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
A Study of Valemetostat Tosylate Plus Pembrolizumab versus Pembrolizumab Alone in First-Line NSCLC Without Actionable Genomic Alterations
Inoguchi Akihiro
Daiichi Sankyo Co., Ltd.
1-2-58, Hiromachi, Shinagawa-ku, Tokyo
+81-3-6225-1111
dsclinicaltrial_jp@daiichisankyo.com
Contact for Clinical Trial Information
Daiichi Sankyo Co., Ltd.
1-2-58, Hiromachi, Shinagawa-ku, Tokyo
+81-3-6225-1111
dsclinicaltrial_jp@daiichisankyo.com
Pending
Feb. 01, 2025
137
Interventional
randomized controlled trial
open(masking not used)
active control
parallel assignment
treatment purpose
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:
- Has no prior systemic therapy for advanced or metastatic disease.
- 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.
- 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.
- 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.
1. Has received prior treatment with any of the following, including in the adjuvant/neoadjuvant setting:
- 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).
- 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-Guerin, 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:
- Mean QT interval corrected for heart rate using Fridericia's formula >470 ms (based on the average of screening triplicate 12-lead ECG determinations)
- Myocardial infarction within 6 months prior to Screening
- Uncontrolled angina pectoris within 6 months prior to Screening
- New York Heart Association Class 3 or 4 congestive heart failure
- 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.
18age old over
No limit
Both
Advanced or Metastatic Non-Small Cell Lung Cancer
Experimental: Phase 1b: Pembrolizumab + 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.
Drug: valemetostat tosylate
Valemetostat will be administered orally once daily until RP2D of valemetostat is determined.
Drug: pembrolizumab
One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.
Experimental: Phase 2: Pembrolizumab + 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)
Drug: valemetostat tosylate
Valemetostat will be administered orally once daily until RP2D of valemetostat is determined.
Drug: pembrolizumab
One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.
Active Comparator: Phase 2: Pembrolizumab
Participants will be provided with pembrolizumab at standard dose of 200 mg IV Q3W
Drug: pembrolizumab
One IV infusion Q3W on D1 of each 21-day cycle for a maximum of 35 cycles.
Phase 1b: Number of Participants with Dose-Limiting Toxicities [Time Frame: 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 [Time Frame: 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 [Time Frame: 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.
Phase 2: Objective Response Rate [Time Frame: 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 [Time Frame: 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 [Time Frame: 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 [Time Frame: 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 [Time Frame: 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.
Daiichi Sankyo Co., Ltd.
TBD
TBD, Tokyo
Not approval
Yes
De-identified individual participant data (IPD) on completed studies and applicable supporting clinical trial documents may be available upon request at https://vivli.org/. In cases where clinical trial data and supporting documents are provided pursuant to our company policies and procedures, Daiichi Sankyo will continue to protect the privacy of our clinical trial participants. Details on data sharing criteria and the procedure for requesting access can be found at this web address: https://vivli.org/ourmember/daiichi-sankyo/
Supporting Information:
- Study Protocol
- Statistical Analysis Plan (SAP)
- Informed Consent Form (ICF)
Time Frame: Completed studies that has reached a global end or completion with all data set collected and analyzed, and for which the medicine and indication have received European Union (EU) and United States (US), and/or Japan (JP) marketing approval on or after 01 January 2014 or by the US or EU or JP Health Authorities when regulatory submissions in all regions are not planned and after the primary study results have been accepted for publication.
Access Criteria: Formal request from qualified scientific and medical researchers on IPD and clinical study documents on completed clinical trials supporting products submitted and licensed in the United States, the European Union and/or Japan from 01 January 2014 and beyond for the purpose of conducting legitimate research. This must be consistent with the principle of safeguarding study participants' privacy and consistent with provision of informed consent.
URL: https://vivli.org/ourmember/daiichi-sankyo/
