Testing the Combination of Two Anticancer Drugs M1774 (Tuvusertib) and Avelumab to Evaluate Their Safety and Effectiveness in Treating Merkel Cell Skin Cancer, MATRiX Trial

A Randomized Phase 2 Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell Carcinoma: The MATRiX Trial

This phase II trial compares tuvusertib in combination with avelumab to tuvusertib alone to determine whether the combination therapy will lengthen the time before the cancer starts getting worse in patients with Merkel cell cancer that has not responded to previous treatment (refractory). Tuvusertib is a drug that inhibits an enzyme called ataxia telangiectasia and Rad3 related (ATR) kinase, which is an enzyme that plays a role in repair of damaged deoxyribonucleic acid (DNA) as well as tumor cell replication and survival. It may lead to tumor cell death by inhibiting ATR kinase activity. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tuvusertib in combination with avelumab may lengthen the time before Merkel cell cancer starts getting worse compared to giving avelumab alone.

Study Overview

• Status: Recruiting
• Conditions: Metastatic Merkel Cell Carcinoma; Refractory Merkel Cell Carcinoma; Locally Advanced Merkel Cell Carcinoma; Unresectable Merkel Cell Carcinoma; Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8; Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8
• Intervention / Treatment: Drug: Avelumab; Procedure: Magnetic Resonance Imaging; Procedure: Biopsy; Procedure: Positron Emission Tomography; Procedure: Computed Tomography; Drug: Tuvusertib; Procedure: Biospecimen Collection

Detailed Description

PRIMARY OBJECTIVE:

I. To compare the potential efficacy, using progression free survival (PFS), of ATR inhibition alone to ATR inhibition plus anti-PD-(L)1 therapy through a randomized clinical trial for patients with advanced Merkel cell carcinoma (MCC) who have progressed on anti-PD(L)1 therapy.

SECONDARY OBJECTIVES:

I. To compare the clinical activity of ATR inhibition alone to that in combination with avelumab through a randomized clinical trial for patients with advanced MCC that has progressed after PD-1 pathway blockade.

II. To identify gene expression-based immunologic (replication stress / neuroendocrine [NE] differentiation) signatures predictive of response to ATR inhibition in advanced immunotherapy-refractory MCC tumors through ribonucleic acid sequencing (RNAseq).

EXPLORATORY OBJECTIVES:

I. To examine the association of various biomarkers with the clinical activity of ATR inhibition alone or in combination with PD-(L)1 pathway blockade.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM 1: Patients receive tuvusertib orally (PO) once daily (QD) on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo computed tomography (CT), positron emission tomography (PET)/CT, or magnetic resonance imaging (MRI), biopsy, and collection of blood and stool/rectal swabs at screening and on study. Patients with documented progression may cross over to Arm 2.

ARM 2: Patients receive tuvusertib PO QD on days 1-14 of each cycle and avelumab intravenously (IV) over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool/rectal swabs at screening and on study.

