Clinical Trials Logo

Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT05947500
Other study ID # NCI-2023-05259
Secondary ID NCI-2023-0525910
Status Recruiting
Phase Phase 2
First received
Last updated
Start date May 21, 2024
Est. completion date January 1, 2028

Study information

Verified date May 2024
Source National Cancer Institute (NCI)
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

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.


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 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.


Recruitment information / eligibility

Status Recruiting
Enrollment 50
Est. completion date January 1, 2028
Est. primary completion date January 1, 2028
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility 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 Response Evaluation Criteria in Solid Tumors (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) or = 1.5 x ULN for subjects with Gilbert's disease - 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 during screening shows no evidence of progressive brain metastases and it has been at least 4 weeks since central nervous system (CNS) directed therapy - 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 exceeding 10 mg prednisone daily (or equivalent) are excluded. Chronic corticosteroid use lower than this range is permitted - Patients with a QTcF (using the Fridericia correction calculation) of > 470 msec

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
Avelumab
Given IV
Procedure:
Biopsy
Undergo biopsy
Biospecimen Collection
Undergo collection of blood and stool
Computed Tomography
Undergo CT or PET/CT
Magnetic Resonance Imaging
Undergo MRI
Positron Emission Tomography
Undergo PET/CT
Drug:
Tuvusertib
Given PO

Locations

Country Name City State
United States Johns Hopkins University/Sidney Kimmel Cancer Center Baltimore Maryland
United States University of Virginia Cancer Center Charlottesville Virginia
United States Northwestern University Chicago Illinois
United States Siteman Cancer Center at West County Hospital Creve Coeur Missouri
United States Keck Medicine of USC Koreatown Los Angeles California
United States Los Angeles General Medical Center Los Angeles California
United States USC / Norris Comprehensive Cancer Center Los Angeles California
United States Yale University New Haven Connecticut
United States Laura and Isaac Perlmutter Cancer Center at NYU Langone New York New York
United States USC Norris Oncology/Hematology-Newport Beach Newport Beach California
United States University of Oklahoma Health Sciences Center Oklahoma City Oklahoma
United States UC Irvine Health/Chao Family Comprehensive Cancer Center Orange California
United States University of Pittsburgh Cancer Institute (UPCI) Pittsburgh Pennsylvania
United States Virginia Commonwealth University/Massey Cancer Center Richmond Virginia
United States Siteman Cancer Center at Christian Hospital Saint Louis Missouri
United States Siteman Cancer Center-South County Saint Louis Missouri
United States Washington University School of Medicine Saint Louis Missouri
United States Siteman Cancer Center at Saint Peters Hospital Saint Peters Missouri
United States Huntsman Cancer Institute/University of Utah Salt Lake City Utah
United States Fred Hutchinson Cancer Center Seattle Washington
United States Memorial Hospital East Shiloh Illinois

Sponsors (1)

Lead Sponsor Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type Measure Description Time frame Safety issue
Other 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
Primary 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 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
Secondary 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
Secondary 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
Secondary 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
See also
  Status Clinical Trial Phase
Recruiting NCT04261855 - Targeted Therapy and Avelumab in Merkel Cell Carcinoma Phase 1/Phase 2
Active, not recruiting NCT03816332 - Tacrolimus, Nivolumab, and Ipilimumab in Treating Kidney Transplant Recipients With Selected Unresectable or Metastatic Cancers Phase 1
Recruiting NCT05269381 - Personalized Neoantigen Peptide-Based Vaccine in Combination With Pembrolizumab for Treatment of Advanced Solid Tumors Phase 1/Phase 2
Active, not recruiting NCT03304639 - Testing the Addition of Radiation Therapy to Immunotherapy for Merkel Cell Carcinoma Phase 2
Active, not recruiting NCT03599713 - A Study of INCMGA00012 in Metastatic Merkel Cell Carcinoma (POD1UM-201) Phase 2
Recruiting NCT05896839 - Immunotherapy in Combination With Prednisone and Sirolimus for Kidney Transplant Recipients With Unresectable or Metastatic Skin Cancer Phase 1/Phase 2
Approved for marketing NCT03089658 - Expanded Access to Avelumab for Treatment of Metastatic Merkel Cell Carcinoma (mMCC)