A Study of Valemetostat Tosylate Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations

Phase 1

Recruiting

• Conditions: Non-small Cell Lung Cancer; Lung Cancer
• Interventions: Drug: valemetostat tosylate; Drug: pembrolizumab

• Registration Number: NCT06644768
• Lead Sponsor: Daiichi Sankyo

Brief Summary

This study will compare Valemetostat Tosylate Plus Pembrolizumab vs Pembrolizumab Alone in First-line NSCLC Without Actionable Genomic Alterations

Detailed Description

This trial will evaluate the safety and efficacy of valemetostat tosylate (DS-3201b) in combination with fixed-dose pembrolizumab versus pembrolizumab alone in participants with advanced or metastatic NSCLC without actionable genomic alterations, whose tumor has PD-L1 TPS ≥50%, and who have not received prior systemic therapy for advanced or metastatic NSCLC. The trial will be in 2 phases, dose escalation and dose expansion phases.

Study Timeline

• Study First Submitted: 2024-10-01
• Study First Submitted QC: 2024-10-14
• Study First Posted: 2024-10-16
• Study Start: 2024-10-30
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-12
• Last Update Posted: 2024-11-14
• Primary Completion: 2028-03-30
• Study Completion: 2030-04-30

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 137

Inclusion Criteria

1. Has signed and dated the ICF, prior to the start of any trial-specific qualification procedures.

2. Is an adult ≥18 years of age or the minimum legal age (whichever is greater) at the time of informed consent. (Follow local regulatory requirements if the legal age of adult voluntary consent for trial participation is >18 years old).

3. Has histologically documented NSCLC that meets all of the following criteria:

   1. Has no prior systemic therapy for advanced or metastatic disease.

   2. Has Stage IIIB or IIIC disease and is not a candidate for surgical resection or definitive chemoradiation, or Stage IV NSCLC disease at the time of enrollment/randomization (based on the American Joint Committee on Cancer, Eighth Edition). Participants with early-stage NSCLC who have relapsed should be restaged during Screening to ensure their eligibility for the trial.

   3. Has documented negative test results for EGFR, ALK, and ROS1 actionable genomic alterations based on analysis of tumor tissue. If test results for EGFR, ALK, and ROS1 are not available, participants are required to undergo testing performed locally for these genomic alterations.

      Participants with squamous NSCLC are only required to undergo EGFR, ALK, and ROS1 testing if they have no history of tobacco smoking or were diagnosed with NSCLC at <40 years of age.

   4. Has no known actionable genomic alterations in NTRK, BRAF, RET, MET, or other actionable oncogenic drivers with locally approved therapies (testing for genomic alterations besides EGFR, ALK, and ROS1 is not required prior to enrollment/randomization). Participants whose tumors harbor KRAS mutations are eligible for the trial.

4. Has measurable disease on CT or MRI based on local imaging assessment using RECIST v1.1

5. Has a tumor expressing PD-L1 TPS ≥50% as determined by local testing using 22C3 pharmDx PD-L1 IHC assay. In regions where PD-L1 (TPS ≥50%) testing by 22C3 pharmDx is not considered SOC, PD-L1 expression levels will be determined by central testing (minimum of 6 slides).

6. Has provided a formalin-fixed tumor tissue sample for the assessment of biomarkers. This tissue requirement is in addition to the tissue required for PD-L1 testing for tissue screening purposes. If a documented law or regulation prohibits (or does not approve) sample collection, then such sample will not be collected.

7. Has an ECOG PS of 0 or 1 at Screening.

Key Exclusion Criteria

1. Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting:

   1. Any anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX40, or CD137).
   2. Has previously been treated with any enhancer of zeste homolog inhibitors.

2. Participants who received adjuvant or neoadjuvant therapy other than those listed in the exclusion criterion above are eligible if the adjuvant/neoadjuvant therapy was completed at least 6 months prior to the current diagnosis of advanced or metastatic disease.

3. Has received a live vaccine or live attenuated vaccine within 30 days prior to the first dose of trial intervention. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccines. Note: Administration of killed vaccines is allowed.

4. Has an active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of systemic disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.

