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

Study Overview
=================
Brief Summary
-----------------
Background: EP0057 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 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. CT scan Injection of EP0057 (twice per cycle) Olaparib prescription <TAB> 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.

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 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 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 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 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 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 Male or female 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 ECOG Performance Status of 0, 1 or 2 Phase II Male or female patients (Bullet) 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 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 (IV Q 2weeks) plus olaparib (PO BID days 3-13 and days 17-26 administered in 28-day cycles, until disease progression or development of intolerable side effects. The MTD of the combination will be used in Phase II. Patients in Phase II will receive, the RP2D at DL4R EP0057 12 mg/m^2 and olaparib 250 mg BID. Blood, tumor and hair samples will be collected at multiple time points for PK, PD analyses. Hair sample collection is optional. Tumor biopsies are optional for SCLC and UC patients and mandatory for mCRPC patients (only baseline biopsy is mandatory). Toxicity will be graded according to CTCAE version 4.0. Tumor assessments will be made using CT scans (chest, abdomen and pelvis) at baseline and after every 2 cycles (3 cycles for mCRPC) according to RECIST version 1.1. After discontinuation of study treatment, follow-up for survival will be carried out every 3 months. The maximum number of patients on the phase I portion of the trial is 30, the SCLC cohort in phase II may accrue up to 27 evaluable patients, urothelial carcinoma expansion cohort may accrue up to 34 patients and mCRPC may accrue up to 25 patients. Thus, the maximum number of evaluable patients who may enroll on this trial is 116. In order to allow for a small number of in-evaluable patients, the accrual ceiling will be set at 123. It is anticipated that approximately 1 to 2 patients per month may enroll onto this trial; the trial is expected to complete accrual in 6-8 years.

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

Conditions
-----------------
Urothelial Carcinoma, Urothelial Cancer, Lung Neoplasms, Small Cell Lung Cancer, Prostate Cancer

Intervention / Treatment
-----------------
* Drug: EP0057
* Drug: olaparib


Participation Criteria
=================
Eligibility Criteria
-----------------
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. 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 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 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, 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). Negative urine pregnancy test < =3 days prior to 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 SCLC Age >=18 years. Patients must have histologically or cytologically confirmed diagnosis of SCLC from a 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. 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 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 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 (>= 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 (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 ...

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1/Phase I<br>EP0057 + olaparib | Drug: EP0057<br>* EP0057 IV Q 2weeks Day 1 and Day 15, administered in 28 day cycles, until disease progression or development of intolerable side effects Plus olaparib (PO days 3-13* and days 17-26*) administered in 28 day cycles, until disease progression or development of intolerable side effects. P1: Dose Escalation P2: RP2D (* On days 13 and 26, only one dose of olaparib will be administered in the morning)<br>Drug: olaparib<br>* olaparib (PO days 3-13* and days 17-26* administered in 28 day cycles, until disease progression or development of intolerable side effects Plus EP0057 (IV Q 2weeks, Day 1 and Day 15) administered in 28 day cycles, until disease progression or development of intolerable side effects P1: Dose Escalation P2: RP2D (* On days 13 and 26, only one dose of olaparib will be administered in the morning)<br>|
| Experimental: 2/Phase II<br>EP0057 + olaparib at MTD/RP2D | Drug: EP0057<br>* EP0057 IV Q 2weeks Day 1 and Day 15, administered in 28 day cycles, until disease progression or development of intolerable side effects Plus olaparib (PO days 3-13* and days 17-26*) administered in 28 day cycles, until disease progression or development of intolerable side effects. P1: Dose Escalation P2: RP2D (* On days 13 and 26, only one dose of olaparib will be administered in the morning)<br>Drug: olaparib<br>* olaparib (PO days 3-13* and days 17-26* administered in 28 day cycles, until disease progression or development of intolerable side effects Plus EP0057 (IV Q 2weeks, Day 1 and Day 15) administered in 28 day cycles, until disease progression or development of intolerable side effects P1: Dose Escalation P2: RP2D (* On days 13 and 26, only one dose of olaparib will be administered in the morning)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expansion: To determine overall response rate of EP0057 plus olaparib in patients with mCRPC | Determine if slightly more than 50% of patients may be identified as being without progression by 12 weeks. | 12 weeks | 
| Expansion: To determine overall response rate of EP0057 plus olaparib in patients with urothelial carcinoma | Best response recorded from the start of the treatment until disease progression/recurrence. | 8 weeks | 
| Phase I: Determine the MTD/RP2D of EP0057 plus olaparib in patients with refractory cancers. | Number of DLTs during the first cycle. | 28 days | 
| Expansion: Determine the PFS rate in the combination of olaparib plus EP0057 at 16 weeks in SCLC patients. | Determine if slightly more than 50% of patients may be identified as being without progression by 16 weeks | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine safety in patients on expansion cohorts: table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen | List of adverse event frequency | Start of treatment through 30 days post last dose | 
| To determine 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. | Every 3 months post-treatment | 
| To determine duration of response and PSA on mCRPC expansion cohort | PSA levels in blood. | Every 12 weeks until progression | 
| Explore further the safety of the combination: table of toxicities including type, severity, time of onset, time of resolution and probable association with study regimen | List of adverse event frequency | Start of treatment through 30 days post last dose | 
| Evaluate the pharmacokinetic profile of EP0057 (both the total drug and released camptothecin) and olaparib in plasma | Drug levels in blood. | Cycles 1 and 6 | 
| Evaluate the pharmacodynamic (PD) activity of EP0057 in blood, surrogate tissue and tumor biopsy specimens. | Drug levels in blood. | Baseline, Cycle 1, then every 2 cycles, and at progression | 
| Determine the duration of response (DOR), overall survival (OS), and progression-free survival (PFS) of the combination | DOR is measured from the time measurement criteria are met for CR or 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. PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. | Every 3 months post-treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Topoisomerase I (Top1), Camptothecins, Nanoparticle Drug Conjugate, PARP Inhibitor, Solid Tumors