IRB Study Number 25-1020
Status Recruiting
Phases Phase 2, Phase 3
Locations Fairview Family Medicine, Hillcrest Hospital, Cleveland Clinic Main Campus
Institute Taussig Cancer Institute
Description
Phase 2 Dose Selection
To evaluate PFS of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate OR of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate disease control of BMS- 986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate TTOR of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate DOR of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
Phase 3
To compare PFS of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To compare OS of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate OR of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate disease control of BMS- 986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate DOR of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate investigator-assessed PFS of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants with mNSCLC with homozygous MTAP deletion
To evaluate investigator-assessed PFS2 of BMS-986504 + pembrolizumab + chemotherapy vs placebo + pembrolizumab + chemotherapy in previously untreated participants withmNSCLC with homozygous MTAP deletion
Inclusion Criteria
Participants must have signed and dated an IRB/IEC-approved written ICF in accordance with regulatory, local, and institutional guidelines. This ICF must be obtained before performing any protocol-related procedures that are not part of normal patient care.
Note: Participants must agree to comply with the requirements and restrictions listed in the ICF and in this protocol.Metastatic (Stage IV or recurrent) NSCLC (as defined by the American Joint Committee on Cancer, Ninth Edition) with no prior systemic anti-cancer therapy for metastatic disease. Note: Prior systemic chemo-immunotherapy (neoadjuvant, adjuvant, or peri-operative) or chemoradiation for locally advanced or unresectable disease is allowed if the last dose of prior systemic treatment was at least 6 months prior to enrollment. Participants with locally advanced disease with recurrence after chemoradiation therapy (Stage III disease specifically refers to patients with no curative options) are eligible to enroll.
Histologically confirmed diagnosis of NSCLC and homozygous MTAP deletion or MTAP loss detected in tumor tissue using a Sponsor-provided central test or a Sponsor pre-approved local test. Tumor tissue (fresh or archival if obtained within 6 months prior to signing the prescreening informed consent) must be submitted by the site. Intervening systemic treatment or radiation to the site of tissue is not allowed, and one of the following must be submitted:
• A FFPE tissue block OR
• Unstained slides cut within 6 months from a FFPE tumor tissue block.
Note: FFPE tissue blocks are preferred for submission. Participants are required to provide a minimum of 15 slides (25 slides are recommended) for Sponsor-provided central testing, retrospective testing, and additional CDx-related testing. The FFPE block must contain sufficient tissue to support the minimum number of slides. If the desired number of slides cannot be met, participants may still be eligible to enroll upon approval from the Medical Monitor (or designee). Tumor biopsies conferring significant risk should not be performed for the purpose of determining eligibility. Please see Laboratory Manual for additional information.
Note: For participants who will receive one cycle of optional SoC treatment prior to randomization, tumor tissue must be obtained prior to the start of therapy.Any PD-L1 expression (0 to 100%) as determined by the Sponsor pre-approved local PD-L1 IHC assays (VENTANA PD-L1 [SP263] assay, Agilent PD-L1 IHC 22C3 pharmDx, or Agilent PD-L1 IHC 28-8 pharmDx), from tissue collected within 6 months prior to signing the pre-screening informed consent, performed in accordance with the intended use of the assays. If, despite best efforts, a quantifiable result is not possible, non-evaluable or non-quantifiable results may be acceptable upon Medical Monitor (or designee) approval for a maximum of 10% of total participants. Testing must comply with local diagnostic regulations, and documentation of which PD-L1 test used must be provided.
At least 1 measurable lesion as per RECIST v1.1.
Prior palliative radiotherapy to non-CNS lesions must have been completed at least 1 week prior to randomization. Participants with symptomatic tumor lesions at baseline that may require palliative radiotherapy are strongly encouraged to receive palliative radiotherapy prior to randomization.
For participants who receive one cycle of SoC prior to randomization, TRAEs associated with this first cycle of SoC must resolve to Grade ≤ 1 or baseline prior to randomization, except those with alopecia, Grade 2 fatigue, or endocrine-related AEs requiring treatment or hormone replacement.
ECOG performance status of 0-1 (see APPENDIX 7).
Adequate organ function, as determined by laboratory testing within the screening period:
• ANC ≥ 1500/mm3 (≥ 1.5 × 109/L)
• Platelet count ≥ 100,000/mm3 (≥ 100 × 109/L; platelet transfusions are not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
• Hemoglobin ≥ 9 g/dL (receipt of packed red blood cells is not allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
• INR or PT ≤ 1.5× ULN; if receiving anticoagulant therapy, PT or aPTT should be within therapeutic range.
• Total bilirubin < 1.5× ULN (if associated with liver metastases or Gilbert’s disease, < 3× ULN)
• AST and ALT < 3× ULN (if associated with liver metastases, < 5× ULN)
• CrCl ≥ 60 mL/min calculated using a validated prediction equation (eg, Cockcroft-Gault, 24-hour urine CrCl, or per local standard).Aged ≥ 18 years (or the legal age of consent in the jurisdiction in which the study is taking place) at the time of signing the ICF.
Note: The investigator or designee shall counsel IOCBP participants (as defined in APPENDIX 3) and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
Note: The investigator or designee shall evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
Note: Local laws and regulations may require the use of alternative and/or additional contraceptive methods.Female (as assigned at birth) participants:
Note: Female (as assigned at birth) participants who are not of childbearing potential (as defined in APPENDIX 3) must have documented proof.
Note: Documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.
Note: Individuals who are not of childbearing potential are exempt from contraceptive requirements.
• IOCBP must have a negative highly sensitive urine or serum (as required by local regulation) pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study intervention.
Note: If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive.
Note: The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy.
• IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception as described below and included in the ICF.
i. IOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception and must use an additional non-hormonal highly effective method of contraception (as described in APPENDIX 3).
• A female (as assigned at birth) is eligible to participate if they are not pregnant or breastfeeding and at least 1 of the following conditions applies:
i. Is not an IOCBP OR
ii. Is an IOCBP using a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal method alone that is highly effective (with a failure rate of < 1% per year), as described in APPENDIX 3, during the intervention period and for at least 7 months after the last dose of study intervention, or according to approved local product label requirements for individual immunotherapy and chemotherapy agents, whichever is longer. IOCBP participants must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period.Male (as assigned at birth) participants:
Note: Azoospermic males are not exempt from contraceptive requirements and will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant.
• Male (as assigned at birth) participants will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding. Male (as assigned at birth) participants should continue to use a condom during the intervention period and for at least 6 months after the last dose of study intervention, or according to approved local product label requirements for individual immunotherapy and chemotherapy agents, whichever is longer.
• IOCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the intervention period and for at least 6 months after the last dose of study intervention, or according to approved local product label requirements for individual immunotherapy and chemotherapy agents, whichever is longer, for the male participant.
• Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral), even if the participant has undergone a successful vasectomy, during the intervention period and for at least 6 months after the last dose of study intervention or according to approved local product label requirements for individual immunotherapy and chemotherapy agents, whichever is longer.
• Male (as assigned at birth) participants must refrain from donating sperm during the intervention period and for at least 6 months after the last dose of study intervention, or according to approved local product label requirements for individual immunotherapy and chemotherapy agents, whichever is longer.
• Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms.
Exclusion Criteria
Participants with nonsquamous histology with documented targetable oncogenic mutations or AGAs for which there is a SoC available as 1L therapy (ie, EGFR, ALK, ROS1).
Note: Participants with unknown AGA status of NTRK, BRAF, MET exon 14 skipping, RET, or those without access to the approved targeted inhibitor therapies of these AGAs as 1L therapy may be enrolled.Symptomatic brain metastases or spinal cord compression.
Note: Participants are eligible if CNS metastases have been definitively treated and are clinically stable (except for residual effects from treatment). Participants must have discontinued corticosteroids or be on a stable/decreasing dose of 10 mg or less of prednisone (or equivalent) daily for at least 2 weeks before initiating treatment. Baseline imaging required at screening must be performed at least 14 days after definitive treatment for CNS metastases is completed. CNS metastases must be radiographically stable.Leptomeningeal disease.
Active autoimmune disease that required systemic treatment in the past 2 years (ie, use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days prior to randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
History of interstitial lung disease, slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis (including non-infectious pneumonitis that required steroids), or multiple allergies.
Known or suspected impairment of gastrointestinal function that may prohibit the ability to absorb or swallow an oral medication without chewing or crushing.
