Soft Tissue Sarcoma
Conditions
Brief summary
ATLAS-IT-04 is a two part, single arm study designed to determine the safety and effectiveness of LTX-315 to induce T-cell infiltration prior to TIL expansion in patients with soft tissue sarcoma. Following intratumoural injection of LTX-315 to a selected lesion, the lesion will be extracted for T-cell culture, expansion and infusion.
Detailed description
Patients with advanced/metastatic tumours who have received at least one approved standard of care treatment will be recruited. All patients must have at least two lesions, one that can injected with LTX-315 and another that can used to assess response. In the first part of the study, LTX-315 will be administered intratumorally on 4-6 dosing days over a 2-4 week period to an index lesion which will be biopsied or removed after treatment for T-cell expansion. The second part will involve culturing and expanding T-cells for infusion of tumour infiltrating lymphocytes (TILs) following an induction regimen. The safety and efficacy of the LTX-315 and TIL treatment will be assessed. Patients will be followed up for 15 months.
Interventions
COMBINATION_PRODUCTLTX-315 and TILs
Intratumoural injection of LTX-315 and infusion of TILs
Sponsors
Herlev Hospital
Lytix Biopharma AS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
LTX-315 and TILs
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Advanced/metastatic soft tissue sarcoma that is stable or has progressed on or after minimum 1 line of systemic treatment of advanced/metastatic disease * At least 1 index lesion accessible for injection * At least 1 measurable non-injected lesion that can be used for response willing to undergo repeat biopsy and tumour resection procedures * Age between 18 and 75 years * ECOG performance status of 0-1 * Meet following blood laboratory criteria: ANC \>/= 1.5, Platelet count \>/=75, - Haemoglobin \>/=6mmol/L, AST and ALT \</=2.5 x ULN, Creatinine \</=1.5 ULN * Willing to comply with the protocol requirements and follow-up * Signed informed consent
Exclusion criteria
* A history of clinically significant active systemic autoimmune disease requiring anti inflammatory or immunosuppressive therapy within the last 3 months * Other active malignancy within the previous 5 years except for carcinoma in situ of cervix, ductal r lobular carcinoma in situ of the breast * Received an investigational drug within 4 weeks prior to receipt of study drug * Received external radiotherapy or cytotoxic chemotherapy within 4 weeks prior to LTX-315 administration or have not recovered from AEs (to\</= grade 1) Palliative radiotherapy to non target and lesions planned for LTX-315 injection within 4 weeks of LTX-315 administration is allowed * Currently taking any agent with a known effect on the immune system. Stable doses of corticosteroids(up to 10mg prednisolone or equivalent) are permitted for at least 2 weeks prior to LTX-315 administration * Any serious illness or medical condition such, but not limited to: uncontrolled infection or infection requiring antibiotics, uncontrolled cardiac failure, uncontrolled systemic and gastrointestinal inflammatory conditions, bone marrow dysplasia * Known to test positive for HIV/AIDs, syphilis, human T-cell leukemia-lymphoma virus, active Epstein Barr, hepatitis B or C. * history of cerebro- or cardio-vascular disorders and would be of particular risk of sequelae following a hypotensive episode * If of child bearing potential, not willing to use effective form of contraception * Breastfeeding and/or have a positive pregnancy test * Donate sperm from start to 3 months after study treatment * Expected to need any other anticancer treatment or immunotherapy during the treatment period * Clinically active or unstable central nervous system metastases
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total T-cell Level in Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to End of Step 1 (Step 1, Week 3-5) | 15 to 42 days | The total T-cell level was measured at baseline and end of Step 1. Change from baseline was listed as absolute change. Data cannot be presented on subject-level and are therefore presented as the arithmetic mean value for the factor increase (+) or decrease (-) in number of cells/mm2 from baseline to end of Step 1. |
| Adverse Events (AE) Related to LTX-315 or to the Combination of LTX-315 and Adoptive T-cell Therapy From Baseline (Step 1, Week 1, Day 1) to End of Treatment (EoT) (Step 2, Week 7) | Up to 133 days | AEs were events occurring during or after administration of the IMP. AEs were coded using MedDRA version 21.1 and were classified by System Organ Class (SOC), Preferred Term (PT) and Lowest Level Term (LLT). Adverse events related to LTX-315 were events where causality to LTX-315 was marked on the adverse events page. Adverse events related to the combination of LTX-315 and adoptive T-cell therapy were events where both causality to LTX-315 and at least one of the other IMPs (TILs, Sendoxan®, Fludara® and Proleukin®) were marked on the adverse event page. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % CD3+CD8+ T-cells of Total CD3+ in TIL Infusion Product | 41 to 49 days between Step 1 and Step 2 | The composition of the TIL infusion product was evaluated for the subjects for whom it was possible to grow TILs. |
| Objective Response Rate | EoT (Step 2, Week 7) and up to 15 months after EoT. | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Clinical Benefit Rate | Up to 15 months | The clinical benefit rate (CBR) was defined as proportion of subjects who according to RECIST 1.1 had achieved complete response, partial response or stable disease at EoT (Step 2, Week 7) and up to 15 months after EoT. CBR was evaluated at Step 2, Week 7 and Week 13. |
