| 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
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