Clinical trial NCT02805725
Conditions: Soft-tissue Sarcomas
Keywords: Advanced solid tumor Advanced pretreated soft tissue sarcomas Phase I/II trial Dose escalation PK study
Sponsor: Institut Bergonié
Start date: 2015-12-01; Completion date: 2021-12-01
Enrollment: 50 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
Assessment of the efficacy and safety of trabectedin and metronomic cyclophosphamide (CP) in patients with advanced pretreated soft-tissue sarcomas, once the Maximum Tolerated Dose (MTD) have been determined (phase I trial).

Detailed description:
Phase I: Multicenter Phase I trial based on a dose escalation study design (3+3 traditional design). Phase II: One-arm, multicenter Phase II trial based on two-stage optimal Simon's design.

Arms: arm 1: Trabectedin 0.30 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 1 of dose escalation.

Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

1 cycle = 28 days arm 2: Trabectedin 0.40 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 2 of dose escalation.

Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

1 cycle = 28 days arm 3: Trabectedin 0.50 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 3 of dose escalation.

Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

1 cycle = 28 days arm 4: Trabectedin 0.60 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in cohort 4 of dose escalation.

Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

1 cycle = 28 days arm 5: Trabectedin 0.50 mg/m2 will be administered intravenously (IV), 3-hour infusion weekly for three consecutive weeks (days 1, 8 and 15) every 4 weeks, in the phase II part of the study.

Cyclophosphamide (CP) will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule.

1 cycle = 28 days
Interventions: intervention 1: Phase 1: Trabectedin intervention 2: Phase 2: Trabectedin intervention 3: Phase 1: Cyclophosphamide intervention 4: Phase 2: Cyclophosphamide
Intervention descriptions: intervention 1: Phase I trial based on a dose escalating study design (3+3 traditional design) assessing four dose levels of Trabectedin in combination with metronomic cyclophosphamide (CP).

A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) intervention 2: Patients will be included in a single-arm phase II trial. Administrated dose will be the RP2D defined in the dose escalation part of the trial. The design will follow a two-stage Simon's optimal design.

All patients will be treated at the RP2D of trabectedin defined in the preliminary phase I trial with the same schedule as in the phase I trial. intervention 3: A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or any other changes unacceptable for further treatment, etc.) Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off schedule. intervention 4: All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 1 sur 11 
TARGETING MICROENVIRONMENT AND CELLULAR IMMUNITY IN SARCOMAS 
WEEKLY TRABECTEDIN COMBINED WITH METRONOMIC 
CYCLOPHOSPHAMIDE IN PATIENTS WITH ADVANCED PRETREATED SOFT-
TISSUE SARCOMAS 
A PHASE I/II STUDY FROM THE FRENCH SARCOMA GROUP 
 
Protocol TARMIC 
 
VERSION N°6.0 DU |11|12|2018|- N° : IB 2015-04 
 
Intégrant la modification substantielle n°1 du 20/01/2016 
Intégrant la modification substantielle n°2 du 28/10/2016 
Intégrant la modification substantielle n°3 du 26/04/2017 
Intégrant la modification substantielle n°4 du 19/10/2017 
Intégrant la modification substantielle n°5 du 11/12/2018 
 
 
 
EudraCT n° 2015-002760-16 
 
 
 
 
 
 
Coordinating Investigator 
Antoine ITALIANO, MD, PhD 
Department of Medical Oncology 
Medical Oncologist  
Institut Bergonié 
 
229, cours de l’Argonne – 33076 BORDEAUX Cedex, France 
 
Tél : 05.56.33.78.05 – Fax : 05.56.33.04.85 – E-mail : a.italiano@bordeaux.unicancer.fr 
 
 
 
 
Clinical Research Unit 
Simone MATHOULIN-PÉLISSIER, MD, PhD 
Institut Bergonié, Bordeaux 
Responsable UREC 
Marina PULIDO, MsC 
Institut Bergonié, Bordeaux 
Biostatisticien, UREC 
Sabrina SELLAN-ALBERT, MsC 
Institut Bergonié, Bordeaux 
Attachée de Recherche Clinique, UREC 
 
 
 
Pharmacist and Vigilance Unit 
 
Emilie TOULZA, PharmD 
Institut Bergonié, Bordeaux 
 
 
 
 
 
 
 
 
SPONSOR 
INSTITUT BERGONIE 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 2 sur 11 
APPROVAL AND SIGNATURES OF PROTOCOL  
Protocol title : Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly trabectedin combined with Metronomic 
Cyclophosphamide in Patients with Advanced Pretreated Soft-tissue Sarcomas. A Phase I/II study from the French Sarcoma 
Group. 
 
