Clinical trial NCT06644768: A Study of Valemetostat Tosylate Plus Pembrolizumab Versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations
Official title: A Multicenter, Randomized, Open-Label, Phase 1b/2 Trial Of Valemetostat Tosylate Plus Pembrolizumab Vs Pembrolizumab Alone in Participants With Advanced or Metastatic Non-Small Cell Lung Cancer Whose Tumors Express PD-L1 With Tumor Proportion Score ≥50% Without Actionable Genomic Alterations
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Non-small Cell Lung Cancer
Lung Cancer
Keywords: NSCLC
Tumor
pembrolizumab
valemetostat tosylate
DS-3201b
Immune checkpoint inhibitor
Programmed Cell Death 1 Ligand 1
MK-3475
Lead sponsor: Daiichi Sankyo
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2024-10-16
Enrollment: 137
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: This is an open-label study.
Primary purpose: TREATMENT

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.

Eligibility criteria: Key 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.

Primary outcomes:
measure: Phase 1b: Number of Participants with Dose-Limiting Toxicities
timeFrame: 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
measure: Phase 1b: Number of Participants with Treatment-Emergent Adverse Events
timeFrame: From date of first dose to 30 days after last dose, up to approximately 31 months
measure: Phase 2: Progression-Free Survival by BICR
timeFrame: From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
Secondary outcomes:
measure: Phase 2: Objective Response Rate
timeFrame: From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
measure: Phase 2: Duration of Response
timeFrame: From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
measure: Phase 2: Disease Control Rate
timeFrame: From date of randomization up to approximately 31 months
measure: Phase 2: Overall Survival
timeFrame: From date of randomization the date of death from any cause, up to approximately 31 months
measure: Phase 2: Progression-Free Survival by Investigator
timeFrame: From date of randomization to the date of radiographic disease progression, or death from any cause, whichever occurs first, up to approximately 31 months
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: University of California San Diego (Ucsd)-Moores Cancer Center
state: California
city: Los Angeles
country: United States
facility: California Research Institute
state: California
city: Los Angeles
country: United States
facility: Valkyrie Clinical Trials
state: California
city: Jacksonville
country: United States
facility: Mayo Clinic Hospital
state: Florida
city: Lexington
country: United States
facility: University of Kentucky Medical Center,
state: Kentucky
city: Pikeville
country: United States
facility: Pikeville Medical Center
state: Kentucky
city: Rochester
country: United States
facility: Mayo Clinic - Rochester
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Philadelphia
country: United States
facility: Thomas Jefferson University, Sidney Kimmel Cancer Center
state: Pennsylvania
city: Reston
country: United States
facility: Virginia Cancer Specialist
state: Virginia
city: Buenos Aires
country: Argentina
facility: Instituto Alexander Fleming
city: Ciudad Autonoma Buenos Aires
country: Argentina
facility: Hospital Italiano de Buenos Aires
city: Cordoba
country: Argentina
facility: Sanatorio Allende
city: N Salvador De Jujuy
country: Argentina
facility: Fundacion Ars Medica
city: Pergamino
country: Argentina
facility: Centro de Investigacion Pergamino Sa
city: Rosario
country: Argentina
facility: Instituto Medico de La Fundacion Estudios Clinicos
city: Viedma
country: Argentina
facility: Clinica Viedma S.A.
city: Blumenau
country: Brazil
facility: Centro de Pesquisas Clinica Reichow
city: ItajaĂ-
country: Brazil
facility: Clínica de Neoplasias Litoral Ltda.
city: Manaus
country: Brazil
facility: Cinpam Centro Integrado de Pesquisa Da Amazonia
city: Natal
country: Brazil
facility: Liga Norte-Rio-Grandense Contra O Căncer
city: Porto Alegre
country: Brazil
facility: Hospital Nossa Senhora Da Conceição
city: Santo Andre
country: Brazil
facility: Cepho - Centro de Estudos E Pesquisas de Hematologia E Oncologia
city: Sao Jose Rio Preto
country: Brazil
facility: Fundacao Faculdade Regional de Medicina de Sao Jose Do Rio Preto
city: Changchun
country: China
facility: Jilin Province Tumor Hospital
city: Changchun
country: China
facility: The First Hospital of Jilin University
city: Chengdu
country: China
facility: Chengdu Shang Jin Nan Fu Hospital
city: Haerbin
country: China
facility: Harbin Medical University Cancer Hospital
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine
city: Shanghai
country: China
facility: Jiamusi Cancer Hospital
city: Shanghai
country: China
facility: Shanghai East Hospital
city: Shenyang City
country: China
facility: The First Hospital of China Medical University
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute & Hospital
city: Zhengzhou
country: China
facility: Henan Cancer Hospital
city: Fukuoka
country: Japan
facility: Kyushu University Hospital
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East
city: Seoul
country: Korea, Republic of
facility: Severance Hospital, Yonsei University Health System
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea, St. Vincent'S Hospital
Study officials:
References: