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

Study Overview
=================
Brief Summary
-----------------
This phase II trial compares tuvusertib in combination with avelumab to tuvusertib alone for controlling disease 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. Tuvusertib inhibits the activity of ATR, which disrupts DNA damage repair and leads to tumor cell death. 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 be more effective at lengthening the time Merkel cell cancer patients can live without their cancer getting worse compared to just giving avelumab alone.

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). III. To correlate circulating tumor DNA levels (relative changes in circulating tumor DNA [ctDNA] within patients pre- and on-treatment) with Response Evaluation Criteria in Solid Tumors (RECIST) response, PFS and overall survival (OS) outcome data to assess how well ctDNA may serve as an early/aggregate biomarker for tumor burden. 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. 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.

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

Conditions
-----------------
Clinical Stage III Merkel Cell Carcinoma AJCC v8, Clinical Stage IV Merkel Cell Carcinoma AJCC v8, Locally Advanced Merkel Cell Carcinoma, Metastatic Merkel Cell Carcinoma, Refractory Merkel Cell Carcinoma, Unresectable Merkel Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: Avelumab
* Procedure: Biopsy
* Procedure: Biospecimen Collection
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography
* Drug: Tuvusertib


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1 (tuvusertib)<br>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. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood and stool/rectal swabs<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Drug: Tuvusertib<br>* Given PO<br>* Other names: M1774;|
| Experimental: Arm 2 (tuvusertib, avelumab)<br>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<br>* Given IV<br>* Other names: MSB0010718C;Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Procedure: Biospecimen Collection<br>* Undergo collection of blood and stool/rectal swabs<br>* Other names: Specimen Collection;Procedure: Computed Tomography<br>* Undergo CT or PET/CT<br>* Other names: tomography;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: Structural MRI;Procedure: Positron Emission Tomography<br>* Undergo PET/CT<br>* Other names: PT;Drug: Tuvusertib<br>* Given PO<br>* Other names: M1774;|

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, 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 | 
| Circulating tumor deoxyribonucleic acid (ctDNA) levels | ctDNA will be correlated with RECIST response, PFS and OS outcome data to assess how well ctDNA may serve as an early/aggregate biomarker for tumor burden. In addition, ctDNA will be summarized descriptively (with mean, standard deviation, median, and interquartile range) at each collected time point for each arm. | Up to 2 years |