Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03985722 |
| Other study ID # |
GEIS 58 |
| Secondary ID |
2017-004771-32 |
| Status |
Active, not recruiting |
| Phase |
Phase 1
|
| First received |
|
| Last updated |
|
| Start date |
September 21, 2018 |
| Est. completion date |
May 5, 2024 |
Study information
| Verified date |
March 2023 |
| Source |
Grupo Espanol de Investigacion en Sarcomas |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Phase I, multicentre clinical trial of olaratumab plus trabectedin in patients with advanced
soft-tissue sarcoma.
Olaratumab plus trabectedin could be synergistic and with a manageable toxicity profile in
advanced STS.
The study is a phase I, non-randomised, one-armed, multicenter trial, open-label.
The dose escalation rules include patients in blocks of 3 o 6 patient. Treatment is a
combination of unlimited cycles of oralatumab and trabectedin.
Primary clinical study endpoint of phase I:
- Determine the maximum tolerated dose (MTD) or the recommended dose of olaratumab combined
with trabectedin in advanced soft tissue sarcoma
Secondary clinical study endpoints:
- Objective Response Rate (ORR): ORR is defined as the number of subjects with a Best
Overall Response (BOR) according to RECIST 1.1.
- Progression free survival (PFS): time to progression or death from treatment initiation.
- Overall survival (OS): Time from treatment initiation until death. Efficacy measured
through tumor response according to Choi criteria. The evaluation criteria will be based
on the identification of target lesions in baseline and their follow-up until tumor
progression.
- Correlation of clinical outcome with translational biomarkers.
- Quality of life (QoL) measured per QLQ-C30 questionnaire of EORTC
Description:
PHASE I DESIGN
The number of evaluable patients to be included in this trial is 25. However 28 patients will
be enrolled considering the possibility of 3 non-evaluable cases.
The dose escalation rules proceed as follows: escalating in cohorts of 3-6 patients per dose
level. Three patients are treated at a given dose level. If at least 2 patients are observed
to have dose-limiting toxicity (DLT), the prior dose level is defined as the maximum
tolerable dosage (MTD) (unless only 3 patients have been treated at that level, in which case
it is the tentative MTD). If 0 of the 3 patients are observed to have DLT, the dose level is
escalated one step for the next cohort of 3 patients, and the process continues as above. If
exactly 1 of the 3 patients treated show DLT, 3 additional patients are treated at the
current dose level. If none of these additional 3 patients show DLT, the dose level is
escalated for the next cohort of 3 patients, and the process continues as above; otherwise,
the prior dose level is defined as the MTD.
Dose-limiting toxicity (DLT) is usually defined as cycle 1 grade 3 or above toxicity,
excepting grade 3 neutropenia unaccompanied by either fever or infection. More specifically,
for this clinical trial, DLT will be applied only to either of the following toxicities
occurring during the first treatment cycle:
Hematological toxicity:
- Febrile neutropenia with documented Grade ≥3 infection or sepsis
- Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia complicated by haemorrhage
- Grade 4 neutropenia lasting 7 days or longer
Non-hematological toxicities:
Grade 3-4 events, excluding:
- Nausea or vomiting without appropriate antiemetic treatment.
- Grade 3 transaminitis will not be considered Dose Limiting Toxicity unless this would
entail a delay in the treatment administration. This Adverse Event (AE) is well known as
secondary effect of trabectedin in the first two cycles and has no clinical impact.
Dose-escalation levels:
LEVEL -1: Olaratumab 15 mg/Kg D1 and D8 + Trabectedin 0.9 mg/m2 D1 This is a security level
in case level 0 causes DLT.
LEVEL 0*: Olaratumab 15 mg/Kg D1 and D8 + Trabectedin 1.1 mg/m2 D1
LEVEL 1: Olaratumab 15 mg/Kg D1 and D8 + Trabectedin 1.3 mg/m2 D1
LEVEL 2: Olaratumab 15 mg/Kg D1 and D8 + Trabectedin 1.5 mg/m2 D1
LEVEL 3**: Olaratumab 20 mg/kg Cycle 1, Day 1 (C1D1) and Cycle 1, Day 8 (C1D8) (induction) +
Trabectedin 1.5 mg/m2 D1 Olaratumab 15 mg/kg D1 and D8 (maintenance) + Trabectedin 1.5 mg/m2
D1
* Dose starting level is 0.
**In the LEVEL 3 Olaratumab dose of 20 mg/kg will be considered only for the first 2 doses
(as induction doses, cycle 1 days 1 and 8)) and then, the maintenance dose will be 15 mg/m2
for the rest of cycles.
Each cycle encompasses 21 days. It is not allowed dose-escalation for one given patient.
For safety reasons the first patient will be followed for 1 week before any other patient can
be enrolled, given than the combination of trabectedin and olaratumab hasn't been
administered to any patient so far.
For the inclusion of the third patient in a given dose-level it is necessary to have all the
safety information of the first cycle of the previous 2 patients included in the same
dose-level. Before moving on to the next dose-level, at least three patients must have been
followed during 3 weeks (1 cycle).
The proposed trabectedin dose-level escalation is supported by previous phase I trials
focusing on trabectedin combination. In STS, the lowest level for trabectedin was 0.9 mg/m2
for combination with doxorubicin 60 mg/m2 and showed to be active61. With other
antiangiogenic agents, combination produced prolonged cytopenias. Therefore, starting level 0
uses Trabectedin 1.1mg/m2.
* Tumor samples to be collected: The most recent archive tumor sample (1 block) must be
donated for diagnosis confirmation and for biomarker analysis and another tumor sample after
2 cycles of olaratumab and trabectedin is also mandatory..
When feasible another tumor block should be collected after treatment.
* Translational study:
1. Evaluate the signalling pathways underlying the response to the combination of
olaratumab and trabectedin in formalin-fixe, paraffin-embedded (FFPE) samples, from STS
patients (HTG Molecular Oncology Biomarker Panel (OBP) Assay).
2. Correlate the potential predictive biomarkers (immunomodulatory signature) of the
response to olaratumab and trabectedin, with clinic results, such as progression-free
survival (PFS), overall survival (OS) and response assessment.
3. To correlate the activity of olaratumab plus trabectedin with gene expression profiling
in 3-methylcholanthrene (3-MCA) fibrosarcoma immunocompetent mice models.
Samples:
1. FFPE samples (pre-treatment), before enrolment and after cycle 2. Both biopsies are
mandatory. If the patient did not received any treatment in the last 6 months,
previously to the enrolment, any biopsy taken within this period will be acceptable to
the translational study.
2. When feasible, optionally for the patient, another tumor block should be collected after
the end of treatment.
3. Peripheral blood samples taken at baseline, cycle 1 days 8, pre-cycle 2 day 2, pre-cycle
3 day 1 and after documented response of progression and after progression in 1 PAXgene
tube and 2 BD Vacutainer® Cellular Preparation Tube (CPT)™.
