febrile neutropenia. The most common grade 3/4 adverse events were neutropenia (59%), anemia (24%), thrombocytopenia (24%), and febrile neutropenia (21%). MTD and RP2D were determined to be 185 mg/m2 and 150 mg/m2, respectively. The objective response rate in the evaluable population was 11%. Partial response was observed in angiosarcoma and endometrial stromal sarcoma. A dose-dependent increase was observed in both total and released epirubicin concentrations.Conclusions:NC-6300 was well tolerated with a manageable side effect profile, despite the MTD and RP2D being higher than conventional epirubicin doses. A signal of preliminary activity was observed in angiosarcoma. NC-6300 warrants further investigation in patients with advanced solid tumors, including sarcoma.

Purpose:Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up.Patients and Methods:Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose.Results:At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2]; median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients.Conclusions:With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

Purpose: Lurbinectedin suppresses the oncogenic transcription factor EWS-FLI1 through relocalization to the nucleolus, and delays tumor growth in mice bearing Ewing sarcoma xenografts. On the basis of this rationale, lurbinectedin was evaluated in patients with relapsed Ewing sarcoma. Patients and Methods: This open-label, single-arm, Basket phase II trial included a cohort of 28 treated adult patients with confirmed Ewing sarcoma, measurable disease as per Response Evaluation Criteria In Solid Tumors (RECIST) v.1.1, Eastern Cooperative Oncology Group performance status ≤2, adequate organ function, no central nervous system metastasis, and pretreated with ≤2 chemotherapy lines for metastatic/recurrent disease. Patients received lurbinectedin 3.2 mg/m2 as a 1-hour infusion every 3 weeks. Primary endpoint was overall response rate (ORR) as per RECIST v.1.1. Secondary endpoints included time-to-event parameters and safety profile. Results: ORR was 14.3% [95% confidence interval (CI), 4.0%–32.7%], with median duration of response of 4.2 months (95% CI, 2.9–5.5 months). Median progression-free survival was 2.7 months (95% CI, 1.4–4.3 months), clinical benefit rate was 39.3%, and disease control rate was 57.1%. With 39% censoring, median overall survival was 12.0 months (95% CI, 8.5–18.5 months). Most common grade 3/4 adverse events were neutropenia (57%), anemia, thrombocytopenia, and treatment-related febrile neutropenia (14% each). No deaths or discontinuations were due to toxicity. Conclusions: Lurbinectedin was active in the treatment of relapsed Ewing sarcoma and had a manageable safety profile. Lurbinectedin could represent a valuable addition to therapies for Ewing sarcoma, and is currently being evaluated in combination with irinotecan in advanced Ewing sarcoma in a phase Ib/II trial.

PURPOSE CMB305 is a heterologous prime-boost vaccination regimen created to prime NY-ESO-1–specific CD8 T-cell populations and then activate the immune response with a potent TLR-4 agonist. This open-label randomized phase II trial was designed to investigate the efficacy and safety of adding the CMB305 regimen to atezolizumab (anti–programmed death ligand-1 therapy) in comparison with atezolizumab alone in patients with synovial sarcoma or myxoid liposarcoma. PATIENTS AND METHODS Patients with locally advanced, relapsed, or metastatic synovial sarcoma or myxoid liposarcoma (any grade) were randomly assigned to receive CMB305 with atezolizumab (experimental arm) or atezolizumab alone (control arm). The primary end points were progression-free survival (PFS) and overall survival (OS) analyzed using the Kaplan-Meier method. Safety and immune responses were assessed. RESULTS A total of 89 patients were enrolled; 55.1% had received ≥ 2 prior lines of chemotherapy. Median PFS was 2.6 months and 1.6 months in the combination and control arms, respectively (hazard ratio, 0.9; 95% CI, 0.6 to 1.3). Median OS was 18 months in both treatment arms. Patients treated with combination therapy had a significantly higher rate of treatment-induced NY-ESO-1–specific T cells ( P = .01) and NY-ESO-1–specific antibody responses ( P < .0001). In a post hoc analysis of all dosed patients, OS was longer (36 months) in the subset who developed anti-NY-ESO-1 T-cell immune response (hazard ratio, 0.3; P = .02). CONCLUSION Although the combination of CMB305 and atezolizumab did not result in significant increases in PFS or OS compared with atezolizumab alone, some patients demonstrated evidence of an anti-NY-ESO-1 immune response and appeared to fare better by imaging than those without such an immune response. Combining prime-boost vaccines such as CMB305 with anti–programmed death ligand-1 therapies merits further evaluation in other clinical contexts.

Background: This Phase 1/2 study is based on the hypothesis that immune checkpoint inhibitors are more effective when given earlier in the course of the disease for advanced soft tissue sarcoma. Methods: Phase I endpoints—maximum tolerated dose in previously treated patients; Phase II endpoints—best response, progression free survival and overall survival and incidence of adverse events in previously untreated patients; Phase I treatments—escalating doses of trabectedin (1.0, 1.2, 1.5 mg/m2) as continuous intravenous infusion over 24 h every 3 weeks, 1 mg/kg of ipilimumab given intravenously every 12 weeks, and 3 mg/kg of nivolumab given intravenously every 2 weeks; Phase II treatments—maximum tolerated dose of trabectedin and defined doses of ipilimumab and nivolumab. Results: Phase I (n = 9)—the maximum tolerated dose of trabectedin was 1.2 mg/m2; Phase II (n = 79)—6 complete responses, 14 partial responses, 49 stable disease, 25.3% best response rate, 87.3% disease control rate; median progression-free survival, 6.7 months (CI 95%: 4.4–7.9), median overall survival, 24.6 months (CI 95%: 17.0–.); Grade 3/4 therapy-related adverse events (n = 92)—increased ALT (25%), fatigue (8.7%), increased AST (8.7%), decreased neutrophil count (5.4%) and anemia (4.6%). Conclusion: SAINT is a safe and effective first-line treatment for advanced soft tissue sarcoma.

