Olaratumab Plus Trabectedin in Advanced Soft-tissue Sarcoma Patients Soft-tissue Sarcoma Patients

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)™.