Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Pembrolizumab

Immunomodulating Agents

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Enrolled patients will receive combination treatment for whole study duration (2 years). For first cycle, patient will start tazemetostat one week prior to start every 3 week pembrolizumab intravenous infusion (pembrolizumab will be given day 8 only for the first cycle, rest of cycles will be day 1 of each cycle).

combination of oral tazemetostat and intravenous pembrolizumab treatment for patients with advanced non-small cell lung cancer

Tazemetostat

Daniel S Shin, MD PhD

Samantha M Tran

This is an open label, single arm, phase Ib/II clinical trial of checkpoint blockade, pembrolizumab and EZH2 inhibitor, tazemetostat combination therapy for patients with advanced non-small cell lung cancer who have progressed from front or second-line treatment. Patients will be enrolled at multiple Veterans Affairs Medical Centers.

It is pleasing to witness the fulfillment of the promise of cancer immunotherapy becoming a reality for patients with many types of advanced cancer. However, even with this remarkable progress, majority of patients are not responding and substantial number of patients are progressing after initial response to checkpoint blockade immunotherapy. The field is undertaking major task to identify suitable combinatorial approach to improve the efficacy of checkpoint blockade immunotherapy and biomarker for better patient selection. Evidence suggests that EZH2 (Enhancer Zeste Homolog: enzymatic component of Polycomb Repressive Complex 2) plays a significant role in prognosis of patients with non-small cell lung cancer and animal studies showed that EZH2 targeting can improve the efficacy of immunotherapy.

Based on this, it was hypothesized that EZH2 inhibitor, tazemetostat can re-sensitive cancer cells to respond to PD-1 blockade, pembrolizumab and designed phase Ib/II single arm, open label study to test this hypothesis for patients with advanced non-small cell lung cancer who progressed from front or second line of therapy (expecting majority of patients experienced checkpoint blockade immunotherapy). The primary objectives of this study are safety/tolerability and Objective Response Rate (ORR: Complete Response and Partial Response) evaluated by RECIST v1.1. Key secondary objectives are disease control rate, progression free survival at 1 year, and duration of response. The study will employ safety lead-in phase Ib using 3+3 standard dose escalation scheme with 3 dose levels for tazemetostat, starting 400, up to 600 and 800 mg orally twice daily. Tazemtostat will be administered for 7 days prior to pembrolizumab 200 mg intravenous every 3 weeks that is defined as run-in phase (only prior to first cycle). It is estimated that 6 to 18 patients will be enrolled to determined recommended dose for phase II (RP2D). The sample size for phase II was calculated using Simon optimum two-stage design in order to determine the futility at early time. In the first stage, 15 subjects will be enrolled. If 2 or more responses are observed, an additional 39 subjects will be accrued during second phase. If in total there are 8 or more responses, we will consider the drug combination worthy of further clinical development, provided other factors such as toxicity and progression-free survival also appear favorable. For this phase II portion, up to 54 subjects are enrolled. This design has a one-sided alpha of 5% and a power of 80%. Planned duration of enrollment is 2 years, correlative studies (methyl marker: H3K27me3 and PD-L1, exome, RNA, circulating ctDNA sequencing and immune monitoring) are proposed using tumor biopsies (on treatment biopsy is optional) and blood samples before and after the treatment.

Phase IB: Determine RP2D of tazemetostat by using 3+3 standard dose escalation model with 3 dose levels, 400, 600 and 800 mg twice daily in combination of standard pembrolizumab 200 mg IV every 3 weeks. Tazemetostat 800 mg twice daily is current approved dose for advanced sarcoma or follicular lymphoma.

Phase II: Based on Simon Optimum two stage design, our total number of patients for phase II is 54 patients (patients treated with RP2D from phase IB will be included in the analysis). We will enroll 15 patients at first stage to determine futility of the trial and complete the remaining 39 patients during stage II.