Purpose: Monopolar spindle 1 (MPS1) kinase inhibitor, BAY 1217389 (BAY) synergizes with paclitaxel. This phase I study assessed the combination of BAY with paclitaxel using a novel randomized continuous reassessment method (rCRM) to improve dose determination. Patients and Methods: Patients with solid tumors were randomized to receive oral BAY (twice daily 2-days-on/5-days-off) with weekly paclitaxel (90 mg/m2) or paclitaxel monotherapy in cycle 1. Dose escalation was guided by CRM modeling. Primary objectives were to assess safety, establish the MTD of BAY, and to evaluate the pharmacokinetic profiles for both compounds. Simulations were performed to determine the contribution of the rCRM for dose determination. Results: In total, 75 patients were enrolled. The main dose-limiting toxicities were hematologic toxicities (55.6%). The MTD of BAY was established at 64 mg twice daily with paclitaxel. Inclusion of a control arm enabled the definitive attribution of grade ≥3 neutropenia to higher BAY exposure [AUC0–12 (P< 0.001)]. After determining the MTD, we included 19 patients with breast cancer at this dose for dose expansion. Other common toxicities were nausea (45.3%), fatigue (41.3%), and diarrhea (40.0%). Overall confirmed responses were seen in 31.6% of evaluable patients. Simulations showed that rCRM outperforms traditional designs in determining the true MTD. Conclusions: The combination of BAY with paclitaxel was associated with considerable toxicity without a therapeutic window. However, the use of the rCRM design enabled us to determine the exposure–toxicity relation for BAY. Therefore, we propose that the rCRM could improve dose determination in phase I trials that combine agents with overlapping toxicities.

Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few treatment options. We designed a phase 2 randomized trial to determine the activity and tolerability of single-agent cediranib or sunitinib in patients with advanced metastatic ASPS.Patients 16 years of age and older were randomized to receive cediranib (30 mg) or sunitinib (37.5 mg) in 28-day cycles. Patients could crossover to the other treatment arm at disease progression. The primary endpoint was to measure the objective response rate (ORR) for each agent. Median progression-free survival (mPFS) for the 2 arms was also determined.Results: Twenty-nine of 34 enrolled patients were evaluable for response. One patient on each of the initial 2 treatment arms had a partial response (ORR: 6.7% and 7.1% for cediranib and sunitinib, respectively). Twenty-four patients had a best response of stable disease (86.7% and 78.6% for cediranib and sunitinib, respectively). There were no significant differences in mPFS for the 2 treatment arms. Clinical benefit (i.e., objective response or stable disease for a minimum of 4 or 6 cycles of therapy) on the first-line tyrosine kinase inhibitor (TKI) therapy did not predict benefit on the second-line TKI. Both drugs were well tolerated. As of August 2021, 1 patient (unevaluable for ORR) remains on study.The study did not meet its endpoints for ORR. Although both TKIs provided clinical benefit, the outcomes may have been attenuated in patients who had progressed ≤6 months before enrollment, potentially accounting for the low response rates.

Lurbinectedin; Neuroendocrine tumours; Small cell Lurbinectedina; Tumores neuroendocrinos; Célula pequeña Lurbinectedina; Tumors neuroendocrins; Cèl·lula petita Background Patients with neuroendocrine tumours (NETs) need alternative therapies after failure of first-line therapy. Patients and methods This phase II trial evaluated lurbinectedin, a selective inhibitor of oncogenic transcription, at 3.2 mg/m2 as a 1-h intravenous infusion every 3 weeks in 32 NETs patients treated in the second- or third-line setting. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1 assessed by the investigators. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results Two of 31 evaluable patients had confirmed partial responses (ORR = 6.5%; 95%CI, 0.8–21.4%). Median DoR was 4.7 months (95% CI, 4.0–5.4 months), median PFS was 1.4 months (95% CI, 1.2–3.0 months) and median OS was 7.4 months (95% CI, 3.4–16.2 months). Lurbinectedin showed an acceptable, predictable and manageable safety profile. The most common grade 3/4 toxicity was neutropenia (40.6%; grade 4, 12.4%; febrile neutropenia, 3.1%). Conclusions Considering the exploratory aim of this trial that evaluated a heterogeneous population of NETs patients, and the signs of antitumour activity observed (two confirmed partial responses and seven long disease stabilisations), further development of lurbinectedin is warranted in a more selected NETs population.

Recombinant interleukins (IL) have had limited clinical success due to inefficient tumor targeting and short pharmacokinetics (PK), requiring frequent dosing that leads to aberrant immunostimulation and toxicity. IL-12 is a promising cancer treatment due to its activation of T and natural killer (NK) lymphocytes to produce interferon (IFN)-γ, yet dosing strategies have failed to provide adequate therapeutic benefit in humans. To address these issues, we developed a novel platform that delivers either mono- or bifunctional immunomodulator(s) linked to a Fully-Human, Albumin Binding scFv domain (FHAB®), which provides enhanced tumor targeting and retention through albumin binding to over-expressed FcRn, GP60, and SPARC, an improved PK profile, a dose-sparing effect that decreases the toxicity risk, and a broader therapeutic index. Excellent tumor growth inhibition was seen using a “cold” immunosuppressive B16F10 melanoma model for comparing the efficacy of IL12-FHAB with rIL-12, resulting in significant increases in activated NK, NKT, Th1, and cytotoxic CD8 T cells. We are conducting a first-in-human, dose-escalation trial to evaluate the safety and tolerability of SON-1010 (IL12-FHAB) and to determine the maximum tolerated dose (MTD) in patients with advanced solid tumors. The study has a traditional 3+3 design, modified to take advantage of the known tachyphylaxis of IL-12 with the introduction of a desensitizing first dose to allow administration of higher maintenance doses. No dose-limiting toxicities have been encountered in the first 3 dose cohorts and the MTD is at least 300 ng/kg. While adverse events seen in other studies of IL-12 have occurred, they have been transient and tolerable, allowing further dose escalation. Increases in IFN-γ were dose-related, controlled, and prolonged. The levels peaked at 24 to 48 hours and returned to baseline after 2 to 4 weeks. Low levels of IL-10 were induced in a dose-dependent manner. No drug-related increase was seen with IL-1β, IL-6, IL-8, or TNF-α and there was no evidence of cytokine release syndrome at these doses. The preliminary geomean elimination half-life (T½) was 122 hrs with first-order kinetics, compared with 12 hrs for SC rhIL-12. The accumulation estimates are within the margin of error and are not likely to be physiologically significant with subcutaneous dosing of SON-1010 every 3 weeks. Eight of 11 patients had stable disease at the first follow-up CT, 4 of whom were progressing at study entry. Two patients were stable at 4 months and 2 had unconfirmed progressive disease; 1 patient remains stable after 8 months on SON-1010 with evidence of tumor regression. SON-1010 may have a positive synergistic effect with an immune checkpoint inhibitor (ICI), particularly with ‘cold’ tumors that over-express SPARC. The next stage of development will be to explore the MTD of SON-1010 in combination with an ICI, then to compare that approach with the standard of care in Phase 2. Citation Format: Sant P. Chawla, Victoria S. Chua, Erlinda M. Gordon, John Cini, Susan Dexter, Manual DaFonseca, Justus Bingham, Grantham W. Hogeland, Richard T. Kenney. Clinical development of a novel form of interleukin-12 with extended pharmacokinetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT245.

