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Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Talimogene laherparepvec

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Patients receive talimogene laherparepvec IT and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days for cycle 1 then every 14 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo, CT scan or PET/CT on study. Patients also undergo blood sample collection and biopsies on study.

Biopsy

Biospecimen Collection

Computed Tomography

Laboratory Biomarker Analysis

Positron Emission Mammography

Talimogene Laherparepvec

Ann (Annie) W Silk

This phase II trial studies how well talimogene laherparepvec and nivolumab work in treating patients with lymphomas that do not responded to treatment (refractory) or non-melanoma skin cancers that have spread to other places in the body (advanced) or do not responded to treatment. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving talimogene laherparepvec and nivolumab may work better compared to usual treatments in treating patients with lymphomas or non-melanoma skin cancers.

PRIMARY OBJECTIVE:

I. To determine the frequency of patients responding (response rate) to talimogene laherparepvec monotherapy.

SECONDARY OBJECTIVES:

I. To determine the local response rate to talimogene laherparepvec in injected tumors.

II. To determine the response rate to talimogene laherparepvec + nivolumab (NIVO).

III. To identify potential pre-treatment and on-treatment correlative biomarkers of local and systemic immune response.

OUTLINE:

Patients receive talimogene laherparepvec intratumorally (IT) and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for cycle 1 then every 14 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or positron emission tomography (PET)/CT scan on study. Patients also undergo blood sample collection and biopsies on study.

After completion of study treatment, patients are followed up every 12 weeks for 3 years.

Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers

A Phase II Study of Talimogene Laherparepvec Followed by Talimogene Laherparepvec + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors

Will be analyzed using descriptive statistics. A test of proportions will be performed.

Will be analyzed using descriptive statistics. Logistic regression of response rate on the variable will be performed.

Will be analyzed using descriptive statistics. Test of proportions and logistic regression will be performed.

Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Will be defined as complete response or partial response lasting \>= 6 months.

Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.

National Cancer Institute (NCI)

Avelumab

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunologic Factors

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.

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.

Undergo collection of blood and stool/rectal swabs

Magnetic Resonance Imaging

Positron Emission Tomography

Tuvusertib

Site Public Contact

Gino K. In

Ling Gao

Jeffrey J. Ishizuka

Sunandana Chandra

Alice Zhou

Evan J. Lipson

Maya Dimitrova

Minh Phan

Melissa A. Burgess

Siwen Hu-Lieskovan

Varinder Kaur

Andrew Poklepovic

Paul Nghiem

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.

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.

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

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.

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).

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.

The sum of complete and partial responses per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Evaluated using the Mantel-Haenszel test.

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.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers	NCT02978625	Adenoid Cystic ... Adnexal Carcino... Anaplastic Larg... Anaplastic Larg... Apocrine Carcin... Cylindrocarcino... Digital Papilla... Endocrine Mucin... Extramammary Pa... Extraocular Cut... Hidradenocarcin... Keratoacanthoma Malignant Sweat... Merkel Cell Car... Microcystic Adn... NK-Cell Lymphom... Papillary Adeno... Porocarcinoma Primary Cutaneo... Recurrent Matur... Recurrent T-Cel... Refractory Anap... Refractory Matu... Refractory Merk... Refractory Myco... Refractory Prim... Refractory Skin... Refractory T-Ce... Sezary Syndrome Signet Ring Cel... Skin Basal Cell... Skin Basosquamo... Skin Squamous C... Spiradenocarcin... Squamoid Eccrin... Squamous Cell C... Sweat Gland Car... Trichilemmal Ca... Vulvar Squamous...	Biopsy Biospecimen Col... Computed Tomogr... Laboratory Biom... Nivolumab Positron Emissi... Talimogene Lahe...	18 Years -	National Cancer Institute (NCI)
Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers	NCT02978625	Adenoid Cystic ... Adnexal Carcino... Anaplastic Larg... Anaplastic Larg... Apocrine Carcin... Cylindrocarcino... Digital Papilla... Endocrine Mucin... Extramammary Pa... Extraocular Cut... Hidradenocarcin... Keratoacanthoma Malignant Sweat... Merkel Cell Car... Microcystic Adn... NK-Cell Lymphom... Papillary Adeno... Porocarcinoma Primary Cutaneo... Recurrent Matur... Recurrent T-Cel... Refractory Anap... Refractory Matu... Refractory Merk... Refractory Myco... Refractory Prim... Refractory Skin... Refractory T-Ce... Sezary Syndrome Signet Ring Cel... Skin Basal Cell... Skin Basosquamo... Skin Squamous C... Spiradenocarcin... Squamoid Eccrin... Squamous Cell C... Sweat Gland Car... Trichilemmal Ca... Vulvar Squamous...	Biopsy Biospecimen Col... Computed Tomogr... Laboratory Biom... Nivolumab Positron Emissi... Talimogene Lahe...	18 Years -	National Cancer Institute (NCI)
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	NCT05947500	Clinical Stage ... Clinical Stage ... Locally Advance... Metastatic Merk... Refractory Merk... Unresectable Me...	Avelumab Biopsy Biospecimen Col... Computed Tomogr... Magnetic Resona... Positron Emissi... Tuvusertib	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for refractory merkel cell carcinoma