Zymafos (palifosfamide) / Alaunos Therap - LARVOL DELTA

COLLATERAL SENSITIVIES EMERGE DURING THE EVOLUTION OF CHEMORESISTANCE TO MAP CHEMOTHERAPY IN OSTEOSARCOMA (CTOS 2025) - "Objective: We aimed to model the evolution of chemoresistance to methotrexate, doxorubicin, and cisplatin (MAP) in vitro and to characterize collateral drug sensitivity and resistance patterns over time, potentially informing second-line treatment strategies in chemo resistant primary or recurrent disease. Five evolutionary replicates of MG63.3 osteosarcoma cells were treated with six complete cycles of pulsed, clinically relevant doses of cisplatin and doxorubicin, alternating with methotrexate...Collateral resistance emerged to etoposide, vincristine, and topotecan, while sensitivity increased to gemcitabine, cabozantinib, and palifosfamide... Our model reveals temporally dynamic, heterogeneous collateral responses during the development of chemoresistance to MAP in osteosarcoma. While cross-resistance to several agents emerged, collateral sensitivity to gemcitabine and cabozantinib supports a second line use for these agents. These data may inform rational sequencing..."

Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Adenoviral Vector Monotherapy or Combination With Chemotherapy in Subjects With Recurrent/Metastatic Breast Cancer. (clinicaltrials.gov) - P2 | N=12 | Terminated | Sponsor: Alaunos Therapeutics | The SRC reduced 140 mg to 100 mg, then to 80 mg. The study ended with one subject enrolled at 80 mg daily.

Monotherapy • Trial termination • Breast Cancer • Oncology • Solid Tumor • IL12A • MUC1

Evofosfamide Enhances Sensitivity of Breast Cancer Cells to Apoptosis and Natural-Killer-Cell-Mediated Cytotoxicity Under Hypoxic Conditions. (PubMed, Cancers (Basel)) - "Evofosfamide is converted into bromo-isophosphoramide mustard, a potent DNA cross-linking agent that is expected to enhance the killing of cancer cells under hypoxic conditions, where these cells typically exhibit resistance. qPCR analysis revealed that Evofosfamide was capable of restoring type I interferon signaling in hypoxic breast cancer cells, leading to the subsequent cytolytic activity of NK cells against the tumor cells. Thus, conditioning the breast cancer cells with Evofosfamide resulted in enhanced cell killing under hypoxia, further underscoring its potential as a sensitizer to target hypoxia-driven tumors."

Journal • Breast Cancer • Oncology • Solid Tumor • CASP3 • CASP7

EXPLORING THE EFFICACY OF DIVERSE CHEMOTHERAPY AGENTS TO OVERCOME CISPLATIN RESISTANCE IN GERM CELL TUMOR CELL LINES (SIOP 2024) - "Aim: To assess the in vitro efficacy of Ifosfamide, Azacytidine, Paclitaxel, and Carboplatin in cisplatin-resistant GCTs... Palifosfamide treatment resulted in a higher IC50 (1.6 fold, p ≤ 0.01) in NTERA-2R (210.8 μM) compared to NTERA-2P (135.3 μM)... Paclitaxel and Azacitidine demonstrated comparable responses in both cisplatin-sensitive and -resistant GCTs, suggesting their potential to restore chemotherapy sensitivity in vitro. These findings provide valuable insights into the behavior of cisplatin-resistant GCTs under different chemotherapy regimens."

Preclinical • Tumor cell • Embryonal Tumor • Germ Cell Tumors • Oncology • BRCA1

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells. (PubMed, Front Vet Sci) - "Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action."

Journal • Musculoskeletal Pain • Oncology • Osteosarcoma • Pain • Prostate Cancer • Sarcoma • Solid Tumor

Evofosfomide potentiates the efficacy of a novel anti-PD-L1/PD-L2 monoclonal antibody against immune excluded tumors (SITC 2023) - "Background Evofosfamide (Evo) is a hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard...1 Moreover, in a phase 1 clinical trial, the combination of Evo with the anti-CTLA-4 Ipilimumab resulted in objective responses in patients with cold tumors...Conclusions These data indicate that Evo and IMGS-001 in combination improves upon the efficacy of either treatment alone, and those improvements are not observed for Evo in combination with anti-PD-1 treatment. This novel combination treatment will continue to be tested in preclinical models and has potential to be tested in a clinical trial."

