DS-3201b and Irinotecan in Treating Patients with Recurrent Small Cell Lung Cancer
- Signed informed consent form (ICF).
- Ability to comply with the study protocol as per the investigator‘s judgment.
- Life expectancy >= 12 weeks.
- Karnofsky performance status >= 70%.
- Pathologically confirmed diagnosis of 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 progression of disease after prior treatment with a platinum doublet regimen.
- Patients who received a platinum doublet regimen in combination with immunotherapy are still eligible for the study.
- Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
- Adequate tissue sample available for both immunohistochemistry (IHC) testing of IHC testing of SLFN11 and H3K27me3 and molecular profiling (archived tissue block or 20 unstained slides). Tissue sample can be either from an initial pre-platinum-based chemotherapy sample OR from a repeat biopsy sample after progression on platinum-based chemotherapy.
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (1500/uL) without granulocyte colony-stimulating factor support (obtained within 14 days prior to initiation of study treatment).
- Hemoglobin >= 9 g/dL (transfusions to meet this criterion are allowed) (obtained within 14 days prior to initiation of study treatment).
- Platelets >= 150 x 10^9 /L without transfusion (obtained within 14 days prior to initiation of study treatment).
- Creatinine clearance >= 50 mL/min as calculated using the modified Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) formula OR serum creatinine =< 1.5 x upper limit of normal (ULN)
- Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) =< 3 x ULN with the following exceptions: * Patients with documented liver metastases: AST, ALT and ALP =< 5 x ULN.
- Total bilirubin =< 2.0 mg/dL.
- For patients not receiving therapeutic anticoagulation: * Institutional normalized ratio (INR) =< 1.5 x ULN. * Activated partial thromboplastin time (aPTT) =< 1.5 x ULN.
- For patients receiving therapeutic anticoagulation: * Stable anticoagulant regimen.
- Patients with baseline clinical symptoms or laboratory abnormalities that do not meet the definition of dose-limiting toxicity (DLT) are eligible for treatment on this study.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 6 months after the last dose of DS-3201b or irinotecan, whichever date is later. * 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 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.
- For men of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom with female partners of childbearing potential or pregnant female partners during the treatment period and for at least 6 months after the last dose of DS-3201b or irinotecan, whichever date is later. * Men must refrain from donating sperm during this same period as defined above. * 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.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of study procedures.
- Untreated central nervous system (CNS) metastases.
- Patients with treated CNS metastases are allowed on the study as long as their clinical symptoms are adequately controlled and the daily dose of steroid use is equivalent to or less than 10 mg of prednisone.
- Is receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4/5 within 7 days of first receipt of DS-3201b. * Consumption of herbs/fruits that may have an influence on PK of DS-3201b (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 DS-3201b or other inhibitors of enhancer of zeste homologue-2 (EZH2).
- Prior exposure to topoisomerase inhibitors, including topotecan and irinotecan.
- 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 DS-3201b in the opinion of the treating physician and/or primary investigator (PI).
- Currently receiving anticancer therapies or who have received anticancer therapies within 2 weeks prior to the initiation of study treatment. Anticancer therapies include chemotherapy, biologics, targeted therapies, immunologics, or other investigational therapy.
- Currently receiving radiation therapy, or who have received radiation within 2 weeks prior to the initiation of study treatment.
- Patients receiving palliative radiation therapy within the safety evaluation period for dose-limiting toxicity during cycle 1
- Patients who have not recovered to grade =< 1 or baseline from adverse events due to prior anticancer therapy.
- 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.
- QT interval prolongation * Prolongation of corrected QT interval where the mean corrected QT (QTc) interval is > 450 milliseconds (ms) for men and > 470 ms for females or if there are any other additional risk factors for torsade de pointes (i.e. active congestive heart failure or cardiomyopathy with New York Heart Association (NYHA) grade 3/4 dyspnea, clinically significant cardiac rhythm abnormalities, hypokalemia, family history of long QT syndrome). Single electrocardiograms (EKGs) will be obtained at screening and at each pre-specified timepoint as indicated in the table of assessments. For any EKG assessment, if the initial EKG shows a prolonged QTc, then two additional EKGs will be obtained and the mean of the 3 EKGs will be used to determine eligibility and for grading of treatment-related adverse events (TRAEs).
- Patients who are currently taking medications that are known to prolong the QT interval and are clearly associated with a known risk of torsades de pointes (TdP) even when taken as recommended. Patients who are able to discontinue any prohibited medication prior to the start of study drug at Day -7 will still be considered eligible for the study.
- 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 DS-3201b.
- Active tuberculosis.
- Active hepatitis B virus (HBV) infection (chronic or acute), defined as having a positive hepatitis B surface antigen (HBsAg) test at screening. * 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 ribonucleic acid (RNA) test at screening. * The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
- 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.
I. To assess the safety, tolerability, and maximum tolerated dose (MTD) of valemetostat tosylate (DS-3201b) in combination with fixed-dose irinotecan in patients with recurrent small cell lung cancer (SCLC). (Phase I)
II. To determine the recommended phase II dose (RP2D) of DS-3201b in combination with irinotecan in patients with recurrent SCLC. (Phase I)
III. To determine the objective response rate (ORR) to treatment with DS-3201b at the RP2D in combination with irinotecan in patients with recurrent SCLC. (Phase II)
I. To assess the plasma pharmacokinetics (PK) after a single dose of DS-3201b in combination with irinotecan. (Phase I)
II. To determine the progression-free survival and overall survival of patients with recurrent SCLC treated with DS-3201b in combination with irinotecan. (Phase II)
III. To determine the duration of response or duration of stable disease in patients with recurrent SCLC treated with DS-3201b in combination with irinotecan. (Phase II)
IV. To explore SLFN11 expression by immunohistochemistry as a potential predictive biomarker of response to DS-3201b and correlate with trimethylation of H3K27 as measured by immunohistochemistry in pretreatment, on-treatment and post-treatment tissue samples as well as in circulating tumor cells (CTCs). (Phase II)
V. To explore changes in the genomic landscape of pre-treatment, on-treatment and post-treatment tumor tissue using next-generation sequencing (NGS). (Phase II)
VI. To assess the plasma pharmacokinetics (PK) after a single dose of DS-3201b in combination with irinotecan. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of EZH1/2 inhibitor DS-3201 followed by a phase II study.
Patients receive EZH1/2 inhibitor DS-3201b orally (PO) once daily (QD) for 7 days prior to cycle 1 and on days 1-21 of cycle 1 and subsequent cycles. Patients also receive irinotecan intravenously (IV) on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months for at least 2 years.
Trial Phase Phase I/II
Trial Type Treatment
Memorial Sloan Kettering Cancer Center
Wei-Chu Victoria Lai
- Primary ID 18-553
- Secondary IDs NCI-2019-02286
- Clinicaltrials.gov ID NCT03879798