Dr. Sam Saibil
Inclusion Criteria:
- REGISTRATION ELIGIBILITY: Patients must have a history of pathologically confirmed
locally advanced/unresectable Merkel cell carcinoma or metastatic Merkel cell
carcinoma
- REGISTRATION ELIGIBILITY: Patients must have evaluable disease per Response
Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- REGISTRATION ELIGIBILITY: 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. If participants are receiving or received cytotoxic
chemotherapy as most recent therapy prior to screening for this trial, there must be
clinically and/or radiologically documented progressive disease on or after
chemotherapy prior to being eligible for this study. If the patient is receiving
bridging chemotherapy, the most recent administration must be ≥ 14 days prior to
planned cycle 1 day 1 (C1D1) of the clinical trial to be eligible
- REGISTRATION ELIGIBILITY: Age >= 18 years. Because no dosing or adverse event data
are currently available on the use of M1774/tuvusertib in combination with avelumab
in patients < 18 years of age, children are excluded from this study
- REGISTRATION ELIGIBILITY: Eastern Cooperative Oncology Group (ECOG) performance
status =< 2 (Karnofsky >= 60%)
- REGISTRATION ELIGIBILITY: Absolute neutrophil count >= 1,000/mcL
- REGISTRATION ELIGIBILITY: Platelets >= 100,000/mcL
- REGISTRATION ELIGIBILITY: Total bilirubin =< institutional upper limit of normal
(ULN) or ≤ 1.5 x ULN for subjects with Gilbert's disease
- REGISTRATION ELIGIBILITY: Aspartate aminotransferase (AST)(serum
glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum
glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
- REGISTRATION ELIGIBILITY: Creatinine =< institutional ULN
- REGISTRATION ELIGIBILITY: Estimated glomerular filtration rate (eGFR) >= 60
mL/min/1.73 m^2
- REGISTRATION ELIGIBILITY: Hemoglobin >= 9.0 g/dL
- REGISTRATION ELIGIBILITY: Human immunodeficiency virus (HIV)-infected patients on
effective anti-retroviral therapy with undetectable viral load within 6 months are
eligible for this trial
- REGISTRATION ELIGIBILITY: For patients with evidence of chronic hepatitis B virus
(HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated
- REGISTRATION ELIGIBILITY: 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
- REGISTRATION ELIGIBILITY: 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
- REGISTRATION ELIGIBILITY: 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
- REGISTRATION ELIGIBILITY: 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
- REGISTRATION ELIGIBILITY: The effects of M1774(tuvusertib) 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 (tuvusertib)
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 (tuvusertib) and
avelumab administration
- REGISTRATION ELIGIBILITY: 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
- CROSSOVER ELIGIBILITY: Patient was initially assigned to arm 1 (M1774/tuvusertib
monotherapy) and completed at least 21 of 28 possible doses of M1774/ tuvusertib
- CROSSOVER ELIGIBILITY: Patients must have documented progressive disease per RECIST
v 1.1
- CROSSOVER ELIGIBILITY: ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
- CROSSOVER ELIGIBILITY: Absolute neutrophil count ≥ 1,000/mcL (within 14 days of
crossover registration)
- CROSSOVER ELIGIBILITY: Platelets ≥ 100,000/mcL (within 14 days of crossover
registration)
- CROSSOVER ELIGIBILITY: Total bilirubin ≤ institutional upper limit of normal (ULN)
or ≤ 1.5 x ULN for subjects with Gilbert's disease (within 14 days of crossover
registration)
- CROSSOVER ELIGIBILITY: AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN (within 14 days
of crossover registration)
- CROSSOVER ELIGIBILITY: Creatinine ≤ institutional ULN (within 14 days of crossover
registration)
- CROSSOVER ELIGIBILITY: Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73
m^2 (within 14 days of crossover registration)
- CROSSOVER ELIGIBILITY: Hemoglobin ≥ 9.0 g/dL (within 14 days of crossover
registration)
- CROSSOVER ELIGIBILITY: Human immunodeficiency virus (HIV)-infected patients on
effective anti-retroviral therapy with undetectable viral load within 6 months are
eligible for this trial
- CROSSOVER ELIGIBILITY: For patients with evidence of chronic hepatitis B virus (HBV)
infection, the HBV viral load must be undetectable on suppressive therapy, if
indicated
- CROSSOVER ELIGIBILITY: 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