Competent 
authority 
Name : ANSM 
Date de l’autorisation initiale 
Autorisation de la modification substantielle 1 
Autorisation de la modification substantielle 2 
Autorisation de la modification substantielle 3 
Autorisation de la modification substantielle 4 
Autorisation de la modification substantielle 5 
19/10/2015 
10/03/2016 
29/12/2016 
13/10/2017 
02/05/2018 
06/02/2019 
Référence :  
151077A-12 
Ethic  
Committee 
Name : CPP du Sud-Ouest et 
d'Outre-Mer III 
Date de l’avis favorable initial 
Autorisation de la modification substantielle 1 
Autorisation de la modification substantielle 2 
Autorisation de la modification substantielle 3 
Autorisation de la modification substantielle 4 
Autorisation de la modification substantielle 5 
30/09/2015 
24/02/2016 
30/11/2016 
31/05/2017 
31/01/2018 
27/02/2019 
Référence :  
2015/94 
 
Name and 
responsability 
Address 
Date 
Signature 
Managing Director 
Pr François-Xavier MAHON 
Institut Bergonié – Bordeaux  
Tél:05.56.33.33.33 / Fax: 05.56.33.33.30 
Mail : f.mahon@bordeaux.unicancer.fr  
11/12/2018 
 
Coordinating 
Investigator 
Pr Antoine ITALIANO  
Institut Bergonié – Bordeaux  
Tél 05.56.33.78.05 / Fax : 05.56.33.04.85 
Mail : a.italiano@bordeaux.unicancer.fr  
11/12/2018 
Clinical Research 
Manager 
Pr Simone MATHOULIN-PÉLISSIER 
Institut Bergonié – Bordeaux  
Tél:05.56.33.33.98 / Fax: 05.56.33.04.66 
Mail : s.mathoulin@bordeaux.unicancer.fr  
11/12/2018 
Biostatistician  
Marina PULIDO 
Institut Bergonié – Bordeaux  
Tél:05.24.07.19.29/Fax: 05.24.07.19.49 
Mail : m.pulido@bordeaux.unicancer.fr  
11/12/2018 
Clinical Research 
Assistant 
Sabrina SELLAN-ALBERT 
Institut Bergonié – Bordeaux  
Tél:05.56.33.78.05/Fax:05.56.33.04.85 
Mail : s.albert@bordeaux.unicancer.fr  
11/12/2018 
Pharmacist 
Emilie TOULZA 
Institut Bergonié – Bordeaux  
Tél:05.47.30.60.53/Fax: 05.56.33.04.85 
Mail : e.toulza@bordeaux.unicancer.fr  
11/12/2018 
I acknowledge having read the whole protocol, and I pledge to lead this protocol in accordance with the Good Clinical Practice 
(decision of 24 November 2006), the Public Health Law No. 2006-806 of August 09, 2004 and the implementing Decree n° 
2006-477 of April 26, 2006 and as described in this document.  
I assume my responsibilities as referent investigator including:  
- Collection of informed consent, dated and signed by patients before any selection procedure in the protocol, 
- Validation of case report forms, completed for each patient included in the study,  
- Direct access to source documents for verification by the clinical research assistant (CRA) commissioned by the sponsor,  
- Archiving of critical documents of the study for a 15 year-period. 
 
