Valemetostat and Atezolizumab for the Treatment of Extensive-Stage Small Cell Lung Cancer

Inclusion Criteria

• Signed informed consent form (ICF)
• Ability to comply with the study protocol as per the investigator’s judgment
• Age ≥ 18 years at the time of signing the ICF
• Life expectancy ≥ 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
• Pathologically confirmed diagnosis of newly diagnosed extensive-stage small cell lung cancer. Patients with a diagnosis of combined small cell lung cancer with other histologies may be considered for inclusion if the predominant histology is SCLC and only after discussion with the study principal investigator (PI)
• Radiographically documented Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 stable disease, partial or complete response after initial treatment with a platinum doublet regimen in combination with atezolizumab for 4 cycles. It is acceptable to have no measurable disease at the start of this study
• Must be able to begin therapy within 4 weeks of completing the fourth cycle of chemotherapy and immunotherapy
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/µL) (obtained within 14 days prior to initiation of study treatment) * Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to screening laboratory tests
• Hemoglobin ≥ 9 g/dL (obtained within 14 days prior to initiation of study treatment) * Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to screening laboratory tests
• Platelets ≥ 100 x 10^9/L (obtained within 14 days prior to initiation of study treatment) * Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor (G-CSF) administration is not allowed within 2 weeks prior to screening laboratory tests
• Creatinine clearance ≥ 30 mL/min as calculated using the Cockcroft-Gault equation (obtained within 14 days prior to initiation of study treatment)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤ 3 x upper limit of normal (ULN) (obtained within 14 days prior to initiation of study treatment) with the following exception: * Patients with documented liver metastases: AST, ALT and ALP ≤ 5 x ULN
• Total bilirubin (TBIL) ≤ 1.5 x ULN (obtained within 14 days prior to initiation of study treatment) with the following exceptions: * Subjects with Gilbert’s syndrome can have total bilirubin ≤ 3 x ULN and direct bilirubin ≤ 1.5 x ULN * Patients with liver metastases can have a total bilirubin ≤ 3 x ULN
• For patients not receiving therapeutic anticoagulation: International normalized ratio (INR) ≤ 1.5 x ULN (obtained within 14 days prior to initiation of study treatment)
• For patients not receiving therapeutic anticoagulation: Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN (obtained within 14 days prior to initiation of study treatment)
• For patients receiving therapeutic anticoagulation: Stable anticoagulant regimen (obtained within 14 days prior to initiation of study treatment)
• Female patients of reproductive age group and male patients must use highly effective methods of contraception through defined periods during and after study treatment as specified below: * Female patients must meet 1 of the following criteria: ** Postmenopausal for at least 1 year before the screening visit, or ** Permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose of study drug or confirmed by follicle stimulating hormone (FSH) test > 40 mIU/mL and estradiol < 40 pg/mL (< 140 pmol/L), or ** If she is of childbearing potential, agree to practice 1 highly effective method and 1 additional effective (barrier) method of contraception, at the same time, from the time of signing the informed consent through 6 months after the last dose of study drug, or ** Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * Female patients must agree to not donate or retrieve eggs (ova) for their own use during the course of this study or 6 months after receiving their last dose of study drug(s) ** A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus) ** Examples of highly effective contraceptive methods (with a failure rate of < 1% per year) include bilateral tubal ligation, male sterilization, and established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices ** The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception * Male patients, even if surgically sterilized (i.e., status post vasectomy), must agree to 1 of the following: ** Practice highly effective barrier contraception during the entire study treatment period and through 6 months after the last dose of study drug, or ** Practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, postovulation methods for the female partner] withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * Male patients must agree to not freeze or donate sperm during the course of this study or 6 months after receiving their last dose of study drug(s)
• Patient is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions

