Repurposing statins as adjuvants for cancer patients receiving therapy with immune checkpoint inhibitors: the STARK trial

Prior treatment

• Prior treatment with any anti-PD-1/PD-L1 immune checkpoint inhibitor within 12 months from randomization.
• Anticipation of need for major surgical procedure during the trial, with the exclusion of definitive breast surgery in Cohort 1.
• Currently taking, or have taken at any point within the 6 months prior to study entry, any cholesterol-lowering therapy (such as red yeast rice, supplements, statins, fibrates, ezetimibe, PCSK9 inhibitors)
• Current therapy with drugs that increase risk of statin induced myopathy or rhabdomyolysis (i.e., Niacin, protease inhibitors, verapamil, cyclosporine, clofibrate/fenofibrate or any CYP3A4 inhibitor)
• Co-existing active infection or concurrent illness that, at the judgment of the investigator, contra-indicate the inclusion of the patient in the study.

Other illness

• Active B or C hepatitis or human immunodeficiency virus (HIV) infection, or occasional finding of active hepatitis B/C infection during screening tests before chemotherapy initiation, as defined as positive polymerase chain reaction (PCR) testing for HBV-DNA and HCV-RNA and qualitative PCR for HIV-RNA, or requiring active treatment at study enrollment
• Lack of physical integrity of the upper gastrointestinal tract, clinically significant malabsorption syndrome, or inability to take oral medications.
• Patients who, based individual cardiovascular risk factors, require immediate initiation of statin therapy for primary prevention of cardiovascular disease.
• Current or recent therapy with known strong Cytochrome P450 3A4 inhibitors (abbreviated CYP3A4) (e.g., clarithromycin, HIV protease inhibitors, and itraconazole). See for reference https://www.fda.gov/drugs/drug-interactions-labeling/healthcare-professionals-fdas-examples-drugs-interact-cyp-enzymes-and-transporter-systems and Section 10.1.3.1 in this protocol)
• Known severe hypersensitivity to any of the study drugs or excipients or known severe hypersensitivity reactions to monoclonal antibodies.
• Any medical or other condition that in the Investigator’s opinion renders the patient unsuitable for this study due to unacceptable risk.
• Psychiatric disorders or altered mental status precluding understanding of the informed consent process and/or completion of the necessary study assessment and procedures.
• History of allogenic organ transplantation.
• Subjects with a condition requiring systemic treatment (e.g. corticosteroids > 10 mg daily prednisone equivalent or other immunosuppressive drugs) within 14 days of treatment initiation. Corticosteroids with minimal systemic absorption (e.g. budesonide) and adrenal replacement steroid doses > 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease.
• Subjects with active, known, or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enroll.

Lab values

• Known hypersensitivity to the active substance or to any excipients of atorvastatin. Conditions of rare hereditary problems of galactose intolerance, Lapp lactose deficiency or glucose-galactose malabsorption

Other

• Any known forms of Familial hypercholesterolemia
• Current pregnancy and/or lactation
• Subjects assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.
• Refusal to adopt adequate contraception methods.

• Ability to understand and willingness to sign a written informed consent document.
• Female patients are not of childbearing potential if they meet at least one of the following criteria: a. Have undergone a documented hysterectomy and/or bilateral oophorectomy b. Have medically confirmed ovarian failure c. Achieved post-menopausal status, defined as: ≥ 12 months of non- therapy-induced amenorrhea or surgically sterile (absence of ovaries); in women <45 years of age FSH level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy.
• Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Willingness and consent to undergo biologic samples collection scheduled by the protocol.
• Age ≥18 years at the time of signing the Informed Consent Form (ICF).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1.
• Adequate organ and marrow function as defined below, unless the investigator deems the deviation to be clinically insignificant and after discussion with the Study Sponsor: o Absolute Neutrophil Count (ANC) ≥ 1.5x109/L o Platelets ≥ 100x109/L o Hemoglobin ≥ 9 g/L o Total Bilirubin < 1.5 institutional upper limit of normal (ULN) except for patients with Gilbert syndrome who may only be included if the total bilirubin is < 3.0 x institutional ULN or direct bilirubin < 1.5 x institutional ULN o Transaminases (AST/ALT) <3x institutional ULN or ≤5x institutional ULN in presence of liver metastases o Creatinine < 1.5 x institutional ULN
• Cohort 1 (TNBC) i) Pathologically documented breast cancer: locally assessed HER2-negative (Immunohistochemistry (IHC) 0-1, 2+ with In Situ Hybridization (ISH)-), estrogen receptor [ER] and progesterone receptor [PgR] negative ii) Untreated stage II-III iii) Intended to definitive breast surgery after neoadjuvant therapy. iv) Candidate to receive neoadjuvant pembrolizumab plus chemotherapy, according Clinical practice v) Available T0 tumor sample (FFPE tumor specimen (1 block)) collected before the initiation of the study treatment.
• Cohort 2 (NSCLC) i) Pathologically documented lung cancer: Histologically confirmed diagnosis of Stage IIIB−not amenable to radical treatment or Stage IV lung carcinoma. ii) Non-oncogene addicted (EGFR, ALK, ROS1, BRAF, MET, RET, KRAS wild type) NSCLC. Patients must have undergone molecular testing to confirm the absence of these mutations before inclusion. iii) No prior treatment for advanced NSCLC iv) Patients with measurable or non-measurable disease are eligible. Measurable disease per RECIST 1.1 criteria is not required for enrollment. v) PD-L1 highly positive (≥50%) as assessed by local pathology vi) Candidate to receive first-line ICI according to clinical practice. vii) Available T0 tumor sample (FFPE tumor sample - at least 1 block or 12 slices – has to be collected during screening period. Archival T0 tumor sample may be eligible if the tumor specimen was obtained within 12 months prior to enrollment provided there have been no anticancer therapies given after the sample was obtained. In case the tumor sample will be freshly collected, at least 1 core of the tumor tissue will be snap-frozen in liquid nitrogen and stored at –80°C).
• Male patients and Female patients of childbearing potential must agree to sexual abstinence or to use two highly effective methods of contraception throughout the study. Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Examples of contraceptive methods with a failure rate of < 1% per year include tubal ligation, male sterilization, hormonal implants, established, proper use of combined oral or injected hormonal contraceptives, and certain intrauterine devices. Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of < 1% per year. Barrier methods must always be supplemented with the use of a spermicide. A patient is of childbearing potential if, in the opinion of the Investigator, she is biologically capable of having children and is sexually active.