Purpose: Entrectinib potently inhibits tropomyosin receptor kinases (TRKAs)/B/C and ROS1, and previously induced deep [objective response rate (ORR) 57.4%] and durable [median duration of response (DoR) 10.4 months] responses in adults with NTRK fusion-positive solid tumors from three phase I/II trials. This article expands prior reports with additional patients and longer follow-up. Patients and Methods: Patients with locally advanced/metastatic NTRK fusion-positive solid tumors and ≥12 months' follow-up were included. Primary endpoints were ORR and DoR by blinded independent central review (BICR); secondary endpoints included progression-free survival (PFS), intracranial efficacy, and safety. The safety-evaluable populations included all patients who had received ≥1 entrectinib dose. Results: At clinical cut-off (August 31, 2020), the efficacy-evaluable population comprised 121 adults with 14 tumor types and ≥30 histologies. Median follow-up was 25.8 months; 61.2% of patients had a complete (n = 19) or partial response (n = 55). Median DoR was 20.0 months [95% confidence interval (CI), 13.0–38.2]; median PFS was 13.8 months (95% CI, 10.1–19.9). In 11 patients with BICR-assessed measurable central nervous system (CNS) disease, intracranial ORR was 63.6% (95% CI, 30.8–89.1) and median intracranial DoR was 22.1 (95% CI, 7.4–not estimable) months. The safety profile of entrectinib in adults and pediatric patients was aligned with previous reports. Most treatment-related adverse events (TRAEs) were grade 1/2 and manageable/reversible with dose modifications. TRAE-related discontinuations occurred in 8.3% of patients. Conclusions: With additional clinical experience, entrectinib continues to demonstrate durable systemic and intracranial responses and can address the unmet need of a CNS-active treatment in patients with NTRK fusion-positive solid tumors.

Purpose This Phase 1/2 study evaluated safety and efficacy of a topical submicron particle paclitaxel (SPP) in an anhydrous ointment base (SOR007), primarily in breast cancer patients with cutaneous metastases (CM). Methods One of three concentrations of SOR007 SPP (0.15%, 1.0%, or 2.0%) was applied twice daily over an area of 50 cm2 under a 3 + 3 phase 1 design for up to 28 days, with the option for expansion to an additional 28 days at the highest dose under a Phase 2a once safety was established. Efficacy was analyzed by lesion measurements and photographs to determine overall response rate (ORR), complete response (CR), and progression free survival by day 28 or 56. Results Twenty-three subjects were enrolled, 21 with cutaneous metastases of breast cancer (CMOBC). Four subjects received SOR007 0.15% for a median of 28 days (range = 17–29), three at a dose of 1.0% for a median of 28 days (range = 6–29), and sixteen at 2.0% for a median of 55 days (range = 6–60). All doses were well tolerated, and 19 subjects were evaluable for efficacy. At day 28 across all dose levels, 16% (95% CI 3.4 to 39.6%) of subjects achieved an ORR and another 63% (95% CI 34.9–96.8%) had stable disease (SD). The proportion of patients being progression free at 28 days across all treatments was 79% (95 CI 54–94%). Conclusion Application of SOR007 0.15%, 1.0%, and 2.0% to CM was safe and well tolerated with some reduction in lesion pain, and minimal systemic absorption of paclitaxel. Lesion stabilization was observed in most subjects over the study period. A randomized, placebo-controlled trial to confirm these findings is warranted. ClinicalTrials.gov identifier NCT03101358.

Background NC-6300 is a novel epirubicin (EPI) drug conjugated polymeric micelle developed using cutting-edge micellar nanoparticle technology. The nanoparticle epirubicin conjugates EPI to a polymer via a pH-sensitive linker which enables the selective EPI release into tumor. Tumor activity was observed in a monotherapy phase Ib trial, where two of two patients with angiosarcoma achieved a partial response. To further explore the activity of NC-6300 in angiosarcoma, an expansion cohort was undertaken. Methods Ten patients with angiosarcoma were enrolled in the expansion cohort. Patients were dosed using the recommended dose of 150 mg/m2 intravenously (IV) once every 3 weeks. The primary endpoint was progression-free survival. Results The most common adverse events (AEs) of any grade, regardless of the causal relationship with NC-6300, were neutropenia (90%), fatigue, and thrombocytopenia (60% each) and nausea (50%). The most common grades 3 and 4 AEs were neutropenia (80%), thrombocytopenia (40%), and anemia and leukopenia (20% each). The median progression-free survival (mPFS) for all subjects was 5.4 months. The mPFS was 3.8 months in subjects with prior anthracycline treatment and 8.2 months in subjects without prior anthracycline treatment. Conclusion NC-6300 was well tolerated, showing promising activity in angiosarcoma patients without prior anthracycline treatment. NC-6300 warrants further investigation (ClinicalTrials.gov Identifier: NCT03168061).

Background: Murine double minute 2 (MDM2) is a negative regulator of tumor suppressor protein p53. MDM2 induces degradation of p53 and promotes tumorigenesis. MDM2 amplification occurs in many cancers but is documented in up to 100% of well-differentiated or de-differentiated liposarcomas (WD/DDLPS) [Cancer Genome Atlas Research Network. Cell 2017]. Inhibition of the MDM2-p53 interaction is a promising therapeutic approach to restore p53 tumor suppressor activity in WD/DDLPS. Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor that inhibits the MDM2-p53 interaction and restores p53 function at nanomolar concentrations. In a phase 1 study, milademetan showed promising efficacy in 53 patients with WD/DDLPS when administered on an intermittent schedule (260 mg QD on Days 1-3 and 15-17 on a 28-day cycle), with a median progression-free survival (PFS) of 7.4 months [Gounder et al. AACR-NCI-EORTC 2020]. WD/DDLS are relatively resistant to chemotherapy, and systemic treatment options for patients with advanced disease are limited. MANTRA (RAIN-3201) is a randomized, multicenter, open-label, phase 3 registration study designed to evaluate the efficacy and safety of milademetan versus trabectedin in patients with unresectable or metastatic DDLPS with disease progression on ≥1 prior systemic therapies. Methods: Eligible patients are ≥18 years of age with histologically confirmed unresectable and/or metastatic DDLPS, with or without a WD component, who have received ≥1 prior systemic therapies, including ≥1 anthracycline-based regimen, with radiographic evidence of progression by RECIST v1.1 within 6 months before study entry. Prior treatment with trabectedin or an MDM2 inhibitor is not permitted. Patients will be randomly assigned (1:1) to receive milademetan (260 mg once daily orally Days 1-3 and 15-17 on a 28-day cycle) or trabectedin (1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks). Randomization is stratified by Eastern Cooperative Oncology Group performance status (0 or 1) and number of prior treatments for WD/DDLPS (≤2 or >2). Tumor response will be evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: PFS by blinded independent central review. Secondary endpoints: overall survival; disease control rate; objective response rate; duration of response; PFS by investigator assessment; safety; health-related quality of life. Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%. ClinicalTrials.gov: NCT04979442. Citation Format: Mrinal M. Gounder, Gary K. Schwartz, Robin L. Jones, Sant P. Chawla, Victoria S. Chua-Alcala, Silvia Stacchiotti, Andrew J. Wagner, Gregory M. Cote, Robert G. Maki, Hanna Kosela-Paterczyk, Dale R. Shepard, Naisargee Shah, Richard Bryce, Robert C. Doebele, Shreyaskumar Patel. MANTRA: A randomized, multicenter, phase 3 study of the MDM2 inhibitor milademetan versus trabectedin in patients with de-differentiated liposarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT235.

