Trial Title:
Testing Low-Dose Common Chemotherapy (Liposomal Doxorubicin) in Combination With an Anti-Cancer Drug, Peposertib, in Advanced Sarcoma
NCT ID:
NCT05711615
Condition:
Metastatic Dedifferentiated Liposarcoma
Metastatic Leiomyosarcoma
Metastatic Myxofibrosarcoma
Metastatic Sarcoma
Metastatic Synovial Sarcoma
Metastatic Undifferentiated Pleomorphic Sarcoma
Unresectable Dedifferentiated Liposarcoma
Unresectable Leiomyosarcoma
Unresectable Myxofibrosarcoma
Unresectable Sarcoma
Unresectable Synovial Sarcoma
Unresectable Undifferentiated Pleomorphic Sarcoma
Conditions: Official terms:
Sarcoma
Leiomyosarcoma
Liposarcoma
Sarcoma, Synovial
Histiocytoma, Malignant Fibrous
Doxorubicin
Liposomal doxorubicin
Peposertib
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Procedure
Intervention name:
Biopsy
Description:
Undergo tissue biopsy
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood and tissue sample collection
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT scan
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
CAT
Other name:
CAT Scan
Other name:
Computed Axial Tomography
Other name:
Computerized Axial Tomography
Other name:
Computerized axial tomography (procedure)
Other name:
Computerized Tomography
Other name:
Computerized Tomography (CT) scan
Other name:
CT
Other name:
CT Scan
Other name:
tomography
Intervention type:
Procedure
Intervention name:
Magnetic Resonance Imaging
Description:
Undergo MRI
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
Magnetic Resonance
Other name:
Magnetic Resonance Imaging (MRI)
Other name:
Magnetic resonance imaging (procedure)
Other name:
Magnetic Resonance Imaging Scan
Other name:
Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance
Other name:
MR
Other name:
MR Imaging
Other name:
MRI
Other name:
MRI Scan
Other name:
MRIs
Other name:
NMR Imaging
Other name:
NMRI
Other name:
Nuclear Magnetic Resonance Imaging
Other name:
sMRI
Other name:
Structural MRI
Intervention type:
Drug
Intervention name:
Pegylated Liposomal Doxorubicin Hydrochloride
Description:
Given IV
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
ATI-0918
Other name:
Caelyx
Other name:
Dox-SL
Other name:
Doxil
Other name:
Doxilen
Other name:
Doxorubicin HCl Liposomal
Other name:
Doxorubicin HCl Liposome
Other name:
Doxorubicin Hydrochloride Liposome
Other name:
Duomeisu
Other name:
Evacet
Other name:
LipoDox
Other name:
Lipodox 50
Other name:
Liposomal Adriamycin
Other name:
Liposomal Doxorubicin Hydrochloride
Other name:
Liposomal-Encapsulated Doxorubicin
Other name:
Pegylated Doxorubicin HCl Liposome
Other name:
Pegylated Liposomal Doxorubicin
Other name:
S-Liposomal Doxorubicin
Other name:
Stealth Liposomal Doxorubicin
Other name:
TLC D-99
Intervention type:
Drug
Intervention name:
Peposertib
Description:
Given PO
Arm group label:
Treatment (peposertib, liposomal doxorubicin)
Other name:
3-Pyridazinemethanol, alpha-(2-Chloro-4-fluoro-5-(7-(4-morpholinyl)-4-quinazolinyl)phenyl)-6-methoxy-, (alphaS)-
Other name:
M 3814
Other name:
M-3814
Other name:
M3814
Other name:
MSC 2490484A
Other name:
MSC-2490484A
Other name:
MSC2490484A
Other name:
Nedisertib
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 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-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.
