relapsed Ewing sarcoma MedDRA version: 20.0 Level: PT Classification code 10015564 Term: Ewing's sarcoma recurrent System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10015562 Term: Ewing's sarcoma metastatic System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 20.0 Level: PT Classification code 10015560 Term: Ewing's sarcoma System Or
Conditions
Interventions
Product Name: niraparib
Pharmaceutical Form: Capsule
INN or Proposed INN: niraparib
CAS Number: 1038915-60-4
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
T
Sponsors
Sarcoma Alliance for Research Through Collaboration (SARC)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1) Histologically confirmed Ewing sarcoma 2) Evidence of EWS translocation by FISH or RT-PCR 3) Patient willing to undergo tumor biopsy at study entry for biologic correlates 4) Patient =18 years, must be willing to undergo on-treatment tumor biopsy unless medically contra-indicated. (On treatment biopsy optional in patients under 18 years) 5) Recurrent/refractory tumors with no known curative treatment options 6) Age =13 years 7) Life expectancy =3 months 8) ECOG performance status 0-2 9) Measurable disease on CT or MRI by RECIST v1.1 10) Adequate organ function: - Absolute Neutrophil Count (ANC) =1.0 x 10*9/L, Haemoglobin = 8g/dL, Platelets =100 x 10*9/L - Serum creatinine =1.5x upper limit of normal (ULN) or 24 hour creatinine clearance =50 mL/min - Serum bilirubin =1.5 X ULN, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =2.5 X ULN (if hepatic metastases present, AST and ALT must be =5 X ULN) 11) Patients must have received as a minimum a first line chemotherapy regimen consisting of at least 2 of the following agents: doxorubicin, cyclophosphamide, ifosfamide, etoposide 12) Time elapsed from previous therapy must be =3 weeks for systemic therapy, =2 weeks for radiation therapy or major surgery. Patients must be recovered sufficiently from adverse effects from prior treatments (= CTCAE grade 2) 13) Patients who have undergone autologous hematopoietic stem cell transplantation (HSCT) are eligible once they have recovered from all toxicities from therapy (= CTCAE grade 2) 14) Patients who have received allogeneic HSCT will be eligible 6 months after the procedure provided there is no evidence of active graft-versus-host disease and immunosuppressive treatment has been discontinued for at least 30 days 15) Patients with central nervous system (CNS) disease are eligible if they have received prior radiotherapy or surgery to sites of CNS metastatic disease, have been off glucocorticoids for at least 4 weeks, have no overt evidence of neurological deficit and are = 6 weeks from completion of brain irradiation 16) Able to provide written informed consent 17) Females of childbearing potential as well as males and their partners must agree to use an effective form of contraception during the study and for 6 months following the last dose of study medication. An effective form of contraception is - use of a double barrier method or commitment to sexual abstinence. Are the trial subjects under 18? yes Number of subjects for this age range: 15 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 30 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 0
Exclusion criteria
Exclusion criteria: 1) Clinically significant unrelated illness which would compromise the patient’s ability to tolerate the investigational agent or be likely to interfere with the study procedures or results 2) Patients with baseline QTcF >480 msec 3) Inability to swallow capsules 4) Known hypersensitivity to any of the components of niraparib or prior hypersensitivity reactions to that class of drugs 5) Known hypersensitivity temozolomide or any of its components, or dacarbazine (DTIC) 6) Concomitant use of any other investigational or anticancer agent 7) Pregnant patients or patients who are breast feeding. 8) Other clinically significant malignant disease diagnosed within the previous 5 years, excluding intra-epithelial cervical neoplasia or non-melanoma skin cancer 9) Active central nervous system disease 10) Known history of MDS. 11) Known persistent (> 4 weeks) = Grade 2 neutropenia, = Grade 2 thrombocytopenia or > Grade 3 anemia from prior cancer therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary aim of the study is to find the optimal dose of a combination of niraparib and temozolomide or irinotecan that can safely be given to patients with relapsed Ewing sarcoma (the maximum tolerated dose) and what side effects limit the doses we can give (dose limiting toxicities). ;Secondary Objective: - Tumour response rate (how much the tumour/s shrink on scans) - Progression free survival (how long it takes for tumour/s to grow) - Investigate how the drug combination affects the tumour and blood cells - Evaluate expression of genes and proteins in tumour cells;Primary end point(s): The primary outcome measure is the maximum tolerated dose of the combination of niraparib and temozolomide (Arm 1) and noraparib and irinotecan (Arm 2).;Timepoint(s) of evaluation of this end point: Patients will have blood tests every 3 days for first cycle and clinical assessment including history examination and vital signs weekly to assess for dose-limiting toxicities in order to determine the maximum tolerated dose.. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): 1. Tumour response rate (per RECIST 1.1) of patients with ES treated with niraparib and TMZ or Irinitecan. 2. Progression free survival (PFS), duration of response, and 4- and 6-month PFS rate of patients treated with niraparib and TMZ or Irinotecan. 3. Evaluation of pharmacodynamic markers of response to PARP inhibition in combination with TMZ or Irinotecan including measurement of PAR, ?H2Ax induction and other markers of DNA repair and DNA damage. 4.Evaluation and comparison of expression of candidate metastasis-associated genes and proteins in paired samples obtained from primary and relapsed tumors including CXCR4, MKL1, MKL2 and LGR5. ;Timepoint(s) of evaluation of this end point: 1. Tumour response will be radiologically assessed every 2 cycles for the first 6 cycles, then every 3 cycles. 2. PFS and duration of response will be calculated every 8-12 weeks on the basis of radiological assessment. 3. Blood samples will be taken to evaluate PD markers at seven time points according to the protocol. Tumour samples will be taken pre-treatment, on treatment on Cycle 2 Day 8 as well as at the end of the treatment (optional). 4. This will be evaluated comparing archival tumour samples and biopsy tissue sample on study entry. | — |
Countries
France, Germany, United Kingdom, United States
Contacts
Public ContactDr Sandra Strauss
University College London Hospital NHS Foundation Trust
Outcome results
None listed