e23570 Background: Intratumoral injection of Talimogene Laherparepvec (TVEC) has a local oncolytic effect and evokes a cytotoxic immune response. The combination of Trabectedin (T) and Nivolumab (N) ...is a safe and effective therapy in soft tissue sarcoma (STS). Here, we report an update on an ongoing Phase 2 study that aims to determine the efficacy and safety of adding TVEC to the combination of T and N in advanced leiomyosarcoma (LMS). Objectives: Primary: To assess progression-free survival (PFS). Secondary: (1) To evaluate the best overall response, (2) PFS rate at 6 and 9 months, (3) Overall survival (OS) rate at 6, 9, and 12 months, (4) Incidence of conversion from unresectable to the resectable tumor, and (5) Incidence of treatment-related adverse events (TRAEs). Patients and Methods: Eligible patients included patients ≥ 18 years of age with locally advanced unresectable or metastatic LMS, measurable disease by RECIST v1.1, and at least one accessible tumor for TVEC intratumoral injection. N (3 mg/kg q2 weeks), T (1.2 mg/m2 q3 weeks), and TVEC (1x10 8 PFU/ml q 2 weeks depending on tumor size) were administered. A starting dose of TVEC (1x10 6 PFU/ml) was initially given, followed by a total dose of 1x10 8 PFU/ml q 2 weeks depending on tumor size) three weeks later. Results: Efficacy: Per protocol, there were 17 evaluable subjects (Modified Intention to Treat mITT patients who had completed at least one treatment cycle and had a follow-up CT scan). The median number of prior lines of therapy was 4 (range 1-9). The disease control rate (PR+SD) was 94% with 1 PR, and 15 SD. The median PFS was 8.0 months (95% CI:4.8-11.28) with a 6-month PFS rate of 71%; median OS 19.2 months (95% CI:12.7- 25.7); 6-month OS rate, 82%. Safety: 22 patients (Intention to treat ITT who had received at least one-time drug administration) were evaluated for safety analysis. The > Grade 3 TRAEs include anemia (n = 3), thrombocytopenia (n = 3), neutropenia (n = 1), increased ALT (n = 1), increased GGT (n = 1), decreased LVEF (n = 1), dehydration (n = 1), hyponatremia (n = 1). There were no new safety signals noted in this study. Conclusions: Taken together, the data confirms our previous report that (1) the combination regimen using Talimogene laherparepvec, Nivolumab & Trabectedin may be more effective and treatment for previously treated patients with advanced leiomyosarcoma with manageable toxicity, and (2) The best responders are patients with HR+ uterine LMS. Clinical trial information: NCT03886311 .
e23569 Background: Metronomic dosing of gemcitabine, doxorubicin and docetaxel causes less severe side effects than standard chemotherapy for advanced sarcoma. Hypothesis: The addition of nivolumab ...to this regimen will have synergistic effects and improve treatment outcomes. Objectives: Primary objective: To assess progression-free survival (PFS); 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 (OS) rate at 6, 12 months, and (4) Incidence of treatment-related adverse events (TRAEs). Methods: 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 the toxicity grade is <1. Results: Efficacy (n = 70). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. Best Overall Response = 14 PR, 47 SD, 9 PD. ORR = 20%; DCR (CR+PR+SD) was 87%. Median PFS was 8.2 (95% CI: 5.85-10.55) months; 6- month PFS rate of 59%. Median OS was 17.6 (95% CI: 13.53-21.67) months, with 6-month OS of 84%. Safety (n = 75): Grade 3/4 TRAEs include thrombocytopenia (n = 26), white blood cell count decreased (n = 17), neutropenia (n = 16), fatigue (n = 15), anemia (n = 13), nausea (n = 9), anorexia (n = 5), diarrhea (n = 2), emesis (n = 1), febrile neutropenia (n = 1), sepsis (n = 1), rectal bleeding (n = 1), transaminitis (n = 1), dizziness (n = 1), shortness of breath (n = 1). There were no unexpected adverse events reported. Conclusions: Taken together, the data suggests that nivolumab plus metronomic doses of gemcitabine, doxorubicin and docetaxel (1) may have synergistic activity, and (2) by indirect comparison, may be as effective as standard first line therapy for advanced sarcoma with manageable toxicity. Clinical trial information: NCT04535713 .