Criteria for eligibility:
Criteria:
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 300 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
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase
[SGPT]) =< 3 x institutional ULN
- Hemoglobin >= 8 g/dL
- Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2 (per institutional estimate
based on creatinine level)
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial
- For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV
viral load must be undetectable on suppressive therapy, if indicated
- Patients with a history of hepatitis C virus (HCV) infection must have been treated
and cured. For patients with HCV infection who are currently on treatment, they are
eligible if they have an undetectable HCV viral load
- Patients with treated brain metastases are eligible if follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression while
off steroid support
- Patients with a prior or concurrent malignancy whose natural history or treatment
does not have the potential to interfere with the safety or efficacy assessment of
the investigational regimen are eligible for this trial
- Patients with known history of clinically significant cardiac disease, or current
symptoms of cardiac disease, or history of treatment with cardiotoxic agents should
have a clinical risk assessment of cardiac function using the New York Heart
Association Functional Classification. To be eligible for this trial, patients
should be class 2B or better and have an left ventricular ejection fraction (LVEF)
above the institutional upper limit of normal if LVEF measurement is available
- Female patients of childbearing potential must have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study
medication. If the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required
- Female patients of childbearing potential must be willing to use an adequate
method of contraception for the course of the study through 3 months after the
last dose of peposertib (M3814) and 6 months after the last dose of liposomal
doxorubicin
- Male patients of reproductive potential must agree to avoid impregnating a partner
while receiving study drug and for 3 months after the last dose of peposertib
(M3814) and 6 months after the last dose of liposomal doxorubicin by complying with
adequate methods of contraception
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred
contraception for the patient
- Ability to understand and the willingness to sign a written informed consent
document
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 1. 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 CYP2C19. Concomitant use of CYP3A4/5 substrates with a narrow
therapeutic index are also excluded. 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
- Strong inhibitors of CYP2C9: >= 1 week prior to study treatment
- Patients who cannot discontinue concomitant proton-pump inhibitors (PPIs). Patients
may confer with the study doctor to determine if such medications can be
discontinued. These must be discontinued >= 5 days prior to study treatment.
Patients do not need to discontinue calcium carbonate
- LVEF measurement and baseline electrocardiogram (ECG) should be performed as
clinically indicated based on cardiac risk assessment of the investigator; patients
with known LVEF < the institutional lower limit of normal (LLN) are excluded
- Patients with uncontrolled intercurrent illness
- Patients who cannot swallow tablets whole
- Patients with new or progressive brain metastases (active brain metastases) or
leptomeningeal disease are eligible if the treating physician determines that
immediate central nervous system (CNS) specific treatment is not required and is
unlikely to be required during the first cycle of therapy
- Pregnant women are excluded from this study because peposertib (M3814) is an
ATP-competitive inhibitor of DNA-PKcs with the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with peposertib
(M3814), breastfeeding should be discontinued if the mother is treated with
peposertib (M3814). These potential risks may also apply to other agents used in
this study
- Patients may not have received prior treatment with a DNA-PK inhibitor
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
National Cancer Institute Developmental Therapeutics Clinic
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
800-411-1222
Investigator:
Last name:
A P. Chen
Email:
Principal Investigator
Facility:
Name:
Dana-Farber - Harvard Cancer Center LAO
Address:
City:
Boston
Zip:
02115
Country:
United States
Status:
Recruiting
Contact:
Last name:
Candace L. Haddox
Phone:
617-652-5204
Email:
Candace_haddox@dfci.harvard.edu
Investigator:
Last name:
Candace L. Haddox
Email:
Principal Investigator
Facility:
Name:
Dana-Farber Cancer Institute
Address:
City:
Boston
Zip:
02215
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-442-3324
Investigator:
Last name:
Candace L. Haddox
Email:
Principal Investigator
Facility:
Name:
University of Michigan Comprehensive Cancer Center
Address:
City:
Ann Arbor
Zip:
48109
Country:
United States
Status:
Suspended
Facility:
Name:
University of Pittsburgh Cancer Institute (UPCI)
Address:
City:
Pittsburgh
Zip:
15232
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
412-647-8073
Investigator:
Last name:
Melissa A. Burgess
Email:
Principal Investigator
Facility:
Name:
M D Anderson Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-632-6789
Email:
askmdanderson@mdanderson.org
Investigator:
Last name:
Elise F. Nassif
Email:
Principal Investigator
Start date:
February 6, 2024
Completion date:
May 3, 2025
Lead sponsor:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
National Cancer Institute (NCI)
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05711615
