Platinum-resistant epithelial cancer of the ovary, fallopian tube or primary peritoneum (here termed ‘ovarian cancer’), who have been treated with 3 or more prior chemotherapy regimens.
Conditions
Interventions
Product Name: Acelarin
Product Code: NUC-1031
Pharmaceutical Form: Solution for injection
INN or Proposed INN: Proposed INN to be confirmed in May 2017
CAS Number: 1562406-27-2
Current Sponsor code: N
Sponsors
NuCana plc
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Provision of signed written informed consent. Patients with easily accessible tumour must also consent to the collection of fresh biopsy tumour tissue to participate in the study. Patients who do not have easily accessible tumour for biopsy should not be put at undue risk for sample collection and these patients remain eligible for the study. 2. Original diagnosis and/or histological confirmation of high-grade serous, high-grade endometrioid, undifferentiated/unclassifiable epithelial ovarian, fallopian tube or primary peritoneal cancer. 3. Platinum-free interval since last line of platinum of less than 6 months (182 days). 4. Received at least 3 prior chemotherapy-containing regimens. Prior treatment with only non-cytotoxic agents (e.g. hormones, antibodies or PARP inhibitors) is permitted, but should not be considered as one of the ‘3 prior chemotherapy-containing regimens’. Adjuvant chemotherapy should be counted as a prior line of chemotherapy. 5. Age =18 years. 6. ECOG performance status of 0 or 1. 7. Measurable disease as defined by RECIST. 8. Adequate bone marrow function as defined by: absolute neutrophil count (ANC) =1.5×10^9/l, platelet count =100×10^9/l and hemoglobin level =10.0 g/dl. 9. Adequate liver function, as defined by: serum total bilirubin =1.5×upper limit of normal (ULN), AST and ALT =2.5×ULN (or =5×ULN if liver metastases are present). 10. Adequate renal function assessed as Cr =65 years) yes F.1.3.1 Number of subjects for this age range 14
Exclusion criteria
Exclusion criteria: 1. Disease classified as primary platinum refractory (i.e. progression while receiving initial line of platinum-based therapy or within 4 weeks of the last platinum dose of the initial regimen). 2. Received fewer than 3 prior chemotherapy-containing regimens. 3. Prior therapy with single-agent gemcitabine (prior gemcitabine plus carboplatin combination treatment is permitted). 4. Prior history of hypersensitivity to gemcitabine. 5. History of allergic reactions attributed to the components of the diluents used with NUC-1031. 6. Mucinous, low-grade serous, low-grade endometrioid, carcinosarcoma, clear cell or undifferentiated/unclassifiable histology. 7. Symptomatic CNS or leptomeningeal metastases. 8. Prior chemotherapy, radiotherapy (other than short cycle of palliative radiotherapy for bone pain), treatment with a VEGF inhibitor, PARP inhibitor or immunotherapy within 21 days of first receipt of study drug (within 6 weeks for nitrosoureas and mitomycin C); hormone therapy within 14 days of first receipt of study drug; or blood transfusion, or use of hematopoietic growth factors within 28 days of first receipt of study drug. 9. Residual toxicities from chemotherapy or radiotherapy, which have not regressed to Grade =1 severity (NCI CTCAE v4), except for neuropathy (Grade 2 allowed) or alopecia. 10. Patients who have a history of another malignancy diagnosed within the past 5 years, with the exception of adequately treated non-melanoma skin cancer curatively treated carcinoma in situ of the cervix or ductal carcinoma in situ (DCIS) of the breast. Patients with previous invasive cancers are eligible if treatment was completed more than 5 years prior to initiating the current study treatment, and the patient has had no evidence of recurrence since then. 11. Presence of an uncontrolled concomitant illness or active infection requiring IV antibiotics. 12. Presence of any serious illnesses, medical conditions, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient's participation in the study, or with the interpretation of the results. 