Adoptive Cell Therapy Following a Non-myeloablative, Lymphodepleting Induction Regimen in Metastatic Melanoma Patients

NCT03166397 | Recruiting Phase 2 DMC

• 1 other identifier: SHEBA-16-3566-JS-CTIL
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) in combination with lymphodepletion and high-dose interleukin 2 (IL-2) has demonstrated reproducible objective response rates of approximately 50 percent in patients with highly advanced, refractory metastatic melanoma. Recent developments in theTIL ACT procedure facilitate the use of a reduced-intensity, non-myeloablative, lympho-depleting preparative regimen which is expected to be both less toxic and equally efficient compared to previous regimens. Recently patients recruited post Anti PD-1 therapy had inferior responses in comparison to the pre immune checkpoint inhibitors era. Therefore 2 new arms were added:

1. 1.TIL-ACT with combination of 2 doses of Nivolumab fixed dose 480mg, pre and post TIL.
2. 2.TIL-ACT with FMT given using colonoscopy once and 2 maintenance doses of 12 orally ingested capsules, concurrently with a single dose of Ipilimumab 1 mg/kg up to 100 mg.

Conditions

Malignant Melanoma Stage IV

Outcome Measures

Primary Outcomes (2)

• Objective tumor responses

  Radiological follow up via CT to determine the sum of Complete Responders (CR) + Partial Responders (PR) + Stable Disease (SD) as assessed by RECIST 1.1

  3 years

• Assess adverse events using NCI CTCAE v4.03 during treatment and follow-up

  Adverse events will be assessed using NCI CTCAE v4.03 during treatment and follow-up

  3 years

Secondary Outcomes (4)

• Overall Survival (OS)

  3 years

• Response Rate (RR)

  3 years

• Progression-Free Survival (PFS)

  3 years

• Quality of Life (QoL)

  3 years

Study Arms (3)

ACT TIL

EXPERIMENTAL

1. Reduced Intensity, non-myeloablative, lymphodepleting induction regimen using Cyclophosphamide 30mg/kg/day with Fludarabine (25 mg/m2/d) followed by 3 consecutive days of Fludarabine 25mg/m2/d.. 2. Preparation and administration of TIL 3. Bolus high-dose (720,000 IU/kg) IL-2 will be administered to each patient every 8 hours, to tolerance. A maximum of 10 doses will be administered per patient.

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: TIL; Drug: IL-2

ACT TIL + Anti PD-1

EXPERIMENTAL

1. Single dose of Nivolumab 480 mg fixed dose 2. Reduced Intensity, non-myeloablative, lymphodepleting induction regimen using Cyclophosphamide 30mg/kg/day with Fludarabine (25 mg/m2/d) followed by 3 consecutive days of Fludarabine 25mg/m2/d.. 3. Preparation and administration of TIL 4. Bolus high-dose (720,000 IU/kg) IL-2 will be administered to each patient every 8 hours, to tolerance. A maximum of 10 doses will be administered per patient. 5. Second dose of Nivolumab 480 mg fixed dose (at least 4 weeks from the first dose)

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: TIL; Drug: IL-2; Drug: Nivolumab

ACT TIL FMT + Anti CTLA4

EXPERIMENTAL

1. FMT loading dose given via colonoscopy 2. FMT 12 oral capsules as maintenance - given 2 times 3. Single dose of Ipilimumab 1mg/kg up to 100 mg 4. Reduced Intensity, non-myeloablative, lymphodepleting induction regimen using Cyclophosphamide 30mg/kg/day with Fludarabine (25 mg/m2/d) followed by 3 consecutive days of Fludarabine 25mg/m2/d.. 5. Preparation and administration of TIL 6. Bolus high-dose (720,000 IU/kg) IL-2 will be administered to each patient every 8 hours, to tolerance. A maximum of 10 doses will be administered per patient.

Drug: Fludarabine; Drug: Cyclophosphamide; Biological: TIL; Drug: IL-2; Drug: Ipilimumab; Drug: FMT Protocol

Interventions

Fludarabine DRUG

Cyclophosphamide 30mg/kg/day with Fludarabine (25 mg/m2/d) followed by 3 consecutive days of Fludarabine 25mg/m2/d.

ACT TIL; ACT TIL + Anti PD-1; ACT TIL FMT + Anti CTLA4

Cyclophosphamide DRUG

Cyclophosphamide 30mg/kg/day with Fludarabine (25 mg/m2/d) followed by 3 consecutive days of Fludarabine 25mg/m2/d.

