Three year results of Blessed: Expanded access for DeltaRex-G for an intermediate size population with advanced pancreatic cancer and sarcoma (NCT04091295) and individual patient use of DeltaRex-G for solid malignancies (IND# 19130).

Background: Innovative treatments are urgently needed for metastatic cancer. DeltaRex-G, a tumor-targeted retrovector encoding a dominant-negative/cytocidal cyclin G1 (CCNG1 gene) inhibitor construct-has been tested in over 280 cancer patients worldwide in phase 1, phase 2 studies and compassionate use studies, demonstrating long term (>10 years) survivorship in patients with advanced cancers, including pancreatic cancer, osteosarcoma, malignant peripheral nerve sheath tumor, breast cancer, and B-cell lymphoma. Patient and Methods: Endpoints: Survival, response, treatment-related adverse events. Study one is entitled "Blessed: Expanded Access for DeltaRex-G for Advanced Pancreatic Cancer and Sarcoma (NCT04091295)". Study two is entitled "Individual Patient Use of DeltaRex-G for Solid Malignancies (Investigational New Drug#19130). In both studies, patients will receive DeltaRex-G at 1-3 x 10e11 cfu i.v. over 30-45 min, three x a week until significant disease progression or unacceptable toxicity or death occurs. Results: Seventeen patients were enrolled, nine sarcoma, two pancreatic adenocarcinoma, one non-small cell lung cancer, two breast carcinoma, one prostate cancer, one cholangiocarcinoma and one basal cell carcinoma and actinic keratosis. Three patients were enrolled in Study 1 and 14 patients were enrolled in Study 2. Twelve of 17 enrolled patients were treated with DeltaRex-G monotherapy or in combination with United States Food and Drug Administration-approved cancer therapies. Five patients died before receiving DeltaRex-G. Efficacy Analysis: Of the 12 treated patients, 5 (42%) are alive 15-36 months from DeltaRex-G treatment initiation. Two patients with early-stage HR + HER2+ positive or triple receptor negative invasive breast cancer who received DeltaRex-G as adjuvant/first line therapy are alive in complete remission 23 and 16 months after DeltaRex-G treatment initiation respectively; three patients with metastatic chordoma, chondrosarcoma and advanced basal cell carcinoma are alive 36, 31, and 15 months after DeltaRex-G treatment initiation respectively. Safety Analysis: There were no treatment-related adverse events reported. Conclusion: Taken together, the data suggest that 1) DeltaRex-G may evoke tumor growth stabilization after failing standard chemotherapy, 2) DeltaRex-G may act synergistically with standard chemotherapy/targeted therapies, and 3) Adjuvant/first line therapy with DeltaRex-G for early-stage invasive carcinoma of breast may be authorized by the USFDA when patients refuse to receive toxic chemotherapy.

A phase 1B/2 study of aldoxorubicin in patients with soft tissue sarcoma.

BACKGROUND: Aldoxorubicin, a prodrug of doxorubicin, covalently binds to serum albumin, allowing for the administration of much higher doses of doxorubicin in a previous clinical study. The current phase 1B/2 study evaluated the safety of aldoxorubicin, including preliminary efficacy and safety of its maximum tolerated dose (MTD). METHODS: Patients aged 18 to 70 years with recurrent/refractory malignant solid tumors received aldoxorubicin at a dose of 230 mg/m(2) , 350 mg/m(2) , or 450 mg/m(2) (170 mg/m(2) , 260 mg/m(2) , or 335 mg/m(2) doxorubicin equivalents, respectively) by intravenous infusion once every 21 days for up to 8 consecutive cycles. RESULTS: A total of 25 patients were enrolled, including 17 patients (68%) with advanced soft tissue sarcoma (STS). The MTD of aldoxorubicin was 350 mg/m(2) ; dose-limiting toxicities included grade 4 neutropenia and grade 3 febrile neutropenia (NCI CTCAE v4.0). Drug-related adverse events included myelosuppression, nausea, fatigue, alopecia, stomatitis, vomiting, and oropharyngeal pain. No clinically significant cardiac toxicities were reported. Seven patients (28%) had elevated serum troponin levels while taking part in the study, but these elevations were not clinically significant or associated with cardiac findings. A partial response was achieved in 20% of patients, and stable disease was reported in 40% of patients. The median progression-free survival was 4.80 months, and the median overall survival was 11.25 months. Among patients with STS who were treated at the MTD (13 patients), a partial response was achieved in 38% and stable disease in 46%; the median progression-free survival was 11.25 months and the median overall survival was 21.71 months. CONCLUSIONS: Aldoxorubicin at a dose of 350 mg/m(2) administered once every 21 days for up to 8 cycles was found to be acceptably safe and demonstrated preliminary efficacy in patients with advanced solid tumors, including STS. Further investigation of aldoxorubicin is ongoing.

