Testing of Tazemetostat in Combination With Topotecan and Pembrolizumab in Patients With Recurrent Small Cell Lung Cancer
Extensive Stage Lung Small Cell Carcinoma · Limited Stage Lung Small Cell Carcinoma · Platinum-Resistant Lung Small Cell Carcinoma · Platinum-Sensitive Lung Small Cell Carcinoma · Recurrent Extensive Stage Lung Small Cell Carcinoma · Recurrent Lung Small Cell Carcinoma
De qué trata este estudio
El registro no identifica actualmente este estudio como reclutando. Consulta su estado antes de planificar una evaluación.
- Tipo de estudio
- De intervención
- Fase
- Fase 1
- Rango de edad
- 18 años - No especificado
- Sexo admitido
- Todos los sexos
- Voluntarios sanos
- No aceptados
- Participantes
- 22 Real
Estos son puntos de partida, no una decisión de elegibilidad. El equipo debe revisar todos los requisitos.
Withdrawal of tazemetostat supply led to early study closure.
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Acerca de la investigación
This phase I trial tests the safety, side effects, and best dose of tazemetostat in combination with topotecan and pembrolizumab in treating patients with small cell lung cancer that has come back after a period of improvement (recurrent). Tazemetostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as topotecan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving tazemetostat in combination with topotecan and pembrolizumab may shrink or stabilize recurrent small cell lung cancer.
Leer la descripción completa
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated dose (MTD) of tazemetostat hydrobromide (tazemetostat) in combination with topotecan hydrochloride (topotecan) and pembrolizumab in patients with recurrent extensive stage (ES)-small cell lung cancer (SCLC), by reviewing dose-limiting toxicities (DLTs) in cycle 1 (21 days). (Dose-Escalation Cohort) II. To select the recommended phase II dose (RP2D) for a combination of tazemetostat, topotecan and pembrolizumab, based on pharmacodynamic (PD) parameters as well as overall efficacy and tolerability. (Dose-Escalation Cohort) III. To evaluate safety and tolerability of tazemetostat in combination with topotecan and pembrolizumab. (Expansion Cohort)
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To determine in a very preliminary fashion, the efficacy of a combination of tazemetostat, topotecan and pembrolizumab in recurrent ES-SCLC by assessing overall response rate (ORR), progression-free survival (PFS), duration of response (DOR) and overall survival (OS).
EXPLORATORY OBJECTIVES:
I. To perform molecular profiling assays on malignant and normal tissues, including, but not limited to ribonucleic acid (RNA) sequencing (RNA-Seq).
II. To assess modulation of EZH2 targets including SLFN11 and MHC among others. III. To identify potential predictive biomarkers of response. IV. To identify mechanisms of drug sensitivity and resistance using deoxyribonucleic acid (DNA)- and RNA-based assessment platforms.
V. To contribute genetic analysis data from de-identified biospecimens to Genomic Data Commons (GDC), a well annotated cancer molecular and clinical data repository, for current and future research; specimens will be annotated with key clinical data, including presentation, diagnosis, staging, summary treatment, and if possible, outcome.
VI. To bank formalin-fixed, paraffin-embedded (FFPE) tissue, blood (for cell-free DNA analysis), and nucleic acids obtained from patients at the Early-Phase and Experimental Clinical Trials Biospecimen Bank (EET Biobank) at Nationwide Children's Hospital.
VII. To characterize circulating cell-free DNA (cfDNA).
OUTLINE: This is a dose-escalation study of tazemetostat followed by a dose-expansion study.
Patients receive tazemetostat orally (PO) twice daily (BID) for 7 days prior to cycle 1 and then on days 1-21 of each cycle, pembrolizumab intravenously (IV) over 30 minutes on day 1 of each cycle, and topotecan IV over 30 minutes on days 1-3 or days 1-5 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan throughout the study and undergo biopsy and collection of blood on study.
After completion of study treatment, patients are followed every 3 months after removal from study treatment until study closure or death, whichever occurs first.
¿Quién podría participar?
La lista siguiente contiene el texto del patrocinador. Puede incluir condiciones, tratamientos previos, resultados de pruebas y otros requisitos. Aparecer en tu búsqueda no significa que califiques.