Name and address of the hospital 
 
Name of the Coordinating Investigator :  
 
Date : |__|__| |__|__| |__|__|__|__| 
 
Signature : 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 3 sur 11 
 
Title of the study  
Targeting Microenvironment and Cellular Immunity in Sarcomas Weekly trabectedin 
combined with Metronomic Cyclophosphamide in Patients with Advanced Pretreated 
Soft-tissue Sarcomas. A Phase I/II study from the French Sarcoma Group 
Abbreviation  
of the trial 
TARMIC 
Sponsor Identification 
Institut Bergonié, Regional Comprehensive Cancer Center 
Coordinating 
Investigator 
Professor Antoine ITALIANO  
Department of Medical Oncology 
Number of 
investigational sites 
planned 
Phase I:  
1 centre 
- Institut Bergonié 
Phase II:  
1 centre 
- Institut Bergonié  
Number of patients 
Phase I: 12 - 24 patients 
Phase II: 47 patients 
Duration of the study 
Planned enrollment period: 48 months 
Treatment duration : until progression 
Follow-up: 12 months 
Study period: 5 years 
Medical conditions 
Adult patients with unresectable locally advanced or metastatic soft-tissue sarcoma 
Study design 
Phase I: Monocentric Phase I trial based on a dose escalation study design (3+3 traditional 
design).  
Phase II: One-arm, monocentric Phase II trial based on two-stage optimal Simon’s design. 
Objectives 
Phase I: 
Primary objective:  
To establish the recommended phase II dose (RP2D), the maximum tolerated dose (MTD) 
evaluated on the first cycle (D1 to D28), the safety profile, and the dose limiting toxicities 
(DLT) of trabectedin given in combination with CP.  
 
Secondary objectives:  
• 
To evaluate preliminary signs of antitumor activity of trabectedin given in combination 
with CP in terms of objective response under treatment (as per RECIST v1.1 criteria), 6-
month non-progression (as per RECIST v1.1 criteria), 1-year progression-free survival 
(PFS) (as per RECIST v1.1 criteria) and 1-year overall survival (OS).  
• 
To describe the pharmacokinetics (PK) of trabectedin given in combination with CP. 
• 
Biomarker study: To perform pharmacodynamic (PD)/mechanism of action (MOA) 
biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic and 
immunologic biomarkers in blood at baseline and different study time points). 
• 
Ancillary study: To assess pharmacodynamics changes of Tissue Associated Macrophage 
(TAM) infiltration and additional tumor markers on fresh pre-treatment and on-treatment 
tumor biopsies. 
 
Phase II:  
Primary objective:  
To evaluate the antitumor activity of trabectedin in association with CP in terms of non-
progression at 6 months (complete or partial responses or stable disease more than 24 weeks, as 
per RECIST v1.1 criteria) after centralized radiological review, in patients with advanced STS 
who already failed anthracycline-containing chemotherapy (CT). 
 
