* INCLUSION CRITERIA: - Phase I
* Patients must have histologically or cytologically confirmed advanced solid tumor that is resistant or refractory to standard therapy.
* A minimum of 2 weeks will be required from any prior therapy, including chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade \<= 1 from all reversible toxicities related to prior therapy is required at study entry.
* Patients do not need to have measurable disease to enroll on phase I.
* Age 18 years.
* Eastern cooperative Oncology Group (ECOG) performance status \<=2
* Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed.
* Patients must have normal organ and marrow function as defined below:
* leukocytes \>=3,000/mcL
* absolute neutrophil count \>=1,500/mcL without growth factor support
* platelets \>=100,000/mcL without growth factor support
* hemoglobin \>=9 g/dL, and no blood transfusion within 4 weeks.
OR
* Hemoglobin \>10 g/dL, and no blood transfusion within 2 weeks.
* total bilirubin \<=1.5 x upper limit of normal (ULN) (unless Gilbert's Disease)
* Aspartate aminotransferase (AST) serum glutamic oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT)\<=2.5 X institutional upper limit of normal (\<= 5X ULN if liver mets)
* creatinine \<= ULN
OR
* creatinine clearance \>= 51 mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal.
-The effects of EP0057 (formerly CRLX101) and olaparib on the developing human fetus are unknown. For this reason and because these agents as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 120 days (both male and female) following last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Fertile females of childbearing potential are defined as women physically capable of becoming pregnant unless the female patient cannot have children because of surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
* Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for women under 50,
* radiation-induced oophorectomy with last menses \>1 year ago,
* chemotherapy-induced menopause with \>1 year interval since last menses,
* or surgical sterilization (bilateral oophorectomy or hysterectomy).
* Negative urine pregnancy test \< =3 days prior to cycle 1 day 1 (C1D1) (women of childbearing potential only)
* Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.
INCLUSION CRITERIA: - Phase II Small Cell Lung Cancer (SCLC)
* Age \>=18 years.
* Patients must have histologically or cytologically confirmed diagnosis of SCLC from a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.
* Have received and progressed during or after a platinum-based standard chemotherapy regimen and/or an immune-checkpoint inhibitor
* Patients could have received any number of therapies for relapsed or progressive disease, including re-treatment with original frontline regimen. A minimum of 2 weeks will be required from any prior therapy, including chemotherapy, immunotherapy and/or radiation. In addition, recovery to Grade \<= 1 from all reversible toxicities related to prior therapy is required at study entry. No previous irradiation to the site of measurable or evaluable disease, unless that site had subsequent evidence of progression.
* Patients must have measurable disease as per Response Evaluation Criteria in Solid Tumors, version (RECIST 1.1).
* Radiographic evidence of disease progression after initial therapy should have been documented.
* Eastern Cooperative Oncology Group (ECOG) performance status \<=2.
* Patients with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the patient is off steroids or is on a stable dose of steroids. Patients with brain metastases should not require use of enzyme-inducing antiepileptic drugs (e.g., carbamazepine, phenytoin, or phenobarbital) within 14 days before first dose and during study. Use of newer antiepileptics that do not produce enzyme induction drug-drug interactions (DDIs) is allowed.
* Patients must have normal organ and marrow function as defined below:
* Leukocytes \>=3,000/mcL
* absolute neutrophil count \>=1,500/mcL without growth factor support
* platelets \>=100,000/mcL without growth factor support
* hemoglobin \>=9 g/dL, and no blood transfusion within 4 weeks.
OR
* hemoglobin \>10 g/dL, and no blood transfusion within 2 weeks.
* total bilirubin \<=1.5 x upper limit of normal (ULN) (unless Gilbert's Disease)
* AST(SGOT)/ALT(SGPT) \<=2.5 X institutional upper limit of normal (\<= 5X ULN if liver mets)
* creatinine \<= ULN
OR
* creatinine clearance \>=51 mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal.
* The effects of EP0057 and olaparib on the developing human fetus are unknown. For this reason and because these agents are known to be teratogenic, women of child-bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 120 days (both male and female) following last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Fertile females of childbearing potential are defined as women physically capable of becoming pregnant unless the female patient cannot have children because of surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
* LH and FSH levels in the post-menopausal range for women under 50,
* radiation-induced oophorectomy with last menses \>1 year ago,
* chemotherapy-induced menopause with \>1 year interval since last menses,
* or surgical sterilization (bilateral oophorectomy or hysterectomy).
INCLUSION CRITERIA: for Urothelial Carcinoma Expansion Cohort (accrual to the cohort ended with amendment version 08/17/2022)
* Patients must have a histologically confirmed diagnosis of urothelial carcinoma of the bladder, urethra, ureter, or renal pelvis from a CLIA-certified laboratory, with measurable disease by RECIST (version 1.1) including lymphadenopathy and visceral metastatic disease
* Male or female patients \>= 18 years of age.
* Patient must have received at least one platinum-based regimen of chemotherapy and/or an immune-checkpoint inhibitor if appropriate with progressive disease.
* Prior antiangiogenic and radiation therapy are permitted (2-week washout from therapy is required).