After completion of study treatment, patients are followed up at 30 days and then every 6 months for 2 years.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90033
      • Recruiting
      • USC / Norris Comprehensive Cancer Center
      • Contact: Site Public Contact; Phone Number: 323-865-0451
      • Principal Investigator: Gino K. In
    • Los Angeles, California, United States, 90020
      • Recruiting
      • Keck Medicine of USC Koreatown
      • Contact: Site Public Contact; Phone Number: 213-388-0908
      • Principal Investigator: Gino K. In
    • Los Angeles, California, United States, 90033
      • Recruiting
      • Los Angeles General Medical Center
      • Principal Investigator: Gino K. In
      • Contact: Site Public Contact; Phone Number: 323-865-0451; Email: uscnorrisinfo@med.usc.edu
    • Newport Beach, California, United States, 92663
      • Recruiting
      • USC Norris Oncology/Hematology-Newport Beach
      • Contact: Site Public Contact; Phone Number: 323-865-0451
      • Principal Investigator: Gino K. In
    • Orange, California, United States, 92868
      • Recruiting
      • UC Irvine Health/Chao Family Comprehensive Cancer Center
      • Contact: Site Public Contact; Phone Number: 877-827-8839; Email: ucstudy@uci.edu
      • Principal Investigator: Ling Gao
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Recruiting
      • Yale University
      • Contact: Site Public Contact; Phone Number: 203-785-5702; Email: canceranswers@yale.edu
      • Principal Investigator: Jeffrey J. Ishizuka
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Northwestern University
      • Contact: Site Public Contact; Phone Number: 312-695-1301; Email: cancer@northwestern.edu
      • Principal Investigator: Sunandana Chandra
    • Shiloh, Illinois, United States, 62269
      • Recruiting
      • Memorial Hospital East
      • Contact: Site Public Contact; Phone Number: 314-747-9912; Email: dschwab@wustl.edu
      • Principal Investigator: Alice Zhou
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Recruiting
      • Johns Hopkins University/Sidney Kimmel Cancer Center
      • Contact: Site Public Contact; Phone Number: 410-955-8804; Email: jhcccro@jhmi.edu
      • Principal Investigator: Evan J. Lipson
  • Missouri
    • Creve Coeur, Missouri, United States, 63141
      • Recruiting
      • Siteman Cancer Center at West County Hospital
      • Contact: Site Public Contact; Phone Number: 800-600-3606; Email: info@siteman.wustl.edu
      • Principal Investigator: Alice Zhou
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University School of Medicine
      • Contact: Site Public Contact; Phone Number: 800-600-3606; Email: info@siteman.wustl.edu
      • Principal Investigator: Alice Zhou
    • Saint Louis, Missouri, United States, 63129
      • Recruiting
      • Siteman Cancer Center-South County
      • Contact: Site Public Contact; Phone Number: 800-600-3606; Email: info@siteman.wustl.edu
      • Principal Investigator: Alice Zhou
    • Saint Louis, Missouri, United States, 63136
      • Recruiting
      • Siteman Cancer Center at Christian Hospital
      • Contact: Site Public Contact; Phone Number: 800-600-3606; Email: info@siteman.wustl.edu
      • Principal Investigator: Alice Zhou
    • Saint Peters, Missouri, United States, 63376
      • Recruiting
      • Siteman Cancer Center at Saint Peters Hospital
      • Contact: Site Public Contact; Phone Number: 800-600-3606; Email: info@siteman.wustl.edu
      • Principal Investigator: Alice Zhou
  • New York
    • New York, New York, United States, 10016
      • Recruiting
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone
      • Contact: Site Public Contact; Email: CancerTrials@nyulangone.org
      • Principal Investigator: Maya Dimitrova
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • Recruiting
      • University of Pittsburgh Cancer Institute (UPCI)
      • Contact: Site Public Contact; Phone Number: 412-647-8073
      • Principal Investigator: Melissa A. Burgess
  • Utah
    • Salt Lake City, Utah, United States, 84112
      • Recruiting
      • Huntsman Cancer Institute/University of Utah
      • Contact: Site Public Contact; Phone Number: 888-424-2100; Email: cancerinfo@hci.utah.edu
      • Principal Investigator: Jeffery S. Russell
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • Recruiting
      • University of Virginia Cancer Center
      • Principal Investigator: Varinder Kaur
      • Contact: Site Public Contact; Phone Number: 434-243-6303; Email: uvacancertrials@hscmail.mcc.virginia.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients must have a history of pathologically confirmed locally advanced/unresectable Merkel cell carcinoma or metastatic Merkel cell carcinoma
• Patients must have evaluable disease per RECIST version (v)1.1
• Patients must have had prior treatment with anti-PD-1 or anti-PD-L-1 antibody (e.g., pembrolizumab, avelumab, etc.) and have experienced progressive disease during treatment or within 120 days from the last dose of anti-PD-(L)1 therapy. Anti-PD-(L)1 therapy administered in combination with other agent(s) including ipilimumab is also allowed as prior therapy, if patients experienced progressive disease during treatment or within 120 days from the last dose of anti-PD-(L)1 therapy
• Age >= 18 years. Because no dosing or adverse event data are currently available on the use of M1774 in combination with avelumab in patients < 18 years of age, children are excluded from this study
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• Absolute neutrophil count >= 1,000/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< 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
• Creatinine =< institutional ULN
• Estimated glomerular filtration rate (eGFR) >= 60 mL/min/1.73 m^2
• Hemoglobin >= 9.0 g/dL
• 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
• 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
• The effects of M1774 on the developing human fetus are unknown. For this reason and because ATR inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and, for the duration of study participation, and 6 months after completion of M1774 and avelumab administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of M1774 and avelumab administration
• Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants

Exclusion Criteria:

• Patients with life-threatening immune-related adverse events (IRAEs) related to prior anti-PD-(L)1 antibody. Patients with a history of IRAE of grade 4 (G4) severity (excluding thyroid or endocrine disorders now controlled) or IRAE of any severity that required permanent treatment discontinuation with prior immune checkpoint inhibitor (ICI) therapy due to toxicity
• Patients with a prior history of ataxia telangiectasia
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to M1774 or avelumab
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous
• Pregnant women are excluded from this study because M1774 and avelumab have 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 M1774 and avelumab breastfeeding should be discontinued if the mother is treated with M1774 or avelumab and for at least 1 month after the last dose of study medications. These potential risks may also apply to other agents used in this study
• Patients who are not able to swallow orally administered medication or have gastrointestinal disorders likely to interfere with absorption of the study medication
• Patients who cannot discontinue proton-pump inhibitors (PPIs)
• 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 and neuropathy, which may be =< grade 2. Patients with endocrinopathies requiring hormone replacement (such as hypothyroidism, autoimmune diabetes mellitus, adrenal insufficiency) will be allowed

