TerminatedNCT01369875Updated Dec 10, 2019Results posted

Modified Tumor Infiltrating Lymphocytes for Metastatic Melanoma

A Phase 2 interventional study of Cyclophosphamide and Fludarabine in Metastatic Melanoma and Skin Cancer, sponsored by National Cancer Institute (NCI). Terminated at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-12-10.

Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment

Why this study was terminated

Premature closure. Protocol did not meet its primary objective.

Phase: Phase 2
Study type: Interventional
Enrollment: 2
Allocation: Non-randomized
Ages: 18 Years and older
Sex: All

Study summary

Background:

Tumor infiltrating lymphocytes (TIL) are white blood cells that have been taken from tumor tissue. The cells are modified to help them kill tumor cells, then given back to the person with cancer. By giving these cells to patients, researchers hope to improve the current treatments available for patients with melanoma that has not responded to standard therapies. The TIL will be given after treatments that will suppress the immune system. This makes it easier for the TIL to attack the cancer cells. The TIL will also be given with aldesleukin (IL-2), which is designed to help keep the TIL cells alive in the body.

Objectives:

To study the safety and effectiveness of specially modified tumor infiltrating lymphocytes to treat melanoma that has not responded to other treatments.

Eligibility:

Individuals at least 18 years of age who have metastatic melanoma that has not responded to other treatments.

Design:

Participants will be screened with a physical exam and medical history. They will also have blood tests and imaging studies.
A piece of tumor will be collected and white blood cells will be separated to make the TIL for the treatment.
Participants will take drugs to suppress the immune system for 7 days before the start of treatment.
Participants will receive the TIL in a single dose. Then they will receive IL-2 every 8 hours for up to 15 doses. Participants will remain in the hospital for up to 2 weeks after treatment. They will be monitored with frequent blood tests and other studies.
After leaving the hospital, participants will have regular followup visits every 1 to 4 months for the first year. Then they will return for followup every 3 to 4 months, as directed by the study researchers.

Read the detailed description

Background:

Tumor Infiltrating Lymphocyte (TIL) administration and high dose interleukin (IL)-2 following lymphodepletion can mediate durable complete responses in patients with refractory melanoma. Obstacles to administration of this therapy include failure to establish TIL in vitro for about 20% of patients, long delays between tumor resection and TIL establishment resulting in poor TIL attributes for therapy and patient ineligibility due to progression, and requirements for large numbers of feeder cells for TIL expansion to therapeutic numbers.
The K562 cell line was engineered to express the 4-1BBL costimulatory molecule and CD64 (the high affinity Fc receptor for loading with antibodies such as OKT3). The K562.CD64.4-1BBL Engineered Cells with Costimulation Enhancement (ECCE) replaced up to 75% of feeder cells in large scale TIL expansions. ECCE added to tumor cell suspensions provided costimulation in trans resulting in rapid and reliable lymphocyte growth even from tumors with no TIL growth under standard conditions.
A cloned K562.CD64.4-1BBL-7F11 ECCE line was produced under Good Manufacturing Practice (GMP) conditions and a master cell bank has been generated. An optimized protocol was established to rapidly expand (REP) young TIL using minimum feeders and 7F11. These ECCE REPed TIL retained tumor recognition and some other attributes of standard TIL, but differed from standard TIL by containing fewer CD4+ cells and more natural killer cells.

When 7F11ECCE were added directly to single cell tumor suspensions, young TIL cultures were reliably generated even from patients who otherwise would not have a standard young TIL culture for treatment.

Objectives:

Primary objectives:

In cohort 1, to evaluate whether young TIL that are rapidly expanded using 7F11 ECCE to replace some feeder cells and administered with IL-2 in patients following a non -myeloablative conditioning regimen will result in clinical tumor regression in patients with refractory metastatic melanoma.
In Cohort 2, to evaluate whether young TIL generated using in trans costimulation with 7F11 ECCE in patients for whom standard young TIL did not grow can mediate tumor regression after a nonmyeloablative conditioning with high dose IL-2 in patients with refractory metastatic melanoma.
Determine the toxicity of ECCE young TIL in these treatment regimens

Eligibility:

Patients who are 18 years of age or older must have:

metastatic melanoma;
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
One or more lesions 2 cm or greater suitable for resection for TIL culture

Patients may not have:

Concurrent major medical illnesses;
Any form of immunodeficiency;
Severe hypersensitivity to any of the agents used in this study;
Contraindications for high dose IL-2 administration.

