Soft-tissue Sarcomas
Conditions
Keywords
Advanced solid tumor, Advanced pretreated soft tissue sarcomas, Phase I/II trial, Dose escalation, PK study
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.
Interventions
DRUGPhase 1: Trabectedin
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.)
DRUGPhase 2: Trabectedin
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.
DRUGPhase 1: Cyclophosphamide
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.
DRUGPhase 2: Cyclophosphamide
All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial.
Sponsors
PharmaMar
Institut Bergonié
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with soft-tissue sarcoma histologically confirmed by central review 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 outside any previously irradiated field, 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, 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: 1. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell \[RBC\] transfusion, if clinically indicated); absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/l, and platelet count ≥ 100 x 10\^9/l 2. Alanine aminotransferase (ALT), aspartate aminotransferase (AST)\< or = 2.5 x upper limit of normality (ULN) ( \< or = 5 in case of extensive liver involvement) and alkaline phosphatase (AP) \< or = 2.5 x ULN 3. Total bilirubin \< or = ULN. 4. Albumin ≥ 25 g/l 5. Serum Creatinine \< or =1.5 x ULN or calculated creatinine clearance (CrCl) ≥ 30 ml/min (according to Cockroft formula). 6. Creatine Phosphokinase (CPK) \< or = 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 French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code), 16. Voluntarily signed and dated written informed consent prior to any study specific procedure.
Exclusion 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 * 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP. | During the first cycle (28 days) | MTD was determined by testing increasing doses of trabectedin up to 0.60 mg/m2 via IV on dose escalation cohorts 1 to 4 with 3 to 6 participants each.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. See subsequent primary outcome measure for the DLT definition. |
| Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | During the first cycle (28 days) | A DLT was defined as a treatment-related (at least possibly related) adverse event using the CTCAE V4.0, occuring during the fist cycle of treatment (28 days), that meets one of the following criteria: * Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic treatment) * Grade-3 non-haematological toxicity lasting \> 7days (except for 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 * Is unrelated to disease, disease progression, inter-current illness, or concomitant medications. |
| Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1) | Phase II : 6 months after the start of treatment | Non-progression is defined as complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD); Stable disease (SD) is defined as Neither sufficient shrinkage (compared to baseline) to qualify for PR or CR nor sufficient increase (taking as reference the SSD or while on study, whichever is smallest) to qualify for progressive disease (PD). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | Throughout the treatment period, an average of 6 months | Objective response is defined as complete or partial response (CR, PR) as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD). |
| Phase II: Median Overall Survival | From start of treatment, and during treatment until death for any cause for up to 12 months. | Overall survival is defined as the time from the study initiation to death (any cause). Median overall survival was reported using kaplan-Meier method for calculation. |
| Phase II: Median Profression-free Survival | From start of treatment, and during treatment until progression or death for any cause for up to 12 months. | Progression-free survival is defined as the time from study treatment initiation to disease progression or death (of any cause), whichever occurs first. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. Median PFS was reported using kaplan-Meier method for calculation. |
Countries
France
Participant flow
Recruitment details
Phase I (dose escalation sudy): 20 patients ; Phase II (interim analysis) : 16 patients ; Phase II (overall study): 30 patients.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Trabectedin 0.30 mg/m2 IV + CP 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
Phase 1: Trabectedin: 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.)
Phase 1: Cyclophosphamide: 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. | 3 |
| Cohort 2: Trabectedin 0.40 mg/m2 IV + CP 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
Phase 1: Trabectedin: 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.)
Phase 1: Cyclophosphamide: 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. | 3 |
| Cohort 3: Trabectedin 0.50 mg/m2 IV + CP 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
Phase 1: Trabectedin: 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.)
Phase 1: Cyclophosphamide: 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. | 7 |
| Cohort 4: Trabectedin 0.60 mg/m2 IV + CP 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
Phase 1: Trabectedin: 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.)
Phase 1: Cyclophosphamide: 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. | 7 |
| Phase II: Trabectedin 0.50 mg/m2 IV + CP 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
Phase 2: Trabectedin: 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.
Phase 2: Cyclophosphamide: All patients will be treated with metronomic cyclophosphamide with the same schedule as in the phase I trial. | 30 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Phase I (Dose escalation part) | Adverse Event | 0 | 0 | 1 | 2 | 0 |
| Phase I (Dose escalation part) | Clinical progression | 0 | 0 | 1 | 0 | 0 |
| Phase II | Protocol Violation | 0 | 0 | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Cohort 1: Trabectedin 0.30 mg/m2 IV + CP | Total | Phase II: Trabectedin 0.50 mg/m2 IV + CP | Cohort 4: Trabectedin 0.60 mg/m2 IV + CP | Cohort 3: Trabectedin 0.50 mg/m2 IV + CP | Cohort 2: Trabectedin 0.40 mg/m2 IV + CP |
|---|---|---|---|---|---|---|
| Age, Continuous | 61 years | 62.5 years | 67 years | 57 years | 61 years | 67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 50 Participants | 30 Participants | 7 Participants | 7 Participants | 3 Participants |
| Region of Enrollment France | 3 participants | 50 participants | 30 participants | 7 participants | 7 participants | 3 participants |
| Sex: Female, Male Female | 2 Participants | 23 Participants | 13 Participants | 3 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 27 Participants | 17 Participants | 4 Participants | 5 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 2 / 3 | 4 / 5 | 4 / 5 | 20 / 30 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 5 / 5 | 5 / 5 | 30 / 30 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 2 / 5 | 2 / 5 | 20 / 30 |
Outcome results
Primary
Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1)
Non-progression is defined as complete or partial response (CR, PR) or stable disease (SD), as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD); Stable disease (SD) is defined as Neither sufficient shrinkage (compared to baseline) to qualify for PR or CR nor sufficient increase (taking as reference the SSD or while on study, whichever is smallest) to qualify for progressive disease (PD).
