Inclusion Criteria:
- - Presence of histologically confirmed, advanced or metastatic Merkel cell carcinoma
(MCC), which is considered incurable with standardly available therapies.
- - Presence of at least one MCC tumor, considered measurable per Response Evaluation
Criteria in Solid Tumors (RECIST) version (v)1.1.
(NOTE: Both men and women, and members of all races and ethnic groups
are eligible for this trial.)
- - Eastern Cooperative Oncology Group (ECOG) performance score of 0-2.
- - Must have previously received at least one prior systemic treatment regimen with an
anti-PD-(L)1 agent (administered as monotherapy or in combination with another
treatment)
- Must meet the following criteria defining anti-PD-(L)1 refractory MCC: Best response
of progressive disease (PD) or development of PD after best response of complete
response (CR), partial response (PR), or stable disease (SD) after receiving at least
6 weeks of therapy with an anti-PD-(L)1 agent; PD must develop within 6 months of the
last administration of anti-PD-(L)1 agent.
- - Absolute neutrophil count (ANC) >= 1 x 10^9/L.
- - Platelet count >= 100 × 10^9/L.
- - Hemoglobin >= 9 g/dL (may have been transfused)
- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin
level =< 2 x the upper limit of normal (ULN) (or total bilirubin =< 2.5 x ULN in
patients with Gilbert's syndrome, and AST, ALT =< 2.5 x ULN in patients with hepatic
metastases)
- Estimated creatinine clearance >= 30mL/min according to the Cockcroft-Gault formula or
according to local institutional standard.
- - Activated partial thromboplastin time (aPTT) and international normalized ratio (INR)
or prothrombin time (PT) =< 1.5 x ULN unless on therapeutic anticoagulants.
- - Troponin I (TnI) =< institutional ULN.
(Note: Patients with unexplained elevated TnI
at baseline may undergo a cardiac evaluation and be considered for treatment following
a discussion with the principal investigator or designee.)
- - Must consent to undergo serial tumor biopsies at study defined timepoints, unless
deemed unsafe or technically not feasible by the study investigator.
- - Must have an ability to understand and the willingness to sign a written informed
consent document.
- - Women of childbearing potential must have a negative serum or urine pregnancy test at
screening.
- - Both male and female subjects must be willing to use highly effective contraception,
as stipulated in national or local guidelines, throughout the study and for at least
180 days after last treatment administration, if the risk of conception exists.
Exclusion Criteria:
- - Residual adverse event(s) from prior therapy grade > 1 (National Cancer Institute
[NCI]-Common Terminology Criteria for Adverse Events [CTCAE] v 5.0) that could
interfere with study endpoints or put patient safety at risk.
- - Known active central nervous system (CNS) metastases and/or prior history of
carcinomatous meningitis.
(NOTE: Participants with previously treated brain metastases
may participate provided that they are stable, without evidence of progression by
brain imaging performed within the screening period and at least 4 weeks after the
treatment of brain metastases, and any neurologic symptoms must have stabilized.
Patients must not have any evidence of new or enlarging brain metastases or increasing
CNS edema and must not have required steroids for this purpose for at least 7 days
before the first dose of study treatment.)
- - History of serious immune-related adverse events (IRAEs) from prior immunotherapy that
resulted in permanent discontinuation of anti-PD-(L)1 and could jeopardize patient
safety with the investigational regimen.
(NOTE: Any prior grade 2 or higher IRAE must
be discussed with the Principal Investigator or designee for risk/benefit assessment.)
- - Known allergy or hypersensitivity to any component of the study drugs formulation
(including excipients and additives) that could interfere with study endpoints or put
patient safety at risk.
- - Previous malignant disease (other than MCC) diagnosed within 3 years from day 1 of
study treatment that could interfere with study endpoints or put patient safety at
risk.