Design:

Patients will undergo resection to obtain tumor for generation of autologous young TIL cultures.
Parallel TIL cultures will be established using a) the standard technique with IL-2 only and b) the Engineered Cells with Costimulation Enhancement (ECCE) protocol using irradiated K562.CD64.4-1BBL-7F11 (7F11) cells.
After 10 to 20 days cultures will undergo evaluation for TIL establishment. Standard TIL will be used preferentially and patients who have TIL established by standard methods will be assigned to Cohort 1
Cohort 1:
- TIL will undergo ECCE REP by exposure to OKT-3, IL-2, feeder cells and irradiated 7F11.
- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day intravenous (IV)) on days -7 and -6 and fludarabine (25 mg/m\^2/day IV) on days -5 through -1.
- On day 0 patients will receive the infusion of autologous young TIL and then begin highdose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
- Clinical and immunologic response will be evaluated about 4-6 weeks after treatment.
- Using an optimal two-stage Phase II design, initially 18 patients will be enrolled, and if three or more of the first 18 patients have a clinical response (partial response (PR) or complete response (CR)), accrual will continue to 35 patients, targeting a 30% goal for objective response.
If standard young TIL fail to grow then ECCE young TIL will be evaluated and patients who have ECCE TIL available will be assigned to Cohort 2 .
Cohort 2:
- Cultures from patients in Cohort 2 will be evaluated for ECCE TIL establishment. If adequate ECCE TIL are available, TIL will undergo ECCE REP by exposure to OKT-3, IL-2, feeder cells and irradiated 7F11.
- Patients will receive a non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide (60 mg/kg/day IV) on days -7 and -6 and fludarabine (25 mg/m\^2/day IV) on days -5 through -1.
- On day 0 patients will receive the infusion of autologous young TIL and then begin highdose aldesleukin (720,000 IU/kg IV every 8 hours for up to 15 doses).
- Clinical and immunologic response will be evaluated about 4-6 weeks after TIL infusion.
- Using a small optimal two-stage Phase II design, initially 9 patients will be enrolled, and if one or more of the first 9 patients has a clinical response (PR or CR), accrual will continue to 24 patients, targeting a 25% goal for objective response.
If TIL cultures were not established by either standard methods or ECCE young TIL protocols, patients will be eligible for re-resection and evaluation of TIL from a different site.

Conditions studied

Metastatic Melanoma
Skin Cancer

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Keywords

Immunotherapy
Cell Therapy
Metastatic Cancer
Melanoma
Metastatic Melanoma
Skin Cancer

In context

Melanoma

3,006 studies on the registry are indexed under Melanoma; 520 are open to participants now.

This study's enrollment of 2 is below the median of 38 across 2,351 interventional studies indexed under Melanoma.

Browse Melanoma studies →

Lead sponsor

National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.

Of its 402 completed or terminated interventional studies of FDA-regulated products, 365 (91%) have results posted.

Counted across the registry records on this site, refreshed daily.

Who can participate

Ages eligible: 18 Years and older
Sexes eligible: All
Accepts healthy volunteers: No

Inclusion criteria

Measurable metastatic melanoma with at least one lesion that is resectable for tumor infiltrating lymphocytes (TIL) generation.
1. Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
2. Greater than or equal to 18 years of age.
3. Willing to sign a durable power of attorney
4. Able to understand and sign the Informed Consent Document
5. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1.
6. Life expectancy of greater than three months.
7. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after receiving the preparative regimen.
8. Serology:
  1. Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients engineered cells with costimulation enhancement (ECCE) TIL 14 who are HIV seropositive can have decreased immune-competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  2. Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by reverse transcription polymerase chain reaction (RT-PCR) and be hepatitis C virus ribonucleic acid (HCV RNA) negative.
  3. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the preparative chemotherapy on the fetus.
9. Hematology:
  1. Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim.
  2. White blood cell (WBC) (> 3000/mm\^3).
  3. Platelet count greater than 100,000/mm\^3.
  4. Hemoglobin greater than 8.0 g/dl.
10. Chemistry:
  1. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) less or equal to 2.5 times the upper limit of normal.
  2. Serum creatinine less than or equal to 1.6 mg/dl.
  3. Total bilirubin less than or equal to 1.5 mg/dl, except in patients with Gilbert's Syndrome who must have a total bilirubin less than 3.0 mg/dl.
11. 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 within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.
12. Six weeks must have elapsed since any prior anti-cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody therapy to allow antibody levels to decline.
13. Patients who have previously received any anti-CTLA4 antibody and have documented gastrointestinal (GI) toxicity must have a normal colonoscopy with normal colonic biopsies.

