Trial record 1 of 1231 for:
The MATRiX Trial
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
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| ClinicalTrials.gov Identifier: NCT05947500 |
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Recruitment Status :
Recruiting
First Posted : July 17, 2023
Last Update Posted : May 20, 2024
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Sponsor:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Clinical Stage III Cutaneous Merkel Cell Carcinoma AJCC v8 Clinical Stage IV Cutaneous Merkel Cell Carcinoma AJCC v8 Locally Advanced Merkel Cell Carcinoma Metastatic Merkel Cell Carcinoma Refractory Merkel Cell Carcinoma Unresectable Merkel Cell Carcinoma | Drug: Avelumab Procedure: Biopsy Procedure: Biospecimen Collection Procedure: Computed Tomography Procedure: Magnetic Resonance Imaging Procedure: Positron Emission Tomography Drug: Tuvusertib | Phase 2 |
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 (Clinical Trial) |
| Estimated Enrollment : | 50 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | A Randomized Phase 2 Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell Carcinoma: The MATRiX Trial |
| Estimated Study Start Date : | September 13, 2024 |
| Estimated Primary Completion Date : | January 1, 2028 |
| Estimated Study Completion Date : | January 1, 2028 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Avelumab
| Arm | Intervention/treatment |
|---|---|
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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.
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Procedure: Biopsy
Undergo biopsy
Other Names:
Procedure: Biospecimen Collection Undergo collection of blood and stool/rectal swabs
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Procedure: Computed Tomography Undergo CT or PET/CT
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Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Tuvusertib Given PO
Other Names:
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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.
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Drug: Avelumab
Given IV
Other Names:
Procedure: Biopsy Undergo biopsy
Other Names:
Procedure: Biospecimen Collection Undergo collection of blood and stool/rectal swabs
Other Names:
Procedure: Computed Tomography Undergo CT or PET/CT
Other Names:
Procedure: Magnetic Resonance Imaging Undergo MRI
Other Names:
Procedure: Positron Emission Tomography Undergo PET/CT
Other Names:
Drug: Tuvusertib Given PO
Other Names:
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Primary Outcome Measures :
- Composite progression-free survival (PFS) [ Time Frame: From registration to progressive disease or death whichever occurs first, assessed up to 2 years ]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.
Secondary Outcome Measures :
- Overall response rate (ORR) [ Time Frame: Up to 2 years ]The sum of complete and partial responses per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Evaluated using the Mantel-Haenszel test.
- Duration of response [ Time Frame: 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 ]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.
- Overall survival (OS) [ Time Frame: Up to 2 years ]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.
- Gene expression-based immunologic signatures predictive of response [ Time Frame: Up to 2 years ]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.
Other Outcome Measures:
- Biomarker levels [ Time Frame: Up to 2 years ]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).
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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 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
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05947500
Locations
Show 19 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Paul Nghiem | Fred Hutchinson Cancer Center |
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT05947500 |
| Other Study ID Numbers: |
NCI-2023-05259 NCI-2023-05259 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 10592 ( Other Identifier: Fred Hutchinson Cancer Center ) 10592 ( Other Identifier: CTEP ) P30CA015704 ( U.S. NIH Grant/Contract ) |
| First Posted: | July 17, 2023 Key Record Dates |
| Last Update Posted: | May 20, 2024 |
| Last Verified: | January 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| 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. |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Carcinoma, Merkel Cell Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Polyomavirus Infections DNA Virus Infections Virus Diseases Infections Tumor Virus Infections Carcinoma, Neuroendocrine |
Neuroendocrine Tumors Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Adenocarcinoma Neoplasms, Nerve Tissue Avelumab Antibodies, Monoclonal Antineoplastic Agents, Immunological Antineoplastic Agents Immunologic Factors Physiological Effects of Drugs |