Condition médicale (spécialité visée)
Choix aire thérapeutique
Cancérologie / Radio-oncologie/ tumeurs solides
Stades de cancer
Récurrent
Avancé
Métastatique
Biomarqueur
Autre :
MSI-H
dMMR
Profil des participants
Sexe(s) des participants
Hommes
Femmes
Aptitude des participants
Majeurs aptes
Critères de sélection
Critères d'inclusion
[INC #1] Is at least 18 years of age at the time of signing the Pre-screening informed consent form (ICF).
[INC #2] Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the Pre-screening ICF and in this protocol.
[INC #3] Has a histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor.
[INC #4] Has an unknown MMR/MSI status at the time of Pre-screening. MMR/MSI status will be determined by central reference laboratory.
[INC #5] Provides an archival or fresh (preferred) FFPE sample. Cytological specimens such as fine needle aspirates or cell blocks are not acceptable. [INC #6] Intends to receive GSK5460025 as next treatment.
[INC #7] Is at least 18 years of age at the time of signing the Screening ICF.
[INC #8] Is capable of giving signed informed consent, including compliance with the requirements and restrictions listed in the study Main ICF and in this protocol.
[INC #9] Has an ECOG performance status of 0-2, with no deterioration in the 2 weeks before the first dose of study intervention.
[INC #10] Is expected to have a minimum of 3 months life expectancy.
Has adequate organ function as defined as :
[INC #11] ≥1500/μL (≥1.5 x 109/L) Platelets
[INC #12] ≥100 000/μL (≥100 x 109/L)
[INC #13] Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L Renal
[INC #14] eCrClb Albumin ≥60 mL/min
[INC #15] ≥2.5 g/dL Coagulation
[INC #16] INR or PT aPTT ≤1.5x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
[INC #17] For participants with biopsiable disease and when medically feasible: must provide a fresh biopsy at Screening and must be willing to undergo another on-treatment biopsy. If it is not feasible to obtain a fresh biopsy during Screening, an archival tumor tissue, preferably taken after completion of participant’s most recent line of therapy, may be acceptable with agreement from the medical monitor. Archival tissues samples will only be acceptable when the anatomic location or medical condition of the participant would be compromised by procuring a fresh biopsy.
[INC #18] Has a tumor demonstrating either:
• dMMR: Mismatch repair-deficient (dMMR) status as assessed by immunohistochemistry (IHC) for expression of the MMR proteins (MLH1, MSH2, MSH6, PMS2) and where loss of 1 or more of these proteins indicates dMMR;
OR
• MSI-H: Microsatellite instability-high (MSI-H) phenotype as determined by polymerase chain reaction (PCR) or by tissue NGS.
[INC #19] Is willing to use adequate contraception: A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is a PONCBP (participant of non-childbearing potential)
OR
• Is a POCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, from a minimum of 28 days prior to and during the study intervention period and for at least 8 months after the EOI visit, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The Investigator should evaluate the potential for contraceptive method failure (e.g., noncompliance, recently initiated) in relationship to the first dose of study intervention.
• Participants using hormonal contraceptive must also use male condoms or may consider non-hormonal, highly effective methods of contraception.
• A POCBP must have a negative highly sensitive pregnancy test (urine or serum, as required by local regulations) within 72 hours prior to the first dose of study intervention.
• The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. Male participants are eligible to participate if they agree to the following during the study intervention period and for at least 4 months, corresponding to time needed to eliminate study intervention (i.e., 5 terminal half-lives) plus an additional 90 days (a spermatogenesis cycle).
• Refrain from donating sperm PLUS either:
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agree to remain abstinent
OR
• Must agree to use contraception/barrier as detailed below:
• Agree to use a male condom [with female partner use of an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a POCBP who is not currently pregnant.
• Agree to use a male condom when engaging in any activity that allows for passage of ejaculate to another person.
[INC #20] Has adhered to the appropriate treatment washout periods prior to receiving experimental therapy.
Part 1: Monotherapy dose escalation
[INC #21] Has met inclusion criteria 7-20.
[INC #22] Has histologically diagnosed advanced (unresectable, metastatic or recurrent) solid tumor and has exhausted all standard of care treatment options.
[INC #23] For backfilled participants only: Has also met eligibility criteria for Part 2. Part 2: Monotherapy dose expansion
[INC #24] Has met inclusion criteria 7-20.
[INC #25] Has histologically diagnosed advanced (unresectable, metastatic or recurrent) CRC or EC.
[INC #26] Has received at least 1 but no more than 3 lines of systemic anti-cancer therapy for their advanced (unresectable, metastatic or recurrent) disease (i.e., participants are being treated on study in a 2nd to 4th line metastatic setting), including at least one line of ICI therapy.