11577 Background: Advanced soft tissue sarcoma is most often associated with a fatal outcome. This report is an update on the results of the SOC-1702 Phase 2 study for previously untreated STS. ...Methods: Objectives, Primary: Evaluate best response rate by RECIST v1.1; Secondary: Assess progression-free survival (PFS) at 6 months and overall survival. Patients and 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) 1 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. Results: Efficacy: Ninety-one patients were evaluated for efficacy. These subjects completed at least two treatment cycles and had at least one follow-up CT scan. The best responses were 9CR, 14PR, 54SD and 14PD with 25% ORR, 85% DCR. PFS rate at 6 months was 56%; Median PFS was 7.4 (95% CI: 5.6-9.2) months; Median OS was 32.0 (95% CI: 19.8-44.2) months. The best responders (CR and PR) were patients with LMS, UPS, LPS, synovial sarcoma, myxofibrosarcoma, endometrial stromal sarcoma, clear cell sarcoma, DSRCT, and chondrosarcoma. Notably, out of the 91 patients who participated in the study between 2017 and 2022, 23 (25%) patients are still alive as of January 1, 2024, the data cut-off date. Safety: Grade 3/4 TRAEs related to Trabectedin include both hematologic and non-hematologic toxicities: fatigue, nausea, vomiting, fever, exhaustion, dehydration, asthenia, cellulitis of port, anemia, neutropenia, thrombocytopenia, transaminitis, elevated CK. There were no hematologic toxicities related to Nivolumab or Ipilimumab. Grade 3/4 TRAEs include decreased TSH, increased T4, increased TSH, transaminitis, hyponatremia, dehydration, pruritus, and psoriasis. Conclusions: Taken together we have confirmed that (1) Trabectedin in combination with Ipilimumab and Nivolumab is a safe and effective regimen for previously untreated advanced STS, and (2) Randomized studies are needed to confirm whether this regimen is superior to standard first line therapy for advanced soft tissue sarcoma. Clinical trial information: NCT03138161 .
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 <1. Results: This is an Interim Report on the modified Intent-to-treat population (n = 43). This population completed at least one treatment cycle and had a follow-up CT or MRI scan at week 6. The most common histological subtypes in this group include leiomyosarcoma (n = 15), pleomorphic sarcoma (n = 4), synovial sarcoma (n = 4), liposarcoma (n = 3), osteosarcoma (n = 3) and other (n = 10). Best Overall Response = 2 CR (surgical CR), 6 PR, 30 SD, 5 PD. The disease control rate (CR+PR+SD) was 88.4%. Median PFS was > 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.
Background and Rationale
Switching from standard-half-life (SHL) to extended-half-life (EHL) recombinant factor VIII (rFVIII) products allows patients to maintain hemostasis with less frequent dosing ...and improves the treatment burden for people with hemophilia A (PWHA), leading to an overall improvement in quality of life. Currently, the most common approach is to rely on assumptions informed by patient characteristics and clinical history with or without PK analysis. This ‘trial and error’ approach can lead to suboptimal protection and can cause harmful bleeds, or an excessive use of rFVIII products leading to an economic impact without easing treatment burden. Currently, there is no defined consensus for determining the most therapeutically and economically appropriate prophylaxis (PPX) regimen for PWHA switching from a SHL to EHL product. While the literature contains documented phenotypic and biologic variables with a high predictive potential for determining the optimal regimen for PWHA who may wish to switch to an EHL product, these criteria have not yet been studied prospectively, neither individually nor in combination. The PREDICT study aims to assess a new scoring system based on the best known phenotypic and biologic variables to select the optimal (individualized and most appropriate) regimen, for a favorable outcome when switching from a SHL rFVIII product to the EHL rFVIII product damoctocog alfa pegol.
