Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer

Background: EP0057 (formerly CRLX101) consists of a sugar molecule cyclodextrin linked to a chemotherapy drug called camptothecin. The combined molecule or "nanoparticle drug conjugate" travels through the blood. Once inside cancer cells, the chemotherapy drug is released from the molecule. Olaparib is a drug that may stop cancer cells from repairing the deoxyribonucleic acid (DNA) damage caused by chemotherapy. Researchers want to see how safe it is to give EP0057 and olaparib together and to see how well the combination treats a specific type of lung cancer called small cell lung cancer (SCLC). Objectives: To test the safety and maximum dose of EP0057 and olaparib together. To test how well they treat small cell lung cancer. Eligibility: Adults 18 and older with small cell lung cancer. Design: Participants will be screened with standard cancer care tests. Participants will get the 2 study drugs in 28-day cycles. EP0057 will be given every 2 weeks, through a small plastic tube in an arm vein. Olaparib will be taken by mouth twice a day most days. Participants will keep a pill diary. For Cycle 1, participants will have 3 visits. All other cycles will have 2 visits. At study visits, participants may have: * Blood and hair samples taken * History and Physical exam * Questions about health and side effects * Pregnancy test * Optional tumor biopsy where a piece of tumor is removed by needle after numbing the skin. * Computed tomography (CT) scan * Injection of EP0057 (twice per cycle) * Olaparib prescription Participants will have a follow-up visit 4 weeks after finish taking the drugs. They will have a physical exam and blood tests. They may have a tumor biopsy. The study team will call the patient every 3 months for follow up after completing the study treatment.

Background: * Small cell lung cancer (SCLC) is an aggressive cancer with a poor prognosis. * Although highly responsive to chemotherapy initially, SCLC relapses quickly and becomes refractory to treatment within a few months. * Urothelial Carcinoma (UC) of the Bladder is the fourth most common malignancy in men and the ninth most common in women. * Prostate cancer is the most common cancer among men in the United States. While prostate cancer is initially responsive to androgen deprivation therapy (ADT), the median duration of sensitivity is 24-36 months. Moreover, patients develop resistance to current treatment options. * The use of poly adenosine diphosphate ribose polymerase (PARP) inhibitors in combination with chemotherapy builds upon pre-clinical data in lung cancer and other cancers supporting the notion that PARP inhibitors potentiate the effect of deoxyribonucleic acid (DNA) damaging therapies. * Despite their highly synergistic activity in preclinical models, human studies combining PARP inhibitors and camptothecins have not translated into clinical benefit due to enhanced toxicity with the combination. * One approach to improve ability to combine camptothecins with agents that sensitize their activity like PARP inhibitors is to use alternative formulations that minimize toxicity to the normal tissues. * EP0057 (formerly CRLX101) is a nanoparticle drug conjugate composed of 20 (S)-camptothecin (a potent and highly selective topoisomerase I inhibitor) conjugated to a linear, cyclodextrin polyethylene glycol-based polymer. * Olaparib is a PARP inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline breast cancer gene (BRCA) mutated advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy. Olaparib has an established safety profile, and it is under investigation in a number of different cancers. Objectives: * Phase I: To determine the maximum tolerated dose (MTD)/recommended Phase 2 dose (RP2D) of EP0057 in combination with olaparib in patients with refractory cancers. * Phase II: To determine the antitumor activity of olaparib plus EP0057 with respect to progression free survival at 16 weeks in SCLC patients with resistant or sensitive relapse. * Expansion Cohorts: To determine overall response rate of EP0057 plus olaparib in patients with mCRPC and urothelial carcinoma. Eligibility: Phase I * Adult patients \>=18 years of age * Histologically or cytologically confirmed, advanced solid tumor that is refractory to standard therapy and/or for whom no further standard therapy is available * Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1 or 2 Phase II * Adult patients \>= 18 years old * Have a pathologically (histology or cytology) confirmed diagnosis of SCLC * Disease progression on or after at least one platinum-based standard chemotherapy regimen and/or an immune-checkpoint inhibitor for either limited or extensive stage disease. * Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 * ECOG performance status of 0, 1 or 2 Phase II Expansion Cohorts * Have a pathologically (histology or cytology) confirmed diagnosis of urothelial carcinoma or metastatic, progressive, castrate resistant prostate cancer (mCRPC) * Disease progression on or after at least one platinum-based standard chemotherapy regimen and/or an immune-checkpoint inhibitor (except prostate cohort) * Have measurable disease per RECIST 1.1 (except prostate cohort) * Prior treatment with enzalutamide and/or abiraterone (prostate cancer cohort only) * Patients must have castrate levels of testosterone (\<50 ng/dl \[1.74 nmol/l\]) (Prostate cohort only) Design: * Patients meeting eligibility criteria will receive EP0057 (intravenous (IV) every (Q) 2weeks) plus olaparib (by mouth (PO) twice a day (BID), days 3-13 and days 17-26 administered in 28-day cycles, until disease progression or development of intolerable side effects. The maximum tolerated dose (MTD) of the combination will be used in Phase II. * Patients in Phase II will receive, the recommended phase 2 dose (RP2D) at DL4R EP0057 12 mg/m\^2 and olaparib 250 mg twice a day (BID). * Blood, tumor and hair samples will be collected at multiple time points for pharmacokinetics (PK), pharmacodynamics (PD) analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and ulcerative colitis (UC) patients and mandatory for metastatic castration-resistant prostate cancer (mCRPC) patients (only baseline biopsy is mandatory). * Toxicity will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. * Tumor assessments will be made using computed tomography (CT) scans (chest, abdomen and pelvis) at baseline and after every 2 cycles (3 cycles for metastatic castration-resistant prostate cancer (mCRPC) according to RECIST version 1.1. * After discontinuation of study treatment, follow-up for survival will be carried out every 3 months.