Exclusion criteria

EXCLUSION CRITERIA:

Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
Systemic steroid therapy required.
Active systemic infections, coagulation disorders or other major medical illnesses of the cardiovascular, respiratory or immune system, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).
Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who ECCE TIL 15 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.
History of coronary revascularization or ischemic symptoms
Any patient known to have an left ventricular ejection fraction (LVEF) less than or equal to 45%.
Documented LVEF of less than or equal to 45% 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
- Age greater than or equal to 60 years old
Documented forced expiratory volume 1 (FEV1) less than or equal to 60% predicted tested in patients with:
- A prolonged history of cigarette smoking
- Symptoms of respiratory dysfunction

Study design

Phase: Phase 2
Primary purpose: Treatment
Allocation: Non-randomized
Intervention model: Single group
Masking: None (open label)
Enrollment: 2 participants (actual)

Study arms

Experimental
Standard Young TIL
Tumor Infiltrating Lymphocytes : intravenous (IV) over 30 minutes on day 0 Aldesleukin : 720,000 IU/kg IV over 15 min every 8 hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (max. 15 doses.) Fludarabine : 25 mg/m2/day intravenous piggy back (IVPB) daily over 30 minutes for 5 days (days -5 to -1) Cyclophosphamide : 60 mg/kg/day X 2 days IV over 1 hour on days -7 and -6
Drug: Cyclophosphamide · Drug: Fludarabine · Biological: Aldesleukin · Biological: Tumor Infiltrating Lymphocytes
Experimental
ECCE Young TIL
Tumor Infiltrating Lymphocytes : IV over 30 minutes on day 0 Aldesleukin : 720,000 IU/kg IV over 15 min every 8 hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (max. 15 doses.) Fludarabine : 25 mg/m2/day IVPB daily over 30 minutes for 5 days (days -5 to -1) Cyclophosphamide : 60 mg/kg/day X 2 days IV over 1 hour on days -7 and -6
Drug: Cyclophosphamide · Drug: Fludarabine · Biological: Aldesleukin · Biological: Tumor Infiltrating Lymphocytes

Interventions

DrugCyclophosphamide
60 mg/kg/day X 2 days intravenous (IV) over 1 hour on days -7 and -6
Also known as: Cytoxan
DrugFludarabine
25 mg/m\^2/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days (days -5 to -1)
Also known as: Fludara
BiologicalAldesleukin
720,000 IU/kg intravenous (IV) over 15 min every 8 hours (+/- 1hr) beginning within 24 hours of cell infusion and continuing for up to 5 days (max. 15 doses.)
Also known as: IL-2
BiologicalTumor Infiltrating Lymphocytes
Intravenous (IV) over 30 minutes on day 0

What researchers measure

Primary outcomes

Number of Participants With Clinical Tumor Regression.
Clinical tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.
Time frame: up to approximately 8 months

Secondary outcomes

Number of Participants With Serious and Non-Serious Adverse Events
Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
Time frame: Date treatment consent signed to date off study, up to approximately 8 months.

Results

Posted Mar 21, 2013

Participant flow

Participant flow — Overall Study
Milestone	Standard Young TIL	ECCE Young TIL
Started	1	1
Completed	1	1
Not completed	0	0

Outcome measures

PrimaryNumber of Participants With Clinical Tumor Regression.

Clinical tumor regression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Partial response (PR) is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Progression (PD) is at least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.

