Metastatic Sarcoma Clinical Trial
Official title:
A Phase 1 Study of Peposertib (M3814) and Low-Dose Liposomal Doxorubicin ( (Doxil®) in Patients With Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas
This phase I trial tests the safety, side effects, and best dose of combination therapy with liposomal doxorubicin and peposertib in treating patients with sarcoma that has spread from where it first started, to other places in the body (metastatic), or cannot be removed by surgery (unresectable) and for which no known cure is available (advanced). Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Liposomal doxorubicin is a form of the anticancer drug doxorubicin that is contained inside very tiny, fat-like particles. Liposomal doxorubicin may have fewer side effects and work better than other forms of the drug. Peposertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also enhance the activity of chemo- and radiotherapy. There is some pre-clinical evidence in animal models that combining peposertib with liposomal doxorubicin can shrink or stabilize certain types of cancer for longer than either drug alone, but it is not known if this will happen in people. Combination therapy with liposomal doxorubicin and peposertib may be effective in patients with advanced sarcoma.
PRIMARY OBJECTIVES: I. To evaluate the safety and tolerability of peposertib in combination with low-dose pegylated liposomal doxorubicin hydrochloride (liposomal doxorubicin) as evaluated by the dose-limiting toxicity (DLT) rate at each tested dose level. (Dose Escalation) II. To determine the recommended phase 2 dose (RP2D) of liposomal doxorubicin and peposertib combination and determine the maximal tolerated dose (MTD) if identified. (Dose Escalation) III. To obtain a more precise determination of adverse events (e.g. dose limiting toxicities estimate at the selected dose). (Dose Expansion) SECONDARY OBJECTIVES: I. To assess the pharmacokinetics of peposertib and liposomal doxorubicin used in combination with each other. (Dose Escalation) II. To estimate the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in patients with leiomyosarcoma treated with peposertib and low-dose liposomal doxorubicin. (Dose Expansion) III. To estimate the progression free survival (PFS) in patients with leiomyosarcoma treated with peposertib and low-dose liposomal doxorubicin. (Dose Expansion) IV. To assess the pharmacokinetics of peposertib and liposomal doxorubicin used in combination with each other. (Dose Expansion) V. To assess whether DNA damage is exaggerated by the low-dose liposomal doxorubicin in combination with peposertib in patients with homologous recombination (HR)-deficiency. (Dose Expansion) CORRELATIVE OBJECTIVES: I. To test the hypothesis that soft tissue sarcomas (STS) with homologous recombination deficiency (HRD) like leiomyosarcomas (LMS) will be more susceptible to deoxyribonucleic acid (DNA)-PKi in combination with low-dose liposomal doxorubicin. II. To test the hypothesis that gammaH2AX and pNBS1 can be used as pharmacodynamic biomarkers of response to DNA-PKi in combination with low-dose liposomal doxorubicin. III. To test the hypothesis that disease activity correlates with circulating tumor DNA levels in the plasma. OUTLINE: This is a dose-escalation study of peposertib and liposomal doxorubicin followed by a dose-expansion study. Patients receive peposertib orally (PO) twice daily (BID) and pegylated liposomal doxorubicin hydrochloride intravenously (IV) once daily (QD) during treatment cycles on study. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients also undergo blood sample collection and tissue biopsy during screening and on the trial. Patients are followed for 30 days after removal from study or until death, whichever occurs first. ;
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