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Immunotherapy Using Tumor Infiltrating Lymphocytes for Patients With Metastatic Human Papillomavirus-Associated Cancers

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ClinicalTrials.gov Identifier: NCT01585428
Recruitment Status : Completed
First Posted : April 25, 2012
Results First Posted : March 23, 2017
Last Update Posted : March 7, 2018
Sponsor:
Information provided by (Responsible Party):
Steven Rosenberg, M.D., National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Cervical Cancer
Oropharyngeal Cancer
Vaginal Cancer
Anal Cancer
Penile Cancer
Interventions Drug: Fludarabine
Drug: Cyclophosphamide
Biological: Young TIL
Drug: Aldesleukin
Enrollment 29

Recruitment Details  
Pre-assignment Details  
Arm/Group Title Cervical NonCervical
Hide Arm/Group Description

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin.

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Period Title: Overall Study
Started 18 11
Completed 17 11
Not Completed 1 0
Reason Not Completed
Death during treatment             1             0
Arm/Group Title Cervical NonCervical Total
Hide Arm/Group Description

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin.

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Total of all reporting groups
Overall Number of Baseline Participants 18 11 29
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 11 participants 29 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
18
 100.0%
11
 100.0%
29
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 11 participants 29 participants
43.4  (11.4) 54.9  (4.5) 47.8  (10.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 11 participants 29 participants
Female
18
 100.0%
6
  54.5%
24
  82.8%
Male
0
   0.0%
5
  45.5%
5
  17.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 11 participants 29 participants
Hispanic or Latino
0
   0.0%
0
   0.0%
0
   0.0%
Not Hispanic or Latino
18
 100.0%
11
 100.0%
29
 100.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 11 participants 29 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   5.6%
0
   0.0%
1
   3.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
17
  94.4%
11
 100.0%
28
  96.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 18 participants 11 participants 29 participants
18 11 29
1.Primary Outcome
Title Number of Participants With an Objective Clinical Response
Hide Description Patients must have a partial response (PR) or complete response (CR) at least 4 months after cell infusion to count towards clinical response. Clinical response is assessed by the Response Criteria in Solid Tumors (RECIST) v1.0. Partial response is at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD. Complete response is disappearance of all target lesions. Progression 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 is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum LD.
Time Frame 4 months after cell infusion
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cervical NonCervical
Hide Arm/Group Description:

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Overall Number of Participants Analyzed 18 11
Measure Type: Count of Participants
Unit of Measure: Participants
Partial Response
3
  16.7%
2
  18.2%
Complete Response
2
  11.1%
0
   0.0%
Progressive Disease
12
  66.7%
8
  72.7%
Stable Disease
1
   5.6%
1
   9.1%
2.Secondary Outcome
Title Number of Patients With Serious and Non-serious Adverse Events
Hide Description Here is the number of serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v3.0). 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. A non-serious adverse event is any untoward medical occurrence.
Time Frame 51 months and 18 days
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Cervical NonCervical
Hide Arm/Group Description:

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin.

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Overall Number of Participants Analyzed 18 11
Measure Type: Count of Participants
Unit of Measure: Participants
18
 100.0%
11
 100.0%
Time Frame 51 months and 18 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Cervical NonCervical
Hide Arm/Group Description

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin.

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Patients will receive a non-myeloablative lymphocyte depleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous (IV) infusion of Young tumor infiltrating lymphocytes (TIL) plus high dose IV aldesleukin

Fludarabine: Fludarabine 25 mg/m(2)/day intravenous piggyback (IVPB) daily over 30 minutes for 5 days.

Cyclophosphamide: Cyclophosphamide 60 mg/kg/day X 2 days intravenous (IV) in 250 ml in 5% dextrose in water (D5W) over 1 hr.

Young TIL: Cells will be infused intravenously (i.v.) on the Patient Care Unit over 20 to 30 minutes (between one and four days after the last dose of fludarabine).

Aldesleukin: Aldesleukin 720,000 IU/kg intravenous (IV) (based on total body weight) over a 15 minute period approximately every eight hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