   Inhaled, intranasal, intraocular, intra-articular, or topical steroids and adrenal replacement steroids are permitted in the absence of active autoimmune disease.

5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (at doses exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial intervention. Note: Short-course systemic corticosteroids (eg, prevention of/treatment for transfusion reaction) or steroid use for a noncancer indication (eg, adrenal replacement) is permissible.

6. Has a known active or untreated CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate, provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note: repeat imaging should be performed during trial screening), clinically stable, and without requirement of steroid treatment for at least 14 days before the first dose of trial intervention. Note: A CT scan or MRI scan of the brain at Baseline is required for all participants. For participants in whom CNS metastases are first discovered at Screening, the treating investigator should delay trial intervention to complete any necessary treatment followed by a proper washout period and document the stability of CNS metastases with repeat imaging at least 4 weeks later (in which case repetition of all screening activities may be required).

7. Has uncontrolled or significant cardiovascular disease, including the following:

   1. Mean QT interval corrected for heart rate using Fridericia's formula >470 ms (based on the average of screening triplicate 12-lead ECG determinations)
   2. Myocardial infarction within 6 months prior to Screening
   3. Uncontrolled angina pectoris within 6 months prior to Screening
   4. New York Heart Association Class 3 or 4 congestive heart failure
   5. Uncontrolled hypertension (resting systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg)

8. Has a history of (noninfectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at Screening.

9. Has a history of radiation pneumonitis.

10. Has had an allogenic tissue/solid organ transplant.

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 2: Pembrolizumab + Valemetostat Tosylate	valemetostat tosylate	Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W, and valemetostat will be provided per recommended phase 2 dose (RP2D)
Phase 1b: Pembrolizumab + Valemetostat Tosylate	valemetostat tosylate	Participants will be provided with pembrolizumab at standard dose of 200 mg intravenously (IV) Q3W, and valemetostat will be provided per a dose escalation schedule, with an initial starting dose of 150 mg by mouth once daily.
Phase 1b: Pembrolizumab + Valemetostat Tosylate	pembrolizumab	Participants will be provided with pembrolizumab at standard dose of 200 mg intravenously (IV) Q3W, and valemetostat will be provided per a dose escalation schedule, with an initial starting dose of 150 mg by mouth once daily.
Phase 2: Pembrolizumab + Valemetostat Tosylate	pembrolizumab	Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W, and valemetostat will be provided per recommended phase 2 dose (RP2D)
Phase 2: Pembrolizumab	pembrolizumab	Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W

Primary Outcome Measures

Name	Time	Method
Phase 1b: Number of Participants with Dose-Limiting Toxicities	From day of first dose on Day 1 to Day 21 in Cycle 1 (21 days), or before the administration of Cycle 2, up to 24 days	Total number of participants with A Dose-Limiting Toxicity (DLT) at each dose level of valemetostat in combination with pembrolizumab per National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0.
Phase 1b: Number of Participants with Treatment-Emergent Adverse Events	From date of first dose to 30 days after last dose, up to approximately 31 months	Incidence of TEAEs, Grade 3 or 4 TEAEs, deaths, TESAEs, TEAEs leading to dose modifications (including interruption, reduction, and discontinuation), and AESIs using the National Cancer Institute - Common Terminology Criteria for Adverse Events version 5.0
Phase 2: Progression-Free Survival by BICR	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months	PFS is the time from the date of randomization to the date of radiographic disease progression as assessed by blinded independent central review (BICR) per RECIST v1.1 or death from any cause, whichever occurs first.

Secondary Outcome Measures

Name	Time	Method
Phase 2: Objective Response Rate	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months	Objective Response Rate (ORR) is the proportion of participants with a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) assessed by BICR.
Phase 2: Duration of Response	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months	Duration of Response (DoR) is the time from the date of first documentation of objective tumor response (CR or PR) that is subsequently confirmed to the date of the first documentation of objective tumor progression or to death from any cause, whichever occurs first, assessed by BICR.
Phase 2: Disease Control Rate	From date of randomization up to approximately 31 months	Disease control rate (DCR) is the proportion of participants who achieved a BOR of confirmed CR, confirmed PR, or stable disease (SD), assessed by BICR.
Phase 2: Overall Survival	From date of randomization the date of death from any cause, up to approximately 31 months	Overall Survival (OS ) is the time from the date of randomization to the date of death from any cause.
Phase 2: Progression-Free Survival by Investigator	From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months	PFS is the time from the date of randomization to the date of radiographic disease progression as assessed by the investigator per RECIST v1.1 or death from any cause, whichever occurs first.