[INC #27] Has at least 1 target lesion per RECIST 1.1 at Screening, as determined by the Investigator. Measurable lesions that have been previously irradiated and have been shown to be progressing following irradiation may be considered as target lesions.
Critères d'exclusion
[EXC #1] Has ongoing adverse reaction(s) from prior therapy that has(have) not recovered to ≤ Grade 1 or to the baseline status preceding prior therapy, excluding alopecia, hearing loss, vitiligo, endocrinopathy managed with replacement therapy, and Grade 2 neuropathy, or that the Investigator, with the agreement of the sponsor, considers to be not clinically relevant for the tolerability of study intervention in the current clinical study.
[EXC #2] Has received prior treatment with a Werner (WRN) inhibitor or Nucleotide Excision Repair Targeting (NERT) agent.
[EXC #3] Is unable to swallow and retain orally administered study treatment.
[EXC #4] Has untreated brain or CNS metastases or brain/CNS metastases that have progressed [e.g., evidence of new or enlarging brain metastasis or new neurologic symptoms attributable to brain/CNS metastases]. Participants with previously treated and clinically stable brain/CNS metastases and who have completed all corticosteroid therapy for ≥2 weeks prior to Screening are not excluded from participation.
[EXC #5] Has had major surgery within 4 weeks of enrollment into the study or participant has not recovered from any effects of any major surgery. [EXC #6] Has a known additional malignancy that progressed or required active treatment within the past 24 months because reoccurrence of another malignancy would confound interpretation by RECIST 1.1 criteria. Exceptions include basal or squamous cell carcinomas of the skin or in situ carcinomas [e.g., breast, cervix, bladder] that have been resected with no evidence of metastatic disease.
[EXC #7] Has any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., severe ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection), except for prior gastrectomy.
[EXC #8] Has a history in prior year of clinically significant or uncontrolled cardiac disease, acute myocardial infarction, New York Heart Association Class III or IV congestive heart failure [NYHA, 1994], or clinically significant arrhythmia not controlled by standard of care therapy.
[EXC #9] Has a history of any serious and/or unstable medical, psychiatric disorder or other condition(s) (including laboratory assessment abnormalities) that might confound the results of the study, or could interfere with the participant’s safety, consent, or compliance to the study procedures.
[EXC #10] Has an ALT value >2.5x ULN (or an ALT value >5x ULN for participants with documented liver metastases/tumor infiltration).
[EXC #11] Has a total bilirubin value >1.5x ULN.
[EXC #12] Has cirrhosis or current unstable liver or biliary disease per Investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal/gastric varices, persistent jaundice.
[EXC #13] Has evidence of a prolonged QTcF >470 msec or has a bundle branch block (BBB).
[EXC #14] Has documented presence of HBsAg, and/or HBcAb at Screening or within 3 months prior to the first dose of study intervention.
[EXC #15] Has a positive HCV antibody test result at Screening or within 3 months prior to the first dose of study intervention.
[EXC #16] Has a positive HCV RNA test result at Screening or within 3 months prior to the first dose of study intervention.
[EXC #17] Has a known HIV infection AND meets at least 1 of the following criteria: a. Has documented evidence of plasma HIV-1 RNA ≥50 c/mL within 3 months prior to or at Screening. In the 3 to 12 months prior to Screening, plasma HIV1 RNA levels consistently <50 c/mL are required for enrollment; if multiple instances of plasma HIV-1 RNA values ≥50 c/mL occurred 3 to 12 months prior to Screening, the participant is not eligible for enrollment unless, per the Investigator’s assessment, the elevations were neither persistent nor associated with antiretroviral resistance;
OR
b. Has not had CD4 cell counts measured in the past 12 months (i.e., at least 2 separate measurements taken a minimum of 28 days apart, 1 of which must be conducted at Screening);
OR
c. Has had any CD4 cell count values 350 cells/mm3 in the past 12 months;
OR
• Has had 1 or more changes in their combination antiretroviral therapy regimen or has received an antiretroviral therapy regimen that is inconsistent with locally recommended guidelines during the 3 months prior to Screening;
OR
• Has a history of HIV-associated non-Hodgkin lymphoma within 5 years prior to Screening or a history of HIV-associated invasive cervical cancer; OR
d. Has received treatment with an HIV1 immunotherapeutic vaccine within 90 days of Screening.
[EXC #18] Documented active or chronic tuberculosis infection.
[EXC #19] Has known hypersensitivity to any of the study interventions or excipients, or other allergy that, in the opinion of the Investigator or medical monitor, contraindicates participation in the study.
[EXC #20] For participants with CRC: has a tumor that in the Investigator’s judgment is causing symptomatic bowel obstruction or otherwise requires urgent/emergent local intervention.