All-Cause Mortality
Cervical NonCervical
Affected / at Risk (%) Affected / at Risk (%)
Total   1/18 (5.56%)      0/11 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Cervical NonCervical
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   4/18 (22.22%)      2/11 (18.18%)    
Blood and lymphatic system disorders     
Neutrophils/granulocytes (ANC/AGC)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Platelets  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Hemoglobin  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Lymphopenia  1  1/18 (5.56%)  1 1/11 (9.09%)  1
Gastrointestinal disorders     
Dysphagia (difficulty swallowing)  1  0/18 (0.00%)  0 1/11 (9.09%)  1
General disorders     
Death not associated with CTCAE term: Disease progression NOS  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Infections and infestations     
Febrile neutropenia  1 [1]  1/18 (5.56%)  1 2/11 (18.18%)  2
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils  1 [2]  1/18 (5.56%)  1 0/11 (0.00%)  0
Infection  1 [3]  1/18 (5.56%)  1 0/11 (0.00%)  0
Metabolism and nutrition disorders     
Creatinine  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Nervous system disorders     
Confusion  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Syncope (fainting)  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Renal and urinary disorders     
Renal failure  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Cystitis  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Obstruction, GU::Ureter  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Hypoxia  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Dyspnea (shortness of breath)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
[1]
(fever of unknown origin without clinically or microbiologically documented infection)(ANC <1.0 x 10e9/L, fever >=38.5 degrees C)
[2]
(ANC <1.0 x 10e) ::Blood
[3]
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)::Oral cavity-gums (gingivitis)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Cervical NonCervical
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   17/18 (94.44%)      11/11 (100.00%)    
Blood and lymphatic system disorders     
Hemoglobin  1  16/18 (88.89%)  16 8/11 (72.73%)  8
Leukocytes (total WBC)  1  10/18 (55.56%)  10 8/11 (72.73%)  8
Lymphopenia  1  17/18 (94.44%)  18 10/11 (90.91%)  10
Neutrophils/granulocytes (ANC/AGC)  1  17/18 (94.44%)  17 11/11 (100.00%)  11
Platelets  1  17/18 (94.44%)  17 11/11 (100.00%)  11
Cardiac disorders     
Hypotension  1  2/18 (11.11%)  2 3/11 (27.27%)  3
Gastrointestinal disorders     
Constipation  1  1/18 (5.56%)  1 1/11 (9.09%)  1
Diarrhea  1  2/18 (11.11%)  2 1/11 (9.09%)  1
Nausea  1  3/18 (16.67%)  3 0/11 (0.00%)  0
Vomiting  1  2/18 (11.11%)  2 1/11 (9.09%)  1
Hemorrhage, GI:: Lower GI NOS  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Incontinence, anal  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Hemorrhage, GI::Rectum  1  1/18 (5.56%)  1 0/11 (0.00%)  0
General disorders     
Fatigue (asthenia, lethargy, malaise)  1  5/18 (27.78%)  5 3/11 (27.27%)  3
Pain::Abdomen NOS  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Rigors/chills  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Infections and infestations     
Febrile neutropenia  1 [1]  6/18 (33.33%)  6 3/11 (27.27%)  3
Infection  1 [2]  6/18 (33.33%)  6 6/11 (54.55%)  6
Colitis, infectious (e.g., Clostridium difficile)  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Infection (documented clinically or microbiologically)  1 [3]  1/18 (5.56%)  1 0/11 (0.00%)  0
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils  1 [4]  0/18 (0.00%)  0 1/11 (9.09%)  1
Infection with normal ANC or Grade 1 or 2 neutrophils::Blood  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Metabolism and nutrition disorders     
Albumin, serum-low (hypoalbuminemia)  1  2/18 (11.11%)  2 1/11 (9.09%)  1
Creatinine  1  1/18 (5.56%)  1 3/11 (27.27%)  3
Phosphate, serum-low (hypophosphatemia)  1  2/18 (11.11%)  2 1/11 (9.09%)  1
Potassium, serum-low (hypokalemia)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Alkaline phosphatase  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Sodium, serum-low (hyponatremia)  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Musculoskeletal and connective tissue disorders     
Muscle weakness, generalized or specific area (not due to neuropathy)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Pain::Back  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Pain::Chest wall  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Pain::Joint  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Nervous system disorders     
Confusion  1  2/18 (11.11%)  2 2/11 (18.18%)  2
Psychosis (hallucinations/delusions)  1  2/18 (11.11%)  2 2/11 (18.18%)  2
Syncope (fainting)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Mental status  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Pain::Head/Headache  1  0/18 (0.00%)  0 1/11 (9.09%)  1
Renal and urinary disorders     
Hemorrhage, GU::Urinary NOS  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Renal/Genitourinary - Other (Oliguria)  1  2/18 (11.11%)  2 0/11 (0.00%)  0
Obstruction, GU::Ureter  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Reproductive system and breast disorders     
Hemorrhage, GU::Vagina  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Respiratory, thoracic and mediastinal disorders     
Cough  1  1/18 (5.56%)  1 0/11 (0.00%)  0
Dyspnea (shortness of breath)  1  7/18 (38.89%)  7 5/11 (45.45%)  5
Hypoxia  1  7/18 (38.89%)  7 2/11 (18.18%)  2
Pleural effusion (non-malignant)  1  1/18 (5.56%)  1 0/11 (0.00%)  0
1
Term from vocabulary, CTCAE (3.0)
Indicates events were collected by systematic assessment
[1]
(fever of unknown origin without clinically or microbiologically documented infection)(ANC <1.0 x 10e9/L, fever >=38.5 degrees C)
[2]
(documented clinically or microbiologically) with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)::Blood
[3]
with Grade 3 or 4 neutrophils (ANC <1.0 x 10e9/L)::Upper airway NOS
[4]
(ANC <1.0 x 10e9/L)::Urinary tract NOS
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: D. Steven Rosenberg
Organization: National Cancer Institute
Phone: 301-496-4164
Responsible Party: Steven Rosenberg, M.D., National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01585428     History of Changes
Other Study ID Numbers: 120116
12-C-0116
First Submitted: April 24, 2012
First Posted: April 25, 2012
Results First Submitted: February 1, 2017
Results First Posted: March 23, 2017
Last Update Posted: March 7, 2018