| Best Overall Tumour Response Rate | Assessed at Visit 25 (Step 2, Week 7, Day 42) | Best overall tumour response rate (BOR) was defined in the CSP as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). |
| Progression Free Survival | Days from screening (Baseline) until date of progressive disease or up to 15 months after EoT. | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. |
| Change in CD3+CD8+ T Cell Density in Non-injected Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to EoT (Step 2, Week 7) | Up to 133 days | The change is described as factor change in CD8+ cells/mm2. |
| Total Number of CD3+CD8+ T-cells in TIL Infusion Product | 41 to 49 days between Step 1 and Step 2 | The composition of the TIL infusion product was evaluated for the subjects for whom it was possible to grow TILs. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells | Up to 15 months | Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells antigen specificity assessed by enzyme-linked immuno-spot assay (ELISPOT) and flowcytometry analysis of cytokines including interferon gamma (IFNγ) and tumour necrosis factor alpha (TNF⍺) |
| Changes in Immunological Parameters From Baseline (Step 1, Week 1, Day 1) to 15 Months After EoT | Up to 15 months | Systemic immune effect of the treatment was assessed by sequencing the TCR repertoire in the peripheral blood mononuclear cells (PBMCs), the TIL product and the biopsies. The outcome of this endpoint is described as the number of subjects for whom a systemic immune effect (in terms of expansion of a significant number of T-cell clones in the blood) was observed. |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LTX-315 Plus TIL Infusion LTX-315 intratumoural injection, TILs expansion and infusion.
LTX-315 and TILs: Intratumoural injection of LTX-315 and infusion of TILs | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Unsuccessful TIL expansion | 2 |
Baseline characteristics
| Characteristic | LTX-315 Plus TIL Infusion |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Region of Enrollment Denmark | 6 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 |
Outcome results
Primary
Adverse Events (AE) Related to LTX-315 or to the Combination of LTX-315 and Adoptive T-cell Therapy From Baseline (Step 1, Week 1, Day 1) to End of Treatment (EoT) (Step 2, Week 7)
AEs were events occurring during or after administration of the IMP. AEs were coded using MedDRA version 21.1 and were classified by System Organ Class (SOC), Preferred Term (PT) and Lowest Level Term (LLT). Adverse events related to LTX-315 were events where causality to LTX-315 was marked on the adverse events page. Adverse events related to the combination of LTX-315 and adoptive T-cell therapy were events where both causality to LTX-315 and at least one of the other IMPs (TILs, Sendoxan®, Fludara® and Proleukin®) were marked on the adverse event page.
Time frame: Up to 133 days
Population: AEs related to LTX-315 treatment were evaluated for the 6 subjects completing Step 1. AEs related to LTX-315 treatment in combination with adoptive T-cell therapy were evaluated for the 4 subjects completing Step 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LTX-315 plus TIL infusion | Adverse Events (AE) Related to LTX-315 or to the Combination of LTX-315 and Adoptive T-cell Therapy From Baseline (Step 1, Week 1, Day 1) to End of Treatment (EoT) (Step 2, Week 7) | AEs related to LTX-315 treatment during Step 1. | 14 events |
| LTX-315 plus TIL infusion | Adverse Events (AE) Related to LTX-315 or to the Combination of LTX-315 and Adoptive T-cell Therapy From Baseline (Step 1, Week 1, Day 1) to End of Treatment (EoT) (Step 2, Week 7) | AEs related to LTX-315 treatment in combination with adoptive T-cell therapy during Step 2 | 0 events |
Primary
Change in Total T-cell Level in Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to End of Step 1 (Step 1, Week 3-5)
The total T-cell level was measured at baseline and end of Step 1. Change from baseline was listed as absolute change. Data cannot be presented on subject-level and are therefore presented as the arithmetic mean value for the factor increase (+) or decrease (-) in number of cells/mm2 from baseline to end of Step 1.
Time frame: 15 to 42 days
Population: For 1 subject evaluation was not possible due to complete necrosis of the injected lesion
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LTX-315 plus TIL infusion | Change in Total T-cell Level in Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to End of Step 1 (Step 1, Week 3-5) | 1.9 factor change in cells/mm2 |
Secondary
Best Overall Tumour Response Rate
Best overall tumour response rate (BOR) was defined in the CSP as the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started).
Time frame: Assessed at Visit 25 (Step 2, Week 7, Day 42)
Population: Evaluated for the 4 subjects who progressed to Step 2.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LTX-315 plus TIL infusion | Best Overall Tumour Response Rate | Stable disease | 3 Participants |
| LTX-315 plus TIL infusion | Best Overall Tumour Response Rate | Progressive disease | 1 Participants |
Secondary
% CD3+CD8+ T-cells of Total CD3+ in TIL Infusion Product
The composition of the TIL infusion product was evaluated for the subjects for whom it was possible to grow TILs.