Time frame: Phase II : 6 months after the start of treatment
Population: Stage 1 of Simon's design (interim analysis): 16 patients were included at this stage and 13 were evaluable for the primary endpoint.~Stage 2 Simon's design (Final analysis): 30 patients were included at this stage and 24 were evaluable for the primary endpoint.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I: Evaluable for Safety | Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1) | Interim analysis (Stage 1 of Simon's design) | 23.1 percentage of participants |
| Phase I: Evaluable for Safety | Phase II: Percentage of Patients in Non-progression at 6 Months (RECIST V1.1) | Overall (stage 2 of Simon's design) | 12.5 percentage of participants |
Primary
Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP.
MTD was determined by testing increasing doses of trabectedin up to 0.60 mg/m2 via IV on dose escalation cohorts 1 to 4 with 3 to 6 participants each.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. See subsequent primary outcome measure for the DLT definition.
Time frame: During the first cycle (28 days)
Population: 4 patients were not evaluable for MTD/DLT assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Evaluable for Safety | Phase I: Maximum Tolerated Dose (MTD) of Trabectedin When Administered in Association With CP. | 0.50 mg/m^2 |
Primary
Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs)
A DLT was defined as a treatment-related (at least possibly related) adverse event using the CTCAE V4.0, occuring during the fist cycle of treatment (28 days), that meets one of the following criteria: * Any grade-4 toxicity (except for vomiting without maximal symptomatic/prophylactic treatment) * Grade-3 non-haematological toxicity lasting \> 7days (except for 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 * Is unrelated to disease, disease progression, inter-current illness, or concomitant medications.
Time frame: During the first cycle (28 days)
Population: 4 patients were not evaluable for DLT evaluation as they did not complete the DLT assessment period: 2 in cohort 3 and 2 in cohort 4
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase I: Evaluable for Safety | Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort 2: Trabectedin 0.40 mg/m2 IV + CP | Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort 3: Trabectedin 0.50 mg/m2 IV + CP | Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | 0 Participants |
| Cohort 4: Trabectedin 0.60 mg/m2 IV + CP | Phase I: Number of Patients Who Experienced Dose-Limiting Toxicities (DLTs) | 2 Participants |
Secondary
Phase II: Median Overall Survival
Overall survival is defined as the time from the study initiation to death (any cause). Median overall survival was reported using kaplan-Meier method for calculation.
Time frame: From start of treatment, and during treatment until death for any cause for up to 12 months.
Population: Stage 1 of Simon's design (interim analysis): 16 patients were included at this stage and 13 were evaluable for efficacy endpoints.~Stage 2 Simon's design (Final analysis): 30 patients were included at this stage and 24 were evaluable for efficacy endpoints.~The upper limit for the 95%CI for OS was not reached due to insufficient number of participants with events, and thus entered as NA (Not available).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Evaluable for Safety | Phase II: Median Overall Survival | 12.0 months |
Secondary
Phase II: Median Profression-free Survival
Progression-free survival is defined as the time from study treatment initiation to disease progression or death (of any cause), whichever occurs first. Progression is defined using RECIST v1.1, as a 20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), or a unequivocal progression of existing non-target lesions, or the appearance of one or more new lesions. Median PFS was reported using kaplan-Meier method for calculation.
Time frame: From start of treatment, and during treatment until progression or death for any cause for up to 12 months.
Population: Stage 1 of Simon's design (interim analysis): 16 patients were included at this stage and 13 were evaluable for efficacy endpoints.~Stage 2 Simon's design (Final analysis): 30 patients were included at this stage and 24 were evaluable for efficacy endpoints.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I: Evaluable for Safety | Phase II: Median Profression-free Survival | 1.9 months |
Secondary
Phase I: Percentage of Patients With Objective Response (RECIST V1.1)
Objective response is defined as complete or partial response (CR, PR) as per RECIST v1.1. According to RECIST v1.1: Complete Response (CR) is defined as disappearance of all target lesions; Partial Response (PR) is defined as a \>=30% decrease in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at baseline (SSD).
Time frame: Throughout the treatment period, an average of 6 months
Population: 4 patients were not evaluable for DLT evaluation as they did not complete the DLT assessment period: 2 in cohort 3 and 2 in cohort 4
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I: Evaluable for Safety | Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | 0 percentage of participants |
| Cohort 2: Trabectedin 0.40 mg/m2 IV + CP | Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | 0 percentage of participants |
| Cohort 3: Trabectedin 0.50 mg/m2 IV + CP | Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | 0 percentage of participants |
| Cohort 4: Trabectedin 0.60 mg/m2 IV + CP | Phase I: Percentage of Patients With Objective Response (RECIST V1.1) | 0 percentage of participants |