* Bisphosphonates and denosumab are permitted if on a stable dose for \>=4 weeks.
* ECOG 0-2
* Patients must have normal organ and marrow function as defined below:
* leukocytes \>=3,000/mcL
* absolute neutrophil count \>=1,500/mcL without growth factor support
* platelets \>=100,000/mcL without growth
* factor support
* hemoglobin \>=9 g/dL, and no blood transfusion within 4 weeks.
OR
* hemoglobin \>10 g/dL, and no blood transfusion within 2 weeks.
* total bilirubin\<TAB\> \<=1.5 x ULN (unless Gilbert's Disease)
* AST(SGOT)/ALT(SGPT) \<=2.5 X institutional upper limit of normal (\<= 5X ULN if liver mets)
* creatinine \<= ULN
-The effects of EP0057 and olaparib on the developing human fetus are unknown. For this reason and because these agents are known to be teratogenic, women of child-bearing potential and men must agree to use highly effective contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and for 120 days (both male and female) following last dose of study drug. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Fertile females of childbearing potential are defined as women physically capable of becoming pregnant unless the female patient cannot have children because of surgery or other medical reasons (effective tubal ligation, ovaries or the uterus removed, or are post-menopausal). Post-menopausal is defined as:
* Amenorrheic for 1 year or more following cessation of exogenous hormonal treatments,
* LH and FSH levels in the post-menopausal range for women under 50,
* radiation-induced oophorectomy with last menses \>1 year ago,
* chemotherapy-induced menopause with \>1 year interval since last menses,
* or surgical sterilization (bilateral oophorectomy or hysterectomy).
* Patients must be able to tolerate oral medications and not have gastrointestinal illnesses that would preclude absorption of olaparib.
* Ability to understand and the willingness to sign a written informed consent document.
* Willingness to release archival tissue sample for research purposes, if available
INCLUSION CRITERIA for mCRPC Expansion Cohort (accrual to the mCRPC cohort ended with amendment version 7/27/2021)
* Patients must have metastatic, progressive, castrate resistant prostate cancer (mCRPC).
* Documented histopathological confirmation of prostate cancer from a CLIA-certified laboratory.
* All patients must have at least one lesion deemed safe to biopsy and be willing to undergo a mandatory baseline biopsy.
* Patients must have received prior treatment with enzalutamide and/or abiraterone with the exception of patients who were treated with docetaxel and androgen deprivation therapy for metastatic castrate-sensitive prostate cancer and progressed on docetaxel treatment or who progress within one month of the last docetaxel dose.
* Patients must have castrate levels of testosterone (\<50 ng/dl \[1.74 nmol/l\])
* Patients must have undergone bilateral surgical castration or must agree to continue on gonadotropin-releasing hormone (GnRH) agonists/antagonists for the duration of the study.
* ECOG performance status \<= 2
* Patients must have adequate bone marrow, hepatic, and renal function with:
* leukocytes \>=3,000/mcL
* absolute neutrophil count \>=1,500/mcL without growth factor support
* platelets \>=100,000/mcL without growth factor support
* Hemoglobin \>=9 g/dL, and no blood transfusion within 4 weeks.
OR
* hemoglobin \>10 g/dL, and no blood transfusion within 2 weeks.
* total bilirubin \<=1.5 x ULN (\<=3 (SqrRoot) ULN for subjects with Gilbert's Disease)
* AST(SGOT)/ALT(SGPT) \<=3 X institutional upper limit of normal (\<= 5X ULN if liver mets)
* creatinine \<= ULN
OR
--creatinine clearance \>=51 mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal.
* Men must be at least 18 years of age.
* Patient must be capable of understanding and complying with protocol requirements and is willing to give informed consent.
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study and for the duration of study participation and for 120 days after last dose of study drug. Sexually active subjects and their female partners must agree to use medically accepted barrier methods of contraception (e.g., male or female condom) during the course of the study and for 3 months after the last dose of study drug(s), even if oral contraceptives are also used. All subjects of reproductive potential must also agree to use both a barrier method and a second method of birth control during the course of the study and for 3 months after the last dose of study drug(s). Should a woman become pregnant or suspect she is pregnant while her partner is participating in this study, she should inform her treating physician immediately.
Patients who were treated for metastatic castrate-sensitive prostate cancer with docetaxel and androgen deprivation therapy who progress on docetaxel treatment or who progress within one month of the last docetaxel dose are eligible.
EXCLUSION CRITERIA: - Phase I and II SCLC and UC Expansion Cohort (note: accrual to the UC cohort ended with amendment version 08/17/2022)
* Patients who are receiving any other investigational agents.
* Persistent toxicities (\>= Common Terminology Criteria for Adverse Events (CTCAE) grade 2) with the exception of alopecia and neuropathy, caused by previous cancer therapy
* Patients who have had prior treatment with olaparib or other camptothecin inhibitors (Ulcerative Colitis (UC) expansion Cohort Only).
* Patients with myelodysplastic syndrome/acute myeloid leukemia or active pneumonitis; or baseline features suggestive of myelodysplastic syndrome or acute myelogenous leukemia on peripheral blood smear or bone marrow biopsy, if clinically indicated.
* Hypersensitivity to study therapies ...
