Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Antineoplastic Agents

All Drugs and Chemicals

Vasodilator Agents

Urological Agents

Nivolumab

Tadalafil

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Phosphodiesterase 5 Inhibitors

Phosphodiesterase Inhibitors

Enzyme Inhibitors

Locally advanced and unresectable and metastatic NSCLC subjects previously treated with anti-programmed cell death-1 (PD-1) will be treated with MILs™ - NSCLC plus nivolumab with or without tadalafil.

To evaluate the safety of MILs™ - NSCLC alone in subjects with locally advanced and unresectable or metastatic NSCLC

MILs™ - NSCLC

To evaluate the efficacy of MILs™ - NSCLC in combination with nivolumab in subjects with locally advanced and unresectable or metastatic NSCLC

nivolumab

To evaluate the efficacy of MILs™ - NSCLC in combination with nivolumab with or without tadalafil in subjects with locally advanced and unresectable or metastatic NSCLC

tadalafil

The purpose of this study is to determine the safety and efficacy of MILs™ - NSCLC alone and in combination with nivolumab with or without tadalafil in subjects with locally advanced and unresectable or metastatic NSCLC who are refractory or relapsing to a PD-1 containing regimen.

This study will examine the safety and efficacy of Marrow Infiltrating Lymphocytes-Non-Small Cell Lung Cancer (MILs™ - NSCLC) combined with nivolumab with or without tadalafil in subjects with locally advanced and unresectable and metastatic NSCLC who were refractory to, or have relapsed on, an anti-PD-1 containing regimen. MILs™ - NSCLC are an adoptive cell therapy product derived via the activation and expansion of bone marrow T cells. Subjects will have bone marrow harvested during the Screening Period which will be used to manufacture the MILs™ - NSCLC. The MILs™ - NSCLC will then be administered on Day 0. Nivolumab will be administered on Day 1 and will continue every four weeks until treatment discontinuation. Tadalafil will be administered on Day 1 and will continue daily until treatment discontinuation.

In Part 1, approximately 3-6 subjects will be treated with MILs™ - NSCLC alone. Following Part 1, approximately 20 subjects will be treated with MILs™ - NSCLC plus nivolumab with or without tadalafil.

Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Locally Advanced and Unresectable or Metastatic NSCLC

A Phase 2a, Open-Label, Multi-Center Study to Assess the Efficacy and Safety of Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Subjects With Locally Advanced and Unresectable or Metastatic NSCLC Previously Treated With Anti-PD-1

Proportion of subjects with reduction in tumor burden of a predefined amount per RECIST 1.1

Duration from first documented evidence of CR or PR until the first documented evidence of PD or death due to any cause, whichever occurs first

Proportion of subjects in the efficacy population who achieve an Investigator-assessed confirmed CR, PR, or SD per RECIST 1.1

Date of first the administration of MILs™ - NSCLC until documented PD or death due to any cause, whichever occurs first

Duration from the date of administration of MILs™ - NSCLC until death due to any cause

Systolic and diastolic blood pressure in mmHg

Clinical chemistry results will be summarized and changes from baseline provided

Hematology results will be summarized and changes from baseline provided

Coagulation results will be summarized in data listings

Urinalysis results will be summarized in data listings

ECGs results will be summarized and changes from baseline provided

Physical examinations will be performed by the Investigators and any new clinically significant or changes in medical conditions will be reported as adverse events

Bristol-Myers Squibb

WindMIL Therapeutics

Skin and Connective Tissue Diseases

Rare Diseases

Melanoma

Melanoma, Cutaneous Malignant

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antirheumatic Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Tin Fluorides

Immunomodulating Agents

Patients who relapsed after or were refractory to at least 1 prior line of systemic therapy including a PD-1 inhibitor.

Patients who were intolerant to a PD-1 inhibitor and have persistent disease after stopping PD-1 therapy.

Patients who had a best response of stable disease despite being treated with at least 4 doses of a PD-1 inhibitor in the previous line of therapy.

ITIL-168 is a cell therapy product derived from a patient's own TILs. A tumor sample is removed from each patient to make a personalized ITIL-168 product. Once ITIL-168 has been made, the patient is treated with 5 days of lymphodepleting chemotherapy including cyclophosphamide and fludarabine, followed by a single infusion of ITIL-168, and up to 8 doses of IL-2.