Secondary objectives:  
• 
To evaluate the antitumor activity of trabectedin in association with CP in terms of 
objective response under treatment (as per RECIST v1.1 criteria), 1-year progression free 
survival (PFS) (as per RECIST v1.1 criteria) and 1-year overall survival (OS).  
• 
To evaluate the toxicity of trabectedin in association with CP (NCI-CTC v4). 
• 
Optional biomarker study: To perform pharmacodynamic (PD)/mechanism of action 
(MOA) biomarkers analysis as well as predictive biomarkers analysis (levels of angiogenic 
and immunologic biomarkers in blood at baseline and different study time points). 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 4 sur 11 
• 
Optional ancillary study: To assess pharmacodynamics changes of TAM infiltration and 
additional tumor markers on fresh pre-treatment and on-treatment tumor biopsies. 
Inclusion criteria 
1. Patients with soft-tissue sarcoma histologically confirmed by central review (Pr. Coindre 
team), except in case of diagnosis was already confirmed by the RRePS Network, 
2. Metastatic or unresectable locally advanced disease, 
3. Age ≥ 18 years, 
4. Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤ 2, 
5. Life expectancy > 3 months, 
6. Measurable disease according to RECIST v1.1 (lesion in previously irradiated field can be 
considered as measurable if progressive at inclusion according to RECIST v1.1), 
7. For patients included in phase II study, progressive disease according to RECIST v1.1 criteria 
diagnosed on the basis of two CT scan or MRI obtained at an interval less than 6 months in the 
period of 12 months prior to inclusion and confirmed by central review. PET-CT are also 
acceptable (two PET-CT or a CT scan compared with a PET-CT), under the following 
conditions:  
a. Target lesions must be evaluable on PET-CT according to RECIST v1.1. This will be 
determined by the central radiologist at the time of the review. If target lesions are not 
evaluable according to RECIST v1.1, patient will not be eligible. 
b. PET-CT is acceptable only for the central review. If not available, an additional CT scan 
(or MRI) must be performed within four weeks prior to Day 1 of cycle 1 (+1 week 
tolerance) to be used as baseline tumor assessment. Patient must be then followed using 
the same technique throughout the duration of the protocol, 
8. Previous use of Anthracyclines, 
9. Have provided tissue from an archival tissue sample, 
10. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological 
treatment and/or radiotherapy, 
11. Adequate hematological, renal, metabolic and hepatic function: 
a. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell [RBC] 
transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 109/l, 
leukocyte count ≥ 2.5 x 109/l and platelet count ≥ 100 x 109/l 
b. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤ 2.5 x upper limit 
of normality (ULN) (≤ 5 in case of extensive liver involvement) and alkaline phosphatase 
(AP) ≤ 2.5 x ULN 
c. Total bilirubin ≤ ULN. 
d. Albumin ≥ 25 g/l 
e. Serum Creatinine ≤ 1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min 
(according to Cockroft formula). 
f. Creatine Phosphokinase (CPK) ≤ 2.5 x ULN 
12. Women of childbearing potential must have a negative serum pregnancy test before study 
entry. Both women and men must agree to use a medically acceptable method of contraception 
throughout the treatment period and for six months after discontinuation of treatment. 
Acceptable methods of contraception include intrauterine device (IUD), oral contraceptive, 
subdermal implant and double barrier, 
13. No prior or concurrent malignant disease diagnosed or treated in the last 2 years except for 
adequately treated in situ carcinoma of the cervix, basal or squamous skin cell carcinoma, or in 
situ transitional bladder cell carcinoma, 
14. Recovery to grade ≤ 1 from any adverse event (AE) derived from previous treatment 
(excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2) according to 
the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE, 
version 4.0), 
15. Patients with a social security in compliance with the French law, 
16. Voluntarily signed and dated written informed consent prior to any study specific procedure.
Non Inclusion criteria 
1. Previous treatment with Trabectedin, 
2. Currently active bacterial or fungus infection (> grade 2 CTC [CTCAE]), HIV1, HIV2, 
hepatitis B or hepatitis C infections, 
3. History of chronic alcohol use and/or cirrhosis, 
4. The following unstable cardiac conditions are not allowed: 
- Congestive heart failure 
- Angina pectoris 
- Myocardial infarction within 1 year before registration 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 5 sur 11 
- Uncontrolled arterial hypertension defined as blood pressure ≥ 150/100 mmHg despite optimal 
medical therapy 
- Arrhythmias clinically significant 
5. Patients unable to receive corticotherapy, 
6. Known central nervous system malignancy (CNS), 
7. Men or women of childbearing potential who are not using an effective method of 
contraception as previously described; women who are pregnant or breast feeding, 
8. Participation to a study involving a medical or therapeutic intervention in the last 30 days, 
9. Previous enrolment in the present study, 
10. Patient unable to follow and comply with the study procedures because of any geographical, 
social or psychological reasons, 
11. Known hypersensitivity to any involved study drug or any of its formulation components. 
12. Recent vaccination (in the last 2 weeks before inclusion) for yellow fever. 
13. Known urinary tract obstruction. 
14. Cardiac dysfunction: 
    - LVEF (Left Ventricular Ejection Fraction) < 40% at baseline; 
    - or clinically symptomatic cardiac dysfunction (any % of LVEF at baseline) 
Route of 
administration 
Cyclophosphamide will be administered bi-daily (50 mg x 2), and given on a week on/week off 
schedule.  
Trabectedin will be administered by intravenous 3-hour infusion weekly for three consecutive 
weeks (days 1, 8 and 15) every 4 weeks. 
Treatment schedule 
Phase I: Dose escalation part 
Regimen Description 
Agent 
Premedication 
Dose 
Route 
Schedule 
Cycle 
Length 
CP 
domperidone, 
metoclopramide, 
setrons allowed 
50mg x 2 
per os 
1 week on /1 
week off 
 
