A Phase 1 Study of Peposertib (M3814) and Low-Dose Liposomal Doxorubicin in Patients With Metastatic Leiomyosarcoma and Other Soft Tissue Sarcomas
Overview
- Phase
- Phase 1
- Status
- Recruiting
- Enrollment
- 30
- Locations
- 29
- Primary Endpoint
- Dose limiting toxicity (DLT) rate
Overview
Brief Summary
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 deoxyribonucleic acid (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 treating patients with advanced sarcoma.
Detailed Description
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 DNA-protein kinase inhibitor (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) on days 1-28 of each cycle and liposomal doxorubicin intravenously (IV) on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients also undergo tissue biopsy and echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and on the trial.
Patients are followed for 30 days after removal from study or until death, whichever occurs first.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must have histologically confirmed sarcoma that is metastatic or unresectable and for which there is no known curative treatment
- •Dose escalation cohort: Patients must have histologic diagnosis of leiomyosarcoma (LMS) or selected soft tissue sarcomas (myxofibrosarcoma \[MFS\], undifferentiated pleomorphic sarcoma \[UPS\], synovial sarcoma, or dedifferentiated liposarcoma \[DDLPS\]). Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study
- •Dose expansion cohort: Patients must have histology diagnosis of LMS. Pathology review and confirmation of diagnosis will occur at the site enrolling the patient on this study
- •Dose escalation cohort: Patients must have evaluable disease that is amenable to biopsy
- •Dose expansion cohort: Patients must have disease which is measurable at study entry according to RECIST 1.1 criteria and amenable to biopsy
- •Patients must have been treated with at least 1 prior line of therapy. Prior anthracycline use is permitted as long as the cumulative dose prior to enrollment does not exceed 360 mg/m\^2
- •Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of peposertib (M3814) in combination with liposomal doxorubicin in patients \< 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%) for both dose escalation and dose expansion
- •Absolute neutrophil count \>= 1,500/mcL
- •Platelets \>= 100,000/mcL
Exclusion Criteria
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
- •Prior palliative radiotherapy within 14 days of cycle 1 day 1 and prior definitive radiotherapy within 42 days of cycle 1 day
- •Adverse effects of radiation therapy must resolve to baseline prior to cycle 1 day 1
- •Patients who are receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to peposertib (M3814) or other agents used in study
- •Patients who cannot discontinue concomitant medications or herbal supplements that are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes CYP3A4/5, CYP2C9, and CYP2C
- •Participants who cannot discontinue substrates with a narrow therapeutic index that are metabolized by CYP1A2, CYP2B6, CYP2C8, and CYP3A4/5 are ineligible. Patients may confer with the study doctor to determine if alternative medications can be used. The following categories of medications and herbal supplements must be discontinued for at least the specified period of time before the patient can be treated:
- •Strong inducers of CYP3A4/5 and CYP2C19: \>= 3 weeks prior to study treatment
- •Strong inhibitors of CYP3A4/5 and CYP2C19: \>= 1 week prior to study treatment
- •Substrates of CYP3A4/5 with a narrow therapeutic index: \>= 1 day prior to study treatment
Arms & Interventions
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Biopsy Procedure (Procedure)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Magnetic Resonance Imaging (Procedure)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Multigated Acquisition Scan (Procedure)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Peposertib (Drug)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Computed Tomography (Procedure)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Echocardiography Test (Procedure)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Pegylated Liposomal Doxorubicin Hydrochloride (Drug)
Treatment (peposertib, liposomal doxorubicin)
Patients receive peposertib PO BID on days 1-28 of each cycle and liposomal doxorubicin IV on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression, unacceptable toxicity or withdrawal of consent. Patients undergo blood sample collection and CT or MRI throughout the trial. Patients also undergo tissue biopsy and ECHO or MUGA during screening and on the trial.
Intervention: Biospecimen Collection (Procedure)
Outcomes
Primary Outcomes
Dose limiting toxicity (DLT) rate
Time Frame: Up to 28 days
The number and type of DLT seen at each dose level will be provided. The adverse events (AEs) will also be summarized by AE type and the maximum grade of the AE experienced by the patient for each dose level. DLT will be used to determine the recommended phase 2 dose of study drugs.
Secondary Outcomes
- Incidence of adverse events(Up to 30 days after the end of study treatment)
- Objective response rate(Up to 28 days)
- Progression free survival(From study enrollment until disease progression (determined by RECIST v1.1) or death due to any cause, whichever occurs first)
- Homologous recombination deficiency (HRD) status(Up to 1 year)
- Deoxyribonucleic acid damage repair activity(Up to 1 year)