Pathotropic targeting advances clinical oncology: tumor-targeted localization of therapeutic gene delivery.

The advent of pathotropic (disease-seeking) targeting has transported genetic medicine across the threshold of history with the progressive clinical validation of Rexin-G, a tumor-targeted nanosized anti-cancer agent. Achieving noteworthy single-agent efficacy and survival benefits in otherwise intractable cancers, the molecular biotechnology platform has stimulated intense interest in the underlying mechanisms-of-action. This report exhibits the effective localization of Rexin-G nanoparticles within a metastatic liver lesion, as observed upon its surgical excision.

Advanced phase I/II studies of targeted gene delivery in vivo: intravenous Rexin-G for gemcitabine-resistant metastatic pancreatic cancer.

Rexin-G, a nonreplicative pathology-targeted retroviral vector bearing a cytocidal cyclin G1 construct, was tested in a phase I/II study for gemcitabine-resistant pancreatic cancer. The patients received escalating doses of Rexin-G intravenously from 1 x 10(11) colony-forming units (cfu) 2-3x a week (dose 0-1) to 2 x 10(11) cfu 3x a week (dose 2) for 4 weeks. Treatment was continued if there was less than or equal to grade 1 toxicity. No dose-limiting toxicity (DLT) was observed, and no vector DNA integration, replication-competent retrovirus (RCR), or vector-neutralizing antibodies were noted. In nine evaluable patients, 3/3 patients had stable disease (SD) at dose 0-1. At dose 2, 1/6 patients had a partial response (PR) and 5/6 patients had SD. Median progression-free survival (PFS) was 3 months at dose 0-1, and >7.65 months at dose 2. Median overall survival (OS) was 4.3 months at dose 0-1, and 9.2 months at dose 2. One-year survival was 0% at dose 0-1 compared to 28.6% at dose 2, suggesting a dose-response relationship between OS and Rexin-G dosage. Taken together, these data indicate that (i) Rexin-G is safe and well tolerated, and (ii) Rexin-G may help control tumor growth, and may possibly prolong survival in gemcitabine-resistant pancreatic cancer, thus, earning US Food and Drug Administration's (FDA) fast-track designation as second-line treatment for pancreatic cancer.

Phase I/II and phase II studies of targeted gene delivery in vivo: intravenous Rexin-G for chemotherapy-resistant sarcoma and osteosarcoma.

Rexin-G, a pathotropic nanoparticle bearing a cytocidal cyclin G1 construct was tested in a phase I/II study for chemotherapy-resistant sarcomas and a phase II study for chemotherapy-resistant osteosarcoma. Twenty sarcoma patients and 22 osteosarcoma patients received escalating doses of Rexin-G intravenously from 8 x 10(11) to 24 x 10(11) colony forming units (cfu)/cycle. Treatment was continued if there was or=3 months and median OS, 6.9 months. These studies suggest that Rexin-G is safe, may help control tumor growth, and may possibly improve survival in chemotherapy-resistant sarcoma and osteosarcoma.