EZH2 Inhibitor, Tazemetostat, and PD-1 Blockade for Treatment of Advanced Non-small Cell Lung Cancer

Phase Ib/II Study of Safety and Efficacy of EZH2 Inhibitor, Tazemetostat, and PD-1 Blockade for Treatment of Advanced Non-small Cell Lung Cancer

Safety and tolerability assessed by CTCAE v5.0

DCR (complete response, partial response and stable disease) assessed by RECIST v1.1

PFS assessed by Kaplan Meyer survival analysis.

VA Greater Los Angeles Healthcare System

VA Office of Research and Development

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

B-cell Lymphoma

Other Dietary Supplements

(R)-N-((4-methoxy-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-1-(1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)ethyl)-1H-indole-3-carboxamide

Enzyme Inhibitors

Indole

Small molecule inhibitor of the enzyme EZH2

CPI-1205

First in human, open-label, sequential dose escalation and expansion study of CPI-1205 in patients with progressive B-cell lymphomas. CPI-1205 is a small molecule inhibitor of EZH2.

A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas

A Phase 1 Study of CPI-1205, a Small Molecule Inhibitor of EZH2, in Patients With B-Cell Lymphomas

Frequency of dose-limiting toxicities (DLTs) associated with CPI-1205 administration during the first cycle (first 28 days) of treatment

Safety and tolerability of CPI-1205 as assessed by: frequency of adverse events and serious adverse events; changes in hematology and clinical chemistry values; changes in physical examination, vital signs, electrocardiogram, and ECOG score

Constellation Pharmaceuticals

Lymphoma, T-Cell

Lymphoma, T-Cell, Peripheral

Peripheral T-cell Lymphoma

Dose Escalation: Level 1 (Starting Dose) Oral AXT-1003 100 mg BID; Level 2 Oral AXT-1003 200mg BID; Level 3 Oral AXT-1003 300mg BID ; Level 4 Oral AXT-1003 450mg BID; Level 5 Oral AXT-1003 600mg BID; Level 6 Oral AXT-1003 750mg BID

Dose Expansion: 1 or 2 cohorts at the dose levels selected from dose escalation part

AXT-1003 capsule is administered orally daily, until disease progression or intolerable toxicity.

AXT-1003

Yong Yuan

Yanfang Guo

This is an open-label, multicenter, phase I study of AXT-1003 to assess the safety, tolerability, and pharmacokinetics in adult subjects with Relapsed/Refractory Non-Hodgkin Lymphomas.

The study is being conducted to assess the safety, tolerability, and pharmacokinetics (PK) of AXT-1003 in subjects with relapsed/refractory non-Hodgkin lymphomas (R/R NHL) and relapsed/refractory peripheral T-cell lymphoma (R/R PTCL), a subtype of R/R NHL.

Study of AXT-1003 in Adult Subjects With Relapsed/Refractory Non-Hodgkin Lymphomas

An Open-Label, Multicenter, Phase I Study of AXT-1003 as a Single Agent in Adult Subjects With Relapsed/Refractory Non-Hodgkin Lymphomas

Dose Escalation only: to characterize the dose limiting toxicities (DLTs) of AXT-1003.

An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Participants with multiple occurrences of an AE within a category were counted once within the category. Relatedness to study drug was assessed by the investigator.

Laboratory parameters included: hematology, blood chemistry, urinalysis and coagulation. Clinical significance of laboratory parameters was determined at the investigator's discretion.

ORR is defined as the proportion of subjects with a CR or PR.

DOR is defined as the time from the initial objective response to progression of disease (PD) or death after the response, whichever occurs first.

Progression-free survival is defined as the time from the first dose of study treatment to the first PD or death for any reason in the absence of documented PD, whichever occurs first

Time to response is defined as the time from first dose of study treatment to the first objective tumor response.

Disease control rate is defined as the proportion of subjects with a CR, PR, or stable disease(SD).

