NCT01585428

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

Completed Phase 2 Results posted Last updated 7 March 2018

What this trial tests

Phase 2 trial testing Fludarabine in Cervical Cancer in 29 participants. Completed in 1 August 2016.

Timeline

13 April 2012

Primary endpoint
9 April 2016

1 August 2016

Quick facts

Lead sponsor	National Cancer Institute (NCI)
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	non randomized
Design	parallel
Masking	none
Primary purpose	treatment
Enrollment	29
Start date	13 April 2012
Primary completion	9 April 2016
Estimated completion	1 August 2016
Sites	1 location across United States

Drugs / interventions tested

• Fludarabine (FLUDARABINE) — full drug profile →
• Cyclophosphamide (cyclophosphamide) — full drug profile →
• Young TIL — full drug profile →
• Aldesleukin (ALDESLEUKIN) — full drug profile →

Conditions studied

• Cervical Cancer — all drugs for Cervical Cancer →
• Oropharyngeal Cancer — all drugs for Oropharyngeal Cancer →
• Vaginal Cancer — all drugs for Vaginal Cancer →
• Anal Cancer — all drugs for Anal Cancer →

Sponsor

National Cancer Institute (NCI)

Who can join

Adults 18 to 70, any sex, with Cervical Cancer or Oropharyngeal Cancer. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Number of Participants With an Objective Clinical Response Primary · 4 months after cell infusion

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 o

Group	Value	95% CI
Cervical	3
NonCervical	2
Cervical	2
NonCervical	0
Cervical	12
NonCervical	8
Cervical	1
NonCervical	1

Number of Patients With Serious and Non-serious Adverse Events Secondary · 51 months and 18 days

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 me

Group	Value	95% CI
Cervical	18
NonCervical	11

Adverse events — posted to ClinicalTrials.gov

Time frame: 51 months and 18 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Cervical

Serious: 4/18 (22%)

Deaths: 1/18

NonCervical

Serious: 2/11 (18%)

Deaths: 0/11

Serious adverse events (17 terms)

Reaction	System	Cervical	NonCervical
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Renal failure	Renal and urinary disorders	—	—
Cystitis	Renal and urinary disorders	—	—
Febrile neutropenia	Infections and infestations	—	—
Neutrophils/granulocytes (ANC/AGC)	Blood and lymphatic system disorders	—	—
Platelets	Blood and lymphatic system disorders	—	—
Creatinine	Metabolism and nutrition disorders	—	—
Death not associated with CTCAE term: Disease progression NOS	General disorders	—	—
Confusion	Nervous system disorders	—	—
Dyspnea (shortness of breath)	Respiratory, thoracic and mediastinal disorders	—	—
Hemoglobin	Blood and lymphatic system disorders	—	—
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils	Infections and infestations	—	—
Infection	Infections and infestations	—	—
Lymphopenia	Blood and lymphatic system disorders	—	—
Obstruction, GU::Ureter	Renal and urinary disorders	—	—
Dysphagia (difficulty swallowing)	Gastrointestinal disorders	—	—
Syncope (fainting)	Nervous system disorders	—	—

Other adverse events (45 terms — click to expand)

Reaction	System	Cervical	NonCervical
Lymphopenia	Blood and lymphatic system disorders	—	—
Neutrophils/granulocytes (ANC/AGC)	Blood and lymphatic system disorders	—	—
Platelets	Blood and lymphatic system disorders	—	—
Hemoglobin	Blood and lymphatic system disorders	—	—
Leukocytes (total WBC)	Blood and lymphatic system disorders	—	—
Dyspnea (shortness of breath)	Respiratory, thoracic and mediastinal disorders	—	—
Hypoxia	Respiratory, thoracic and mediastinal disorders	—	—
Febrile neutropenia	Infections and infestations	—	—
Infection	Infections and infestations	—	—
Fatigue (asthenia, lethargy, malaise)	General disorders	—	—
Hypotension	Cardiac disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Creatinine	Metabolism and nutrition disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Vomiting	Gastrointestinal disorders	—	—
Albumin, serum-low (hypoalbuminemia)	Metabolism and nutrition disorders	—	—
Phosphate, serum-low (hypophosphatemia)	Metabolism and nutrition disorders	—	—
Confusion	Nervous system disorders	—	—
Psychosis (hallucinations/delusions)	Nervous system disorders	—	—
Pain::Abdomen NOS	General disorders	—	—
Renal/Genitourinary - Other (Oliguria)	Renal and urinary disorders	—	—
Pain::Back	Musculoskeletal and connective tissue disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Hemorrhage, GI:: Lower GI NOS	Gastrointestinal disorders	—	—
Hemorrhage, GU::Urinary NOS	Renal and urinary disorders	—	—
Potassium, serum-low (hypokalemia)	Metabolism and nutrition disorders	—	—
Muscle weakness, generalized or specific area (not due to neuropathy)	Musculoskeletal and connective tissue disorders	—	—
Syncope (fainting)	Nervous system disorders	—	—
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Pleural effusion (non-malignant)	Respiratory, thoracic and mediastinal disorders	—	—
Rigors/chills	General disorders	—	—
Incontinence, anal	Gastrointestinal disorders	—	—
Alkaline phosphatase	Metabolism and nutrition disorders	—	—
Sodium, serum-low (hyponatremia)	Metabolism and nutrition disorders	—	—
Mental status	Nervous system disorders	—	—
Colitis, infectious (e.g., Clostridium difficile)	Infections and infestations	—	—
Hemorrhage, GI::Rectum	Gastrointestinal disorders	—	—
Hemorrhage, GU::Vagina	Reproductive system and breast disorders	—	—
Infection (documented clinically or microbiologically)	Infections and infestations	—	—
Infection (documented clinically or microbiologically) with Grade 3 or 4 neutrophils	Infections and infestations	—	—

