Trial Title:
Testing the Combination of Two Anti-cancer Drugs, Peposertib (M3814) and M1774 for Advanced Solid Tumors
NCT ID:
NCT05687136
Condition:
Advanced Malignant Solid Neoplasm
Metastatic Malignant Solid Neoplasm
Unresectable Malignant Solid Neoplasm
Conditions: Official terms:
Neoplasms
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, tuvusertib)
Other name:
BIOPSY_TYPE
Other name:
Bx
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (peposertib, tuvusertib)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Computed Tomography
Description:
Undergo CT
Arm group label:
Treatment (peposertib, tuvusertib)
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, tuvusertib)
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:
Peposertib
Description:
Given PO
Arm group label:
Treatment (peposertib, tuvusertib)
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
Intervention type:
Procedure
Intervention name:
Positron Emission Tomography
Description:
Undergo PET
Arm group label:
Treatment (peposertib, tuvusertib)
Other name:
Medical Imaging, Positron Emission Tomography
Other name:
PET
Other name:
PET Scan
Other name:
Positron emission tomography (procedure)
Other name:
Positron Emission Tomography Scan
Other name:
Positron-Emission Tomography
Other name:
proton magnetic resonance spectroscopic imaging
Other name:
PT
Intervention type:
Drug
Intervention name:
Tuvusertib
Description:
Given PO
Arm group label:
Treatment (peposertib, tuvusertib)
Other name:
ATR Kinase Inhibitor M1774
Other name:
M 1774
Other name:
M-1774
Other name:
M1774
Summary:
This phase I trial tests the safety, side effects and best dose of peposertib (M3814) in
combination with tuvusertib (M1774) in treating patients with solid tumors that have
spread to other places in the body (advanced). Peposertib and tuvusertib stop the growth
of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability of peposertib (M3814) in combination with
M1774. (DOSE ESCALATION AND EXPANSION COHORT) II. To determine the maximum tolerated dose
(MTD) and recommended phase 2 dose (RP2D) of the combination of peposertib (M3814) and
M1774. (DOSE ESCALATION COHORT)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To determine the pharmacokinetic (PK)
profiles of peposertib (M3814) and M1774 when administered in combination.
EXPLORATORY OBJECTIVES:
I. To explore correlations between pharmacodynamic (PD) and predictive biomarkers
(gammaH2AX, phospho-KAP1 and phospho-RPA) with clinical outcomes.
II. To explore correlations between baseline genomic alterations of ataxia-telangiectasia
mutated (ATM) or markers of replicative stress, ATM expression by immunohistochemistry
(IHC), RAD5' foci formation with clinical outcomes.
III. To determine metrics of anticancer activity including the objective response rate
(ORR) and progression-free survival (PFS).
OUTLINE: This a dose-escalation study of peposertib and tuvusertib, followed by a
dose-expansion study.
Patients receive peposertib orally (PO) in combination with tuvusertib PO once (QD) or
twice (BID) daily on days 1-14 of each cycle. Cycles repeat every 28 days in the absence
of disease progression, pregnancy, non-compliance, unacceptable toxicity, termination of
the study or the study drug is no longer available. Patients also undergo tumor biopsy
before cycle(C) 1 day (D)1, C1D10 and at progression and blood sample collection during
prestudy and weeks 1, 2, 3, 4, 5, 6, and at progression. Patients additionally undergo
positron emission tomography (PET), computed tomography (CT), and magnetic resonance
imaging (MRI) at baseline and are repeated every 8 weeks for 24 weeks then every 12 weeks
unless clinically indicated.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Patients must have histologically confirmed solid malignancy that is metastatic or
unresectable and for which standard curative or palliative measures do not exist or
are no longer effective.
- For the dose escalation and dose expansion phases, patients must have genomic
evidence of inactivating ATM mutations, amplification of MYC, mutation of FBXW7,
CCNE1 amplification, SWI/SNF member mutation (ARID1A, PBRM1, SMARCA4, ARID2, ARID1b,
SMARCA2, SS18), and ATRX/DAXX. Other SWI/SNF mutations may be considered after
discussion with the principal investigator (PI).
- Progression on at least one prior standard therapy.
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of peposertib (M3814) in combination with M1774 in patients < 18 years of
age, children are excluded from this study.
- Life expectancy > 3 months.