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 DNA sequencing
- Has a prior history of T-cell lymphoblastic lymphoma (T-LBL), T-cell acute leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL)
Tratamiento, grupos y participación
El registro puede describir tratamientos y duración sin incluir un calendario completo. Pide al equipo las visitas, procedimientos, riesgos, costos y alternativas. Mantén tu atención habitual salvo que tu médico te indique un cambio.
- Asignación
- No aplica
- Enmascaramiento
- Sin enmascaramiento
Treatment (tazemetostat, pembrolizumab, topotecan)
Patients receive tazemetostat PO BID for 7 days prior to cycle 1 and then on days 1-21 of each cycle, pembrolizumab IV over 30 minutes on day 1 of each cycle, and topotecan IV over 30 minutes on days 1-3 or days 1-5 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo CT scan throughout the study and undergo biopsy and collection of blood on study.
Procedure: Biopsy Procedure · Procedure: Biospecimen Collection · Procedure: Computed Tomography · Biological: Pembrolizumab · Drug: Tazemetostat Hydrobromide · Drug: Topotecan Hydrochloride
Biopsy Procedure PROCEDURE
Undergo biopsy
Biospecimen Collection PROCEDURE
Undergo collection of blood
Computed Tomography PROCEDURE
Undergo CT scan
Pembrolizumab BIOLOGICAL
Given IV
Tazemetostat Hydrobromide DRUG
Given PO
Topotecan Hydrochloride DRUG
Given IV
Qué evalúan los investigadores
Estas medidas indican qué se estudia. No prueban que un tratamiento funcione.
Medidas principales
Maximum Tolerated Dose (Dose-escalation Cohort) of Tazemetostat in Combination With Topotecan and Pembrolizumab
Plazo: Up to 21 days (cycle 1)
Maximum tolerated dose (MTD) is the highest dose level with observed toxicity rate less than 33%.
Incidence of Adverse Events (Expansion Cohort) by Type and Grade in the Expansion Cohort
Plazo: Up to 3 years
The incidence of adverse events will be reported by type and grade, for the participants in the expansion cohort. Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Incidence of Grade 3 or Above Adverse Events by Type Related or Possibly Related to Study Treatment in the Dose Escalation Cohort
Plazo: Start of treatment through 30 days post last dose, an average of 112.33 days or 3.22 months
Adverse events were assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. Grade 1 is mild. Grade 2 is moderate. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event.
Medidas secundarias
Overall Response Rate (ORR) (Expansion Cohort)
Plazo: Up to 3 years
ORR will be estimated based on participants evaluable for response and will be presented along with a 95% confidence interval. ORR was assessed by the Immune Related Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. Complete Response (CR) is disappearance of all target lesions. Partial Response (PR) is at least a 30% decrease in the sum of the diameters of target lesions. Stable Disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Progressive Disease (PD) is at least a 20% increase in the sum of diameters of target lesions.
Progression-free Survival (PFS) (Expansion Cohort)
Plazo: From the on-study date until the date of progression or death without progression, assessed up to 3 years
PFS will be estimated using the Kaplan-Meier method, resulting in median survival times with 95% confidence interval. PFS is defined as the duration of time from start of treatment to time of progression or death. PFS was assessed by the Immune Related Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. Progression is defined as at least 1 20% increase in the sum of the diameters of target lesions. Appearance of one or more new lesions is also progression.
Overall Survival (OS) (Expansion Cohort)
Plazo: From the on-study date until the date of death or last follow-up, assessed up to 3 years
OS will be estimated using the Kaplan-Meier method, resulting in median survival times with 95% confidence interval. OS is determined from the on-study date until the date of death without progression. Progression was assessed by the Immune Related Response Evaluation Criteria in Solid Tumors (iRECIST) criteria and is defined as at least a 20% increase in the sum of the diameters of target lesions. Appearance of one or more new lesions is also progression.
Duration of Response (DOR) (Expansion Cohort)
Plazo: From the first date of response to the date of progression, assessed up to 3 years
DOR will be estimated using the Kaplan-Meier method, resulting in median survival times with 95% confidence interval. DOR is calculated from the first date of response to the date of progression. Response was assessed by the Immune Related Response Evaluation Criteria in Solid Tumors (iRECIST) criteria. Progression is defined as at least a 20% increase in the sum of the diameters of target lesions. Appearance of one or more new lesions is also progression.