13. Known HIV positive or known active hepatitis B or C. 14. Any condition (e.g. known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the patient’s ability to sign the informed consent and undergo study procedures. 15. Currently pregnant, lactating or breastfeeding. 16. QTc interval >450 milliseconds. 17. Concomitant use of drugs known to prolong QT/QTc interval. 18. History of radiologically confirmed bowel obstruction (including sub-occlusive disease) relating to ovarian cancer within 6 months prior to the first receipt of study drug. 19. Patients who have received a live vaccination within 4 weeks of first planned NUC-1031 dose administration.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the anti-tumor activity of NUC-1031 as measured by Objective Response Rate measured by RECIST at the selected dose level (500 mg/m2 or 750 mg/m2). Primary assessment will be done by a blinded independent central reviewer.;Secondary Objective: • To assess additional measures of anti-tumor activity, including: - Change from baseline in tumor size. - Duration of Overall Response (per RECIST). - Progression-Free Survival (per RECIST). - Time to Disease Progression (per RECIST). - Disease Control Rate (CR+PR+SD, per RECIST). - Best GCIG Overall Response, combining the change in CA125 from baseline with RECIST assessment (per GCIG criteria). - Overall Survival. • To further assess the safety profile of NUC-1031 administered over multiple cycles. • To explore relationships between NUC-1031 PK, pharmacodynamics and clinical activity. • To describe the effects of NUC-1031 on ovarian cancer symptoms. Exploratory Objectives: • To establish the expression of genomic, transcriptomic and proteomic biomarkers in PBMCs and tissue samples, which may help predict patients who derive additional benefit from NUC-1031. • To explore the impact of treatment and disease state on health state utility by EQ-5D-5L.;Primary end point(s): Objective Response Rate (per RECIST) at the selected dose level (500 mg/m2 or 750 mg/m2), assessed by a blinded independent central reviewer.;Timepoint(s) of evaluation of this end point: Tumour measurements and disease response assessments are to be performed every 8 weeks (±7 days) from C1D1. If the patient stops study treatment for reasons other than radiologically confirmed Progressive Disease (PD), tumour measurements and disease response assessments should continue every 8 weeks (±7 days) from C1D1 thereafter until PD is radiologically confirmed. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy • Change from baseline in tumour size. • Duration of Overall Response (per RECIST). • Progression-Free Survival (per RECIST). • Time to Disease Progression (per RECIST). • Disease Control Rate (CR+PR+SD, per RECIST). • Best GCIG Overall Response, combining the change in CA125 from baseline with RECIST assessment (per GCIG criteria). • Overall Survival. • Assessment of ovarian cancer symptoms using the FOSI-18 questionnaire. Safety • Treatment-emergent adverse events (per NCI CTCAE v4). • Clinically-significant laboratory changes (per NCI CTCAE v4). • Changes in physical exam, vital signs and serial ECGs. Pharmacokinetics The PK of single and multiple-dose NUC-1031 will be assessed, including: • Maximum concentration (Cmax). • Area under the curve (AUC). • Half-life (T1/2). • Volume of distribution (Vd). • Clearance (CL). PK of the following analytes will be measured: • In plasma/urine: NUC-1031, dFdC and dFdU. • In PBMCs: NUC-1031, dFdC, dFdCMP, dFdCDP, dFdCTP and dFdU. Exploratory Endpoints • Assessment of candidate genomic, transcriptomic and proteomic biomarkers of resistance/sensitivity to NUC-1031 in PBMCs and tissue samples. Examples of candidate markers include cytidine deaminase (CDA), deoxycytidine kinase (dCK), human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase M1 (RRM1) and RRM2. • Assessment of impact of treatment and disease state on health state utility by EQ-5D-5L.;Timepoint(s) of evaluation of this end point: End of study. | — |
Countries
United Kingdom, United States
Contacts
Public ContactNuCana Clinical Study Information
NuCana plc
Outcome results
None listed