NIH Clinical Center Search the Studies: Study Number, Study Title

Protocol Details

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

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

16-C-0107

Sponsoring Institute

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 18
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

Adults who are or may become unable to consent;
Pregnant Women and Fetuses;
Neonates;
Children

Special Instructions

Currently Not Provided

Keywords

PARP Inhibitor;
Topoisomerase I (Top1);
Camptothecins;
Nanoparticle Drug Conjugate;
Solid Tumors

Recruitment Keyword(s)

None

Condition(s)

Urothelial Carcinoma;
Urothelial Cancer;
Lung Neoplasms;
Small Cell Lung Cancer;
Prostate Cancer

Investigational Drug(s)

Olaparib
EP0057

Investigational Device(s)

None

Intervention(s)

Drug: EP0057
Drug: olaparib

Supporting Site

National Cancer Institute

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.

--Back to Top--

Eligibility

INCLUSION CRITERIA:

Phase I:

-Patients must have 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 less than or equal to 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 greater than or equal 18 years.

-ECOG performance status less than or equal to 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 greater than or equal to 3,000/mcL

-- absolute neutrophil count >1,500/mcL without growth factor support

-- platelets greater than or equal 100,000/mcL without growth factor support

-- hemoglobin greater than or equal 9 g/dL and no blood transfusion within 4 weeks OR greater than 10 g/dL and no blood transfusion within 2 weeks.

-- total bilirubin less than or equal 1.5 x ULN (unless Gilbert s Disease)

-- AST(SGOT)/ALT(SGPT) less than or equal 2.5 X institutional upper limit of normal (less than or wqual to 5X ULN if liver mets)

-- creatinine less than ULN OR

-- creatinine clearance greater than or equal 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 less than or equal to 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 greater than or equal to18 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 less than or equal to 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 less than or equal to 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 greater than or equal to 3,000/mcL

-- absolute neutrophil count greater than or equal to 1,500/mcL without growth factor support

-- platelets greater than or equal to 100,000/mcL without growth factor support

--hemoglobin greater than or equal to 9 g/dL and no blood transfusion within 4 weeks OR greater than 10 g/dL and no blood transusion within 2 weeks

-- total bilirubin less than or equal to 1.5 x ULN (unless Gilbert s Disease)

-- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal (less than or equal to 5X ULN if liver mets)

-- creatinine less than ULN OR

-- creatinine clearance greater than or equal to 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 childbearing 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:

-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 including lymphadenopathy and visceral metastatic disease.

-Male or female patients greater than or equal to 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 therapy are permitted (2-week washout from therapy is required).

-Bisphosphonates and denosumab are permitted if on a stable dose for greater than equal to 4 weeks.

-ECOG 0-2

-Patients must have normal organ and marrow function as defined below:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL without growth factor support

- platelets greater than or equal to 100,000/mcL without growth factor support

- hemoglobin greater than or equal to 9 g/dL and no blood transfusion within 4 weeks OR hemoglobin >10 g/dL, and no blood transfusion within 2 weeks

- total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN for subjects with Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X institutional upper limit of normal (less than or equal to 5X ULN if liver mets)

- creatinine less than or equal to ULN OR

- creatinine clearance greater than or equal to 51 mL/min (calculated using the Cockroft-Gault formula) for patients with creatinine levels above institutional normal.

- PT/INR and aPTT within 1.25 X ULN institutional limits, except where a lupus anti-coagulant has been confirmed

-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 childbearing 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:

-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 less than or equal to 2

-Patients must have adequate bone marrow, hepatic, and renal function with:

- leukocytes greater than or equal to 3,000/mcL

- absolute neutrophil count greater than or equal to 1,500/mcL without growth factor support

- platelets greater than or equal to 100,000/mcL without growth factor support

- hemoglobin greater than or equal to 9 g/dL and no blood transfusion within 4 weeks OR hemoglobin > 10g/dL, and no blood transfusion within 2 weeks

- total bilirubin less than or equal to 1.5 x ULN (less than or equal to 3 (SqrRoot) ULN for subjects with Gilbert s Disease)

- AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal (less than or equal to 5X ULN if liver mets)

- creatinine less than or equal to ULN OR

- creatinine clearance greater than or equal to 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:

-Patients who are receiving any other investigational agents.

