Sarcoma
Conditions
Keywords
Efficacy of MK 3475 with Metronomic Cyclophosphamide, Advanced Sarcomas, Leiomyosarcoma, Undifferentiated Sarcoma, Other Sarcoma, GIST, Osteosarcoma
Brief summary
This is a multicenter study assessing the efficacy of different therapeutic strategy in patients with advanced sarcomas.
Detailed description
This is a phase 2 trial with 7 strata : * Leiomyosarcoma (strata 1) : 33 patients * Undifferentiated sarcoma (strata 2): 33 patients * Sarcomas others (strata 3) : 33 patients * Osteosarcoma (strata 4) : 33 patients * GIST (strata 5): 31 patients * Advanced soft-tissue sarcoma with immune signature (strata 6): 32 patients * Metastatic soft-tissue sarcoma (strata 7): 32 patients
Interventions
DRUGCombination of MK3475 with Metronomic CP
Combination of MK3475 with Metronomic CP. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule. MK3475 will be administered intraveinously, and given every 3 weeks on day 8. A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
DRUGCombination of MK3475 with Metronomic CP and G100
Combination of MK3475 with Metronomic CP and G100. Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule. MK3475 will be administered intravenously (200 mg), and given every 3 weeks on day 8. G100 will be administered by intra-tumoral injection (20µg), one weekly injection for at least 6 weeks and for a maximum of 12 weeks. G100 will start one week before CP administration (impregnation phase). A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation.
Sponsors
Merck Sharp & Dohme LLC
Ministry of Health, France
Immune Design, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
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. Histology : Leiomyosarcoma, or UPS, or other sarcoma, or GIST or osteosarcoma, or soft-tissue sarcoma with presence of tertiary lymphoid structures (stratum 6) histologically confirmed by central review. 2. Advanced non resectable / metastatic disease for strata 1 to 6. For stratum 7: locally advanced or metastatic disease with at least one injectable lesion. 3. Documented progression according to RECIST criteria. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical obtained at less than 6 months interval within the 12 months before inclusion. 4. For stratum 5, documented disease progression according to RECIST criteria after the first line imatinib and second line sunitinib. 5. Have provided tissue of a tumor lesion from an archival tissue sample obtained on metastasis or on locally advanced disease, or newly obtained core or excisional biopsy. For strata 6 and 7, tissue \< 3 months old and with no subsequent treatment since or from a newly obtained biopsy. 6. For strata 1, 2, 3 and 6: no more of four previous lines of systemic therapy for metastatic disease and no more than 2 previous line for stratum 7. 7. Age ≥ 18 years. 8. ECOG performance status ≤ 1. 9. Measurable disease according to RECIST v1.1 outside any previously irradiated field. At least one site of disease must be uni-dimensionally ≥ 10 mm. 10. Life expectancy \> 3 months (except for stratum 7 \> 6 months). 11. ≥ 1 previous line (s) of chemotherapy in the palliative setting for strata 1 to 5. For other strata, participant must have advanced disease and must not be a candidate for other approved therapeutic regimen known to provide significant clinical benefit based on investigator judgement. 12. No symptomatic central nervous system disease. 13. No chronic use of glucocorticoids. 14. Adequate hematological, renal, metabolic and hepatic function: 1. Hemoglobin ≥ 9 g/dl (patients may have received prior red blood cell transfusion); ANC ≥ 1.5 x 109/l and platelet count ≥ 100 x 109/l. For stratum 7: lymphocyte count ≥ 0.5.109 /l 2. ALT and AST ≤ 2.5 x upper limit of normality (ULN) (≤ 5 in case of liver metastasis) 3. Total bilirubin ≤ 1.5 x ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels ≥ 1.5 x ULN 4. Albumin ≥ 25g/l 5. Serum creatinine ≤ 1.5 x ULN OR CrCl ≥ 60 ml/min for subject with creatinine levels ≥ 1.5 x ULN, 6. Creatine phosphokinase ≤ 2.5 x ULN 7. INR ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 8. aPTT ≤ 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants 15. 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. 16. At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy. 17. Recovery to grade ≤ 1 from any adverse event from previous treatment (excluding alopecia of any grade and non-painful peripheral neuropathy grade ≤ 2 (NCI-CTCAE, v 4.0). 18. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for four months after discontinuation of treatment. Acceptable methods for contraception include intrauterine device, oral contraceptive, subdermal implant and double barrier. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for ≥ 1 year. 19. Voluntary signed and dated written informed consents prior to any specific study procedure. 20. Patients with a French social security in compliance with the Law relating to biomedical research (Article 1121-11 of French Public Health Code).
