Study on Efficacy and Tolerability of Weekly Doxorubicin in Elderly Patients With Advanced or Metastatic Leiomyosarcoma

The overall goal of this Phase 2 study is to determine the efficacy of a lower dose weekly schedule of doxorubicin in patients with unresectable leiomyosarcomas aged 65-100 years old. While doxorubicin is the standard of care therapy for sarcomas not removable by surgery, older or more frail patients may struggle to tolerate side effects of the treatment including immune cell suppression. Previous studies have suggested that similar anti-tumor activity can be obtained using a lower dose, weekly administration schedule of doxorubicin. In this study, the investigators will determine progression-free survival rate at 12 weeks, with secondary endpoints including quality of life and adverse events in this population. Importantly, doxorubicin can also induce immune stimulatory effects when administered at lower doses, based on animal data. Thus, correlative samples including blood and tumor biopsies will also explore the effects of immune cells and foreignness of the tumor prior to and during treatment in study patients.

The study is an open-label, single-arm, investigator-initiated Phase 2 trial enrolling up to 30 patients to obtain 20 evaluable patients with advanced/metastatic leiomyosarcomas. The study will utilize a time-to-event Bayesian optimal Phase 2 design. The design includes one interim futility look after 10 patients are evaluable for progression-free survival rate at 12 weeks. The outcomes will be compared to historical PFS 12 week rate calculated as the mean from two large randomized Phase 3 studies. The treatment will be deemed promising if the number of patients who are stable at 12 weeks is 65%. Early stopping rules for toxicity are included in addition to futility. The primary endpoint of the study is the PFS rate at 12 weeks with secondary endpoints including PFS at 6 months, response rate by RECIST 1.1, duration of response, overall survival, adverse events, and quality of life scores. Correlative studies will include analysis of serial blood samples and baseline and on-treatment tumor biopsies for immune markers including analysis of tumor-infiltrating lymphocytes, tumor immune pathways, analysis of circulating immune cells, and plasma cytokines. Following informed consent and screening, patients will receive doxorubicin 25 mg/m2 administered by bolus with dexrazoxane pre-treatment on days 1 and 8 every 21 days for up to 8 cycles. Patients will receive pegfilgrastim growth factor on day 9. Scans for response imaging will be obtained every 6 weeks during the treatment portion of the study, then every 12 weeks after completing treatment up to 1 year. Patients will have routine safety labs, assessment of adverse events, quality of life questionnaires with treatment visits, and echocardiogram to assess for cardiac toxicity will be performed at cycle 4 of doxorubicin and at the completion of study therapy.