Background: SQ3370, a novel therapy, utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups release Doxorubicin (Dox) at the tumor site while minimizing systemic exposure. In animals, SQ3370 enhanced T-cell infiltration, survival, and showed activity in both injected and non-injected lesions. Minimal to no toxicity, including no cardiotoxicity was seen in up to 9-fold dose increases in animals. Conventional Dox can induce cardiomyopathy with incidences of 6-20% for cumulative doses of 500 mg/m2 in humans. Here we report interim results of the Phase 1 trial (SQ3370-001; NCT04106492). Methods: SQ3370 has 2 components: 1) Intratumoral injection of a protodrug-activating biopolymer (SQL70); 2) then 5 consecutive daily IV infusions of an attenuated protodrug of Dox (SQP33). Key criteria for enrollment include locally advanced to metastatic solid tumors, ≤300 mg/m2 prior exposure to DOX, ECOG status 0 or 1, and no limit to the number of prior systemic therapies. Primary objectives include safety and determining Phase 2 dose. Dose escalation was assessed in 2 stages: 1) accelerated titration; 2) 3+3 design. Dose-limiting toxicity (DLT) was evaluated in cycle 1. Results: As of 26NOV2021 data cut, 17 patients (pts) in 8 dose escalation cohorts have been enrolled. MTD has not been reached. Median age was 59 years (26-79), 53% were females, and were ECOG 1 (59%). Prior procedures included surgery (82%) and radiation (47%). At study entry, 82% of pts had metastases with a median number of metastatic sites being 2 (1-5). Solid tumors were sarcoma (65%), and cancers of the skin, breast, and gynecologic organs were 12% for each, respectively. Sixteen of 17 (94%) pts received prior chemotherapy with 47% receiving prior Dox. Median number of prior systemic therapies was 2 (1-7). Intratumoral injection sites include soft tissue and chest wall. Of the 17 pts, 65% received >500 mg/m2, 53% (>1000), and 29% (>2000) cumulative Dox given as SQP33. Median duration of treatment was 3 cycles (1-10). No DLTs were observed. Most frequent AEs, regardless of causality, included nausea (n = 9), fatigue (n = 6) and anemia (n = 5). No signs of cardiomyopathy were seen in pts with an echo performed within 1 mo. of study start. Although >50% of pts received >1000 mg/m2, ejection fraction (LVEF) remained normal. No AEs that led to discontinuation or death were related to SQ3370. All pts were evaluable for response. At a median follow-up of 10 wks (4-30), 65% of pts had SD as best response. Median duration of SD was 80 days (37-186) with 64% sustaining SD for ≥60 days, corresponding to an overall disease control rate of 65%. The remainder of pts had PD as best response. Over 35% of pts remain on drug. Conclusions: SQ3370 was well tolerated. No DLTs and normal LVEF were seen with pts receiving >1000 mg/m2 Dox cumulative doses. Dose escalation is ongoing. Preliminary evidence of disease control was observed in this heavily pre-treated, high cancer burden, solid tumor pt population. Citation Format: Sant P. Chawla, Kathleen Batty, Vivek Bhadri, Nam Bui, Alexander D. Guminski, Jose M. Mejia Oneto, Sangeetha Srinivasan, James F. Strauss, Vivek Subbiah, Mia C. Weiss, Rosalind Wilson, Nathan A. Yee, Michael Zacharian, Vineet Kwatra. SQ3370 in advanced solid tumors: Interim phase 1 results [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT177.

Background: Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor with few effective treatment options. Cediranib (C) and sunitinib (S) are potent oral inhibitors of all 3 VEGF receptors. Cediranib showed substantial single-agent activity (objective response rate [ORR] = 35%) in our previous trial in patients (pts) with metastatic ASPS (NCT00942877). Here we report a phase 2 randomized multicenter trial of single agent C or S in pts with ASPS (NCT01391962). Methods: We conducted a multicenter phase 2 trial with an optimal 2-stage design targeting an ORR of 40%. Enrolled pts were >16 years with metastatic ASPS, previously not treated (N) and unresectable, or previously treated (T), who have progressed per RECIST 1 within the 6-month period preceding enrollment. Pts were randomized to receive C (30 mg) or S (37.5 mg) orally, once a day, in 28-day cycles and could crossover to the other treatment arm at disease progression. ORR (primary endpoint), median progression-free survival (mPFS), and PFS rate at 24 weeks for the 2 arms (C and S) were evaluated; T and N cohorts were assessed separately in each arm. Arm accrual closed if ≤ 1 of the first 10 enrolled pts responded to the first treatment. Results: Thirty-four pts (47% white, 29.4% black, 17.6% Asian, 5.8% Pacific Islander) were enrolled; 29 pts were evaluable for response. One pt on each of the initial treatment arms had a confirmed partial response (PR), rates of 6.7% (1/154) and 7.1% (1/14) for C and S tx or tx-naive, respectively. Among pts who crossed over, there was 1 PR in a pt receiving C after initially responding (PR) on S (1/9; ORR 11.1%). Twenty-four pts had a best response of stable disease (86.7% and 78.6%) for C and S, respectively. The mPFS was 7.6 months (mo) (95% CI: 3.7-9.9 mo) and 5.5 mo (95% CI: 1.8-14.5 mo) for C and S, respectively administered as first therapy (p=0.92). PFS rate at 24 weeks was 62.5% (95% CI: 29.5-76.2%) and 50% (95% CI: 25.9-70.1%) for pts receiving C and S respectively, as initial therapy. There was no difference in mPFS between T or N pts in the C (6.7 mo [95% CI: 1.4-9.9 mo] vs 8.3 mo [95% CI: 2.7 - 16.6 mo]; P=0.35) arm, but some evidence of a potential difference in the S (4.8 mo [95% CI: 0.9-7.9 mo] vs 14.7 mo 95% CI: 1.8 - 21.6 mo]; P=0.058) arm. Overall, 43.7% (C) and 77.8% (S) of pts experienced grade ≥3 adverse events (AEs) at least possibly related to the study drug. Common grade ≥3 AEs included: diarrhea (C), neutropenia (S), hypertension (C and S). AEs were in line with the known safety profiles of each agent. As of August 2021, 1 pt (unevaluable for ORR) remains on study. Conclusions: The study did not meet its endpoints for ORR. There were no differences in mPFS for the 2 treatment arms. The selection of pts with more aggressive disease, who had progressed in the 6 months prior to enrollment, may account for the low patient response rates compared to our previous study of cediranib in ASPS. Funded by NCI Contract No. HHSN261200800001E. The study was a collaboration between NCI and Pfizer. Citation Format: Naoko Takebe, James Nguyen, Shivaani Kummar, Albiruni Abdul Razak, Sant P. Chawla, Suzanne George, Shreyaskumar R. Patel, Mary Louise Keohan, Sujana Movva, Geraldine O’Sullivan, Khanh Do, Larry Anderson, Lamin Juwara, Brooke Augustine, Seth Steinberg, Laura Kuhlmann, S. Percy Ivy, James H. Doroshow, Alice P. Chen. Randomized phase 2 trial of sunitinib or cediranib in alveolar soft part sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT168.