4 weeks 
Trabected
in 
20 mg 
dexamethasone 
Doses as 
appropriate 
for assigned 
dose level 
IV 
Days 1, 8 and 
15 every 4 
weeks 
A treatment cycle consists of 4 weeks. Treatment may continue until disease progression or 
study discontinuation (withdrawal of consent, intercurrent illness, unacceptable adverse event or 
any other changes unacceptable for further treatment, etc.) 
Patients will be allocated to 4 doses of Trabectedin following a 3 + 3 design: 
 
 
 
 
Phase II: All patients will be treated at the RP2D of trabectedin defined in the preliminary phase 
I trial given in association with metronomic cyclophosphamide with the same schedule as in the 
phase I trial. 
Level 
-1 
1 
2 
3 
4 
Trabectedin (mg/m²) - (3h) 
0.25 
0.3 
0.4 
0.5 
0.6 
Safety and efficacy 
evaluations 
Safety: Dose-limiting toxicities will be assessed for 4 weeks.  
Toxicities will be assessed on Day 8, 15, 28 and every 4 weeks afterwards. 
Efficacy will be assessed every 2 cycles (8 weeks). 
Endpoints 
Phase I trial: 
Primary objective of the phase I trial is to establish the recommended phase II dose (RP2D), the 
maximum tolerated doses (MTD) evaluated on the first cycle (D1 to D28), the safety profile, 
and the dose limiting toxicities (DLT) of trabectedin given in association with metronomic 
cyclophosphamide.  
 
Definitions 
• 
Dose-limiting toxicity (DLT): A DLT is defined as an AE or laboratory abnormality that 
fulfills all the criteria below:  
o 
Occurs during the first cycle (4 weeks) of treatment. 
o 
Is considered to be at least possibly related to the study treatment.  
o 
Meets one of the criteria below, graded as outlined or according to NCI 
CTCAEv4.0 : 
 
Any grade 4 toxicity (except for vomiting without maximal 
symptomatic/prophylactic treatment) 
 
Grade >= 3 non-haematological toxicity lasting > 7days (except for 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 6 sur 11 
1rst episode of nausea without maximal symptomatic/ prophylactic 
treatment and if toxicity is transaminitis, which may last > 7 days if 
total bilirubin is normal or grade =<1)  
 
Grade >=3 hematologic toxicity lasting for > 7days 
 
Grade 4 neutropenia with fever 
 
Grade > 2 thrombocytopenia with bleeding 
o 
Is unrelated to disease, disease progression, inter-current illness, or 
concomitant medications. 
In addition, any AE related to treatment and considered as clinically significant on the opinion 
on the sponsor and of the investigators 
• 
Maximum tolerated dose (MTD): the MTD is defined as the highest dose at which no more 
than 1 in 6 of the patients in the cohort experienced a DLT in the first treatment cycle.  
• 
Recommended phase II dose (RP2D): will be identified by the steering committee based on 
the MTD, additional safety data (all cycles), PK and PD data. Data from all cycles will be 
used to define the dose level to be recommended for further investigations in phase II. An 
IDMC will be requested to assess safety data and validate the RP2D. 
Primary Endpoints: 
• 
Toxicity graded using the common toxicity criteria from the NCI v4.0.  
• 
Incidence rate of DLT at each dose level on cycle 1.  
 