Trial Locations

Locations (41)

University of California San Diego (Ucsd)-Moores Cancer Center; 🇺🇸 La Jolla, California, United States

California Research Institute; 🇺🇸 Los Angeles, California, United States

Valkyrie Clinical Trials; 🇺🇸 Los Angeles, California, United States

Mayo Clinic Hospital; 🇺🇸 Jacksonville, Florida, United States

University of Kentucky Medical Center,; 🇺🇸 Lexington, Kentucky, United States

Pikeville Medical Center; 🇺🇸 Pikeville, Kentucky, United States

Mayo Clinic - Rochester; 🇺🇸 Rochester, Minnesota, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States

Columbia University Irving Medical Center; 🇺🇸 New York, New York, United States

Thomas Jefferson University, Sidney Kimmel Cancer Center; 🇺🇸 Philadelphia, Pennsylvania, United States

Virginia Cancer Specialist; 🇺🇸 Reston, Virginia, United States

Instituto Alexander Fleming; 🇦🇷 Buenos Aires, Argentina

Hospital Italiano de Buenos Aires; 🇦🇷 Ciudad Autonoma Buenos Aires, Argentina

Sanatorio Allende; 🇦🇷 Cordoba, Argentina

Fundacion Ars Medica; 🇦🇷 N Salvador De Jujuy, Argentina

Centro de Investigacion Pergamino Sa; 🇦🇷 Pergamino, Argentina

Instituto Medico de La Fundacion Estudios Clinicos; 🇦🇷 Rosario, Argentina

Clinica Viedma S.A.; 🇦🇷 Viedma, Argentina

Centro de Pesquisas Clinica Reichow; 🇧🇷 Blumenau, Brazil

Clínica de Neoplasias Litoral Ltda.; 🇧🇷 ItajaĂ-, Brazil

Cinpam Centro Integrado de Pesquisa Da Amazonia; 🇧🇷 Manaus, Brazil

Liga Norte-Rio-Grandense Contra O Căncer; 🇧🇷 Natal, Brazil

Hospital Nossa Senhora Da Conceição; 🇧🇷 Porto Alegre, Brazil

Cepho - Centro de Estudos E Pesquisas de Hematologia E Oncologia; 🇧🇷 Santo Andre, Brazil

Fundacao Faculdade Regional de Medicina de Sao Jose Do Rio Preto; 🇧🇷 Sao Jose Rio Preto, Brazil

Jilin Province Tumor Hospital; 🇨🇳 Changchun, China

The First Hospital of Jilin University; 🇨🇳 Changchun, China

Chengdu Shang Jin Nan Fu Hospital; 🇨🇳 Chengdu, China

Harbin Medical University Cancer Hospital; 🇨🇳 Haerbin, China

Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine; 🇨🇳 Hangzhou, China

Jiamusi Cancer Hospital; 🇨🇳 Shanghai, China

Shanghai East Hospital; 🇨🇳 Shanghai, China

The First Hospital of China Medical University; 🇨🇳 Shenyang City, China

Tianjin Medical University Cancer Institute & Hospital; 🇨🇳 Tianjin, China

Henan Cancer Hospital; 🇨🇳 Zhengzhou, China

Kyushu University Hospital; 🇯🇵 Fukuoka, Japan

National Cancer Center Hospital East; 🇯🇵 Kashiwa, Japan

Severance Hospital, Yonsei University Health System; 🇰🇷 Seoul, Korea, Republic of

Samsung Medical Center; 🇰🇷 Seoul, Korea, Republic of

Seoul National University Hospital; 🇰🇷 Seoul, Korea, Republic of

The Catholic University of Korea, St. Vincent'S Hospital; 🇰🇷 Suwon-si, Korea, Republic of