e15048 Background: Defects in cell cycle control are fundamental oncogenic drivers and targeting deregulated cell cycling is under intensive study. Cell cycle cyclin G1 (CCNG1) inhibitor therapy, exemplified by DeltaRex-G, a tumor-targeted retro vector encoding a cytocidal CCNG1 inhibitor gene, has been tested in over 280 cancer patients worldwide in early studies, inducing long term (10-13 years) survival in certain patients with intractable metastatic pancreatic adenocarcinoma, sarcoma, and breast cancer. Hence, further clinical development of DeltaRex-G for cancer patients who have few or no therapeutic options is apropos. Methods: Primary objective: To determine overall survival. Secondary objective: To evaluate disease control, best overall response, and incidence of treatment-related adverse events. Patient and Methods: Study 1 is entitled “Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)”. Study 2 is entitled “Compassionate Use of DeltaRex-G for Advanced Cancers. In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 15-30 minutes, 3 x a week until significant disease progression or unacceptable toxicity occurs. Results: Seventeen patients were enrolled, 9 sarcomas, 2 pancreatic adenocarcinomas, 1 non-small cell lung cancer, 2 breast carcinoma, 1 prostate cancer, 1 cholangiocarcinoma, and 1 basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Two patients were initially enrolled in Study 1 and later enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with FDA-approved cancer therapies. Of the 12 treated patients, 5 are alive 10 to 30 months from DeltaRex-G treatment initiation. Two patients with early-stage triple receptor-positive and triple receptor-negative breast cancer who received DeltaRex-G as adjuvant/first-line therapy are alive one year in complete remission; 2 patients with chemo-resistant Stage 4 sarcoma are alive 2 1/2 years, and one patient with advanced basal cell carcinoma is alive 10 months from treatment initiation. There were no treatment-related adverse events reported. Conclusions: Taken together,the data suggest that (1) Adjuvant/first-line therapy with DeltaRex-G may reduce the incidence of recurrence of early-stage invasive carcinoma of the breast and (2) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy. Phase 2 studies are planned to evaluate if DeltaRex-G (1) will reduce the incidence of recurrence in early-stage invasive carcinoma of breast, (2) improve survival in pancreatic cancer, and (3) prolong progression-free survival and overall survival in advanced sarcoma. Clinical trial information: NCT04091295.

11518 Background: In our experience, combinatorial therapy with lower doses of doxorubicin, gemcitabine, and docetaxel has been effective with a manageable toxicity profile in patients with advanced soft tissue sarcomas. Hypothesis: The addition of nivolumab will have synergistic effects and improve treatment outcomes. Methods: Primary objective: To assess progression-free survival; Secondary objectives: (1) To evaluate best overall response during treatment period confirmed in a 6-week follow-up, (2) PFS rate at 6 and 9 months, (3) Overall survival rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Inclusion criteria: Previously treated male and female subjects, > 18 years of age, pathologically confirmed diagnosis of locally advanced, unresectable, or metastatic sarcoma, measurable disease by RECIST v1.1, and acceptable hematologic and organ functions. Exclusion Criteria: History of autoimmune disorder. Treatment schedule: Metronomic doses of gemcitabine (600 mg/m2 max:1000 mg), doxorubicin (18 mg/m2; max: 32 mg), docetaxel (25 mg/m2; max:42 mg) on Day 1 and Day 8, and nivolumab (240 mg) on Day 1 only. Repeat treatment cycles may be given every three weeks if toxicity grade is 4.6 (range: 1-27) months; 4 month PFS rate 60%. Median OS 6.2 months, with 4-month OS 74%. Historically, the median PFS on preceding lines of therapy was 2 (range: 1-14) months. There were no unexpected side effects noted in this study. The most common grade 3/4 TRAEs include Fatigue (n = 13), Nausea (n = 9), Neutropenia (n = 8), thrombocytopenia (n = 6), Anemia (n = 6). Conclusions: The GALLANT protocol using metronomic Gemcitabine, Doxorubicin (Adriamycin), Nivolumab, and Docetaxel (Taxotere) (1) is an effective regimen as second/third-line therapy for advanced sarcoma with no unexpected side effects, and (2) may have synergistic activity when this metronomic chemotherapy is combined with an immune checkpoint inhibitor. Clinical trial information: NCT04535713.

