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

          -  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 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 RECIST v1.1

          -  Adequate tissue sample available for both 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.

          -  Adequate hematologic and end-organ function, as defined by the following laboratory
             test results obtained within 14 days prior to initiation of study treatment:

               -  Adequate bone marrow function as defined by:

               -  Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (1500/µL) without granulocyte
                  colony-stimulating factor support

               -  Hemoglobin ≥ 9 g/dL (transfusions to meet this criterion are allowed)

               -  Platelets ≥ 150 x 10^9/L without transfusion

          -  Adequate renal function as defined by:

             °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 ULN

          -  Adequate hepatic function as defined by:

               -  AST, 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:

               -  stable anticoagulant regimen

               -  INR ≤ 1.5 x ULN

               -  aPTT ≤ 1.5 x ULN

          -  Patients with baseline clinical symptoms or laboratory abnormalities that do not meet
             the definition of dose-limiting toxicity (DLT).

          -  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.

        Exclusion Criteria:

          -  Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of study procedures.

          -  Untreated 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 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 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 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 NYHA Grade 3/4 dyspnea, clinically significant cardiac
             rhythm abnormalities, hypokalemia, family history of Long QT Syndrome). Single EKGs
             will be obtained at screening and at each pre-specified timepoint as indicated in the
             table of assessments (Table 3). 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 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. Please see Section 11.6 for a full list of excluded
             medications. 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 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.