Clinical • Melanoma • Oncology • Solid Tumor • PD-L2

CDK9 inhibition as a potential therapeutic strategy in Ewing sarcoma (AACR 2023) - P1 | "Alvocidib demonstrated an additive inhibitory response in combination with topotecan, phosphoramide mustard, a biologically active metabolite of cyclophosphamide, and palifosfamide, a biologically active metabolite of ifosfamide, in EWS cell lines after 3-day treatment. TP-1287 may be a potential therapeutic option for the current regimen in EWS. TP-1287 is being investigated for solid tumors including EWS (clinicaltrials.gov, NCT03604783)."

Ewing Sarcoma • Hematological Malignancies • Leukemia • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • EWSR1 • FLI1 • MCL1 • MYC • RAD51

SUNitinib and EVOfosfamide (TH-302) in systemic treatment-naïve patients with G1/G2 metastatic pancreatic neuroendocrine tumors, the GETNE-1408 trial. (PubMed, Oncologist) - "Addition of hypoxia-activated prodrugs has been proposed as a potential mechanism to overcome tumor resistance to antiangiogenic agents. Sunitinib and evofosfamide, which were widely proposed as a potential synergistic option, showed modest efficacy in panNETs, reaching a median ORR of 17.6% and median PFS of 10.4 months. Treatment response does not correlate with the biomarkers analyzed. The high systemic toxicity, with 88.2% of patients discontinuing the treatment, makes this therapeutic approach unfeasible and encourages future research to overcome panNETs resistance to antiangiogenic agents with other therapies with a safer profile."

Clinical • Journal • Endocrine Cancer • Fatigue • Hematological Disorders • Neuroendocrine Tumor • Neutropenia • Oncology • Pancreatic Cancer • Solid Tumor • Thrombocytopenia • ATRX • DAXX • PTEN • SETD2

Predictive value of MRP-1 in localized high-risk soft tissue sarcomas: a translational research associated to ISG-STS 1001 randomized phase III trial. (PubMed, Mol Cancer Ther) - "In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib and avapritinib) in sarcoma cell lines...In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk STS patients treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy."

Clinical • Journal • P3 data • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor

An in vitro cytotoxicity of glufosfamide in HepG2 cells relative to its nonconjugated counterpart. (PubMed, J Egypt Natl Canc Inst) - "The current study reported for the first time cytotoxicity activity of glufosfamide in HepG2 cells in vitro. The obtained results confirmed the higher oncolytic activity of glufosfamide than its aglycone ifosfamide. The generated data warrants further elucidations by in vivo study."

IO biomarker • Journal • Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • BCL2 • CASP3 • CASP9

"#Sarcoma Medical Oncology Investigator experience on clinical trials for: avapritinib vs regorafenib olaratumab vs placebo evofosfamide vs placebo palifosfamide vs placebo nilotinib vs imatinib" (@JTrentMDPhD)

Clinical • Oncology • Sarcoma • Solid Tumor

Phase 2 trial of hypoxia activated evofosfamide (TH302) for treatment of recurrent bevacizumab-refractory glioblastoma. (PubMed, Sci Rep) - "Evofosfamide (Evo or TH302) is a hypoxia-activated prodrug which is reduced leading to the release of alkylating agent bromo-isophosphoramide mustard, which has shown safety and signals of efficacy in a prior phase 1 study in recurrent glioblastoma. The progression free survival of patients on Evo-Bevacizumab met the primary endpoint of progression free survival at 4 months of 31%, although the clinical significance of this may be limited. Given the patient population and Phase II design, these clinical outcomes will need further validation."

Journal • P2 data • Glioblastoma • Oncology • Solid Tumor

Standard frontline therapy for endometrial cancer (OncLive) - "Thomas Herzog, MD: Brad, I think you said it well. If you look at cervical cancer, you're looking at PD-L1 [programmed death-ligand 1] and you're looking at HER2 now....Amanda Nickles Fader published in JCO [Journal of Clinical Oncology] in July of last year. And just as a randomized phase II trial with 61 patients. But it combined with CARBO [carboplatin]-paclitaxel in HER2 over expressors, UPSC, and it was 8 versus 12.6 months in terms of the difference....Michael J. Birrer, MD, PhD: That's right. Again, from a biologic standpoint, there's a lot of rationale to do that....VEGF itself is a very immunosuppressive agent....Bradley Monk, MD, FACOG, FACS: To that point, PEMBRO-lenvatinib is an opportunity for an oral anti-VEGF, anti-PDGF, with pembrolizumab. So that's being studied in multiple tumor types....You were talking about breakthrough designation. We got breakthrough designation in the mismatch repair proficient endometrial group with PEMBRO-lenvatinib."

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