2644 Background: Natural killer (NK) cells play a key role as the main effector cells toward cancer in innate immunity. Thus, a leading approach is to boost NK-cell mediated anti-tumor activity using adoptive transfer of ex vivo activated NK cells. NK cells have always been challenging to grow ex vivo especially when derived from heavily pretreated donors, thus most have focused on universal allogenic donor derived products. SNK01 is a first-in-kind, autologous non-genetically modified NK cell product with significant anti-tumor cytotoxicity and over 90% expression of CD16, NKG2D, NKp46, and DNAM-1, that can be consistently produced even from heavily pre-treated cancer patients (pts). While most if not all NK cell therapy has focused on liquid malignancies, SNK01 has been found to have strong activity against both liquid and solid tumors preclinically. We hypothesized that SNK01 would be safe without need for lymphodepletion and may demonstrate activity against heavily pre-treated solid tumors. Methods: In this Phase 1 dose escalation study (NCT03941262), SNK01 was administered intravenously (IV) weekly for 5 consecutive weeks using a 3+3 design in pts with advanced solid tumors. The starting dose was 1 x 109SNK01 cells and the highest dose was 4 x 109 SNK01 cells. Primary endpoint was safety based on AEs, vitals, laboratory tests, and PEs. Individual NK cell expansion was characterized for increases in cytotoxicity and changes in activating receptor expression. Results: As of Feb 1, 2022, 10 pts with advanced refractory solid tumors have been enrolled. Median age is 50 (range 32 – 75) and 6 were male. Pts had a median 5.5 lines of prior therapy (range 2-10). The subtypes were 4 leiomyosarcoma, 1 chondrosarcoma, 1 NSCLC, 1 small round cell tumor, 1 colorectal, 1 synovial cell sarcoma, 1 angiosarcoma. NK cells were successfully activated and expanded, even from heavily pre-treated pts. Average cytotoxicity was increased over 400% and average activating receptor expression was greater than 90%. There were only two Grade 1 adverse events reported in the 50 total doses given. Best objective response of SD was demonstrated in 7 pts. Of patients who progressed in the dose escalation cohorts, several reported an overall improvement in their QOL. Based on this improvement, patients then became eligible to be treated with additional salvage chemotherapy to which some then showed additional response. Conclusions: SNK01 with high cytotoxicity and activating receptor expression can be consistently produced from heavily pretreated patients. SNK01 was very safe and appears to have some clinical activity against heavily pretreated solid tumors and may even sensitize tumors to additional chemotherapy. SNK01 will be studied further as monotherapy and in various combination regimens. Clinical trial information: NCT03941262.

11517 Background: For patients (pts) with advanced sarcomas in the relapsed/refractory setting, there are very few if any effective salvage treatment options. The likelihood of response and/or tumor control only diminishes with each subsequent line of therapy. Monotherapy of PD-L1 inhibitors has shown modest to no activity in most sarcomas, especially in tumors that have little to no PD-L1 expression. Natural killer (NK) cells have recently been implicated in the antitumor response to immune checkpoint inhibitors with some evidence suggesting a role in PD-L1 negative tumors. SNK01 is a first-in-kind, autologous nongenetically modified NK cell therapy with highly enhanced cytotoxicity and over 90% activating receptor expression which can be consistently produced from heavily pretreated pts. Avelumab is an anti-PD-L1 immunotherapy with dual engagement of both the adaptive and innate immune systems. We hypothesized that this combination would be safe, and together better overcome the immunosuppressive tumor microenvironment. Methods: In this Phase I study (NCT03941262), cohort 4 is comprised of up to 18 pts treated with 800 mg of avelumab + 4 x 109 SNK01 cells every two weeks via IV Infusion. Pts were eligible regardless of PD-L1 status and permitted to continue treatment indefinitely until progression or unacceptable toxicity. The primary endpoint is safety. The secondary endpoints include overall response rate (ORR), progression free survival (PFS), and overall survival (OS). Results: As of February 1, 2022, 15 pts with advanced refractory sarcoma have been enrolled. Median age is 50 (range 20-75) and 8 were male. Pts had a median of 5 lines of prior therapy (range 1-8). The subtypes included 6 leiomyosarcoma, 2 osteosarcoma, 1 pleomorphic liposarcoma, 1 Ewing’s sarcoma, 1 epithelioid sarcoma, 1 epithelioid mesothelioma, 1 endometrial stromal sarcoma, and 1 sarcoma NOS. There were three Grade 2 or 3 adverse events related to avelumab, but unrelated to SNK01. Best objective response by RECIST 1.1 was PR in 2 pts (ORR of 13.3%) and SD in 3 pts. Median PFS is 11.14 weeks. Several pts had PD-L1 negative disease and response appears to be independent of PD-L1 status. Of pts who progressed in this cohort, several reported an overall improvement in their QoL and some pts became eligible to be treated with additional salvage chemotherapy, resulting in some additional clinical response. Conclusions: SNK01 combined with avelumab was safe and well tolerated and appears to have some clinical activity against several types of heavily pretreated advanced sarcoma, independent of PD-L1 status. It may also keep rapidly progressing disease stable enough to allow additional cytotoxic chemotherapy. A proposed study expansion is planned. Clinical trial information: NCT03941262.

TPS11593 Background: Doxorubicin is a standard of care agent for patients with advanced soft tissue sarcoma, with a response rate of around 15%, progression-free survival of 5-7 months and cumulative cardiac toxicity that limits its use. TTI-621 is a recombinant soluble fusion protein that combines the N-terminal portion of human SIRPα (the binding domain for CD47) with the Fc region of human IgG1, generating a decoy receptor for CD47 on the surface of tumor cells that both over-rides CD47-mediated inhibition of phagocytosis and provides a pro-phagocytic stimulation. Many solid tumors express high levels of CD47 which is associated with poor prognosis, thought to be the result of CD47-mediated inhibition of macrophage phagocytosis and escape of immune-mediated clearance. Interruption of the CD47-SIRPα signaling pathway using monoclonal antibodies to CD47 has shown anti-tumor activity in animal models and in some early clinical trials. The combination of doxorubicin with CD47-targeted antibodies results in enhanced anti-tumor activity and increased macrophage-mediated cell killing in animal models and macrophage-mediated phagocytosis of cancer cell lines in vitro, suggesting that combining TTI-621 with doxorubicin might be more effective than doxorubicin alone in tumor types that express CD47 and have high numbers of macrophages, such as LMS. Thus, a Phase 1/2 study was initiated to evaluate this combination in patients with advanced soft tissue sarcoma, including LMS. Methods: TTI-621-03 is a Phase 1/2, open-label study of TTI-621 in combination with doxorubicin in patients with anthracycline-naïve disease. The Phase 1 dose escalation evaluates doses of TTI-621 (0.2 to 2.0 mg/kg) in combination with doxorubicin at 75 mg/m2 in patients with high-grade soft tissue sarcomas. Expansion cohorts will evaluate TTI-621 (0.2 and 2.0 mg/kg) with doxorubicin in patients with LMS, with pathology confirmed at a central laboratory. The primary goals of this study are evaluation of safety of TTI-621 administered in combination with standard-of-care doxorubicin and to further evaluate clinical activity (ORR, PFS, OS), safety, PK and patient-reported quality of life in the LMS subpopulation. The dose escalation portion of the study has been completed without DLT. Enrollment to the expansion portion of the study is underway. Clinical trial information: NCT04996004.

