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

A Phase I/II Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in Patients With Relapsed/Refractory Small Cell Lung, Bladder and Prostate Cancers

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.

Study Overview

• Status: Completed
• Conditions: Lung Neoplasms; Small Cell Lung Cancer; Prostate Cancer; Urothelial Carcinoma; Urothelial Cancer
• Intervention / Treatment: Diagnostic test: Echocardiogram; Drug: EP0057; Drug: olaparib; Diagnostic test: CT scan; Diagnostic test: CT chest, abdomen, and pelvis; Diagnostic test: Bone scan; Diagnostic test: ECG; Procedure: Biopsy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

• 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 ...

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1/Phase I - EP0057 (formerly CRLX101) + Olaparib; EP0057 + olaparib	Diagnostic test: Echocardiogram; At screening.; Other Names: Echo; Drug: EP0057; EP0057 (formerly CRLX101) intravenous (IV) every (Q) 2weeks Day 1 and Day 15, administered in 28-day cycles, until disease progression or development of intolerable side effects. Plus olaparib (by mouth (PO) days 3-13* and days 17-26*) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D). (* On days 13 and 26, only one dose of olaparib will be administered in the morning); Other Names: CRLX101; Drug: olaparib; Olaparib (by mouth (PO) days 3-13* and days 17-26* administered in 28-day cycles, until disease progression or development of intolerable side effects Plus EP0057 (formerly CRLX101) (intravenous (IV) every (Q) 2 weeks, Day 1 and Day 15) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D). (* On days 13 and 26, only one dose of olaparib will be administered in the morning).; Other Names: Lynparza; Diagnostic test: CT scan; Screening and baseline.; Other Names: Computed tomography scan; Diagnostic test: CT chest, abdomen, and pelvis; Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression.; Diagnostic test: Bone scan; Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression.; Other Names: Bone scintigraphy; Diagnostic test: ECG; Screening, baseline, Day 1, Day 15 and cycle 2, Day 1.; Other Names: Electrocardiogram; Procedure: Biopsy; Baseline Day 4 and end of treatment/disease progression.
Experimental: 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D); EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D)	Diagnostic test: Echocardiogram; At screening.; Other Names: Echo; Drug: EP0057; EP0057 (formerly CRLX101) intravenous (IV) every (Q) 2weeks Day 1 and Day 15, administered in 28-day cycles, until disease progression or development of intolerable side effects. Plus olaparib (by mouth (PO) days 3-13* and days 17-26*) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D). (* On days 13 and 26, only one dose of olaparib will be administered in the morning); Other Names: CRLX101; Drug: olaparib; Olaparib (by mouth (PO) days 3-13* and days 17-26* administered in 28-day cycles, until disease progression or development of intolerable side effects Plus EP0057 (formerly CRLX101) (intravenous (IV) every (Q) 2 weeks, Day 1 and Day 15) administered in 28-day cycles, until disease progression or development of intolerable side effects. Phase (P)1: Dose Escalation P2: recommended phase 2 dose (RP2D). (* On days 13 and 26, only one dose of olaparib will be administered in the morning).; Other Names: Lynparza; Diagnostic test: CT scan; Screening and baseline.; Other Names: Computed tomography scan; Diagnostic test: CT chest, abdomen, and pelvis; Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression.; Diagnostic test: Bone scan; Metastatic castration-resistant prostate cancer (mCRPC) participants only at screening, baseline, cycle 2 Day 1, and end of treatment/disease progression.; Other Names: Bone scintigraphy; Diagnostic test: ECG; Screening, baseline, Day 1, Day 15 and cycle 2, Day 1.; Other Names: Electrocardiogram; Procedure: Biopsy; Baseline Day 4 and end of treatment/disease progression.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of EP0057 (CLRX101) in Participants With Refractory Cancers.	MTD/RP2D is the dose level at which no more than 1 of up to 6 participants experience dose-limiting toxicity (DLT) during the DLT evaluation period, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. DLTs will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 4). The following toxicities, occurring during cycle 1 of the study combination, will be considered DLTs if deemed drug-related: Grade 4 neutropenia complicated by fever ≥38.5C and/or documented infection; Grade 4 neutropenia that does not resolve within 7 days; Grade 4 thrombocytopenia that does not resolve within 7 days or grade 3-4 thrombocytopenia complicated with hemorrhage. Grade 4 anemia that does not resolve within 7 days despite optimal therapy; and inability to begin subsequent treatment course within 28 days of the scheduled date, due to study drug toxicity.	First 28 days
Phase I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Olaparib in Participants With Refractory Cancers.	MTD/RP2D is the dose level at which no more than 1 of up to 6 participants experience dose-limiting toxicity (DLT) during the DLT evaluation period, and the dose below that at which at least 2 (of ≤6) participants have DLT as a result of the drug. DLTs will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 4). The following toxicities, occurring during cycle 1 of the study combination, will be considered DLTs if deemed drug-related: Grade 4 neutropenia complicated by fever ≥38.5C and/or documented infection; Grade 4 neutropenia that does not resolve within 7 days; Grade 4 thrombocytopenia that does not resolve within 7 days or grade 3-4 thrombocytopenia complicated with hemorrhage. Grade 4 anemia that does not resolve within 7 days despite optimal therapy; and inability to begin subsequent treatment course within 28 days of the scheduled date, due to study drug toxicity.	First 28 days
Number of Dose Limiting Toxicities (DLTs) During the First Cycle	DLTs will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (Version 4). The following toxicities, occurring during cycle 1 of the study combination, will be considered DLTs if deemed drug-related: Grade 4 neutropenia complicated by fever ≥38.5C and/or documented infection; Grade 4 neutropenia that does not resolve within 7 days; Grade 4 thrombocytopenia that does not resolve within 7 days or grade 3-4 thrombocytopenia complicated with hemorrhage. Grade 4 anemia that does not resolve within 7 days despite optimal therapy; and inability to begin subsequent treatment course within 28 days of the scheduled date, due to study drug toxicity, and any Grade 3-4 non-hematologic toxicity except fatigue/asthenia <2 weeks in duration).	First 28 days