Secondary Endpoints: 
• 
Objective response under treatment defined as complete (CR) or partial response (PR) as 
per RECIST v1.1 criteria. Objective response (CR or PR) under treatment is recorded from 
study treatment initiation until the end of treatment, with confirmation of responses ≥ 4 
weeks after initial documentation, as per RECIST 1.1. Objective response under treatment 
is determined once all the data for the patient is known. 
• 
6-month non-progression defined as CR, PR or stable disease more than 24 weeks 
according to RECIST v1.1 criteria.  
• 
1-year Overall Survival (OS) defined as the time from study treatment initiation to death (of 
any cause). 
• 
1-year Progression-Free Survival (PFS) defined as the time from study treatment initiation 
to disease progression (defined as per RECIST v1.1) or death (of any cause), whichever 
occurs first. 
• 
PK measurements expressed as the AUC, the half-life of trabectedin, CP and concentration 
peak. 
• 
Pharmacodynamic study: 
 Blood: Serum/plasma cytokines levels (INFγ, TNFα, IL2,4,6,10) by ELISA ; 
Serum/plasma VEGF and TPS-1 levels by ELISA, monocytes, Treg, CD4+, CD8+ and 
DR lymphocytes subpopulations monitoring, CD4+/CD8+ ratio (Flow Cytometry),  
 Tumor: Fresh pre-treatment and on-treatment tumor biopsies will be collected to assess 
pharmacodynamics changes of TAM infiltration and additional tumor markers. Frozen 
biopsy samples will be analyzed for:  
- 
Hematoxylin and eosin staining (H&E). 
- 
Immunohistochemistry (IHC) assessments include, but are not limited to the 
following markers: CSF-1R, CD68/CD163, CD68/MHC class II, CD31 
(microvessel density), Ki67 and other exploratory markers. The analysis will be 
prioritized based on the amount of material available. 
 
Phase II trial: 
Primary Endpoints: 
• 
6-month non-progression as defined above for the phase I escalation study.  
• 
Disease status at 6 months will be reviewed by an expert radiologist. Reviewed data will be 
used for this primary endpoint analysis.  
 
Secondary Endpoints: 
Toxicity, objective response under treatment, 1-year OS and 1-year PFS defined above for the 
phase I escalation study except for the PD study which is optional in this phase II trial. 
 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 7 sur 11 
Statistical 
considerations 
Sample Size Considerations:  
Phase I (Dose escalation part): based on a 3 + 3 traditional design with 4 dose levels with a 
minimum of 3 patients and a maximum of 6 patients per dose level:  24 eligible and assessable 
patients maximum will be needed. 
Patients fulfilling the inclusion criteria will be enrolled in successive cohorts of 3 to 6 patients. 
If no DLT is observed during the first 4 weeks of study treatment in 3 patients, the dose of 
trabectedin will be escalated to the dose level (DL) immediately above. If One DLT is observed 
among 3 patients, the cohort will be expanded to 6 evaluable patients. If two patients out of 3 or 
2 /6 patients experience a DLT, the dose will be considered intolerable and the DL immediately 
below will be further explored. The recommended phase II dose (RP2D) will be defined based 
on safety, PK data and PD data (optimal biological dose). 
 
Phase II: 
The EORTC suggest that 3 and 6-month non-progression rates (NPR) are relevant endpoints in 
STS phase II trials. We rely on an optimal two-stage Simon’s design. Using unacceptable and 
acceptable 6-month non-progression rates of 20% and 40% respectively, a 5% type I error rate 
(bilateral), and a 20% type II error rate (80% power), a total of 43 eligible and assessable 
subjects will be necessary, with 13 subjects recruited to the first stage. At the end of the first 
stage, the trial will be terminated if 3 or less responses are observed. Otherwise, the second 
group of 30 subjects will be recruited, and a total of 13 responses or more will be required to 
claim activity of the drug. Assuming, 10% are not eligible or cannot be assessed for the primary 
endpoint, 47 patients will be recruited. 
 
Definition of study populations 
Phase I trial  
Population assessable for safety (primary analysis): all patients who completed the DLT 
assessment period or who developped DLT are included in the analysis.  
 