Gene Expression Estimated by the Ribonucleic Acid (RNA) Sequencing in Participants With Recurrent Extensive Stage Small Cell Lung Cancer (ES-SCLC) (Dose Expansion)
Plazo: Baseline, post Tazemetostat (Day 1 Cycle 1/(1 cycle =21 days), and post 3-drug combination
RNA Seq molecular profiling will be performed on malignant and normal tissue obtained by biopsy.
Otras medidas
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)
Plazo: From the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered, an average of 112.33 days or 3.22 months
Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v50). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Number of Participants With a Dose Limiting Toxicity (DLT)
Plazo: Cycle 1 (21 days)
A DLT is the occurrence of any of the following toxicities, if determined by the Investigator to be possibly, probably or definitely related to study drug administration: Grade 4 nonhematologic toxicity (not laboratory), Neutropenia grade 4 for \>7 days, Grade 3 nonhematologic toxicity (not laboratory) lasting \>3 days despite optimal supportive care, Any grade 3 or 4 nonhematologic laboratory value if medical intervention is required, the abnormality leads to a hospitalization, or the abnormality persists for \>1 week. Febrile neutropenia Grade 3 or Grade 4, Thrombocytopenia \<25,000/mm\^3 if associated with a bleeding event which does not result in hemodynamic instability but requires an elective platelet transfusion, or a life-threatening bleeding event which results in urgent intervention and admission to an Intensive Care Unit. Prolonged delay (.2 weeks) in starting Cycle 2 due to treatment-related toxicity. Grade 5 toxicity.
Revisa las tablas completas y sus limitaciones en el registro oficial.
Abrir resultados oficiales ↗Centros de investigación (15)
El estado general puede diferir del estado de un centro. Confirma la disponibilidad antes de trasladarte.
15 centros
Keck Medicine of USC KoreatownLos Angeles, California, United StatesEstado desconocido
Los Angeles General Medical CenterLos Angeles, California, United StatesEstado desconocido
USC / Norris Comprehensive Cancer CenterLos Angeles, California, United StatesEstado desconocido
USC Norris Oncology/Hematology-Newport BeachNewport Beach, California, United StatesEstado desconocido
University of California Davis Comprehensive Cancer CenterSacramento, California, United StatesEstado desconocido
MedStar Georgetown University HospitalWashington D.C., District of Columbia, United StatesEstado desconocido
Northwestern UniversityChicago, Illinois, United StatesEstado desconocido
University of Kentucky/Markey Cancer CenterLexington, Kentucky, United StatesEstado desconocido
Johns Hopkins University/Sidney Kimmel Cancer CenterBaltimore, Maryland, United StatesEstado desconocido
NCI - Center for Cancer ResearchBethesda, Maryland, United StatesEstado desconocido
Montefiore Medical Center-Einstein CampusThe Bronx, New York, United StatesEstado desconocido
Montefiore Medical Center - Moses CampusThe Bronx, New York, United StatesEstado desconocido
Wake Forest University at ClemmonsClemmons, North Carolina, United StatesEstado desconocido
Wake Forest University Health SciencesWinston-Salem, North Carolina, United StatesEstado desconocido
UT Southwestern/Simmons Cancer Center-DallasDallas, Texas, United StatesEstado desconocido
Equipo y fechas
- Patrocinador principal
- National Cancer Institute (NCI)
- Inicio del estudio
- 27 jul 2022 Real
- Finalización primaria
- 11 feb 2026 Real
- Finalización del estudio
- 21 abr 2026 Real
- Primera publicación
- 29 abr 2022 Real
- Última actualización
- 10 nov 2026 Real
Contactos oficiales del estudio
No hay un contacto central indicado. Revisa los centros y el registro oficial.
Título oficial del estudio
Phase I Dose Escalation and Expansion Study of Tazemetostat in Combination With Topotecan and Pembrolizumab in Recurrent Small Cell Lung Cancer
Consulta a Wellness Clinical Research
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Fuente: API v2 de ClinicalTrials.gov. Patrocinadores e investigadores envían la información. La NLM no aprueba la seguridad ni la ciencia de todos los estudios registrados. Aviso del registro.
Consultado: 11 nov 2026 · Última actualización del registro: 10 nov 2026