- CROSSOVER ELIGIBILITY: 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
- CROSSOVER ELIGIBILITY: 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
- CROSSOVER ELIGIBILITY: 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
- CROSSOVER ELIGIBILITY: The effects of M1774 (tuvusertib) 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 (tuvusertib)
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 (tuvusertib) and
avelumab administration
Exclusion Criteria:
- REGISTRATION EXCLUSION: 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
- REGISTRATION EXCLUSION: Patients with a prior history of ataxia telangiectasia
- REGISTRATION EXCLUSION: Patients who are receiving any other investigational agents
- REGISTRATION EXCLUSION: History of allergic reactions attributed to compounds of
similar chemical or biologic composition to M1774/tuvusertib or avelumab
- REGISTRATION EXCLUSION: Patients with uncontrolled intercurrent illness or any other
significant condition(s) that would make participation in this protocol unreasonably
hazardous
- REGISTRATION EXCLUSION: Pregnant women are excluded from this study because M1774
(tuvusertib) 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 (tuvusertib) and
avelumab breastfeeding should be discontinued if the mother is treated with M1774
(tuvusertib) 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
- REGISTRATION EXCLUSION: Patients who are not able to swallow orally administered
medication or have gastrointestinal disorders likely to interfere with absorption of
the study medication
- REGISTRATION EXCLUSION: Patients who cannot discontinue proton-pump inhibitors
(PPIs)
- REGISTRATION EXCLUSION: 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
- REGISTRATION EXCLUSION: M1774/ tuvusertib 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/ tuvusertib 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
- REGISTRATION EXCLUSION: 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
- REGISTRATION EXCLUSION: Patients with a QTcF (using the Fridericia correction
calculation) of > 470 msec
- CROSSOVER EXCLUSION: Patients with life-threatening immune-related adverse events
(IRAEs) related to prior anti-PD-(L)1 antibody. Patients with a history of IRAE of
G4 severity (excluding thyroid or endocrine disorders now controlled) or IRAE of any
severity that required permanent treatment discontinuation with prior ICI therapy
due to toxicity
- CROSSOVER EXCLUSION: Patients with a prior history of ataxia telangiectasia.
- CROSSOVER EXCLUSION: Patients who are receiving any other investigational agents
- CROSSOVER EXCLUSION: History of allergic reactions attributed to compounds of
similar chemical or biologic composition to M1774/tuvusertib or avelumab
- CROSSOVER EXCLUSION: Patients with uncontrolled intercurrent illness or any other
significant condition(s) that would make participation in this protocol unreasonably
hazardous
- CROSSOVER EXCLUSION: Pregnant women are excluded from this study because M1774
(tuvusertib) 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 (tuvusertib) and
avelumab breastfeeding should be discontinued if the mother is treated with M1774
(tuvusertib) 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
- CROSSOVER EXCLUSION: Patients who are not able to swallow orally administered
medication or have gastrointestinal disorders likely to interfere with absorption of
the study medication
- CROSSOVER EXCLUSION: Patients who cannot discontinue proton-pump inhibitors (PPIs)
- CROSSOVER EXCLUSION: 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. Additionally, anemia
felt related to M1774/tuvusertib may be grade 2 as long as it exceeds requirement of
hemoglobin > 9 g/dL. Patients with endocrinopathies requiring hormone replacement
(such as hypothyroidism, autoimmune diabetes mellitus, adrenal insufficiency) will
be allowed
- CROSSOVER EXCLUSION: M1774/ tuvusertib 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/ tuvusertib 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). Patient Drug Information Handout
and Wallet Card) should be provided to patients. 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
- CROSSOVER EXCLUSION: 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
- CROSSOVER EXCLUSION: Patients with a QTcF (using the Fridericia correction
calculation) of > 470 msec