Expansion: Progression Free Survival (PFS) Rate in the Combination of Olaparib Plus EP0057 (CLRX101) at 16 Weeks in Small Cell Lung Cancer (SCLC) Participants	Determine if slightly more than 50% of participants may be identified as being without progression by 16 weeks. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	16 weeks
Expansion: Overall Response Rate (Complete Response (CR) + Partial Response (PR) of EP0057 (CLRX101) Plus Olaparib in Participants With Urothelial Carcinoma	Overall response rate is the best response recorded from the start of the treatment until disease progression/recurrence. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	8 weeks
Expansion: Overall Response Rate (Complete Response (CR) + Partial Response (PR) of EP0057 (CLRX101) Plus Olaparib in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC)	Determine if slightly more than 50% of participants may be identified as being without progression by 12 weeks. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrences of Toxicities Including Toxicity Type and Severity (Grades 1, 2, and 3) With Probable Association to Study Regimen in Participants on Expansion Cohorts	Occurrence is captured by subjective and objective data via participant assessment ad self-report. Toxicities including toxicity type and severity (Grades 1, 2, 3, and/or 4) with probable association to study regimen in participants on Expansion cohorts was measured by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 is mild. Grade 2 is moderate. Grade 3 is severe. Grade 4 is life-threatening.	Start of treatment through 30 days post last dose, an average of 8.26 months.
Progression-free Survival (PFS) on Expansion Cohorts	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.	Every 3 months post-treatment, up until date of death from any cause or an average of 9.57 months.
Progression-free Survival (PFS) of the Combination	PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progression was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.	Duration of time from start of treatment to time of progression or death, whichever occurs first, up to 2.5 years
Overall Survival (OS) of the Combination	OS is defined as the date of on-study to the date of death from any cause or last follow up.	Date of on-study to the date of death from any cause or last follow up, up to 2.5 years
Prostate-specific Antigen (PSA) on Metastatic Castration-Resistant Prostate Cancer (mCRPC) Expansion Cohort Reported at Time of Documented Partial Response (PR) With an 80% Confidence Interval	PSA levels in blood, date of cycle 1, Day 1 (C1D1) - Best response date. PSA levels were measured by the Enzyme-Linked Immunosorbent Assay (ELISA). Normal PSA level is ≤6.5 ng/mL for age 70-79 and an elevated level is not interpreted good or bad; a very high number is a strong indicator of prostate cancer; since this is a cohort of prostate cancer an elevated number is expected. Partial Response was assessed by the Response Evaluation Criteria in Solid Tumors in Solid Tumors (RECIST) guideline (version 1.1) and Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	40.71 weeks from start of treatment to best response date
Prostate-specific Antigen (PSA) on Metastatic Castration-Resistant Prostate Cancer (mCRPC) Expansion Cohort Reported at Time of Documented Partial Response (PR) an 95% Confidence Interval	PSA levels in blood were measured by the Enzyme-Linked Immunosorbent Assay (ELISA). Normal PSA level is ≤6.5 ng/mL for age 70-79 and an elevated level is not interpreted good or bad; a very high number is a strong indicator of prostate cancer; since this is a cohort of prostate cancer an elevated number is expected; it is noted that this number is decreased from the start of therapy. Partial Response was assessed by the Response Evaluation Criteria in Solid Tumors in Solid Tumors (RECIST) guideline (version 1.1) and Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.	40.71 weeks from start of treatment to best response date.
Duration of Response (DOR) of the Combination	DOR is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented. OS is determined from the start of treatment until death. Response was measured by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Complete response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Partial response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions.	At baseline and after every 2 cycles up until the date of first documented progression or an average of average 11.09 months.
Occurrences of Toxicities Including Toxicity Type and Severity (Grades 1, 2, 3, 4 and/or 5) With Probable Association to Study Regimen in Participants on Solid Tumor Cohorts	Occurrence is captured by subjective and objective data via participant assessment and self-report. Toxicities including toxicity type and severity (Grades 1, 2, 3, and/or 4) with probable association to study regimen in participants on Expansion cohorts was measured by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE).	Start of treatment through 30 days post last dose, up to 3.99 months
Maximum Observed Plasma Concentration of EP0057 (Both the Total Drug and Released Camptothecin) and Olaparib	Blood samples for pharmacokinetic (PK) analysis were collected at pre-dose, mid-infusion (30 minutes), end of infusion (EOI), and 1, 2, 12, 24, and 48 hours (hr) post-EOI. Samples were drawn into sodium heparin tubes, processed to plasma, and stored at -80°C. On Cycle 6 Day 1 (C6D1), additional samples were collected to evaluate EP0057 (CLRX101) accumulation and potential drug interactions. Total plasma concentrations of released camptothecin (CPT) were measured after acidification with 0.1 normality (N) hydrochloric acid (HCl) to stabilize the lactone form, followed by dilution and Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry, (UPLC-MS/MS) analysis. Noncompartmental analysis was used to calculate PK parameters. Concentrations below lower limit of quantification (LLOQ) was excluded. Maximum serum concentration (CMAX) values were recorded as observed.	Cycle 1 (pre-dose, mid-infusion (30 minutes), end of infusion (EOI), and 1, 2, 12, 24, and 48 hours (hr) post-EOI); and Cycle 6 Day 1.
Pharmacodynamic (PD) Activity of EP0057 in Surrogate Tissue Specimens	Drug concentrations in tissue specimens.	Baseline, Cycle 1, then every 2 cycles, and at progression
Pharmacodynamic (PD) Activity of EP0057 in Tumor Biopsy Specimens	Drug concentrations in tumor specimens.	Baseline, Cycle 1, then every 2 cycles, and at progression

