E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Synovial sarcoma and Myxoid/Round Cell Liposarcoma (MRCLS) |
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E.1.1.1 | Medical condition in easily understood language |
Synovial sarcoma and Myxoid/Round Cell Liposarcoma (MRCLS) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10042863 |
E.1.2 | Term | Synovial sarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073137 |
E.1.2 | Term | Myxoid liposarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10073139 |
E.1.2 | Term | Round cell liposarcoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate the efficacy of NY-ESO-1-Specific (c259) T Cells, alone or in combination with other anti-cancer agents, in HLA-A*02:01, HLAA* 02:05 and/or HLA-A*02:06 participants with NY-ESO-1- and/or LAGE-1a positive solid tumors |
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E.2.2 | Secondary objectives of the trial |
- To further evaluate the efficacy of NY-ESO-1 Specific (c259) T Cells alone or in combination with other anti-cancer agents in HLA-A*02:01, HLA-A*02:05 and/or HLA-A*02:06 participants with NY-ESO-1 and/or LAGE-1a positive solid tumors
- To evaluate the safety and tolerability of NY-ESO-1 Specific (c259) T Cells alone or in combination with other anti-cancer agents in HLA-A*02:01, HLA-A*02:05 and/or HLA-A* 02:06 participants with NY-ESO-1- and/or LAGE-1a positive solid tumors
-To characterize in vivo cellular PK profile (levels, expansion, persistence) of NY-ESO-1 specific (c259) T cells |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
SUBSTUDY 1: LETETRESGENE AUTOLEUCEL (LETE-CEL, GSK3377794) IN NY-ESO-1 POSITIVE PREVIOUSLY UNTREATED ADVANCED (METASTATIC OR UNRESECTABLE) SYNOVIAL SARCOMA AND MYXOID/ROUND CELL LIPOSARCOMA
SUBSTUDY 2: LETETRESGENE AUTOLEUCEL (LETE-CEL, GSK3377794) IN NY-ESO-1 POSITIVE PREVIOUSLY TREATED ADVANCED (METASTATIC OR UNRESECTABLE) SYNOVIAL SARCOMA OR MYXOID/ROUND CELL LIPOSARCOMA |
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E.3 | Principal inclusion criteria |
1. For participants <18 years of age, (or the legal minimum age in the relevant country) their legal guardian must give informed consent.Pediatric subjects will be included in age-appropriate discussion in order to obtain assent.
2.Participant must be ≥10 years of age at the time of signing the informed consent.(Germany-Participant must be >= 18 years of age at the time of signing the informed consent). Participant scheduled to receive clinical drug product supply must also weigh ≥40 kg. For participant scheduled to receive intended commercial drug product supply and weighing <40kg, the Investigator must also consult with the Medical Monitor prior to inclusion.
3.Participant has a diagnosis of synovial sarcoma or myxoid/ round cell liposarcoma, confirmed by local histopathology with evidence of disease specific translocation.
Note: Evidence of a relevant disease-specific translocation is required at latest prior to leukapheresis (Inclusion 8).
4. Participant has advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma. Unresectable refers to a tumor lesion in which clear surgical excision margins cannot be obtained without leading to significant functional compromise.
5. Male or female. Contraception requirements will apply at the time of leukapheresis and treatment.
6. A representative tumor tissue specimen (archived or fresh biopsy) with associated pathology report should be available to perform NY-ESO-1 antigen expression analysis, unless a recent NY-ESO-1 expression test result from the same designated central laboratory, following the same procedures, has already been performed under a separate GSK sponsored protocol or under another substudy. For guidance on acceptable specimen material see Tumor Biopsies under Section 5.1 Leukapheresis Eligibility Screening
-Prior to finalizing participant treatment plan, please note that bridging/standard of care anti-cancer therapy is allowed under Section 7.1.2 conditions but that there are washout requirements prior to leukapheresis and prior to lymphodepletion. Additional considerations should be given to accumulated radiotherapy prior to lymphodepletion. All the Inclusion Criteria from Section 6.1.1 must apply
again prior to leukapheresis. In addition, the following criteria must also apply:
7. Life expectancy ≥24 weeks
8. Participant has confirmed evidence of a relevant disease-specific translocation per below:
• For synovial sarcoma, presence of a translocation involving chromosome 18 (SYT gene) and/or chromosome X (SSX1, SSX2 or SSX4 genes);
• For myxoid/round cell liposarcoma, presence of a translocation involving chromosome 12 (DDIT3 gene) and/or chromosome 16 (FUS gene) and/or chromosome 22 (EWSR1 gene).
Note: Methods, such as, but not limited to, fluorescence in situ hybridization (FISH) assay or Next Generation Sequencing (NGS) or Immuno HistoChemistry (IHC) using fusion-specific antibody are commonly used to detect translocations.
9. Participant is either currently being treated with or has completed at least one standard-of-care treatment including anthracycline-containing regimens (e.g., doxorubicin alone, doxorubicin with ifosfamide) for advanced (metastatic or inoperable) disease. Participants who are intolerant to anthracycline may receive ifosfamide alone unless intolerant to or ineligible to receive ifosfamide. Participants who received anthracycline-based therapy in the neoadjuvant/adjuvant setting and progressed will be eligible.
10.Participant must be positive for HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 alleles by a validated test in a designated central lab prior to leukapheresis. NOTE: If a participant was previously tested for HLA type under a different GSK-sponsored protocol, testing of HLA type for 208467 may not be required dependent on the test platform(s) used and whether they meet the 208467 protocol requirements [see Section 6.3 of the Core Protocol]).
