A Phase II Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell Carcinoma

UCI Specialty Area: Cancer

Principal Investigator: Ling Gao

Official Title: A Phase II Study of ATR Inhibition in Advanced PD-(L)1-Refractory Merkel Cell Carcinoma

A Study On:

Other Skin

Study Description

This is a randomized phase 2 clinical trial, where eligible patients who have progressed on anti-PD(L)1 therapy, will be randomized to monotherapy with M1774 or dual therapy with an M1774 plus avelumab. Randomization will be stratified on whether patients have primary ICI-refractory disease or acquired ICI-refractory disease. Randomization will be conducted using a permuted-block design with randomly chosen block sizes.

The primary objective of this phase 2 randomized clinical trial is to compare the efficacy of M1774 monotherapy to that of M1774 combined with avelumab therapy. The primary endpoint for these purposes will be the composite progression-free survival (PFS) with verified disease progression or death as components, and if each occurs the earliest of the two will be taken as the time of failure. The stratified (on disease, acquired versus primary ICI-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 endpoints include the overall response rate (ORR) for all randomized patients, duration of response (DOR) for all randomized patients and overall survival (OS) for all randomized patients. Overall response rate is defined as described in Section 12.1, and for purposes of analysis and stopping rules (see below), ORR will be assessed at timepoints summarized in the protocol study calendar. M1774 alone or in combination with avelumab may induce durable radiographic responses to improve survival times for patients with MCC that has initial or acquired resistance to immune checkpoint inhibition. While secondary endpoints will be formally compared between arms, these outcomes will be more descriptive as the study is not powered to observe statistical differences in secondary endpoints between arms. However, time-to-event secondary outcomes will be compared using the stratified log-rank test, and the Mantel-Haenszel test (stratified on disease severity) will be used to compare binary outcomes.

The exploratory objectives are to examine the association of various immune correlates with the primary and secondary endpoint evaluated for M1774 alone or in combination with avelumab. All patients will be combined for these purposes, and separate examination of correlates will be conducted by treatment group to allow for the possibility that certain correlates will have differing associations with outcome according to treatment group.

Eligibility

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.

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.

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University of California, Irvine - Study Information Sheet

UCI Center for Clinical Research Potential Participant Database

Lead Researcher
Maheswari Senthil, MD
UCI Center for Clinical Research

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Future Research Use
Researchers will use your information to conduct this study. Once the study is done using your information, we may share them with other researchers so they can use them for other studies in the future. We will not share your name or any other private identifiable information that would let the researchers know who you are. We will not ask you for additional permission to share this de-identified information

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