Patient’s replacement  
- 
If a patient cannot complete the full DLT evaluation period (28 days) and goes off-
treatment for reasons other than toxicity, this patient can be replaced.  
- 
Patients with DLT will never be replaced.  
- 
All patients will be fully described in the analysis.  
- 
Only patients who completed the DLT assessment period or who develop DLT are included 
in the analysis for escalation.  
Phase II trial 
• 
Eligible population: All patients included without major violation of eligibility criteria.  
• 
Population evaluable for efficacy:  
- 
All patients eligible and for whom the following conditions are satisfied:  
o 
Diagnosis of STS at inclusion is confirmed after central review, except in case of 
diagnosis was reviewed in the RRePS Network, 
o 
For STS: Diagnosis of progressive disease at inclusion is confirmed after central 
review of the inclusion scans or MRI,  
o 
Received at least one administration of the treatment, 
o 
At least one disease measurement recorded not less than eight weeks after 
treatment onset.  
• 
The following patients will also be included in the population evaluable for efficacy; they 
will be considered as failures for the primary endpoint (i.e. disease progression at six 
months for STS) and not be replaced in the primary efficacy analysis:  
- 
Any eligible patients who received at least one administration of the treatment and 
experienced disease progression or died due to disease progression prior to response 
evaluation (will be considered as an “early progression”).  
- 
Patients withdrawn due to drug-related toxicity without any tumor assessments after 
the start of study treatment.  
- 
Patients who received at least one administration of the treatment AND withdrawn due 
to significant clinical deterioration of unknown reason AND without any tumor 
assessments after the start of study treatment.  
Safety population: all patients having received at least one treatment administration.  
 
Patient’s replacement  


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 8 sur 11 
Any patient not eligible or not assessable for efficacy will be replaced.  
However, any patient who received at least one administration of the study drug will be 
included in the safety analysis. 
 
Statistical analysis 
For the phase I trial, two documents will be produced by the statistician: 
- 
A statistical analyse plan (SAP) before the first patient’s inclusion, 
- 
A statistical report.  
For the phase II trial, four documents will be produced by the statistician:  
- 
Two statistical analyse plans (SAP): one for the interim statistical analysis and one for 
the final statistical analysis.  
- 
Two statistical reports: one for the interim statistical analysis and one for the final 
statistical analysis.  
At the end of the phase I trial, an IDMC will be requested to assess safety data based on the 
statistical report produced by the statistician of the study. Similarly, an IDMC will be requested 
at the end of the first stage of the phase II trial to analyse preliminary safety and efficacy data. 
 
Patient characteristics at baseline  
The patients entered into the study will be described according to the following characteristics:  
• 
Compliance with eligibility criteria,  
• 
Epidemiological characteristics,  
• 
Clinical and laboratory characteristics,  
• 
Treatment characteristics.  
 
Endpoint analysis PHASE I trial  
• 
Primary endpoint will be analyzed on the population assessable for safety of the phase I 
trial.  
• 
Toxicity will be graded using the common toxicity criteria from the NCI v4.0.  
• 
Incidence rate of DLT will be reported at each dose level on cycle 1.  
• 
All analyses for the phase I trial will be descriptive; no p-values will be calculated. Data 
analyses will be provided by dose groups and for all study patients, combined wherever 
appropriate. For continuous variables, summary statistics will include number of patients, 
mean, median, standard deviation, standard error, minimum, and maximum. Categorical 
endpoints will be summarized using number of patients, frequency, percentages, and 
standard errors. Missing data will not be imputed.  
Endpoint analysis PHASE II trials  
• 
Efficacy endpoints will be analyzed on the population assessable for efficacy.  
• 
The safety analysis will be performed on the safety population.  
• 
Quantitative variables will be described using mean and standard deviations if the 
normality assumption is satisfied, else other descriptive statistics (median, range, quartiles) 
will be reported.  
• 
Qualitative variables will be described using frequency, percentage and 95% confidence 
interval (binomial law).  
• 
Objective response rate under treatement, 6-month non-progression rate will be calculated 
using binomial estimates and reported with their 95% confidence interval (CI). 
• 
Survival endpoints will be analysed using the Kaplan-Meier method. The median survival 
rates will be reported with a 95% confidence interval. Median follow-up will be calculated 
using the reverse Kaplan-Meier method. Multivariate analyses can also be carried out based 
on Cox’s proportional risk method and after checking the risk proportionality hypothesis.  
Interim statistical analysis (phase II ONLY)  
An interim statistical analysis will be carried out after the inclusion of the first 13 eligible and 
assessable patients. The trial will be terminated if 3 or less responses are observed. Otherwise, 
the second group of 30 subjects will be recruited. At the end of this first stage, an Independent 
Data Monitoring Committee (IDMC) will be request to analyze preliminary efficacy and safety 
data based on the statistical report produced by the statistician of the study. Inclusion will not be 
suspended during this interim analysis. 
 
