Durvalumab with or without Tremelimumab or Olaparib after Thoracic Radiation Therapy in Treating Patients with Extensive Stage-Small Cell Lung Cancer

Inclusion Criteria

• Participants must have signed and dated an Institutional Review Board (IRB)-approved written informed consent form (ICF) in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol-related procedures that are not part of normal patient care
• Participants must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests and other requirements of the study
• Patients with small cell lung cancer (SCLC) documented by histology or cytology from brushing, washing, fine needle aspiration or core biopsy from a defined lesion, but not from sputum cytology alone; no mixed histologies allowed
• Participants must have presented at initial diagnosis with extensive-stage disease (ES-SCLC)
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Participants must have received 4-6 cycles of platinum-based first-line chemotherapy and must have an ongoing complete response (CR), partial response (PR), or stable disease (SD) after completion. Acceptable combinations (National Comprehensive Cancer Network [NCCN] guidelines), include cisplatin or carboplatin with etoposide or irinotecan * As an exception to the above criterion, participants receiving only 3 cycles of chemotherapy due to toxicity are eligible, if they have an ongoing PR or CR after the 3rd cycle * Participants who have received > 6 cycles of platinum-based chemotherapy are not eligible * Participants receiving checkpoint inhibitor (CPI) monotherapy (anti-PD-1, anti-PD-L1, others) as part of their first line treatment in combination with chemotherapy treatment will be eligible as long as they discontinue the CPI prior to the start of thoracic XRT
• Participants must initiate study treatment with thoracic XRT =< 60 days from the last dose of platinum-based first line chemotherapy
• Whenever possible, a formalin-fixed, paraffin-embedded (FFPE) tumor tissue block or 5-10 unstained slides of tumor sample (archival) should be made available (less material is acceptable)
• This study permits the re-enrollment of a participant not on study due to pre-treatment screening failure (i.e., participant has not been treated). If re-enrolled, the participant must be re-consented
• Patients must have a life expectancy >= 16 weeks
• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and if needed, tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result) and/or, hepatitis C * Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible * Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA) (indicating no current infection)
• Known positive test for human immunodeficiency virus (positive HIV 1/2 antibodies) or known medical history of acquired immunodeficiency syndrome (AIDS)
• ARMS A, B AND D ONLY: Absolute neutrophil count (ANC) >= 1.0 x 10^9/L (measured within 28 days prior to administration of study treatment)
• ARMS A, B AND D ONLY: Platelet count >= 75 x 10^9/L, or (measured within 28 days prior to administration of study treatment)
• ARMS A, B AND D ONLY: Hemoglobin level >= 8.0 g/dL (blood transfusion is allowed prior to the start of systemic therapy) (measured within 28 days prior to administration of study treatment)
• ARM C ONLY: Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (measured within 28 days prior to administration of study treatment)
• ARM C ONLY: Platelet count >= 100 x 10^9 /L, or (measured within 28 days prior to administration of study treatment)
• ARM C ONLY: Hemoglobin level >= 10.0 g/dL (with no blood transfusion in the past 28 days prior to olaparib) (measured within 28 days prior to administration of study treatment)
• ARMS A, B AND D ONLY: Total bilirubin level =< 1.5 times the institutional ULN (except patients with Gilbert syndrome, who are excluded if total bilirubin =< 3 times ULN), or
• ARMS A, B AND D ONLY: Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times the institutional ULN or =< 5 times the institutional ULN if liver metastases are present
• ARM C ONLY: Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
• ARM C ONLY: AST (SGOT)/ALT (SGPT) levels =< 2.5 x institutional ULN unless liver metastases are present in which case they must be =< 5 x ULN
• Measured (by 24-hour urine collection) or calculated (by the Cockroft-Gault formula) CrCl of >= 51 mL/min
• Body weight > 30 kg
• Postmenopausal or evidence of non-childbearing status for women of childbearing potential (WOCBP) with negative urine or serum pregnancy test within 28 days of study treatment and confirmed within 72 hours prior to the start of thoracic XRT
• Women patients must not be breastfeeding
• WOCBP patients, male patients who are sexually active with WOCBP and female partners of male patients (if they are of childbearing potential) must agree to follow instructions for “highly effective methods of contraception” for the duration of treatment with study drug(s) plus the specified washout period
• Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, they must still undergo pregnancy testing as described
• Male participants must be willing to refrain from sperm donation during the entire study and for at least 180 days after the last dose of durvalumab combination therapy, 90 days after the last dose of durvalumab or olaparib monotherapy