Participants who have received one cycle of SoC during pre-screening and have experienced TRAEs that led to permanent drug discontinuation per the product labels of α-PD-(L)1 monoclonal antibodies (including pembrolizumab), pemetrexed, carboplatin, paclitaxel or nabpaclitaxel.
Is unable or unwilling to take folic acid or vitamin B12 supplementation.
Prior organ allograft.
Any major surgery within 3 weeks prior to randomization. Participants must have recovered from the effects of major surgery or significant traumatic injury prior to randomization.
Concurrent malignancy (present during screening) requiring treatment, or history of prior malignancy active within 2 years prior to randomization.
• Participants with a history of prior malignancy are eligible if treatment was completed at least 2 years prior to randomization and participant has no evidence of disease.
• Participants with a history of prior early stage basal/squamous cell skin cancer or noninvasive or in situ cancers that have undergone definitive treatment at any time are also eligible.
• Participants with a history of prostate cancer that is controlled and presents with a very low or low Gleason score are also eligible.Cardiac abnormalities including:
• LVEF < 50%
• QTcF prolongation > 480 msec, except for right bundle branch block, per the Investigator’s assessment.
• Uncontrolled/symptomatic or significant cardiovascular conditions within 6 months prior to randomization, including, but not limited to, any of the following: cardiac angioplasty or stenting, unstable angina pectoris, myocardial infarction, stroke/transient ischemic attack, coronary artery bypass graft surgery, symptomatic peripheral vascular disease, New York Heart Association class III-IV congestive heart failure, pericarditis, myocarditis, atrial fibrillation, or other arrhythmias (eg, ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).Ongoing need for a medication with a known risk of Torsades de Pointes that cannot be switched to alternative treatment prior to study entry.
Active viral hepatitis, including the following:
• Any positive test result for HBV indicating presence of virus (eg, HBV DNA-positive). Participants who are anti-HBsAg positive in line with prior vaccination or resolved infection are eligible to enroll.
• Any positive test result for HCV indicating presence of active viral replication (detectable HCV-RNA). Participants with positive HCV antibody and an undetectable HCV RNA are eligible to enroll.
Note: See APPENDIX 4 for country-specific requirements/differences.Known HIV-positive status with an AIDS-defining opportunistic infection within the last year, or a current CD4 count < 350 cells/μL. Participants with HIV are eligible if they have received established ART for at least 4 weeks prior to randomization and continue on ART as clinically indicated while enrolled on study. Viral serology only to be conducted if locally mandated and, if done, must be performed within 28 days prior to randomization.
Evidence of active infection that requires systemic antibacterial, antiviral, or antifungal therapy ≤ 7 days prior to randomization.
Any other medical condition not previously listed that may impair ability to participate in the study as per the investigator’s assessment.
Inability to comply with restrictions and prohibited treatments as listed in Section 7.7: Concomitant Therapy.
Prior systemic therapy (chemotherapy, immunotherapy, targeted therapy, or biological therapy) for mNSCLC.
Note: One cycle of SoC treatment prior to randomization will be allowed for participants who require immediate treatment if clinically indicated.Prior treatment with a PRMT5 or MAT2A inhibitor.
Live/attenuated vaccine received within 30 days prior to randomization. The use of inactivated seasonal influenza vaccines (eg, Fluzone®) will be permitted on study without restriction.
Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended to treat the disease under study received within 4 weeks prior to randomization. The concurrent use of any botanical preparation is not permitted while on study.
Any investigational agent or device treatment within 4 weeks prior to randomization.
Ongoing need for a medication known as a strong inhibitor or strong inducer of CYP3A4 and/or P-gp or a PPI that cannot be switched to an alternative treatment prior to randomization. The following drug interaction databases and other literature can be utilized to determine the CYP3A4/P-gp inhibitors and inducers. Examples of CYP3A4/P-gp inhibitors and inducers are also provided in APPENDIX 8.
• https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-druginteractions-table-substrates-inhibitors-and-inducers
• https://drug-interactions.medicine.iu.edu/MainTable.aspx.
Note: Please consult with the Sponsor Medical Monitor for any uncertainties regarding potential CYP3A4 and P-gp modulators.History of severe hypersensitivity to study drug(s) and/or any of its excipients.
Prisoners or participants who are involuntarily incarcerated. (Note: Under certain specific circumstances and only in countries where local regulations permit, a person who has been imprisoned while on study may be permitted to continue as a participant. Strict conditions apply).
Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
