A Phase II Study to Determine the Preliminary Efficacy of Novel Combinations of Treatment in Patients With Platinum Refractory Extensive-Stage Small-Cell Lung Cancer

Inclusion criteria (applicable to all arms)

• Adults with histologically or cytologically documented ED SCLC who have demonstrated progressive disease either during first-line platinum-based chemotherapy (platinum refractory) or within 90 days of completing platinum based-chemotherapy (platinum resistant) and have not received further treatment.
• Brain metastases must be asymptomatic or treated and stable off steroids and anti-convulsants for at least 1 month prior to study treatment.
• At least 1 lesion, not previously irradiated, that can be accurately measured at baseline (per RECIST v 1.1 guidelines)
• Life expectancy of at least 8 weeks.
• WHO/ ECOG PS of 0-1 at enrollment.

Inclusion criteria (Arm A specific)

• Body weight >30 kg.
• No prior exposure to immune mediated therapy, excluding therapeutic anticancer vaccines.

Inclusion criteria (Arm B specific) Able and willing to swallow oral medication.

Inclusion criteria (Arm C specific)

Able and willing to swallow oral medication.

Exclusion criteria (applicable to all arms):

• Participation in another clinical study, major surgery, radiation therapy within 28 days.
• Any condition that, in the opinion of the Investigator, would interfere with the evaluation of the IP or interpretation of patient safety or study results.
• Uncontrolled intercurrent illness, including but not limited to interstitial lung disease.
• History of another primary malignancy, leptomeningeal carcinomatosis or spinal cord compression.

Exclusion criteria (Arm A specific)

• Active autoimmune disease, including a paraneoplastic syndrome.
• Active or prior documented autoimmune or inflammatory disorders.
• Any unresolved toxicity (CTCAE Grade >2) from previous anticancer therapy.
• Active infection including tuberculosis, HIV, Hepatitis B or C.

Exclusion criteria (Arm B specific)

• Prior exposure to any WEE1 inhibitors.
• Products known to be sensitive to CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4. Co-administration of rosuvastatin, atorvastatin, simvastatin and lovastatin, aprepitant or fosaprepitant or any herbal preparations. Grapefruit and Seville oranges should be avoided while taking AZD1775.
• Any known hypersensitivity or contraindication to IP or CBDP.
• QTcF > 470 msec or congenital long QT syndrome.
• Any current or within 6 months cardiac diseases NYHA Class 2: unstable angina pectoris, congestive heart failure, acute MI, conduction abnormality not controlled with pacemaker or medication, significant ventricular or supraventricular arrhythmias.
• A recent history of Torsades de pointes.

Exclusion criteria (Arm C specific)

• Cytotoxic chemotherapy within 21 days of Cycle 1 Day 1 is not permitted
• Previous treatment with a PARP inhibitor (including olaparib) or ATR inhibitor
• Concomitant use of known strong CYP3A inhibitors and moderate CYP3A inhibitors
• Concomitant use of known strong and moderate CYP3A inducers
• Persisting (> 4 weeks) severe pancytopenia due to previous therapy
• Cardiac dysfunction
• Refractory nausea and vomitting, chronic gastrointenstinal diseases or previous significant bowel resection
• Patients with uncontrolled seizures
• Intenstinal obstruction or CTCAE grade 3 or grade 4 GI bleeding within 4 weeks before dosing