Most-reported serious reactions: Hypoxia, Renal failure, Cystitis, Febrile neutropenia, Neutrophils/granulocytes (ANC/AGC), Platelets, Creatinine, Death not associated with CTCAE term: Disease progression NOS.

Data from ClinicalTrials.gov NCT01585428 adverse events section.

Sponsor's own description

Background:

The human papillomavirus (HPV) can cause a number of cancers, including cervical and throat cancers. The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy that involves taking white blood cells from patients' tumors, growing them in the laboratory in large numbers, and then giving the cells back to the patient. These cells are called Tumor Infiltrating Lymphocytes, or TIL and we have given this type of treatment to over 200 patients with melanoma. Researchers want to know if TIL shrink s tumors in people with human papilloma virus (HPV)-related cancer. In this study, we are selecting a specific subset of white blood cells from the tumor that we think are the most effective in fighting tumors and will use only these cells in making the tumor fighting cells.

Objective:

The purpose of this study is to see if these specifically selected tumor fighting cells can cause HPV-related cancers to shrink and to see if this treatment is safe.

Eligibility:

\- Adults age 18-66 with HPV-related cancer who have a tumor that can be safely removed.

Design:

Work up stage: Patients will be seen as an outpatient at the National Institutes of Health (NIH) clinical Center and undergo a history and physical examination, scans, x-rays, lab tests, and other tests as needed.

Surgery: If the patients meet all of the requirements for the study they will undergo surgery to remove a tumor that can be used to grow the TIL product.

Leukapheresis: Patients may undergo leukapheresis to obtain additional white blood cells. {Leukapheresis is a common procedure, which removes only the white blood cells from the patient.}

Treatment: Once their cells have grown, the patients will be admitted to the hospital for the conditioning chemotherapy, the TIL cells and aldesleukin. They will stay in the hospital for about 4 weeks for the treatment.

Follow up: Patients will return to the clinic for a physical exam, review of side effects, lab tests, and scans about every 1-3 months for the first year, and then every 6 months to 1 year as long as their tumors are shrinking. Follow up visits will take up to 2 days.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Immunology and Immunotherapy of Head and Neck Cancer.
   Ferris RL. · · 2015 · cited 515× · PMID 26351330 · DOI 10.1200/jco.2015.61.1509
2. Complete regression of metastatic cervical cancer after treatment with human papillomavirus-targeted tumor-infiltrating T cells.
   Stevanović S, Draper LM, Langhan MM, Campbell TE, et al · · 2015 · cited 499× · PMID 25823737 · DOI 10.1200/jco.2014.58.9093
3. Cervical Cancer Immunotherapy: Facts and Hopes.
   Ferrall L, Lin KY, Roden RBS, Hung CF, et al · · 2021 · cited 255× · PMID 33888488 · DOI 10.1158/1078-0432.ccr-20-2833
4. Neoantigen screening identifies broad TP53 mutant immunogenicity in patients with epithelial cancers.
   Malekzadeh P, Pasetto A, Robbins PF, Parkhurst MR, et al · · 2019 · cited 226× · PMID 30714987 · DOI 10.1172/jci123791
5. The precision prevention and therapy of HPV-related cervical cancer: new concepts and clinical implications.
   Hu Z, Ma D. · · 2018 · cited 223× · PMID 30589505 · DOI 10.1002/cam4.1501
6. A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus-associated Epithelial Cancers.
   Stevanović S, Helman SR, Wunderlich JR, Langhan MM, et al · · 2019 · cited 218× · PMID 30518633 · DOI 10.1158/1078-0432.ccr-18-2722
7. HPV in oropharyngeal cancer: the basics to know in clinical practice.
   Elrefaey S, Massaro MA, Chiocca S, Chiesa F, et al · · 2014 · cited 160× · PMID 25709145
8. Challenges and new technologies in adoptive cell therapy.
   Zhang P, Zhang G, Wan X. · · 2023 · cited 153× · PMID 37596653 · DOI 10.1186/s13045-023-01492-8