Study Design and Methods
PREDICT is a multi-center, prospective, open-label, phase 4 clinical study in the US. It aims to enroll 65-70 previously treated patients including women (≥150 exposure days), aged ≥12 years old with congenital hemophilia A, regardless of disease severity, who have received prior PPX treatment with a SHL rFVIII product for ≥1 year prior to study participation, with no history or current evidence of inhibitors (≥0.6 BU/ml). Key exclusion criteria include patients with any other inherited or acquired bleeding disorder, a platelet count <100,000/mm 3 based on last medical record, or a planned major surgery.
Each patient will receive a score at baseline, which is expected to aid in selecting the most appropriate damoctocog alfa pegol regimen for the individual. The scoring system consists of five, individually weighted phenotypic and biologic variables.
In the first 4 weeks of the study, all patients will start treatment with twice weekly (2×W) damoctocog alfa pegol PPX (Figure 1), as per the US product information. Patients with a high-risk total score, will continue with 2×W PPX for the remainder of the study, while patients with a medium risk score will switch to every 5 days (E5D) PPX after the first 4 weeks for the remainder of the study. Patients with a low-risk score will switch to E5D PPX for a further 4 weeks, then switch to a less frequent dosing (e.g., every 7 days).
The primary endpoint is the occurrence of favorable outcomes on the score-selected dosing regimen, analyzed by the proportion of patients with a favorable outcome. A favorable outcome is defined as no change of the risk-score-assigned dosing regimen during the study with one of the following: (1) an improved ABR vs prestudy ABR with either decreased or similar frequency of administration versus prestudy frequency, (2) a decreased dosing frequency and similar ABR versus prestudy. Secondary endpoints include the occurrence of patients with 0 and ≤1 spontaneous bleeds, change from baseline in ABRs, change from baseline in frequency of damoctocog alfa pegol administration and patient-reported outcomes. Descriptive statistical analyses will be performed.
An interim analysis may be performed for publication purposes. The patient score is expected to predict the most appropriate damoctocog alfa pegol regimen leading to a favorable outcome for at least 70% of the patients enrolled in the study. A post-hoc analysis of the PROTECT VIII study data was done to evaluate the potential of the scoring system. Considering that not all variables were available in the PROTECT VIII study, it was determined that it was feasible to proceed with the study. The proposed patient scoring system is expected to be an effective tool for determining the optimal PPX regimen for PWHA switching from SHL rFVIII products to damoctocog alfa pegol and could potentially improve quality of life.
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Young: Apcintex, BioMarin, Genentech/Roche, Grifols, Novo Nordisk, Pfizer, Rani, Sanofi Genzyme, Spark, Takeda, and UniQure: Consultancy; Genentech/Roche, Grifols, and Takeda: Research Funding. Reding: Bayer, Biomarin (institutional research funding): Research Funding; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda: Honoraria; Bayer, CSL Behring, NovoNordisk, Sanofi Genzyme, Takeda (advisory committees): Membership on an entity's Board of Directors or advisory committees; Bayer, CSL Behring, Sanofi Genzyme, Takeda: Speakers Bureau. Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Quon: Orthopaedic Institute for Children: Current Employment. Staber: Bayer, CSL Behring, Sanofi, Takeda: Membership on an entity's Board of Directors or advisory committees. Leissinger: Tulane University: Current Employment; BioMarin: Research Funding; Advisory boards: Bayer, Catalyst, CSL Behring, Dova, Enova, Forma, GBT, Genentech, Sanofi, Takeda, UniQure: Honoraria, Membership on an entity's Board of Directors or advisory committees. Charlet: Bayer: Current Employment. Boukerrou: Bayer: Current Employment.
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.
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.
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/m
2
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.
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