(NOTE: Exception will be made for adequately treated basal or squamous cell
carcinoma of the skin or carcinoma in situ (skin, bladder, cervical, colorectal,
breast) or low grade prostatic intraepithelial neoplasia or grade 1 prostate cancer.
Any other neoplasm, which has been treated adequately and is adjudged by the treating
investigator to have a low risk of recurrence during the study, could be enrolled only
after written approval from the principal investigator or designee.)
- - Known active hepatitis B virus (HBV) or hepatitis C virus (HCV), defined as follows:
- Active HBV is defined as a known positive hepatitis B virus surface antigen
(HBsAg) result or positive total hepatitis B virus core antibody (anti-HBc)
results in the absence of hepatitis B virus surface antibody (anti-HBsAb).
NOTE:
When HBsAg is negative and hepatitis B virus core antibody (HBcAb) is positive,
HBV-deoxyribonucleic acid (DNA) should be measured. When HBV-DNA is negative,
this participant could be enrolled with close monitoring of HBV activities.)
- - Active HCV is defined as a known positive HCV antibody result and quantitative
HCV-ribonucleic acid (RNA) results greater than the lower limits of detection of
the assay.
(NOTE: Participants who have had definitive treatment for HCV are
permitted if HCV-RNA is undetectable.)
- - Known uncontrolled human immunodeficiency (HIV) infection.
(NOTE: HIV-positive
patients may be allowed if all of the following criteria are met: CD4 count >= 300/uL,
undetectable viral load, receiving antiretroviral therapy, and risk/benefit ratio is
deemed favorable when considering enrollment.)
- - Known active autoimmune disease, allograft requiring systemic immunosuppression, or
other condition requiring chronic systemic corticosteroids (> 10 mg/day of prednisone
or equivalent).
(NOTE: Exceptions will be made for patients with autoimmune conditions
such as diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not
requiring immunosuppressive treatment; patients receiving physiologic corticosteroid
replacement therapy at doses =< 10 mg/day of prednisone or equivalent for adrenal or
pituitary insufficiency; patients with a condition such as asthma or chronic
obstructive pulmonary disease that requires intermittent use of bronchodilators,
inhaled steroids, or local steroid injections; or those who required brief courses of
corticosteroids for prophylaxis (e.g., contrast dye allergy) or study
treatment-related standard premedication. Any other situation must be discussed with
the principal investigator or designee for risk/benefit assessment.)
- - Immunosuppressed status due to severe uncontrolled diabetes, concurrent hematological
malignancy, or other comorbidities.
- - Known history of serious, active infections (aside from well-controlled HIV) requiring
systemic antimicrobial agents within 14 days before the first dose of study treatment.
(NOTE: Chronic infections such as herpes simplex virus requiring suppressive therapy
may be allowed after discussion with the Principal Investigator or designee for
risk/benefit assessment)
- - Known history of clinically significant interstitial lung disease, or active
noninfectious pneumonitis.
- - Clinically significant (i.e., active) cardiovascular disease such as cerebral vascular
accident or myocardial infarction (within 6 months prior to first dose of study
treatment), ongoing unstable angina or congestive heart failure ( >= New York Heart
Association Classification class II), or serious cardiac arrhythmia that could
jeopardize patient safety on the study.
- - Receipt of live vaccine(s) within 30 days of planned start of study treatment.
(NOTE:
Examples of live vaccines include but are not limited to measles, mumps, rubella,
varicella-zoster [chickenpox), yellow fever, rabies, bacillus calmette-guerin [BCG],
and typhoid vaccines. Seasonal influenza vaccines for injection are generally
killed-virus vaccines and are allowed; however, intranasal influenza vaccines are
live, attenuated vaccines and are not allowed)
- - Known severe acute or chronic medical conditions such as uncontrolled seizure
disorder, serious psychiatric illness, or laboratory abnormalities, that may increase
the risk associated with study participation or may interfere with the interpretation
of study endpoints and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
- Pregnant or breast-feeding woman