-Persistent toxicities (greater than or equal to 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 and its excipients

-Patients unable to swallow orally administered medication and patients with gastrointestinal disorders likely to interfere with absorption of the study medication.

-History of allergic reactions attributed to compounds of similar chemical or biologic composition to EP0057 and/or olaparib or other agents used in study.

-Patients receiving any medications or substances that are strong and moderate inhibitors or inducers of CYP3A are ineligible.

-Pregnant women are excluded from this study because EP0057 and/or olaparib are agents with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with EP0057 and/or olaparib, breastfeeding should be discontinued if the mother is treated with EP0057 and/or olaparib. These potential risks may also apply to other agents used in this study.

-HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with EP0057 and/or olaparib. In addition, these patients are at increased risk of lethal infections when treated with marrow suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.

-Prolongation of QT/QTc interval (QTc interval >500 msec) using the Fredericia method of QTc analysis or family history of long QT syndrome. If single reading is above these minimum ranges, then repeat test in triplicate and evaluate eligibility based on average value

-Any chronic or concurrent acute liver disease.

-History of stroke, transient ischemic attack (TIA), or myocardial infarction, within 6 months prior to C1D1

-Uncontrolled concurrent disease or illness including but not limited to:

-- symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia

-- unstable or untreated cardiac conditions or ejection fraction of <50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

-- uncontrolled diabetes mellitus

-- psychiatric illness that would limit compliance with study requirements, as determined by the Investigator

-Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.

EXCLUSION CRITERIA-mCRPC EXPANSION COHORT:

-Patients who have had prior treatment with olaparib or other camptothecin inhibitors.

-The patient has received chemotherapy, radiotherapy, biologic agents or enzalutamide within 3 weeks before the first dose of study treatment (nitrosoureas or mitomycin within 6 weeks). However, for patients receiving abiraterone, they must discontinue the medication at least 14 days before the first dose of study treatment.

-The patient has received any other type of investigational agent within 28 days before the first dose of study treatment.

-The patient has received radionuclide treatment within 6 weeks prior to the first dose of the study treatment

-Patients with evidence of CNS metastasis or leptomeningeal disease within 1 year prior to enrollment will be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with a remote history of brain metastases may be considered if they received sterilizing therapy to the CNS (resection or radiation) and have been CNS progression-free for the 1-year period. Baseline imaging to rule out brain metastases is not required for screening, but should be performed prior to study enrollment if clinically indicated.

-Patients receiving any medications or substances that are strong and moderate inhibitors or inducers of CYP3A are ineligible.

-The patient has not recovered to baseline or CTCAE less than or equal to Grade 1 from toxicity due to all prior therapies, including surgery, except alopecia and other non-clinically significant AEs.

-Uncontrolled concurrent disease or illness including but not limited to:

-- symptomatic congestive heart failure, unstable angina pectoris, clinically significant cardiac arrhythmia

-- unstable or untreated cardiac conditions or ejection fraction of <50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)

-- uncontrolled diabetes mellitus

-- psychiatric illness that would limit compliance with study requirements, as determined by the Investigator

-Any of the following within 6 months before the first dose of study treatment:

-- unstable angina pectoris

-- stroke (including TIA, or other ischemic event)

-- myocardial infarction

-Other clinically significant disorders such as:

-- active infection requiring intravenous treatment within 7 days of starting protocol treatment

-- serious non-healing wound/ulcer/bone fracture (excluding stable compression fracture) within 28 days before the first dose of study treatment

-HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with the study agent.

-HBV-or HCV-positive patients are ineligible

-Prolongation of QT/QTc interval (QTc interval >500 msec) using the Fredericia method of QTc analysis or family history of long QT syndrome. If single reading is above these minimum ranges, then repeat test in triplicate and evaluate eligibility based on average

value


--Back to Top--

Citations:

Not Provided

--Back to Top--

Contacts:

Principal Investigator

Referral Contact

For more information:

Anish Thomas, M.D.
National Cancer Institute (NCI)



Linda C. Sciuto, R.N.
National Cancer Institute (NCI)
National Institutes of Health
Building 10
Room 8D44
10 Center Drive
Bethesda, Maryland 20892
(240) 760-6117
lsciuto@mail.nih.gov

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
1-888-NCI-1937

Clinical Trials Number:

NCT02769962

--Back to Top--