ITIL-168

Instil Study Director

DELTA-1 is a phase 2 clinical trial to evaluate the efficacy and safety of ITIL-168 in adult subjects with advanced melanoma who have previously been treated with a PD-1 inhibitor. ITIL-168 is a cell therapy derived from a patient's own tumor-infiltrating immune cells (lymphocytes; TILs).

All enrolled participants are assigned to be treated with a single dose of ITIL-168

ITIL-168 in Advanced Melanoma

A Phase 2, Open-label, Multicenter Study Evaluating the Safety and Efficacy of Autologous Tumor-infiltrating Lymphocytes (TILs) in Subjects With Advanced Melanoma (DELTA-1)

Objective response rate (ORR), defined as the incidence of a complete response (CR) or a partial response (PR) per a modified Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria, as assessed by central review.

For subjects who experience an objective response, duration of response (DOR) is defined as the time from their first objective response to disease progression or death.

Progression-free survival (PFS) is defined as the time from the ITIL-168 infusion date to the date of disease progression or death from any cause.

Overall survival (OS) is defined as the time from the ITIL-168 infusion date to the date of death from any cause.

ORR as determined by investigators is defined as the incidence of a CR or a PR per a modified RECIST v1.1, as determined by study investigators.

Disease control rate (DCR), defined as the incidence of CR, PR, or stable disease (SD) per a modified RECIST v1.1 criteria, as determined by central review.

Instil Bio

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

A single dose of pTTL will be administered after pre-conditioning chemotherapy with Fludarabine (30 mg/m(2) body surface area) x 3 and Cyclophosphamide (300 mg/m(2) body surface area) x 3 on days -7 to -5. pTTL will usually be infused on day 1 (5 days after last chemotherapy) with the option of administering it on day -3 if judged preferable based on the T cell expansion kinetics during pTTL production. pTTL is administered as a fresh product directly after production.

Dose escalation will be applied. Cohort 1 (1 patient): 1 million (with an accepted range of down to -5%) viable cells per kg body weight

Cohort 2 (3 patients): 2.5 million (down to -5%) viable cells per kg body weight

Cohort 3 (3 patients): 5 million (down to -5%) viable cells per kg body weight

Cohort 4 (remaining patients): up to 1 billion viable cells

pTTL is an autologous cell product for adoptive cancer immunotherapy containing in vitro expanded T cells stimulated with patient-specific tumour neoantigens derived from tumour-draining lymph nodes.

pTTL

Samuel Svensson, PhD

Andrea Salmén, MSE

Maximilian Kordes, MD, PhD

Mattias Carlsten, MD, PhD

Abbas Chabok, MD, PhD

Maziar Nikberg, MD, PhD

This is an open-label, non-randomised FIH trial investigating the safety and tolerability of a novel ATMP, pTTL, composed of autologous tumour-draining lymph node-derived T cells stimulated in vitro with personalised cancer neoantigens.

The neoantigens are selected through a process starting with next generation sequencing (NGS) of tumour material from the patient followed by selection of neoantigenic mutations using an in-house software, PIOR®. Selected neoantigen epitopes are expressed as recombinant proteins, NAG, and used to stimulate T cells to promote neoantigen-specific T cell expansion in vitro in pTTL production.

pTTL is thus based on autologous cells stimulated with patient-specific neoantigens. In consequence, every pTTL product is unique and designated for use in one single individual.

pTTL will be administered to patients with stage IV colorectal cancer (CRC) as a single intravenous dose.

STUDY RATIONALE The present trial is an open-label, non-randomised FIH trial investigating the safety and tolerability of pTTL, an immunotherapy consisting of autologous T cells activated and expanded in vitro using tumour-specific personalised neoantigens. The scientific rationale for pTTL relies on the fact that somatic mutations in tumour cells arising during malignant transformation result in altered proteins or peptides, so called neoantigens. Each individual tumour harbours multiple mutations that form a unique mutation profile, which enables personalisation of each therapeutic product. The neoantigens distinguish tumour cells from normal cells and make the tumour cells targetable by the immune system, and also allows targeting of several targets in the tumour simultaneously. In the present trial, up to 36 neoantigens will be targeted.