Exclusion Criteria

• Participants with previous brain metastases are eligible provided that they are treated, are asymptomatic, and have stable disease at the screening tumor assessment. A >= 2-week disease stable interval as confirmed by magnetic resonance imaging (MRI) or computed tomography (CT) brain w/ contrast is required after treatment of brain metastases before initiation of thoracic XRT. In addition, subjects must have been either off corticosteroids, or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
• Participants who have received prior thoracic XRT are excluded
• Carcinomatous meningitis
• Women who are pregnant or breastfeeding
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, systemic lupus erythematosus, rheumatoid arthritis, Wegener syndrome and hypophysitis or uveitis. Patients with an autoimmune paraneoplastic syndrome requiring concurrent immunosuppressive treatment are excluded. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study treatment (excluding thoracic radiotherapy). The following are exceptions to this criterion: * Corticosteroids with minimal systemic absorption (intranasal, inhaled or topical steroids) or local steroid injections (e.g.: intraarticular injections) * Systemic corticosteroids at physiologic doses (adrenal replacement steroid doses) exceeding 10 mg daily prednisone or its equivalent are permitted in the absence of active autoimmune disease * Steroids as premedication for hypersensitivity reactions (e.g.: CT scan premedication)
• Prior CPI therapy with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including any other antibody or drug specifically targeting T cell co-stimulation or checkpoint pathways). EXCEPTION: CPI use with first line chemotherapy that is stopped prior to trial enrollment
• Patients who have received any previous treatment with a PARP inhibitor, including olaparib
• Any evidence of current interstitial lung disease (ILD) or pneumonitis or a prior history of ILD or pneumonitis requiring oral or IV glucocorticoids
• Previous malignancies unless a complete control (no evidence of disease) was achieved >= 2 years prior to study entry AND no additional therapy is required during the study period (EXCEPT: adequately treated non-melanoma skin cancer, curatively treated in situ cancer and stage 1, grade 1 endometrial cancer)
• Known medical condition that, in the investigator’s opinion, would increase the risk associated with study participation or study drug(s) administration or interfere with the interpretation of safety results
• Major surgery or significant traumatic injury that is not recovered at least 14 days before the initiation of thoracic radiation therapy
• All toxicities attributed to prior anti-cancer therapy must have been resolved to grade 1 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) or baseline before administration of study drug(s) EXCEPT: * Patients with toxicities attributed to prior anti-cancer therapy that either are not expected to resolve and/or result in long-lasting sequelae, such as neuropathy after platinum-based therapy, or are not expected to interfere with treatment on study, such as alopecia * Patients with irreversible toxicities not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included after consultation with the study physician
• Patients with known contraindications to radiotherapy, including inherited syndromes associated with hypersensitivity to ionizing radiation (e.g.: ataxia-telangiectasia, Nijmegen breakage syndrome)
• History of allergy or hypersensitivity to any of the study drugs or study drug components
• Prisoners or individuals who are involuntarily incarcerated
• Patients considered a poor medical risk due to a serious, uncontrolled medical disorder, non-malignant systemic disease or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 3 months) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, extensive interstitial bilateral lung disease on high resolution computed tomography (HRCT) scan or any psychiatric disorder that prohibits obtaining informed consent. Individuals who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease) illness
• Patients weighing =< 30 kg will be excluded from enrollment
• History of active primary immunodeficiency
• Concomitant use of CYP3A4 (for olaparib only, arm C only) * Known strong CYP3A inhibitors (e.g. itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or moderate CYP3A inhibitors (e.g. ciprofloxacin, erythromycin, diltiazem, fluconazole, verapamil). The required washout period prior to starting olaparib is 2 weeks * Known strong (e.g. phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John’s Wort) or moderate CYP3A inducers (e.g. bosentan, efavirenz, modafinil). The required washout period prior to starting olaparib is 5 weeks for enzalutamide or phenobarbital and 3 weeks for other agents
• Resting electrocardiogram (ECG) indicating uncontrolled, potentially reversible cardiac conditions, as judged by the investigator (e.g., unstable ischemia, uncontrolled symptomatic arrhythmia, congestive heart failure, corrected QT interval by Fridericia (QTcF) prolongation > 500 ms, electrolyte disturbances, etc.), or patients with congenital long QT syndrome
• Patients with myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or with features suggestive of MDS/AML
• Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication
• Previous allogenic bone marrow transplant or double umbilical cord blood transplantation (dUCBT)
• Involvement in the planning and/or conduct of the study
• Patients receiving any systemic chemotherapy or radiotherapy (except for palliative reasons) 3 weeks prior to study treatment