Time frame: 41 to 49 days between Step 1 and Step 2
Population: The composition of the TIL infusion product was evaluated for the 4 subjects for whom it was possible to grow TILs. For 2 subjects it was not possible to meet the criteria of 4x10\^7 cells as described in the IMPD.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LTX-315 plus TIL infusion | % CD3+CD8+ T-cells of Total CD3+ in TIL Infusion Product | 17 %CD8+ of total CD3+ T-cells in TILs |
Secondary
Change in CD3+CD8+ T Cell Density in Non-injected Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to EoT (Step 2, Week 7)
The change is described as factor change in CD8+ cells/mm2.
Time frame: Up to 133 days
Population: The change in CD3+CD8+ T-cells from baseline to end of Step 2 could only be evaluated for 1 subject.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LTX-315 plus TIL infusion | Change in CD3+CD8+ T Cell Density in Non-injected Tumour Tissues From Baseline (Step 1, Week 1, Day 1) to EoT (Step 2, Week 7) | 3.3 factor change in CD8+ cells/mm2 |
Secondary
Clinical Benefit Rate
The clinical benefit rate (CBR) was defined as proportion of subjects who according to RECIST 1.1 had achieved complete response, partial response or stable disease at EoT (Step 2, Week 7) and up to 15 months after EoT. CBR was evaluated at Step 2, Week 7 and Week 13.
Time frame: Up to 15 months
Population: The endpoint was evaluated for the 4 subjects who progressed to Step 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LTX-315 plus TIL infusion | Clinical Benefit Rate | CBR at EoT (Step 2, Week /) | 3 participants |
| LTX-315 plus TIL infusion | Clinical Benefit Rate | CBR at up to 15 months after EoT (Week 13) | 1 participants |
Secondary
Objective Response Rate
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by CT/MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: EoT (Step 2, Week 7) and up to 15 months after EoT.
Population: ORR was evaluated for the 4 subjects who progressed to Step 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LTX-315 plus TIL infusion | Objective Response Rate | ORR at EoT (Step 2, Week 7) | 0 participants |
| LTX-315 plus TIL infusion | Objective Response Rate | ORR at up tp 15 months after EoT | 0 participants |
Secondary
Progression Free Survival
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time frame: Days from screening (Baseline) until date of progressive disease or up to 15 months after EoT.
Population: Endpoint evaluated for the 4 subjects who progressed to Step 2.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LTX-315 plus TIL infusion | Progression Free Survival | 153 days |
Secondary
Total Number of CD3+CD8+ T-cells in TIL Infusion Product
The composition of the TIL infusion product was evaluated for the subjects for whom it was possible to grow TILs.
Time frame: 41 to 49 days between Step 1 and Step 2
Population: TIL infusion product was evaluated for the 4 subjects for whom it was possible to grow TILs. For 2 subjects it was not possible to meet the criteria of 4x10\^7 cells as described in the IMPD.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LTX-315 plus TIL infusion | Total Number of CD3+CD8+ T-cells in TIL Infusion Product | 8032 million CD8+ T-cells |
Other Pre-specified
Changes in Immunological Parameters From Baseline (Step 1, Week 1, Day 1) to 15 Months After EoT
Systemic immune effect of the treatment was assessed by sequencing the TCR repertoire in the peripheral blood mononuclear cells (PBMCs), the TIL product and the biopsies. The outcome of this endpoint is described as the number of subjects for whom a systemic immune effect (in terms of expansion of a significant number of T-cell clones in the blood) was observed.
Time frame: Up to 15 months
Population: This endpoint was evaluated for 2 subjects only.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LTX-315 plus TIL infusion | Changes in Immunological Parameters From Baseline (Step 1, Week 1, Day 1) to 15 Months After EoT | 2 participants |
Other Pre-specified
Number of Participants With Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells
Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells antigen specificity assessed by enzyme-linked immuno-spot assay (ELISPOT) and flowcytometry analysis of cytokines including interferon gamma (IFNγ) and tumour necrosis factor alpha (TNF⍺)
Time frame: Up to 15 months
Population: Endpoint evaluated for the 4 subjects who progressed to Step 2.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LTX-315 plus TIL infusion | Number of Participants With Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells | Induced T-cell response against cancer testis antigens | 3 participants |
| LTX-315 plus TIL infusion | Number of Participants With Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells | Induced T-cell response against predicted neo-peptides | 1 participants |
| LTX-315 plus TIL infusion | Number of Participants With Tumour-antigen Specific T-cells in Tumour Tissue and Peripheral Blood Mononuclear Cells | Induced T-cell response against autologous tumour cell line | 3 participants |