Neoplasms

Skin and Connective Tissue Diseases

All Conditions

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

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

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

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Carcinoma

Carcinoma, Non-Small-Cell Lung

Carcinoma, Renal Cell

Lung Neoplasms

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Neoplasms, Glandular and Epithelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Carcinoma, Bronchogenic

Bronchial Neoplasms

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Adenocarcinoma

Kidney Neoplasms

Urologic Neoplasms

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Ovarian Cancer

Renal Cell Carcinoma

Ovarian Epithelial Cancer

Clear Cell Renal Cell Carcinoma

Fallopian Tube Cancer

Micronutrients

Hematinics

Vitamins

Folic Acid

Vitamin B Complex

Folic Acid Antagonists

Folinic Acid

Folate

Vitamin B9

Various doses will be tested in participants with EOC, NSCLC and RCC.

Cohort 1: Participants with epithelial ovarian cancer (EOC)

Cohort 2: Participants with non-small cell lung cancer (NSCLC)

Cohort 3: Participants with renal cell carcinoma (RCC)

ITIL-306 is a cell therapy product derived from a participant's own TILs and contains a unique molecule designed to increase TIL activity when it encounters FOLR1 on the tumor. A portion of the participant's tumor is surgically removed to make a personalized ITIL-306 product. Once ITIL-306 has been made, the participant is treated with 3 days of lymphodepleting chemotherapy including cyclophosphamide and fludarabine, followed by 2 days of rest then a single infusion of ITIL-306.

ITIL-306

ITIL-306-201 is a phase 1a/1b, multicenter, clinical trial evaluating the safety and feasibility of ITIL-306 in adult participants with advanced solid tumors whose disease has progressed after standard therapy. ITIL-306 is a cell therapy derived from a participant's own tumor-infiltrating immune cells (lymphocytes; TILs) and contains a unique molecule designed to increase TIL activity when it encounters folate receptor α (FOLR1) on the tumor.

ITIL-306 in Advanced Solid Tumors

A Phase 1a/1b, Open-Label, Multicenter Study Evaluating the Safety and Feasibility of ITIL-306 in Subjects With Advanced Solid Tumors

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 investigator review.

For participants who experience an objective response, DOR is defined as the time from their first objective response to disease progression or death.

PFS is defined as the time from the ITIL-306 infusion date to the date of disease progression or death from any cause.

OS is defined as the time from the ITIL-306 infusion date to the date of death from any cause.

Carcinoma, Squamous Cell

Uterine Cervical Neoplasms

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Squamous Cell

Uterine Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Head and Neck Neoplasms

Pembrolizumab

Participants with cervical cancer whose disease has progressed during or after treatment with platinum-based chemotherapy. Participants with combined positive score ≥ 1 should also have disease that has progressed during or after treatment with CPI.

Participants with head and neck squamous-cell carcinoma (HNSCC) whose disease has progressed during or after platinum-based chemotherapy and previous CPI.

Participants with non-small cell lung cancer (NSCLC) whose disease has progressed during or after platinum-based chemotherapy and a CPI. Participants with targetable mutations (e.g. EGFR/ALK) are required to have disease which has progressed on targeted therapy and platinum-based chemotherapy.

ITIL-168 is a cell therapy product derived from a participant's own TILs. A portion of tumor is resected to make a personalized ITIL-168 product. If appropriate, participants may receive bridging therapy after recovering from the tumor resection during ITIL-168 manufacturing. Once ITIL-168 has been made, the participant is treated with up to 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.

Drug: Pembrolizumab Participants will receive 1 dose of pembrolizumab following tumor resection prior to receiving ITIL-168, and additional doses for up to a year after ITIL-168 infusion.

DELTA-2 is a phase 1 clinical trial to evaluate the safety, feasibility, and preliminary efficacy of ITIL-168 with pembrolizumab in participants with advanced cancer whose disease has progressed after standard therapy. ITIL-168 is a cell therapy derived from a patient's own tumor-infiltrating immune cells (lymphocytes; TILs).

ITIL-168 in Advanced Solid Tumors

A Phase 1, Open-Label, Multicenter Study Evaluating the Safety, Feasibility, and Preliminary Efficacy of ITIL-168 With Pembrolizumab in Subjects With Advanced Solid Tumors

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 investigator review.

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

Blood and Lymph Conditions

Leukemia

Leukemia, Myeloid

Leukemia, Myeloid, Acute

Hematologic Diseases

Myeloid Leukemia

Acute Myeloid Leukemia

Acute Non Lymphoblastic Leukemia

Acute Graft Versus Host Disease

Anti-Infective Agents

Aldesleukin

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. NK cells administration will not be followed by sc IL-2. N=3.

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 3.0 x 10\^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=3

On day 0, patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic UCB-NK cells. Prior to NK cell infusion, patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. IL-2 will be administered in a fixed dose of 6.0 x 10\^6 units starting 4 hours after NK cell infusion and given every other day for 6 doses in total. N=6

Natural killer cells generated from CD34+ hematopoietic progenitor cells derived from an allogeneic umbilical cord blood

UCB-NK cells

IL-2

P.M.M. van Hauten, MSc

H. Dolstra, Ass. Prof.

N.P.M. Schaap

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This study investigates an innovative treatment for relapsed or refractory acute myeloid leukemia (AML) exploiting administration of ex vivo-generated allogeneic natural killer (NK) cells with preceding non-myeloablative conditioning chemotherapy with or without subsequent in vivo IL-2 cytokine support.