ACT TIL; ACT TIL + Anti PD-1; ACT TIL FMT + Anti CTLA4

TIL BIOLOGICAL

TIL administration

ACT TIL; ACT TIL + Anti PD-1; ACT TIL FMT + Anti CTLA4

IL-2 DRUG

Bolus high-dose (720,000 IU/kg) IL-2 will be administered to each patient every 8 hours, to tolerance. A maximum of 10 doses will be administered per patient.

ACT TIL; ACT TIL + Anti PD-1; ACT TIL FMT + Anti CTLA4

Nivolumab DRUG

Nivolumab 480 mg fixed dose

ACT TIL + Anti PD-1

Ipilimumab DRUG

Ipilimumab 1 mg/kg up to 100 mg

ACT TIL FMT + Anti CTLA4

FMT Protocol DRUG

FMT given both directly into the colon via colonoscopy and orally using capsules (12 capsules each time). FMT will be taken from melanoma patients treated with Anti PD-1 who achieved a durable response of more than 12 months.

ACT TIL FMT + Anti CTLA4

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Measurable metastatic Melanoma with at least one lesion that is resectable for TIL generation.
• Refractory to standard treatment
• Patients with one or more brain metastases less than 1 cm each, and any patients with 1 or 2 brain metastases greater than 1 cm must have been treated and stable for 6 weeks.
• Greater than or equal to 18 years of age.
• Willing to practice birth control from the start of chemotherapy until 120 days after release from the hospital.
• Clinical performance status of ECOG 0 or 1
• Hematology:
• Absolute neutrophil count greater than 1000/mm3 without support of filgrastim Normal WBC (greater than 3000/mm3). Hemoglobin greater than 8.0 g/dL Platelet count greater than 100,000/mm3
• Serology:
• Seronegative for HIV antibody. Seronegative for Hepatitis B or Hepatitis C.
• Chemistry:
• Serum ALT/AST less than three times the upper limit of normal (ULN). Serum creatinine less than or equal to 1.6 mg/dL Total bilirubin no more than 1.5 times the ULN, except in patients with Gilbert Syndrome who must have a total bilirubin less than 3 mg/dL.
• Negative pregnancy test in women of child bearing potential because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
• More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients' toxicities must have recovered to a grade 1 or less (except for toxicities such as alopecia or vitiligo). Patients may have undergone minor surgical procedures with the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

You may not qualify if:

• Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the non-myeloablative, lymphodepleting induction regimen on the fetus or infant.
• Systemic steroid therapy required.
• Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
• Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
• Opportunistic infections (the experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
• History of severe immediate hypersensitivity reaction to any of the agents used in this study , including history of an anaphylactic reaction to penicillin or gentamicin
• History of coronary revascularization or ischemic symptoms
• Any patient known to have an LVEF less than or equal to 50 percent .
• Documented LVEF of less than or equal to 50 percent tested in patients with clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block
• Documented FEV1 and DLCO (relative to predicted) less than or equal to 60 percent

Sponsors & Collaborators

• Sheba Medical Center: lead

Study Sites (1)

Sheba Medical Center

Ramat Gan, 5262100, Israel

RECRUITING

Related Publications (1)

• Nissani A, Lev-Ari S, Meirson T, Jacoby E, Asher N, Ben-Betzalel G, Itzhaki O, Shapira-Frommer R, Schachter J, Markel G, Besser MJ. Comparison of non-myeloablative lymphodepleting preconditioning regimens in patients undergoing adoptive T cell therapy. J Immunother Cancer. 2021 May;9(5):e001743. doi: 10.1136/jitc-2020-001743.

  PMID: 33990415 DERIVED

MeSH Terms

Conditions

Melanoma

Interventions

fludarabine; Cyclophosphamide; Interleukin-2; Nivolumab; Ipilimumab; FMT protocol

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Central Study Contacts

Meital Bar

CONTACT

972-3-5305201; meiral.bar@sheba.health.gov.il

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 21, 2017
• First Posted: May 25, 2017
• Study Start: June 5, 2017
• Primary Completion: January 1, 2025
• Study Completion (Estimated): June 1, 2026
• Last Updated: January 26, 2023

Record last verified: 2023-01

Locations

IL (1)