Trial of EP0057, a Nanoparticle Camptothecin With Olaparib in People With Relapsed/Refractory Small Cell Lung Cancer
- Conditions
- Small Cell Lung CancerProstate CancerLung NeoplasmsUrothelial CarcinomaUrothelial Cancer
- Interventions
- Diagnostic Test: CT scanDiagnostic Test: CT chest, abdomen, and pelvisDiagnostic Test: Bone scanDiagnostic Test: ECGDiagnostic Test: EchocardiogramProcedure: Biopsy
- Registration Number
- NCT02769962
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 45
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 1/Phase I - EP0057 (formerly CRLX101) + Olaparib EP0057 EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib olaparib EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib CT scan EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib CT chest, abdomen, and pelvis EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib Bone scan EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib ECG EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib Echocardiogram EP0057 + olaparib 1/Phase I - EP0057 (formerly CRLX101) + Olaparib Biopsy EP0057 + olaparib 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) EP0057 EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) olaparib EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) CT scan EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) CT chest, abdomen, and pelvis EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) Bone scan EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) ECG EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) Echocardiogram EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D) 2/Phase II - EP0057 + Olaparib at Maximum Tolerated Dose/Recommended Phase 2 Dose (MTD/RP2D) Biopsy EP0057 (formerly CRLX101) + olaparib at maximum tolerated dose/recommended phase 2 dose (MTD/RP2D)
- Primary Outcome Measures
Name Time Method Phase I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of EP0057 (CLRX101) in Participants With Refractory Cancers. First 28 days 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.
Phase I: Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of Olaparib in Participants With Refractory Cancers. First 28 days 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.
Number of Dose Limiting Toxicities (DLTs) During the First Cycle First 28 days 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).
Expansion: Progression Free Survival (PFS) Rate in the Combination of Olaparib Plus EP0057 (CLRX101) at 16 Weeks in Small Cell Lung Cancer (SCLC) Participants 16 weeks 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.
Expansion: Overall Response Rate (Complete Response (CR) + Partial Response (PR) of EP0057 (CLRX101) Plus Olaparib in Participants With Urothelial Carcinoma 8 weeks 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.
Expansion: Overall Response Rate (Complete Response (CR) + Partial Response (PR) of EP0057 (CLRX101) Plus Olaparib in Participants With Metastatic Castration-Resistant Prostate Cancer (mCRPC) 12 weeks 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.
- Secondary Outcome Measures
Name Time Method Occurrences of Toxicities Including Toxicity Type and Severity (Grades 1, 2, and 3) With Probable Association to Study Regimen in Participants on Expansion Cohorts Start of treatment through 30 days post last dose, an average of 8.26 months. 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.
Progression-free Survival (PFS) on Expansion Cohorts Every 3 months post-treatment, up until date of death from any cause or an average of 9.57 months. 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.
Progression-free Survival (PFS) of the Combination Duration of time from start of treatment to time of progression or death, whichever occurs first, up to 2.5 years 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.
Overall Survival (OS) of the Combination Date of on-study to the date of death from any cause or last follow up, up to 2.5 years OS is defined as the date of on-study to the date of death from any cause or last follow up.
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 40.71 weeks from start of treatment to best response date 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.
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 40.71 weeks from start of treatment to best response date. 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.
Duration of Response (DOR) of the Combination At baseline and after every 2 cycles up until the date of first documented progression or an average of average 11.09 months. 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.
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 Start of treatment through 30 days post last dose, up to 3.99 months 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).
Maximum Observed Plasma Concentration of EP0057 (Both the Total Drug and Released Camptothecin) and Olaparib 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. 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.
Pharmacodynamic (PD) Activity of EP0057 in Surrogate Tissue Specimens Baseline, Cycle 1, then every 2 cycles, and at progression Drug concentrations in tissue specimens.
Pharmacodynamic (PD) Activity of EP0057 in Tumor Biopsy Specimens Baseline, Cycle 1, then every 2 cycles, and at progression Drug concentrations in tumor specimens.
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States
National Institutes of Health Clinical Center🇺🇸Bethesda, Maryland, United States