The starting material for pTTL is derived from tumour-draining regional lymph nodes (RLNs). The choice of this source of T cells is based on several advantages: The exposure to tumour antigens and, in the case of metastasis, tumour cells causes an enrichment of tumour- specific T cells. These T cells also have the potential to be superior to tumour-infiltrating T cells due to less exposure to tumour-mediated immunosuppression.

The production process for pTTL includes in vitro expansion, which increases the neoantigen-reactive T cell population. The selective T cell expansion is achieved by stimulation with protein constructs containing neoantigen epitopes, based on sequencing data from each patient's own tumour. This improves the chance of effective cancer cell eradication by both increasing the number of cells able to recognise and respond to the tumour, and by breaking immunological tolerance created in vivo by immunosuppressive mechanisms through activation in a non-suppressive environment.

PATIENTS The selected target group of the trial is adults with stage IV CRC. Patients may be considered eligible for inclusion if they have received treatments according to standard of care or if further standard of care treatment options are judged not to be in the patients' best interest (e.g. due to toxicity issues). Patients could also be eligible for inclusion in the trial during a scheduled pause in ongoing palliative therapy, at the discretion of the treating Investigator. Eligible patients must have a primary or metastatic lesion that is accessible to biopsy or surgery to obtain tumour material for NGS analysis. In addition, it is a requirement that the patient can undergo surgical excision of RLNs for use in pTTL production. Eligible patients should also have a good performance status (ECOG 0-1) and organ function, and no pre-existing conditionings deemed to increase their risk for severe side effects of pTTL therapy. Materials for Part I of the trial can be collected, while non-curative therapeutic options remain, and cryopreserved for later use if the patient should become eligible for inclusion in Part II.

METHODOLOGY The trial is composed of 3 parts, referred to as Part I, Part II and Part III.

Patients will be consented separately for Part I and for Part II/III: a first consent is given for tissue collection and pTTL production, and a second consent is given for pTTL treatment, including pre-conditioning chemotherapy and follow-up.

Part I of the trial entails patient identification, recruitment and screening of trial patients. It also comprises production of pTTL, which is performed in 3 steps:

1. Collection of tumour samples and normal samples for NGS and neoantigen selection. Production of stimulatory NAG-coupled beads raw material TC0301.
2. Collection of starting material for pTTL manufacturing from RLN.
3. pTTL manufacturing.

The time required from collection of tumour material and RLNs up until pTTL production and administration to the patient is approximately 8 to 12 weeks. The RLN starting material is cryopreserved after initial processing, enabling flexibility in the timing of pTTL administration.

Part II of the trial entails pre-conditioning and supportive care therapy, treatment with pTTL, and 26 weeks safety follow-up.

Pre-conditioning contains cyclophosphamide and fludarabine, and will be administered between Day -7 and Day -5 before scheduled pTTL administration. Supportive care treatment will start on Day -9 or Day -8. pTTL administration will normally be administered on Day 1, with the option of administration on Day -3 if cell expansion kinetics during pTTL production indicates this would be preferable. Part II will end when the last treated patient has been followed for 26 weeks or earlier in case of death or patient withdrawal.

Part III of the trial is a long-term follow-up initiated after completion of the initial 26 weeks safety follow-up period. Patients will participate in Part III for up to 4.5 years after end of Part II or until death, whichever comes first.

pTTL DOSAGE AND ADMINISTRATION The drug product (DP), i.e. pTTL, is composed of in vitro expanded RLN cells, enriched for neoantigen-specific T cells. It is formulated as a cell suspension with the excipients NaCl (9 mg/mL) and human serum albumin (25 mg/mL) in a transfusion bag intended for intravenous transfusion. The product is administered fresh. Each patient will receive a single administration of pTTL.The cell dose obtained during the manufacturing process will vary depending on the size of the neoantigen-reactive clones present in the starting material and their proliferative capacity. The minimum dose of a pTTL unit is 20 million viable cells and the maximum dose is 1 billion viable cells.