11573 Background: Understanding the bifunctional role that the immune system plays in tumor eradication vs growth promotion is critical in the design and timing of tumoricidal and immunologic therapies for sarcomas. Hypothesis: Immune checkpoint inhibitors that promote sustained T cell activation would be most effective when given as first line therapy, together with a tumoricidal agent. Methods: Eligible patients for this Phase 2 study are males or females ≥ 18 years of age with locally advanced unresectable or metastatic soft tissue sarcoma, previously untreated, with measurable disease by RECIST v1.1. Treatment protocol: (I) mg/kg i.v. q 12 wks, (N) 3 mg/kg i.v. q 2 wks, (T) 1.2 mg/m2 CIV q 3 wks. Treatment Outcome Parameters: (1) Best objective response rate by RECIST v1.1, (2) Progression-free survival (PFS), (3) Overall survival (OS), and (4) Incidence of treatment-related adverse events. Results: Ninety-nine patients were enrolled. Efficacy analysis (n = 88): There were 8CR (1 surgical CR), 11PR, 58SD, 11PD. Overall response rate was 21.6%, Disease Control Rate, 87.5%. The median PFS was 7 (range:1-44) months, median OS, 14 (range: 1-46) months. Grade 3 TRAEs include fatigue (n = 8), adrenal insufficiency (n = 1), dehydration (n = 1), hyponatremia (n = 2), increased AST (n = 8), increased ALT (n = 24), increased ALP (n = 2), port site infection (n = 2), psoriasis exacerbation (n = 1), anemia (n = 9), thrombocytopenia (n = 2), and neutropenia (n = 5). Grade 4 TRAES include anemia (n = 1), neutropenia (n = 1), thrombocytopenia (n = 2), increased AST (n = 2), increased ALT (n = 2), and increased CPK (n = 2). Grade 5 TRAES include rhabdomyolysis (n = 1). There was no incidence of alopecia nor cardiac toxicity reported. Conclusions: Taken together, these data indicate that first-line combinatorial therapy with Ipilimumab, Nivolumab, and Trabectedin (1) may be more effective than standard first line therapy (doxorubicin/ifosfamide/mesna), and (2) is safer than standard first line therapy for advanced soft tissue sarcoma. Clinical trial information: NCT03138161.

TPS11589 Background: Murine double minute 2 (MDM2) is a negative regulator of tumor suppressor protein p53. MDM2 induces degradation of p53 and promotes tumorigenesis. MDM2 amplification occurs in many cancers but is documented in up to 100% of well-differentiated or dedifferentiated liposarcomas (WD/DDLPS) [Cancer Genome Atlas Research Network. Cell 2017]. Inhibition of the MDM2-p53 interaction is a promising therapeutic approach to restore p53 tumor suppressor activity in WD/DDLPS. Milademetan (RAIN-32) is a small-molecule MDM2 inhibitor that inhibits the MDM2-p53 interaction and restores p53 function at nanomolar concentrations. In a phase 1 study, milademetan showed promising efficacy in 53 patients with WD/DDLPS when administered on an intermittent schedule (260 mg QD on Days 1–3 and 15–17 on a 28-day cycle), with a median progression-free survival (PFS) of 7.4 months [Gounder et al. AACR-NCI-EORTC 2020]. WD/DDLS are relatively resistant to chemotherapy, and systemic treatment options for patients with advanced disease are limited. MANTRA (RAIN-3201) is a randomized, multicenter, open-label, phase 3 registration study designed to evaluate the efficacy and safety of milademetan versus trabectedin in patients with unresectable or metastatic DDLPS with disease progression on ≥ 1 prior systemic therapies. Methods: Eligible patients are ≥ 18 years of age with histologically confirmed unresectable and/or metastatic DDLPS, with or without a WD component, who have received ≥ 1 prior systemic therapies, including ≥ 1 anthracycline-based regimen, with radiographic evidence of progression by RECIST v1.1 within 6 months before study entry. Prior treatment with trabectedin or an MDM2 inhibitor is not permitted. Patients will be randomly assigned (1:1) to receive milademetan (260 mg once daily orally Days 1–3 and 15–17 on a 28-day cycle) or trabectedin (1.5 mg/m2 as a 24-hour intravenous infusion every 3 weeks). Randomization is stratified by Eastern Cooperative Oncology Group performance status (0 or 1) and number of prior treatments for WD/DDLPS (≤ 2 or > 2). Tumor response will be evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: PFS by blinded independent central review. Secondary endpoints: overall survival; disease control rate; objective response rate; duration of response; PFS by investigator assessment; safety; health-related quality of life. Exploratory endpoints: molecular markers in peripheral blood and/or tumor tissue; milademetan pharmacokinetics. To demonstrate a 3-month increase in PFS (from 3 to 6 months) corresponding to a hazard ratio of 0.5, approximately 160 patients will be required to observe 105 events with 93.9% power and 2-sided significance level of 5%. Clinical trial information: NCT04979442.

TPS11582 Background: Chondrosarcomas (CS) are the third most common type of primary bone cancer after myeloma and osteosarcoma. Conventional CS represent 85–90% of all cases and are typically treated with surgical resection. However, there are no approved systemic treatment options for patients with unresectable or metastatic conventional CS, and outcomes remain poor. INBRX-109 is a precision-engineered, tetravalent death receptor 5 (DR5) agonist antibody designed to overcome the limitations of earlier-generation agonists and exploit the tumor-specific cell death induced by DR5 activation. DR5 is one of two pro-apoptotic receptors for the trimeric tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Early clinical activity of INBRX-109 was observed in an ongoing phase 1 trial and warrants further investigation. INBRX-109 has been granted an FDA fast-track designation for conventional CS. Methods: This is a multicenter, randomized, blinded, placebo-controlled phase 2 study in patients with unresectable or metastatic conventional CS, measurable disease by RECIST 1.1, and radiologic disease progression within 6 months prior to screening. Any number of prior lines of therapy are allowed, except for prior DR5 agonists. Patients must be ≥18 years of age and have an ECOG performance status of 0/1 and have archival or fresh tissue available. Approximately 201 patients will be randomized (2:1) to INBRX-109 (3 mg/kg intravenously, every 21 days) or placebo, stratified by histologic grade (Grade 1/2 vs 3), isocitrate dehydrogenase (IDH)1 R132/IDH2 R172 status (wildtype vs mutation), and line of systemic therapy (none vs prior). Treatment will continue until disease progression/unacceptable toxicity. Patients treated with a placebo will have the option to cross over to INBRX-109 upon disease progression. The primary endpoint is progression-free survival (PFS) by independent radiology review. Secondary endpoints are overall survival, PFS by investigator assessment, quality of life, overall response rate, duration of response, disease control rate, safety, pharmacokinetics, and immunogenicity. Adverse events will be recorded and graded by NCI CTCAE Version 5.0. Median PFS of 7.0 months is projected for INBRX-109 and 4.0 months for placebo (corresponding hazard ratio of 0.571); INBRX-109 will be declared superior if the 1-sided p-value from the stratified log-rank test is

