| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ewing sarcoma that has come back (relapsed) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015564 |
| E.1.2 | Term | Ewing's sarcoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015562 |
| E.1.2 | Term | Ewing's sarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10015560 |
| E.1.2 | Term | Ewing's sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| 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). |
|
| E.2.2 | Secondary objectives of the trial |
- 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 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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.
|
|
| E.4 | Principal 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
|
|
| E.5 End points |
| E.5.1 | 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). |
|
| E.5.1.1 | 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.. |
|
| E.5.2 | 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, γH2Ax 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.
|
|
| E.5.2.1 | 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.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| new combination of treatment |
|
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 3 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Germany |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the trial will be progression or death of all patients on the trial |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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