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
Condition: Platinum Refractory Extensive-Stage Small Cell Lung Carcinoma
MeSH terms: Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma
Intervention: Durvalumab and Tremelimumab; AZD1775 and carboplatin (CBPT); AZD6738 and olaparib
Intervention description: Durvalumab + tremelimumab via intravenous (IV) infusion every 4 weeks (q4w), starting on Week 0, for up to a total of 4 months (4 cycles) followed by durvalumab monotherapy via IV infusion q4w, starting on Week 16 until PD, or for other discontinuation criteria.; AZD1775 twice daily (oral) for 2.5 days from Day 1 + CBDP area under the curve 5 (Day1) (IV); every 3 weeks.; AZD6738 once a day (oral) for 7 days from Day 1 + olaparib twice a day(oral) for 28 days from Day 1, every 4 weeks
Intervention MeSH terms: Carboplatin; Durvalumab; Olaparib; Tremelimumab; Adavosertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 72.0
Sex: All
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Platinum Refractory Extensive-Stage Carcinoma, Small Cell Lung; Platinum Refractory Extensive-Stage Oat Cell Carcinoma of Lung; Platinum Refractory Extensive-Stage Oat Cell Lung Cancer; Platinum Refractory Extensive-Stage Small Cell Cancer Of The Lung; Platinum Refractory Extensive-Stage Small Cell Lung Cancer

Summary:

      Study design This is a Phase II, open-label, multi-drug, multi-center, multi-arm,
      signal-searching study in patients with extensive-stage small-cell lung cancer (SCLC) who
      have refractory or resistant disease from prior platinum-based chemotherapy.
    

Eligibility criteria:

        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