DS-3201b and Irinotecan for Patients With Recurrent 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

- Karnofsky performance status ≥ 70%

- Pathologically confirmed diagnosis of small cell lung cancer

- 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 ≥ 100 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:

- INR ≤ 1.5 x ULN

- aPTT ≤ 1.5 x ULN

- 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)

- 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) based on each of triplicate ECGs, additional risk factors of 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).

- 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.