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0)	Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.	Adverse Events was monitored/assessed from the first study intervention, Study Day 1 of Cycle 1 through 30 days after the study agent (s) was/were administered, an average of 6.08 months.

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Anish Thomas, M.D., National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Schmidt KT, Huitema ADR, Dorlo TPC, Peer CJ, Cordes LM, Sciuto L, Wroblewski S, Pommier Y, Madan RA, Thomas A, Figg WD. Population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors. Cancer Chemother Pharmacol. 2020 Oct;86(4):475-486. doi: 10.1007/s00280-020-04134-9. Epub 2020 Sep 8.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2016
• Primary Completion (Actual): April 19, 2023
• Study Completion (Actual): March 4, 2025

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 11, 2016
• First Posted (Estimated): May 12, 2016

Study Record Updates

• Last Update Posted (Actual): July 28, 2025
• Last Update Submitted That Met QC Criteria: July 15, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: PARP Inhibitor; Solid Tumors; Topoisomerase I (Top1); Camptothecins; Nanoparticle Drug Conjugate
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Prostatic Neoplasms; Lung Neoplasms; Small Cell Lung Carcinoma; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Olaparib
• Other Study ID Numbers: 160107; 16-C-0107

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request. In addition, all large-scale genomic sequencing data will be shared with subscribers to the database of Genotypes and Phenotypes (dbGaP).
• IPD Sharing Time Frame: Clinical data available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol Genomic Data Sharing (GDS) plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available via subscription to Biomedical Translational Research Information System (BTRIS) and with the permission of the study principal investigator (PI). Genomic data are made available via the database of Genotypes and Phenotypes (dbGaP) through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No