This is a prospective phase I/IIa study. The first phase is a IL-2 dose-escalating safety study in twelve patients. The second phase of the study is designed as a Simon's optimal two-stage single-arm phase IIa study, comprising seventeen patients. Prior to NK cell infusion, all patients will receive cyclophosphamide and fludarabine (Cy/Flu) based lymphodepleting chemotherapy. On day 0, all patients will receive a fixed dose of 1.0-3.0 x 10\^9 allogeneic umbilical cord blood-derived NK cells (UCB-NK cells). These cells are generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit.

In phase I of the study patients will receive UCB-NK cells without subcutaneous (SC) IL-2, with lower dose SC IL-2 or with higher dose SC IL-2 (n=3 per treatment group, n=6 in the highest tolerable dose). After establishing the safety of UCB-NK cells combined with SC IL-2, we will continue with phase IIa of the study, with ten patients in the first stage (including the six patients from phase I with comparable IL-2 dose) and if clinical efficacy is achieved an additional seven patients in the second stage.

The study is divided in two phases. In phase I, we will determine the safety of our UCB-NK cell product with or without sc IL-2, following a non-myeloablative immunosuppressive conditioning regimen in patients with AML. Three patients will receive NK cells without IL-2. If no dose limiting toxicities occur another three patients will receiving NK cells with a low dose IL-2, and if safe, another six patients will receive NK cells with a higher dose IL-2.

The primary objective of phase IIa of the study is to evaluate the effect of UCB-NK cell adoptive immunotherapy in combination with SC IL-2 following a non-myeloablative immunosuppressive conditioning regime on disease activity in patients with AML. Therefore 17 patients will be evaluated using a Simon's optimal two-stage single-arm study design, with 10 patients in the first stage and an additional 7 patients in the second stage. These patients will receive NK cells with the highest tolerable dose IL-2, established after phase I.

Natural Killer-cell Therapy for Acute Myeloid Leukemia

Infusion of ex Vivo-generated Allogeneic Natural Killer Cells in Combination With Subcutaneous IL-2 in Patients With Acute Myeloid Leukemia: a Phase I/IIa Study

Patients will be evaluated intensively using the CTCAE toxicity criteria and graft versus host disease (GvHD) classification criteria, defining dose limiting toxicities (DLTs): 1. Any treatment-emergent non-hematologic grade 3 toxicity lasting \>72 hours, except for transient constitutional symptoms, diarrhea, fatigue or skin rash not requiring systemic steroid therapy. 2. Acute GvHD \>grade 2 within 6 weeks of the first IL-2 dose. If in any of the three patients of each individual cohort of the phase I study a DLT occurs, the cohort will be extended to 6 patients. If 2 patients experience DLT within a cohort of 3 or 6 patients the study will be stopped in case the patients were only receiving NK cells or the study will be continued without IL-2 or the lower dose of IL-2 in case the patients were receiving NK cells in combination with IL-2. Serious, life threatening adverse events or grade 4 toxicity will be a reason to terminate the study or continue without IL-2 cytokine support.

The primary objective of phase IIa of the study is to evaluate the effect of UCB-NK cell adoptive immunotherapy in combination with SC IL-2 following a non-myeloablative immunosuppressive conditioning regime on disease activity in patients with AML. At day 28 a bone marrow biopsy will be performed to evaluate % blasts or % minimal residual disease (MRD) in the bone marrow. A complete remission is defined as BM blasts \<5%; marrow should not be merely 'aplastic': at least 200 cells should be enumerated or cellularity should be at least 10%. MRD will be evaluated by flow cytometry (leukemia associated phenotypes (LAPs)) and/or molecular quantification of patient specific mutations (PCR).

For phase IIa of the study the clinical evaluation data (% blasts and % MRD positivity) will be translated in a clinical response (stable disease, partial remission, complete remission) and quantitative presented.

We will determine the percentage and absolute number of donor-derived NK cells in peripheral blood and bone marrow after infusion using flow cytometry and DNA chimerism analysis. A positive expansion rate of the infused NK cells requires an absolute number of ≥100 donor-derived NK cells per μl blood at day +7 and/or +14.

NK cells from peripheral blood and bone marrow will be obtained. These cells will be stimulated in vitro for 4 hours and subsequently the degranulation marker CD107a and immunoregulatory marker IFNy will be measured by flow cytometry. These results can be compared between patients that did receive IL-2 or did not.

This will be correlated with absolute lymphocyte count and in vivo NK cell persistence and expansion.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
ITIL-168 in Advanced Melanoma	NCT05050006	Advanced Cutane...	ITIL-168	18 Years -	Instil Bio
ITIL-306 in Advanced Solid Tumors	NCT05397093	Epithelial Ovar... Non-small Cell ... Renal Cell Carc...	ITIL-306	18 Years -	Instil Bio
ITIL-168 in Advanced Solid Tumors	NCT05393635	Cervical Cancer Head and Neck S... Non-small Cell ...	ITIL-168	18 Years -	Instil Bio
ITIL-168 in Advanced Melanoma	NCT05050006	Advanced Cutane...	ITIL-168	18 Years -	Instil Bio
Natural Killer-cell Therapy for Acute Myeloid Leukemia	NCT04347616	Acute Myeloid L... Acute Myeloid L...	UCB-NK cells IL-2	18 Years -	Radboud University Medical Center
Natural Killer-cell Therapy for Acute Myeloid Leukemia	NCT04347616	Acute Myeloid L... Acute Myeloid L...	UCB-NK cells IL-2	18 Years -	Radboud University Medical Center

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