Time frame:: up to approximately 8 months
Reported as:: Count of participants · Participants

Number of Participants With Clinical Tumor Regression.
Participants	Standard Young TIL	ECCE Young TIL
Complete Response	0	0
Partial Response	0	0
Progression	1	1
Stable Disease	0	0

SecondaryNumber of Participants With Serious and Non-Serious Adverse Events

Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v3.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Time frame:: Date treatment consent signed to date off study, up to approximately 8 months.
Reported as:: Count of participants · Participants

Number of Participants With Serious and Non-Serious Adverse Events
Participants	Standard Young TIL	ECCE Young TIL
Number of Participants With Serious and Non-Serious Adverse Events	1	1

Adverse events

Collected over Date treatment consent signed to date off study, up to approximately 8 months.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
Group	Deaths	Serious	Other
Standard Young TIL	0/1 (0%)	0/1 (0%)	1/1 (100%)
ECCE Young TIL	0/1 (0%)	0/1 (0%)	1/1 (100%)

Most frequent other events

Showing 10 of 13

Most frequent other events
Event	Standard Young TIL	ECCE Young TIL
HemoglobinBlood and lymphatic system disorders	1/1	1/1
Leukocytes (total WBC)Blood and lymphatic system disorders	1/1	1/1
LymphopeniaBlood and lymphatic system disorders	1/1	1/1
Neutrophils/granulocytes (ANC/AGC)Blood and lymphatic system disorders	1/1	1/1
PlateletsBlood and lymphatic system disorders	1/1	1/1
Fatigue (asthenia, lethargy, malaise)General disorders	1/1	1/1
HypopigmentationSkin and subcutaneous tissue disorders	1/1	0/1
Febrile neutropeniaInfections and infestations	1/1	1/1
Dyspnea (shortness of breath)Respiratory, thoracic and mediastinal disorders	1/1	0/1
HypoxiaRespiratory, thoracic and mediastinal disorders	1/1	0/1

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)	Standard Young TIL	ECCE Young TIL	Total
<=18 years	0	0	0
Between 18 and 65 years	1	1	2
>=65 years	0	0	0

Age, Continuous
Age, Continuous(years)	Standard Young TIL	ECCE Young TIL	Total
Mean	50.0	46.0	48.0 ± 2.8

Sex: Female, Male
Sex: Female, Male(Participants)	Standard Young TIL	ECCE Young TIL	Total
Female	0	0	0
Male	1	1	2

Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)	Standard Young TIL	ECCE Young TIL	Total
Hispanic or Latino	0	0	0
Not Hispanic or Latino	1	1	2
Unknown or Not Reported	0	0	0

Race (NIH/OMB)
Race (NIH/OMB)(Participants)	Standard Young TIL	ECCE Young TIL	Total
American Indian or Alaska Native	0	0	0
Asian	0	0	0
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	0	1	1
White	1	0	1
More than one race	0	0	0
Unknown or Not Reported	0	0	0

Region of Enrollment
Region of Enrollment(Participants)	Standard Young TIL	ECCE Young TIL	Total
United States	1	1	2

Study locations

1 site

National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland 20892, United States

References and documents

Publications

Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007 Jan-Feb;57(1):43-66. doi: 10.3322/canjclin.57.1.43. PubMed 17237035 ↗
Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, Abrams J, Sznol M, Parkinson D, Hawkins M, Paradise C, Kunkel L, Rosenberg SA. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999 Jul;17(7):2105-16. doi: 10.1200/JCO.1999.17.7.2105. PubMed 10561265 ↗
Gogas HJ, Kirkwood JM, Sondak VK. Chemotherapy for metastatic melanoma: time for a change? Cancer. 2007 Feb 1;109(3):455-64. doi: 10.1002/cncr.22427. PubMed 17200963 ↗

Study documents

Protocol and statistical analysis plan · Jul 2, 2012
Informed consent form · Jul 9, 2012

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No

Updates

Tracking since Sep 25, 2026

No changes since tracking began. The registry record was last updated on Dec 10, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗

Registry details

Key details

Study ID: NCT01369875
Lead sponsor: National Cancer Institute (NCI)
Responsible party: Steven Rosenberg, M.D. (Principal Investigator, National Cancer Institute (NCI)) — Principal investigator
First posted: Jun 9, 2011
Start date: Jun 17, 2011
Primary completion: Feb 13, 2012
Completion: Feb 14, 2012
Results posted: Mar 21, 2013
Last update: Dec 10, 2019

Study contacts

Steven A Rosenberg, M.D.

principal investigator · National Cancer Institute (NCI)

Oversight

Data monitoring committee: Yes
FDA-regulated drug: Yes
FDA-regulated device: No

View the source record on ClinicalTrials.gov ↗

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