Exclusion criteria
1. Previous treatment with MK3475 or CP or G100. 2. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 3. Evidence of progressive or symptomatic central nervous system (CNS) or leptomeningeal metastases. 4. 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. 5. Participation to a study involving a medical or therapeutic intervention in the last 30 days. 6. Previous enrolment in the present study. 7. Patient unable to follow and comply with the study procedures because of any geographical, familial, social or psychological reasons. 8. Known hypersensitivity to any involved study drug or of its formulation components. 9. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. 10. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 11. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia, or evidence of active pneumonitis on screening chest CT scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted. 12. Has known active hepatitis B or hepatitis C. 13. Has a known history of HIV (HIV1/2 antibodies). 14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 15. For strata 6 to 7: * patients with oral anticoagulation therapy * known urinary tract obstruction * previous allogenic bone marrow transplant * has an active infection requiring systemic treatment within 14 days prior to study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants in Objective Response at 6 Months | 6 months from treatment initiation | Objective response is defined according to RECIST v1.1 as either complete response (disappearance of all target lesions, with any pathological lymph nodes reduced in short axis to \<10 mm) or partial response (≥30% decrease in the sum of diameters of target lesions compared with baseline). This primary endpoint is part of a dual endpoint encompassing both non-progression and objective response at 6 months (non-progression is presented as a separate primary outcome). ORR at 6 months will be evaluated only in the following strata: Stratum 1: Advanced leiomyosarcoma ; Stratum 2: Advanced undifferentiated sarcoma ; Stratum 3: Advanced other sarcoma ; Stratum 4: Advanced osteosarcoma |
| Percentage of Particpants in Non-progression at 6 Months | 6 months from treatment initiation | Non-progression is defined as the absence of progressive disease according to RECIST v1.1. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). This outcome will be assessed as a stand-alone primary endpoint in the following strata: Stratum 5: Advanced gastrointestinal stromal tumor (GIST) ; Stratum 6: Advanced soft tissue sarcomas with immune signature ; Stratum 7: Metastatic soft tissue sarcoma (STS) In strata 1 to 4, non-progression is considered as part of the dual primary endpoint together with objective response at 6 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | 6 months from treatment initiation | Best overall response is defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known. Each patient has been assigned one of the following categories (RECIST 1.1): complete response (disappearance of all target lesions); partial response (\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); progression (20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and stable disease (nor CR, PR or progression). |
| Median Progression-free Survival | From start of treatment, and during treatment until progression or death for any cause, whichever occurs first, for up to 12 months. | Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. Progression-free survival is estimated as a function of time using Kaplan-Meier method. |
| Median Overall Survival | From start of treatment, and during treatment until death for any cause for up to 30 months | Overall survival (OS) defined as the time from randomization to death (due to any cause). Patients alive were censored at the date of last follow-up or last patient contact. Overall survival was estimated as a function of time using Kaplan-Meier method. |
Countries
France
Participant flow
Recruitment details
8 centers: * Institut Bergonié, Pr Italiano * Centre Léon Bérard, Pr Blay * Institut Gustave Roussy, Dr Le Cesne * Centre Oscar Lambret, Dr Penel * Institut Curie, Dr Piperno-Neumann * Institut Paoli Calmette, Pr Bertucci * Institut Claudius Regaud, Dr Chevreau * Institut de Cancérologie de l'Ouest - Site René Gauducheau, Dr Bompas Planned enrollment period : 72 months Treatment duration : 2-years maximum Follow-up : 12 months Duration of study : 7 years
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1: Advanced Leiomyosarcoma Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 15 |
| Stratum 2: Advanced Undifferentiated Sarcoma Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 16 |
| Stratum 3: Advanced Other Sarcoma Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 16 |
| Stratum 4: Advanced GIST Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 17 |
| Stratum 5: Advanced Soft-tissue Sarcomas Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 10 |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature Treatment strategy A: Combination of MK3475 with Metronomic CP administered to patients with advanced leiomyosarcoma.
MK3475 will be administered intraveinously. Metronomic CP (Cyclophosphamide) will be adminstered orally.
Combination of MK3475 with Metronomic CP:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 35 |
| Stratum 7: Metastatic Soft-tissue Sarcoma. Treatment strategy B: Combination of MK3475 with Metronomic CP and G100. MK3475 will be administered intravenously . Metronomic CP (Cyclophosphamide) will be administered orally. G100 will be administered by intra-tumoral injection.
Combination of MK3475 with Metronomic CP and G100:
Metronomic CP (cyclophosphamide) will be administered per os bi-daily (50 mg x 2), and given on a week on/ week off schedule.
