LTX-315 and Adoptive T-cell Therapy in Advanced Soft Tissue Sarcoma (ATLAS-IT-04)

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open Label Phase II Single Centre Study Investigating the Safety and Efficacy of LTX-315 and Adoptive T-cell Therapy in Patients With Advanced/Metastatic Soft Tissue Sarcoma (ATLAS-IT-04)

Conditions
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Soft Tissue Sarcoma

Intervention / Treatment
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* Combination Product: LTX-315 and TILs


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: LTX-315 and TILs
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LTX-315 plus TIL infusion<br>LTX-315 intratumoural injection, TILs expansion and infusion. | Combination Product: LTX-315 and TILs<br>* Intratumoural injection of LTX-315 and infusion of TILs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 15 to 42 days | 
| 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. | Up to 133 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 133 days | 
| 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. | 41 to 49 days between Step 1 and Step 2 | 
| % 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. | 41 to 49 days between Step 1 and Step 2 | 
| 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. | EoT (Step 2, Week 7) and up to 15 months after EoT. | 
| 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. | Up to 15 months | 
| 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). | Assessed at Visit 25 (Step 2, Week 7, Day 42) | 
| 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. | Days from screening (Baseline) until date of progressive disease or up to 15 months after EoT. |