- Eastern cooperative oncology group (ECOG) performance status =< 2 (Karnofsky >=
60%).
- Measurable disease by response evaluation criteria in solid tumors (RECIST) 1.1
(RECIST) 1.1 non-measurable disease permitted for the dose escalation portion).
- Hemoglobin >= 9 g/dL.
- Absolute neutrophil count >= 1,500/mcL.
- Platelets >= 1000,000/mcL.
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN).
- Asparate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT]/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase [SGPT]) =<
3 × institutional ULN or =< 5.0X the ULN if liver metastases are present.
- Glomerular filtration rate (GFR) >= 60 mL/min/1.73m^2.
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load within 6 months are eligible for this trial.
Anti-retroviral therapy agents must be considered for potential drug-drug
interactions per exclusion.
- 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 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 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.
- Able to swallow whole capsules or tablets.
- Willing to undergo paired biopsies (expansion arm).
- 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 6 months after the
last dose of study medication.
- 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
study drug 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. Participants with impaired decision-making capacity who have a
legally-authorized representative (LAR) and/or family member available will also be
eligible.
Exclusion Criteria:
- Patients who have received immunotherapy within 21 days of Cycle 1 Day 1.
- Patients who have received therapeutic radiation therapy within 21 days, or
palliative radiation therapy within 7 days, of Cycle 1 Day 1.
- Patients who have undergone major surgery within 21 days of Cycle 1 Day 1.
- 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,
controlled endocrine toxicity (e.g., hypothyroidism), and cutaneous toxicity which
will be permitted at Grade 2.
- Patients who are receiving any other investigational agents.
- 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.
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to peposertib (M3814) and M1774.
- Patients who cannot discontinue concomitant medications or herbal supplements that
are strong inhibitors or strong inducers of cytochrome P450 (CYP) isoenzymes
CYP3A4/5, CYP2C19, and CYP2C9. Concomitant use of CYP3A4/5 substrates with a narrow
therapeutic index are also excluded. Concomitant administration of sensitive
substrates of P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 should be avoided (if the use
is unavoidable, carefully monitor patients for signs of increased toxicity).
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,CYP2C19, and CYP2C9: >= 3 weeks prior to study
treatment.
- Strong inhibitors of CYP3A4/5, CYP2C19, and CYP2C9: >= 1 week prior to study
treatment.
- Substrates of CYP3A4/5, , P-gp, BCRP, OCT1, OATP1B1, and OATP1B3 with a narrow
therapeutic index: >= 1 day prior to study treatment.
- Patients who cannot discontinue proton-pump inhibitors (PPIs). H-2-receptor
antagonist should be held during the 2 weeks of concurrent dosing with M1774. There
is no H-2-receptor antagonist restriction during the off weeks without
M1774/peposertib (M3814) dosing.
- Patients who received hematopoietic growth factor (e.g., granulocyte
colony-stimulating factor, erythropoietin) within 14 days prior to the first dose of
study intervention.
- Patients with uncontrolled intercurrent illness including, but not limited to:
ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia, or chronic indwelling drains.
- QTcF (using the Fridericia correction calculation) of > 470 msec
- Pregnant women and women who are breastfeeding are excluded from this study because
the effects of the study drugs on the developing fetus are unknown.
- 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 as assessed by the treating investigator may be included
with the approval of the sponsor-investigator.
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:
National Institutes of Health Clinical Center
Address:
City:
Bethesda
Zip:
20892
Country:
United States
Status:
Active, not recruiting
Facility:
Name:
Massachusetts General Hospital Cancer Center
Address:
City:
Boston
Zip:
02114
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
877-726-5130
Investigator:
Last name:
Gregory M. Cote
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:
NYU Langone Hospital - Long Island
Address:
City:
Mineola
Zip:
11501
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Phone:
212-263-4432
Email:
cancertrials@nyulangone.org
Investigator:
Last name:
Nancy Chan
Email:
Principal Investigator
Facility:
Name:
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Address:
City:
New York
Zip:
10016
Country:
United States
Status:
Recruiting
Contact:
Last name:
Site Public Contact
Email:
CancerTrials@nyulangone.org
Investigator:
Last name:
Nancy Chan
Email:
Principal Investigator
Start date:
June 7, 2024
Completion date:
August 31, 2026
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/NCT05687136