MK3475 will be administered intraveinously (200mg in 30 minutes -5 min/+10 min) and given every 3 weeks on day 8.
G100 will be administered by intra-tumoral injection (20µg), one weekly injection for at least 6 weeks and for a maximum of 12 weeks. G100 will start one week before CP administration (impregnation phase).
A treatment cycle consists of 3 weeks. Treatment may continue until disease progression or study discontinuation. | 20 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Protocol Violation | 2 | 2 | 2 | 2 | 1 | 5 | 3 |
Baseline characteristics
| Characteristic | Stratum 1: Advanced Leiomyosarcoma | Stratum 2: Advanced Undifferentiated Sarcoma | Stratum 3: Advanced Other Sarcoma | Stratum 4: Advanced GIST | Stratum 5: Advanced Soft-tissue Sarcomas | Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Stratum 7: Metastatic Soft-tissue Sarcoma. | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.7 years | 59.1 years | 55.5 years | 42.2 years | 57.9 years | 62.2 years | 62.7 years | 63 years |
| Race and Ethnicity Not Collected | — | — | — | — | — | — | — | 0 Participants |
| Region of Enrollment France | 15 participants | 16 participants | 16 participants | 17 participants | 10 participants | 35 participants | 20 participants | 129 participants |
| Sex: Female, Male Female | 8 Participants | 5 Participants | 6 Participants | 7 Participants | 5 Participants | 16 Participants | 10 Participants | 57 Participants |
| Sex: Female, Male Male | 7 Participants | 11 Participants | 10 Participants | 10 Participants | 5 Participants | 19 Participants | 10 Participants | 72 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 13 / 15 | 14 / 16 | 7 / 16 | 12 / 16 | 3 / 10 | 15 / 35 | 9 / 19 |
| other Total, other adverse events | 15 / 15 | 16 / 16 | 16 / 16 | 16 / 16 | 10 / 10 | 35 / 35 | 19 / 19 |
| serious Total, serious adverse events | 5 / 15 | 10 / 16 | 9 / 16 | 12 / 16 | 9 / 10 | 14 / 35 | 8 / 19 |
Outcome results
Primary
Percentage of Participants in Objective Response at 6 Months
Objective response is defined according to RECIST v1.1 as either complete response (disappearance of all target lesions, with any pathological lymph nodes reduced in short axis to \<10 mm) or partial response (≥30% decrease in the sum of diameters of target lesions compared with baseline). This primary endpoint is part of a dual endpoint encompassing both non-progression and objective response at 6 months (non-progression is presented as a separate primary outcome). ORR at 6 months will be evaluated only in the following strata: Stratum 1: Advanced leiomyosarcoma ; Stratum 2: Advanced undifferentiated sarcoma ; Stratum 3: Advanced other sarcoma ; Stratum 4: Advanced osteosarcoma
Time frame: 6 months from treatment initiation
Population: Population eligible and assessable for the primary endpoint: eligible patients who received at least one administration of PEMBROLIZUMAB and one administration of Metronomic CP.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Participants in Objective Response at 6 Months | 0.0 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Participants in Objective Response at 6 Months | 0.0 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Participants in Objective Response at 6 Months | 0.0 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Participants in Objective Response at 6 Months | 6.7 percentage of participants |
Primary
Percentage of Particpants in Non-progression at 6 Months
Non-progression is defined as the absence of progressive disease according to RECIST v1.1. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). This outcome will be assessed as a stand-alone primary endpoint in the following strata: Stratum 5: Advanced gastrointestinal stromal tumor (GIST) ; Stratum 6: Advanced soft tissue sarcomas with immune signature ; Stratum 7: Metastatic soft tissue sarcoma (STS) In strata 1 to 4, non-progression is considered as part of the dual primary endpoint together with objective response at 6 months.
Time frame: 6 months from treatment initiation
Population: Population eligible and assessable for the primary endpoint: eligible patients who received at least:~* For all strata (except for stratum 7): one administration of PEMBROLIZUMAB and one administration of Metronomic CP~* For stratum 7: one administration of PEMBROLIZUMAB and one administration of Metronomic CP and one administration of G100.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Particpants in Non-progression at 6 Months | 0.0 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Particpants in Non-progression at 6 Months | 7.1 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Particpants in Non-progression at 6 Months | 14.3 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Particpants in Non-progression at 6 Months | 13.3 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Particpants in Non-progression at 6 Months | 11.1 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Particpants in Non-progression at 6 Months | 40 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Particpants in Non-progression at 6 Months | 11.8 percentage of participants |
Secondary
Median Overall Survival
Overall survival (OS) defined as the time from randomization to death (due to any cause). Patients alive were censored at the date of last follow-up or last patient contact. Overall survival was estimated as a function of time using Kaplan-Meier method.