• M1774 is primarily metabolized by aldehyde oxidase and to a lesser extent CYP3A4 and CYP1A2; therefore, concomitant administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, indinavir, nelfinavir and saquinavir) and CYP1A2 or inducers of CYP3A4 (e.g. rifampin, phenytoin, carbamazepine, phenobarbital, St. John's Wort) and CYP1A2 are prohibited. M1774 is an inhibitor of MATE1 and MATE2K and substrates of these transporters are also prohibited. These include metformin, acyclovir, estrone sulfate, ciprofloxacin and cephalexin. Patients who are taking such medications who cannot discontinue or switch them to an acceptable alternative are not eligible

  • Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference for a list of drugs to avoid or minimize use of. One example of such a reference is here (https://go.drugbank.com/categories/DBCAT003956)
  • As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Patients who are on chronic corticosteroid treatment, beyond physiological replacement
• Patients with a QTcF (using the Fridericia correction calculation) of > 470 msec

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 2 (tuvusertib, avelumab); Patients receive tuvusertib PO QD on days 1-14 of each cycle and avelumab IV over 60 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool/rectal swabs at screening and on study.	Drug: Avelumab; Given IV; Other Names: Bavencio; MSB-0010718C; MSB0010718C; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Tuvusertib; Given PO; Other Names: ATR Kinase Inhibitor M1774; M 1774; M-1774; M1774; Procedure: Biospecimen Collection; Undergo collection of blood and stool/rectal swabs; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection
Active Comparator: Arm 1 (tuvusertib); Patients receive tuvusertib PO QD on days 1-14 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, PET/CT, or MRI, biopsy, and collection of blood and stool/rectal swabs at screening and on study. Patients with documented progression may cross over to Arm 2.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Procedure: Positron Emission Tomography; Undergo PET/CT; Other Names: Medical Imaging, Positron Emission Tomography; PET; PET Scan; Positron Emission Tomography Scan; Positron-Emission Tomography; proton magnetic resonance spectroscopic imaging; PT; Positron emission tomography (procedure); Procedure: Computed Tomography; Undergo CT or PET/CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Drug: Tuvusertib; Given PO; Other Names: ATR Kinase Inhibitor M1774; M 1774; M-1774; M1774; Procedure: Biospecimen Collection; Undergo collection of blood and stool/rectal swabs; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite progression-free survival (PFS)	The stratified (on disease, acquired versus primary immune checkpoint inhibitor-refractory disease) log-rank test will be used to compare PFS between arms. The primary analysis will be done on an intent-to-treat basis. An as-treated analysis will also be done as a sensitivity analysis.	From registration to progressive disease or death whichever occurs first, assessed up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	The sum of complete and partial responses per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Evaluated using the Mantel-Haenszel test.	Up to 2 years
Duration of response	Will be evaluated by estimating the probability of response using a cumulative incidence estimate, and then among those who responded, creating a time-to-recurrence curve using a cumulative-incidence estimate. Will be compared between arms using the stratified log-rank test and the Mantel-Haenszel test will be used to compare binary outcomes.	From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years
Overall survival (OS)	Will be evaluated using a stratified log-rank test. Will be compared between arms using the stratified log-rank test and the Mantel-Haenszel test will be used to compare binary outcomes.	Up to 2 years
Gene expression-based immunologic signatures predictive of response	Annotated transcriptome sequences at baseline and on-therapy will be correlated with response in both virus-positive and -negative tumors. Descriptive statistical analyses will be performed. Volcano plots will be evaluated. Gene set enrichment analysis will be used to compare pre-treatment samples from patients with response to treatment to samples from patients experiencing disease progression. The Kolmogorov-Smirnov test will be used to test for statistical differences followed by the Bonferroni correction to adjust for multiple comparisons.	Up to 2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker levels	Will examine the association of various biomarkers with the primary and secondary endpoints. All patients will be combined for these purposes, and separate examination of biomarkers will be conducted by treatment group to allow for the possibility that certain correlates will have differing associations with outcome according to treatment group. This will be done using logistic regression for ORR and Cox regression for OS and PFS. In addition, descriptive statistics for biomarkers will be presented (mean, standard deviation, median, and interquartile range) by treatment group and based on presence or absence of response. Biomarker levels will also be compared between the two treatment groups using the two-sample t-test (or the non-parametric Wilcoxon rank-sum test as needed).	Up to 2 years

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Paul Nghiem, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start (Estimated): September 13, 2024
• Primary Completion (Estimated): January 1, 2028
• Study Completion (Estimated): January 1, 2028

Study Registration Dates

• First Submitted: July 13, 2023
• First Submitted That Met QC Criteria: July 13, 2023
• First Posted (Actual): July 17, 2023

Study Record Updates

• Last Update Posted (Estimated): April 26, 2024
• Last Update Submitted That Met QC Criteria: April 25, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Virus Diseases; Infections; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; DNA Virus Infections; Tumor Virus Infections; Neuroendocrine Tumors; Polyomavirus Infections; Carcinoma, Neuroendocrine; Carcinoma; Carcinoma, Merkel Cell; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Avelumab; Antibodies, Monoclonal
• Other Study ID Numbers: NCI-2023-05259 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA015704 (U.S. NIH Grant/Contract); 10592 (Other Identifier: CTEP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No