A First-In-Human Trial of pTTL in Advanced Colorectal Cancer

A First-In-Human, Phase I/IIa Trial of the Novel T Cell Immunotherapy pTTL in Patients With Advanced Colorectal Cancer

T cell receptor sequencing (TCRseq) will be used to characterise the pTTL product and to trace the identified pTTL clones in sequential peripheral blood samples post treatment.

If feasible, pre- and post-treatment biopsies will be taken for histological assessment of T cell infiltration and characterisation of tumour-infiltrating T cells.

Functional T cell assays (including but not limited to flow cytometry and cytokine release assays) will be used to evaluate neoantigen-specific responses in the pTTL product and in peripheral blood T cells, reflecting the extent of neoantigen reactivity in the different samples.

Serum tumour markers (the choice of markers will be made according to the patient's tumour characteristics) will be assessed as a biomarker of efficacy, as it reflects changes in tumour burden.

Circulating tumour DNA (ctDNA) will be assessed as a biomarker of efficacy, as it reflects changes in tumour burden.

Analysis of the pTTL product and of post therapy peripheral blood samples will be performed to evaluate the functional status, differentiation and lineage-identity of T cells and other immune cells. This is an exploratory outcome measure, where a large set of phenotypical aspects will be assessed in order to understand which characteristics are important for pTTL efficacy and potentially also to side effects. Evaluations of the T cells are performed using assays including, but not limited to, flow cytometry and RNA sequencing, to characterize the T cells with regard to identity, differentiation and functions which could be relevant to the efficacy of pTTL.

Data relevant for the correlation of neoantigen selection to clinical outcome will be stored and assessed. Aspects such as type of genetic alteration, variant allele frequency, RNA expression, and protein type and function will be considered and assessed in the context of clinical outcomes, signals of efficacy and biomarker evaluation. This is an exploratory outcome measure, and multiple assessments will be performed to better understand what neoantigen characteristics that could affect efficacy of pTTL.

To establish that pTTL can be administered to patients with advanced CRC without unacceptable toxicity. Adverse events (AEs) will be collected and assessed according to Common terminology criteria for AEs (CTCAE) v5.0. Special focus will be placed on immunological AEs and AEs known to be associated with T cell therapies, defined as AEs of special interest (AESI). AESI will include autoimmune reactions potentially resulting from off-target toxicity such as colitis, and immune-mediated reactions associated with immune cell activation, such as cytokine release syndrome (CRS).

Measured using radiology (including CT, MR or other applicable examination) and assessed according to iRECIST

The time between administration and documented objective response

The time from when an objective response is initially documented to the time of subsequent tumour progression.

The time to tumour progression after pTTL administration will be assessed using the iRECIST criteria and will take into account the time from inclusion in Part II of the trial until disease progression.

This measurement will be based on iRECIST, and will use radiological examinations (including CT, MR or other applicable examination) before and after pTTL administration in an endeavour to evaluate whether the progression kinetics of the patient's cancer is affected by pTTL administration

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Locally Advanced and Unresectable or Metastatic NSCLC	NCT04069936	Non Small Cell ... Lung Cancer Lung Cancer Met... Lung Cancer, No... Non Small Cell ... NSCLC Non-small Cell ... Non-small Cell ...	MILs™ - NSCLC nivolumab tadalafil	18 Years -	WindMIL Therapeutics
ITIL-168 in Advanced Melanoma	NCT05050006	Advanced Cutane...	ITIL-168	18 Years -	Instil Bio
ITIL-168 in Advanced Melanoma	NCT05050006	Advanced Cutane...	ITIL-168	18 Years -	Instil Bio
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB
Marrow Infiltrating Lymphocytes - Non-Small Cell Lung Cancer (MILs™ - NSCLC) Alone or in Combination With Nivolumab With or Without Tadalafil in Locally Advanced and Unresectable or Metastatic NSCLC	NCT04069936	Non Small Cell ... Lung Cancer Lung Cancer Met... Lung Cancer, No... Non Small Cell ... NSCLC Non-small Cell ... Non-small Cell ...	MILs™ - NSCLC nivolumab tadalafil	18 Years -	WindMIL Therapeutics
A First-In-Human Trial of pTTL in Advanced Colorectal Cancer	NCT05908643	Colorectal Canc...	pTTL	18 Years -	Neogap Therapeutics AB

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