Time frame: From start of treatment, and during treatment until death for any cause for up to 30 months
Population: Population eligible and assessable for the primary endpoint: eligible patients who received at least:~* For all strata (except for stratum 7): one administration of PEMBROLIZUMAB and one administration of Metronomic CP~* For stratum 7: one administration of PEMBROLIZUMAB and one administration of Metronomic CP and one administration of G100.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1: Advanced Leiomyosarcoma | Median Overall Survival | 15.1 months |
| Stratum 2: Advanced Undifferentiated Sarcoma | Median Overall Survival | 6.7 months |
| Stratum 3: Advanced Other Sarcoma | Median Overall Survival | 7.1 months |
| Stratum 4: Advanced Osteosarcoma | Median Overall Survival | 5.6 months |
| Stratum 5: Advanced Soft-tissue Sarcomas | Median Overall Survival | NA months |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Median Overall Survival | 18.3 months |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Median Overall Survival | 25.2 months |
Secondary
Median Progression-free Survival
Progression-free survival (PFS) is defined as the time from study treatment initiation to the first occurrence of disease progression or death (of any cause), whichever occurs first. Progressive disease defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). Patients alive and progression free were censored at the date of last follow-up, death, or last patient contact. Progression is assessed as per RECIST v1.1. Progression-free survival is estimated as a function of time using Kaplan-Meier method.
Time frame: From start of treatment, and during treatment until progression or death for any cause, whichever occurs first, for up to 12 months.
Population: Population eligible and assessable for the primary endpoint: eligible patients who received at least:~* For all strata (except for stratum 7): one administration of PEMBROLIZUMAB and one administration of Metronomic CP~* For stratum 7: one administration of PEMBROLIZUMAB and one administration of Metronomic CP and one administration of G100.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Stratum 1: Advanced Leiomyosarcoma | Median Progression-free Survival | 1.4 months |
| Stratum 2: Advanced Undifferentiated Sarcoma | Median Progression-free Survival | 1.3 months |
| Stratum 3: Advanced Other Sarcoma | Median Progression-free Survival | 1.4 months |
| Stratum 4: Advanced Osteosarcoma | Median Progression-free Survival | 1.4 months |
| Stratum 5: Advanced Soft-tissue Sarcomas | Median Progression-free Survival | 1.4 months |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Median Progression-free Survival | 4.1 months |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Median Progression-free Survival | 1.8 months |
Secondary
Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1.
Best overall response is defined as the best response across all time points (RECIST v1.1). The best overall response is determined once all the data for the participant is known. Each patient has been assigned one of the following categories (RECIST 1.1): complete response (disappearance of all target lesions); partial response (\>=30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters); progression (20% increase in the sum of diameters of target lesions (taking as reference the smallest sum on study) and stable disease (nor CR, PR or progression).
Time frame: 6 months from treatment initiation
Population: Population eligible and assessable for the primary endpoint: eligible patients who received at least:~* For all strata (except for stratum 7): one administration of PEMBROLIZUMAB and one administration of Metronomic CP~* For stratum 7: one administration of PEMBROLIZUMAB and one administration of Metronomic CP and one administration of G100.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 76.9 percentage of participants |
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 0 percentage of participants |
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 0 percentage of participants |
| Stratum 1: Advanced Leiomyosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 23.1 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 0 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 35.7 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 14.3 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 50.0 percentage of participants |
| Stratum 2: Advanced Undifferentiated Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 35.7 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 0 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 57.1 percentage of participants |
| Stratum 3: Advanced Other Sarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 7.1 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 53.3 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 6.7 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 33.3 percentage of participants |
| Stratum 4: Advanced Osteosarcoma | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 6.7 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 0 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 33.3 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 66.7 percentage of participants |
| Stratum 5: Advanced Soft-tissue Sarcomas | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 0 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 33.3 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 26.7 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 36.7 percentage of participants |
| Stratum 6: Advanced Soft-tissue Sarcomas With Immune Signature | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 3.3 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Not evaluable for response (NE) | 0 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Progression (PD) | 70.6 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Stable disease (SD) | 23.5 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Complete response (CR) | 0 percentage of participants |
| Stratum 7: Metastatic Soft-tissue Sarcoma. | Percentage of Patients Remaining Alive With Best Overall Response as Per RECIST v1.1. | Partial response (PR) | 5.9 percentage of participants |