 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 9 sur 11 
Schedule of assessments and procedures – Phase I 
 
 
CYCLE 1 
CYCLE 2 
CYCLE 3 
CYCLE N 
END OF TREATMENT 
 
SCREENING 
Wk1 
Wk 2 
Wk3 
Wk 4 
Wk 5 
Wk 6 
Wk7 
Wk 8 
Wk9 
Wk 10 
Wk11 
Wk 12 
 
 
CP b.i.d 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
D1 to D7 
D15 to D21 
 
Trabectedin i.v 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1, D8 and 
D15 
 
24h-36h Hosp 
 
D1 
 
D15 
 
 
 
 
 
 
 
 
 
 
 
Ambulatory Hosp 
 
 
D8 
 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1, D8 and 
D15 
 
Consultation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
X……………………………………………………………………………………………………………………………………………………………………………………………
…X 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Performance status 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Hematologya 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Xd 
X 
Biochemistryb 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Xd 
X 
ECG  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Toxicity 
 
X……………………………………………………………………………………………………………………………………………………………………………………………
..X 
Tumor measurement 
X 
Repeated every 8 weeks. Documentation (radiologic) must be provided for patients removed from study for progressive disease 
X 
B-HCGc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
PK 
 
D1 
 
D15 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy 
 
X 
 
 
D28 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
X 
Repeated if indicated 
Serious and/ or non- serious 
adverse events collection 
X 
Throughout the study 
X (until 30 days later last 
dose administered and 
beyond this period only 
SAEs related to research 
or IMP) 
 
a: Hemoglobin, platelets, CBC w/diff 
    b: Albumin, Alkaline phosphatase, total bilirubin, bicarbonate, calcium, chloride, creatinine, CPK, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium 
    c: if indicated and repeated if necessary 
    d: on weeks 1, 2 and 3 of each subsequent cycle 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 10 sur 11 
Schedule of assessments and procedures – Phase II 
 
 
CYCLE 1 
CYCLE 2 
CYCLE 3 
CYCLE N 
END OF TREATMENT 
 
SCREENING 
Wk1 
Wk 2 
Wk3 
Wk 4 
Wk 5 
Wk 6 
Wk7 
Wk 8 
Wk9 
Wk 10 
Wk11 
Wk 12 
 
 
CP b.i.d 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
D1 to D7 
D15 to D21 
 
Trabectedin i.v 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1, D8 and 
D15 
 
Ambulatory Hosp 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1 
D8 
D15 
 
D1, D8 and 
D15 
 
Consultation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant treatments 
X 
X……………………………………………………………………………………………………………………………………………………………………………………………
…X 
Physical exam 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Vital signs 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Performance status 
X 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
D1 
X 
Hematologya 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Xd 
X 
Biochemistryb 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
 
Xd 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Toxicity 
 
X……………………………………………………………………………………………………………………………………………………………………………………………
..X 
Tumor measurement 
X 
Repeated every 8 weeks. Documentation (radiologic) must be provided for patients removed from study for progressive disease 
X 
B-HCGc 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers (optional) 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Biopsy (optional) 
 
X 
 
 
D28 
 
 
 
 
 
 
 
 
 
 
Echocardiography 
X 
Repeated if indicated 
Serious and/ or non- serious 
adverse events collection 
X 
Throughout the study 
X (until 30 days later last 
dose administered and 
beyond this period only 
SAEs related to research 
or IMP) 
 
a: Hemoglobin, platelets, CBC w/diff 
    b: Albumin, Alkaline phosphatase, total bilirubin, bicarbonate, calcium, chloride, creatinine, CPK, glucose, LDH, phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium 
    c: if indicated and repeated if necessary 
    d: on weeks 1, 2 and 3 of each subsequent cycle 


Institut Bergonié 
Protocol TARMIC 
PROT_TARMIC_V6.0|11|12|2018| 
 
Page 11 sur 11