Neoplasms

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Genital Diseases

Genital Diseases, Male

Urogenital Diseases

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Carcinoma, Bronchogenic

Bronchial Neoplasms

Small Cell Lung Cancer

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Antineoplastic Agents

All Drugs and Chemicals

Olaparib

Camptothecin

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

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)

EP0057

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)

olaparib

Danielle F Pinkiert, R.N.

Anish Thomas, M.D.

For more information at the NIH Clinical Center contact National Cancer Institute Referral Office

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.

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.

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

.All 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 dbGaP.

Determine if slightly more than 50% of patients may be identified as being without progression by 12 weeks.

Best response recorded from the start of the treatment until disease progression/recurrence.

Determine if slightly more than 50% of patients may be identified as being without progression by 16 weeks

PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer	NCT02769962	Urothelial Carc... Urothelial Canc... Lung Neoplasms Small Cell Lung... Prostate Cancer	EP0057 olaparib	18 Years -	National Institutes of Health Clinical Center (CC)
Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer	NCT02769962	Urothelial Carc... Urothelial Canc... Lung Neoplasms Small Cell Lung... Prostate Cancer	EP0057 olaparib	18 Years -	National Institutes of Health Clinical Center (CC)

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