11.Participant's tumor has been pathologically reviewed by a designated central laboratory with confirmed positive NY-ESO-1 expression defined as ≥30% of cells that are 2+ or 3+ by immunohistochemistry. NOTE: If a participant was previously tested for NY-ESO-1 expression under a different GSK-sponsored protocol, testing of NY-ESO-1 expression for 208467 may not be required dependent on the test platform(s) used and whether they meet the 208467 protocol requirements [see Section 6.3 of the Core Protocol]).
12. Left ventricular ejection fraction ≥45% with no evidence of clinically significant pericardial effusion.
For a detailed list of Inclusion Criteria's please refer to the protocol Page No. 173-178 and 239-245 |
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E.4 | Principal exclusion criteria |
1.Participant has been previously treated for advanced (metastatic or unresectable) synovial sarcoma or myxoid/round cell liposarcoma.
2. Central nervous system metastases.
3. Any other prior malignancy that is not in complete remission.
Exceptions include:
a. completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma (e.g. melanoma in situ, basal cell carcinoma, prostate cancer in-situ, periosteal osteosarcoma)
b. previous malignancies that have been definitively treated, and have been in remission for 5 years may be enrolled upon consultation with sponsor Medical Monitor or designee
4. Previous treatment with genetically engineered NY-ESO-1-specific T cells.
5. Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
6. Prior gene therapy using an integrating vector.
7. Previous allogeneic hematopoietic stem cell transplant.
8. Clinically significant systemic illness: serious active infections or significant cardiac, pulmonary, hepatic or other organ dysfunction, that in the judgment of the Investigator would compromise the subject’s ability to tolerate protocol therapy or significantly increase the risk of complications, or, prior or active demyelinating disease.
Leukapheresis Eligibility Screening: Participants are not eligible for leukapharesis if any of the Exclusion criteria from section 6.2.1 apply. Please note in particular that mandatory washout period restrictions must be respected (Table 5) before starting leukapheresis. In addition, participants are not eligible for leukapharesis if any of the following criteria apply:
9.Participant has history of chronic or recurrent (within the last year prior to leukapheresis) severe autoimmune or immune mediated disease (e.g. Crohn’s disease, systemic lupus) requiring steroids or other immunosuppressive treatments.
10. Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection (including, but not limited to systemic fungal infection)
b. Clinically significant cardiac disease defined by congestive heart failure New York Heart Association (NYHA) Class 3 /Class 4
c. Uncontrolled clinically significant arrhythmia
d. Acute coronary syndrome (angina or myocardial infarction) in last 6 months
e. Interstitial lung disease (participants with existing pneumonitis as a result of radiation are not excluded; however, participants cannot be oxygen dependent)
11. Current active liver or biliary disease.
12. QTc >480 msec
13. Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, other agents used in the study.
14. Pregnant or breastfeeding females (due to risk to fetus or newborn).
15. Prior/concomitant therapy: any prior treatment-related toxicities must be Common terminology criteria for adverse events <=Grade 1 at the time of initiating study intervention (except for non-clinically significant toxicities). Other standard of care lines of therapy are allowed only if guidelines and washout periods are followed.
16. Investigational treatment within 30 days or 5 half-lives (whichever is shorter) prior to leukapheresis. Investigational vaccines (other than NY-ESO-1 vaccines that are not allowed) must follow the washout period specified in Table 6. Exceptions to this rule must be evaluated by the Investigator in agreement with the Sponsor's Medical Monitor
17. Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or HTLV as defined in the protocol
18. has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study. Please note that mandatory washout period restrictions must be respected (Table 5) before starting lymphodepletion. In addition to confirming Treatment fitness per Section 6.2.3.1, participants cannot proceed with lymphodepletion or treatment if any of the following criteria apply
19. Participant has received cytotoxic therapy within 3 weeks prior to lymphodepleting chemotherapy.
20. Systemic corticosteroids or any other immunosuppressive therapy within 2 weeks prior to lymphodepleting chemotherapy.
21. Participant has received ≥50 Gy to a significant volume of the pelvis, long bones or spine, or a cumulative dose of radiation that, in the Investigator's opinion would predispose patients to prolonged cytopenia after lymphodepletion.
22. All of the participant's measurable lesions have been irradiated within 3 months prior to lymphodepletion. An irradiated measurable lesion with unequivocal progression following irradiation may be considered a target lesion regardless of time from last radiotherapy dose.
23.Participant has received live vaccine within 4 weeks prior to lymphodepletion or intends to receive live vaccine during the 3 month period following administration of lete-cel.
For a detailed list of Exclusion Criteria's please refer to the Protocol Page No. 178-182 & 245-249 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate (ORR) per RECIST v1.1 (assessed by investigator for Substudy 1 and assessed by independant review committee for Substudy 2) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
To further evaluate the efficacy of NY-ESO-1
- Time to Response (TTR)
- Duration of Response (DoR)
- Disease Control Rate (DCR)
- Progression Free Survival (PFS)
- Overall Survival (OS) for Substudy 2
To evaluate the safety and tolerability of NYESO-1
- Frequency and severity of Adverse events (AEs), serious adverse events (SAEs) and AEs of special interest (AESI; as defined in protocol).
-Laboratory parameters
-Replication Competent Lentivirus (RCL)
- Instances of Insertional oncogenesis (IO)
To characterize in vivo cellular PK profile:
- Maximum transgene expansion (Cmax)
- Time to Cmax (Tmax)
- Area under the time curve from zero to time t AUC(0-t), as data permit
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 13 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Canada |
United States |
France |
Netherlands |
Spain |
Germany |
Italy |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 3 |