| Eligibility |
Inclusion Criteria:
- Patients enrolled to the primary cohort must have limited- or extensive-disease SCLC
at diagnosis, with relapse at study entry with measurable disease per Response
Evaluation Criteria in Solid Tumors (RECIST) 1.1, and with prior therapy with platinum
doublet. Patients with extensive stage disease should have received
chemo-immunotherapy. Both platinum-sensitive and platinum-resistant patients will be
included.
- Age >= 18 years. Because no dosing or adverse event data are currently available on
the use of pembrolizumab in combination with tazemetostat and topotecan in patients
<18 years of age, children are excluded from this study.
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 70%)
- Leukocytes > 3000/mcL
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin > 9 g/dL or > 5.6 mmol/L
- Total bilirubin =< 1.5 institutional upper limit of normal (ULN) OR direct bilirubin
=< ULN for patients with total bilirubin levels > 1.5 × ULN
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN
- Creatinine =< 1.5 institutional ULN OR glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2 unless data exists supporting safe use at lower kidney function
values, no lower than 30 mL/min/1.73 m^2
- Note: Creatinine clearance (CrCl) should be calculated per institutional
standard. Glomerular filtration rate (GFR) can also be used in place of
creatinine or CrCl
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 × ULN unless
patient is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated (a)PTT =< 1.5 × ULN unless patient is receiving anticoagulant therapy as
long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
therapy with undetectable viral load (CD4 count of greater than 250 cells/mcL) within
6 months are eligible for this trial. They must not be receiving prophylactic therapy
for an opportunistic infection.
- 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 they are symptomatically stable
while off steroid therapy for a minimum of 7 days.
- Patients should be class 2B or better on the New York Heart Association Functional
Classification.
- Ability to understand and the willingness to sign a written informed consent document.
- The effects of pembrolizumab and tazemetostat on the developing human fetus are
unknown. For this reason and because monoclonal antibodies, EZH2 inhibitors as well as
other therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study treatment and for 6 months after the last dose of study treatment. 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 study treatment administration.
Exclusion Criteria:
- Patients who have had chemotherapy, immune checkpoint inhibitors, or radiotherapy
within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.
Note: Patients who have had palliative radiotherapy may be included as long as they
have recovered from any radiotherapy related adverse events (allow at least 3 days
between radiotherapy completion and study treatment)
- Patients who have not recovered from adverse events due to prior anti-cancer therapy
(i.e., have residual toxicities > grade 1)
- Note: Patients with =< grade 2 neuropathy or =< grade 2 alopecia are an exception
to this criterion and may qualify for the study
- Note: If patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy
- Untreated immunodeficiency or receiving systemic steroid therapy or any other form of
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
The use of physiologic doses of corticosteroids may be approved after consultation
with the study principal investigator (PI)
- Patients who are receiving any other investigational agents
- Patients with symptomatic brain metastasis are not eligible due to their extremely
poor prognosis and since it is unclear whether the investigational agent penetrates
the blood-brain barrier. However, subjects who have had treatment for their brain
metastasis and are symptomatically stable while off steroid therapy for a minimum of 7
days may be enrolled. The use of physiologic doses of corticosteroids may be approved
after consultation with the study PI
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to pembrolizumab and tazemetostat or other agents used in study
- Has an active autoimmune disease that has required systemic treatment in the past 2
years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment
- Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis
- Patients with uncontrolled intercurrent illness but not limited to, ongoing or active
infection, interstitial lung disease or active, non-infectious pneumonitis,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- Pregnant women are excluded from this study because pembrolizumab as a monoclonal
antibody, and tazemetostat as a EZH2 inhibitor may 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 pembrolizumab or
tazemetostat, breastfeeding should be discontinued if the mother is treated with these
agents and for 1 week after the last dose of tazemetostat. These potential risks may
also apply to other agents used in this study
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C
- Has received a live vaccine within 30 days of planned treatment start. Seasonal flu
vaccines that do not contain live virus are permitted
- Has thrombocytopenia, neutropenia, or anemia of Grade >= 3 (per Common Terminology
Criteria for Adverse Events [CTCAE] 5.0 criteria) or any prior history of myeloid
malignancies, including myelodysplastic syndrome (MDS)
- Has abnormalities known to be associated with MDS (e.g. del 5q, chromosome [chr] 7
abnormality [abn]) and myeloproliferative neoplasm (MPN) (e.g. JAK2 V617F) observed in
cytogenetic testing and deoxyribonucleic acid (DNA) sequencing
- Has a prior history of T-cell lymphoblastic lymphoma (T-LBL) or T-cell acute leukemia
(T-ALL)
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