Exclusion Criteria

• Any active uncontrolled systemic diseases or other medical conditions considered to be poorly controlled by the investigator including but not limited to bleeding diatheses, that could in the investigator’s opinion, potentially interfere with completion of study procedures or interpretation of study outcomes
• Patients who receive consolidative chest radiation after completion of initial chemotherapy and immunotherapy
• Symptomatic central nervous system (CNS) metastases
• Patients with treated CNS metastases are allowed on the study if their clinical symptoms are adequately controlled and the daily dose of steroid use is equivalent to or less than 10 mg of prednisone
• Receiving concomitant treatment with a moderate or strong inducer of CYP3A within 14 days of first receipt of valemetostat * Consumption of herbs/fruits that may have an influence on pharmacokinetics (PK) of valemetostat (strong CYP3A inhibitors or inducers) such as St. John’s wort, star fruit, Seville orange or Seville orange-containing foods and beverages, grapefruit or grapefruit-containing food or beverages should be avoided from 14 days prior to the start of the study and throughout the entire study
• Prior exposure to valemetostat or other inhibitors of enhancer of zeste homologue-2 (EZH2)
• Refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, or any other condition that significantly affects gut motility or absorption and would preclude adequate absorption of valemetostat in the opinion of the treating physician and/or PI
• Currently receiving radiation therapy, or who have received radiation within 2 weeks prior to the initiation of study treatment, or who plan to receive radiation therapy within the safety evaluation period for dose-limiting toxicity during cycle 1
• Unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, grade ≤ 1 or baseline * NOTE: Participants may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to grade > 2 for at least 3 months prior to enrollment and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, comprised of the following: ** Chemotherapy-induced neuropathy ** Residual toxicities from prior immuno-oncology (IO) treatment: Grade 1 or grade 2 endocrinopathies which may include: *** Hypothyroidism/hyperthyroidism *** Type I diabetes *** Hyperglycemia *** Adrenal insufficiency *** Adrenalitis *** Skin hypopigmentation (vitiligo)
• Patients who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) * NOTE: Procedures such as a percutaneous biopsy, pleural catheter insertion, placement of a central venous catheter or other minor procedures are permitted
• Uncontrolled or significant cardiovascular disease, including the following: * Evidence of prolongation of QT/corrected QT (QTc) interval (e.g., repeated episodes of QT corrected for heart rate using Fridericia’s method [QTcF] > 470 ms). Electrocardiogram must be registered at rest. For any electrocardiogram (ECG) assessment, if the initial ECG shows a prolonged QTc, then two additional ECGs will be obtained, resulting in three specimens taken after a space of 1 minute, and the mean of the 3 ECGs will be used to determine eligibility and for grading of treatment related adverse events (TRAEs) * Myocardial infarction within 6 months prior to screening * Uncontrolled angina pectoris within 6 months prior to screening * New York Heart Association (NYHA) class 3 or 4 congestive heart failure * Uncontrolled hypertension (resting systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg)
• Have a known hypersensitivity to any of the components of or known hypersensitivity to either the study drug itself or any of the inactive ingredients in the study drug product
• Known liver cirrhosis
• Uncontrolled active infection requiring IV antibiotic, antiviral, or anti-fungal medications within 14 days prior to initiation of study treatment * Infections controlled on concurrent anti-microbial agents and anti-microbial prophylaxis per institutional guidelines are acceptable
• Congenital or acquired immunodeficiency, including patients with known history or infection with human immunodeficiency virus (HIV) * NOTE: HIV-positive patients who are taking anti-retroviral therapy are still ineligible due to potential PK interactions with valemetostat
• Active tuberculosis
• Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test followed by a positive HBV ribonucleic acid (RNA) test within 28 days prior to the first dose of study drug. Hepatitis B testing (HBV surface antigen and core antibody) is required only if not done previously * Patients with a past or resolved HBV infection, defined as having a negative HBsAg test and a positive total hepatitis B core antibody (HBcAb) test at screening, are eligible for the study
• Active hepatitis C virus (HCV) infection, defined as having a positive HCV antibody test followed by a positive HCV RNA test within 28 days prior to the first dose of study drug. Hepatitis C testing (HCV antibody) is required only if not done previously * The HCV RNA test will be performed only for patients who have a positive HCV antibody test
• Prior malignancy, active within the previous 3 years, except for locally curable cancer that is currently considered as cured or successfully resected, such as basal or squamous cell carcinoma, superficial bladder cancer, gastric cancer or carcinoma in situ of the prostate, cervix, or breast
• Female patients who have a positive serum pregnancy test during screening or a positive urine pregnancy test on day 1 before first dose of study drug
• Female patients who are lactating and/or plan to breastfeed during the study treatment or at any point leading up to and including 6 months after the last study drug dose