3085 Background: SQ3370, a novel therapy, utilizes Shasqi’s proprietary Click Activated Protodrugs Against Cancer (CAPAC) platform where mutually-reactive click chemistry groups release Doxorubicin (Dox) at the tumor site minimizing systemic exposure. In animals, SQ3370 enhanced survival, T-cell infiltration and antitumor responses in injected and non-injected tumors. Minimal to no toxicity, including no cardiotoxicity was seen in up to 9-fold dose increases in animals. Conventional Dox can induce cardiomyopathy at incidences of 1-20% for cumulative doses from 300-500 mg/m2 in humans and re-treatment with Dox is less effective in heavily pre-treated patients (pts). Here we report interim results of the Phase 1 ( NCT04106492 ). Methods: SQ3370 has 2 components: 1) Intratumoral injection of a protodrug-activating biopolymer (SQL70: 10 mL or 20 mL); 2) 5 consecutive daily IV infusions of an attenuated protodrug of Dox (SQP33). Key eligibility includes locally advanced or metastatic solid tumors, ≤300 mg/m2 prior exposure to Dox, ECOG 0-1 and no limit to prior systemic therapies. Primary objectives include safety and determining Phase 2 dose. Dose escalation was assessed in 2 stages: 1) accelerated titration; 2) 3+3 design. Results: As of 31JAN2022 data cut, 26 pts were treated, 21 with 10 mL biopolymer (bp) and 5 with 20 mL bp over 9 dose escalation protodrug cohorts. MTD has not been reached. Median age was 61 years (26-84), 62% were females, and 69% were ECOG 1. Prior procedures included surgery (89%) and radiation (62%). At study entry, 77% of pts had metastases with a median number of metastatic sites being 2 (1-5); most frequently lung (50%). Tumors were sarcoma (73%), breast cancer (7.7%), gyne (7.7%) and other (11.5%). Twenty-four of 26 (92%) pts received prior systemic therapies with 50% receiving prior Dox. Median number of prior systemic therapies was 2 (1-7). Of the 26 pts, 62% received > 500 mg/m2 cumulative Dox given as SQP33. Median duration of treatment was 2 cycles (1-12). Most frequent AEs, regardless of causality, for the 10 mL bp group included nausea (n = 11), fatigue (n = 9) and anemia (n = 6), and for the 20 mL bp group included anemia (n = 3) and nausea (n = 2). Ejection fraction (LVEF) remained normal during the study period. No AEs that led to discontinuation or death were related to SQ3370 by investigator. At a median follow-up of 9.2 wks (3-37), 21 pts were evaluable. SD was best response in 71%. Median duration of SD was 80-dys (37-186) corresponding to an overall disease control rate (CR+ PR+ SD x 30-dys) of 71% (68% in 10 mL bp; 100% in 20 mL bp). The remainder of pts had PD as best response. Over 38% of pts remain on drug. Conclusions: SQ3370 with 10 mL or 20 mL biopolymer was well tolerated in pts with half being re-treated with Dox. Although > 60% of pts received > 500 mg/m2 cumulative Dox given as SQP33, LVEF remained normal. Preliminary evidence of disease control was observed in pts despite heavy prior pre-treatment and high cancer burden. Dose escalation is ongoing. Clinical trial information: NCT04106492.

BackgroundConventional chemotherapeutics lack specificity for tumor tissue and usually have anarrow therapeutic index. SQ3370, a novel therapy that activates doxorubicin (Dox) at the tumor sitewhile minimizing systemic exposure, is based on intratumoral injection of a protodrug-activatinghyaluronic acid-based biopolymer (SQL70) followed by five daily intravenous (IV) doses of an attenuatedprotodrug of Dox (SQP33). SQ3370 utilizes Shasqi’s proprietary Click Activated Protodrugs AgainstCancer (CAPAC) platform where mutually-reactive click chemistry groups in the two components allowrelease of active Dox specifically at the tumor site. In animals, SQ3370 allowed for an 8.95-fold increase in dosing with minimal systemic adverse eventsand no cardiotoxicity. SQ3370 treatment of mouse tumor models showed improved overall survival,enhanced T-cell infiltration, and a robust anti-tumor response against both biopolymer-injected andnon-injected lesions,1 suggesting that SQ3370 promotes activation of the native immune systemagainst the tumor.MethodsSQ3370-001 (NCT04106492) is a phase 1 trial open to patients with relapsed/refractory soft-tissue sarcoma or other advanced, potentially anthracycline-responsive solid tumors with an injectablelocal or metastatic lesion and =300 mg/m 2 prior exposure to Dox (or equivalent). Primary objectivesinclude safety, tolerability, and recommended Phase 2 dose. Additional objectives include preliminaryefficacy, plasma and tumor biopsy pharmacokinetics (PK), and immune response by peripheral bloodmass cytometry/tumor IHC.ResultsTo date, ten patients have been enrolled. SQ3370 treatment has been well-tolerated with nodose-limiting toxicities observed. Plasma PK appeared consistent with preclinical data; rapid conversionof SQP33 protodrug to active Dox occurred but slowed as the residence time of the injected biopolymerlengthened. Systemic exposure to active Dox peaked on days 1–2 post biopolymer injection, followed bya decline on days 3–5. Preliminary tumor analysis shows that substantial local exposure to Dox continues2 weeks after the last SQP33 dose. Immune response analysis of early patient samples suggestsincreased tumor immune cell infiltration that dynamically changes with each cycle of treatment.ConclusionsSQ3370 appears to be well-tolerated and demonstrates proof-of-concept for the first click-chemistry-based therapy in the clinic. Preclinical and clinical PK are consistent; high tumor exposure canbe achieved, so far without the typical clinical adverse events seen with IV Dox and potentiallyimproving the therapeutic index of a frequently-used chemotherapeutic agent.Trial RegistrationNCT04106492ReferenceSrinivasan S, Yee NA, Wu K, et al. SQ3370 activates cytotoxic drug via click chemistry at tumor andelicits sustained responses in injected and non-injected lesions. Advanced Therapeutics 2021;4(3):2000243.