Axter Therapeutics (Beijing) Co., Ltd

Amino Acids

Lysine

Part I：treated with escalated doses of EZH2 inhibitor SHR2554 respectively； Part II：treated with fixed dose (RP2D) SHR2554 respectively

SHR2554 is a selective small molecule inhibitor of the histone-lysine methyltransferase EZH2.

SHR2554

Weiwei Wang, MD

Jun Zhu, MD

Lin Shen, M.D

This is a Phase 1 multicenter, single-arm, open-label, dose escalation and dose expansion study of enhancer of zeste homolog 2 (EZH2 ) inhibitor SHR2554.

This study will assess the tolerability, safety, pharmacokinetics, and preliminary anti-tumor activity of SHR2554 in participants with relapsed or refractory mature lymphoid neoplasms in part I, and the the efficacy in PTCL patients will be studied in Part II.

A Phase 1 Study of SHR2554 in Subjects With Relapsed or Refractory Mature Lymphoid Neoplasms

A Phase 1 Study to Characterize Safety, Tolerance, Pharmacokinetics and Efficacy of SHR2554 in Subjects With Relapsed or Refractory Mature Lymphoid Neoplasms

Analyze the level of H3K27me3 in the peripheral blood mononuclear cells of the subjects before and after the treatment of escalated doses of SHR2554.

Assess the known mutation of EZH2 gene in tumor cells or tissues, analyze the relationship between efficacy and EZH2 mutation

Assess EZH2 expression level in tumor tissues, analyze the relationship between efficacy and EZH2 expression level

The incidence and severity of treatment-emergent AEs will be collected and the safety and tolerability of SHR2554 will be assessed.

Recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD) will be established according to the incidence of dose-limiting toxicities (DLTs) of escalated doses of SHR2554.

assessed by independent radiology review committee (IRC)

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): Time to peak (Tmax) of plasma concentration

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): Maximum plasma concentration (Cmax)

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): Halflife (T1/2)

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): Clearance/ bioavailability (CL/F)

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): apparent volume of distribution/bioavailability (Vd/F)

Pharmacokinetics profile of a single dose SHR2554 and its metabolite (plasma): Area under curve (AUC)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Area under curve, steady state (AUCss)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Maximum plasma concentration, steady state (Cmax,ss)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Time to peak, steady state (Tmax,ss)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Halflife (T1/2)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Apparent volume of distribution, steady state/bioavailability (Vss/F)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Clearance/ bioavailability (CL/F)

Pharmacokinetics profile of continuous medication of SHR2554 and its metabolite (plasma): Accumulation index (Rac)

Assess the response rate of subjects to the treatment of SHR2554

Assess the survival condition of the subjects after the treatment of SHR2554

Assess the duration of complete/partial response after the treatment of SHR2554

Assess the time to initial response of subjects to the treatment of SHR2554

Assess the overall survival of subjects treated by SHR2554

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
EZH2 Inhibitor, Tazemetostat, and PD-1 Blockade for Treatment of Advanced Non-small Cell Lung Cancer	NCT05467748	Non Small Cell ...	Tazemetostat	18 Years -	VA Office of Research and Development
A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas	NCT02395601	B-Cell Lymphoma	CPI-1205	18 Years -	Constellation Pharmaceuticals
A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas	NCT02395601	B-Cell Lymphoma	CPI-1205	18 Years -	Constellation Pharmaceuticals
A Study Evaluating CPI-1205 in Patients With B-Cell Lymphomas	NCT02395601	B-Cell Lymphoma	CPI-1205	18 Years -	Constellation Pharmaceuticals
Study of AXT-1003 in Adult Subjects With Relapsed/Refractory Non-Hodgkin Lymphomas	NCT05965505	Relapsed or Ref...	AXT-1003	18 Years -	Axter Therapeutics (Beijing) Co., Ltd
A Phase 1 Study of SHR2554 in Subjects With Relapsed or Refractory Mature Lymphoid Neoplasms	NCT03603951	Relapsed or Ref...	SHR2554	18 Years - 70 Years	Jiangsu HengRui Medicine Co., Ltd.

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