Papillomavirus Infections, Cervical Intraepithelial Neoplasia, Carcinoma In Situ, Vulvar Neoplasms, Vulvar Diseases
Conditions
Keywords
Immunotherapy, Human Papillomavirus, Vulvar Intraepithelial Neoplasia, Vulvar High Grade Squamous Intraepithelial Lesion, Vaccine, HPV-related Malignancy, HPV-related Carcinoma, HPV-related Cervical Carcinoma, HPV-related Anal Squamous Cell Carcinoma, HPV Positive Oropharyngeal Squamous Cell Cancer
Brief summary
Background: Human papillomavirus (HPV) can cause cervical, throat, anal, and genital cancers. Cancers caused by HPV have an HPV protein called E7 inside of their cells. In this new therapy, researchers take a person's blood, remove certain white blood cells, and insert genes that make them to target cancer cells that have the E7 protein. The genetically changed cells, called E7 T cell receptor (TCR) cells, are then given back to the person to fight the cancer. Researchers want to see if this can help people. Objective: To determine a safe dose and efficacy of E7 TCR cells and whether these cells can help patients. Eligibility: Adults ages 18 and older with an HPV-16-associated cancer, including cervical, vulvar, vaginal, penile, anal, or oropharyngeal. Design: Participants will list all their medicines. Participants will have many screening tests, including imaging procedures, heart and lung tests, and lab tests. They will have a large catheter inserted into a vein. Participants will have leukapheresis. Blood will be removed through a needle in the arm. A machine separates the white blood cells. The rest of the blood is returned through a needle in the other arm. The cells will be changed in the lab. Participants will stay in the hospital. Over several days, they will get: Chemotherapy drugs E7 TCR cells Shots or injections to stimulate the cells Participants will be monitored in the hospital up to 12 days. They will get support medicine and have blood and lab tests. Participants will have a clinic visit about 40 days after cell infusion. They will have a physical exam, blood work, scans, and maybe x-rays. Participants will have many follow-up visits with the same procedures. At some visits, they may undergo leukapheresis. Participants will be followed for 15 years.
Detailed description
Background: * Metastatic or refractory/recurrent human papillomavirus (HPV)-16+ cancers (cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancers) are incurable and poorly palliated by standard therapies. * HPV-16+ cancers constitutively express the HPV-16 E7 oncoprotein, which is absent from healthy human tissues. * Administration of T cell receptor (TCR) gene engineered T cells can induce objective tumor responses in certain malignancies including HPV-16+ cancers. * T cells genetically engineered with a TCR targeting HPV-16 E7 (E7 TCR) display specific reactivity against human leukocyte antigen (HLA)-A2+, HPV-16+ target cells. Objectives: Phase I Primary Objective \- To determine a safe dose for E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers. Phase II Primary Objective -To determine safety and efficacy of E7 TCR cells plus aldesleukin for the treatment of metastatic HPV-16+ cancers. Eligibility: * Patients greater than or equal to 18 years old with metastatic or refractory/recurrent HPV-16+ cancer. * Prior first line systemic therapy is required unless the patient declines standard treatment. * Patients must be HLA-A\*02:01-positive. Design: * This is a phase I/II clinical trial that will test the safety and efficacy of E7 TCR cells. * All patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine followed by a single infusion of E7 TCR cells. Cell infusion will be followed by high dose aldesleukin. * Re-enrollment will be allowed for a small number of subjects.
Interventions
BIOLOGICALE7 TCR cells
T cells genetically engineered with a T cell receptor (TCR) targeting human papillomavirus (HPV -16 E7 (E7 TCR) that display specific reactivity against human leukocyte antigen (HLA-A2+, HPV-16+ target cells.
DRUGAldesleukin
Following cell infusion, the patient receives high-dose bolus aldesleukin, which is dosed to individual patient tolerance. Aldesleukin improves the survival of E7 T cell receptor (TCR) cells after infusion.
DRUGFludarabine
Part of the non-myeloablative lymphocyte-depleting preparative regimen.
DRUGCyclophosphamide
Part of the non-myeloablative lymphocyte-depleting preparative regimen.
DIAGNOSTIC_TESTEKG
Screening/Baseline. Follow-up (end of treatment).
PROCEDUREBiopsy
Screening/Baseline. Following treatment (6 weeks post treatment preferred) and at disease progression only.
DIAGNOSTIC_TESTChest CT and MRI or PET
Screening/Baseline. Follow-up (end of treatment). 40 days (+/- 2 weeks) after cell infusion; additional visits as indicated.
DIAGNOSTIC_TESTPFT
Screening/Baseline.
DRUGGranisetron
Supportive medication for nausea/vomiting/anorexia. 0.01 mg/kg intravenous (IV) every(q) day as needed (prn).
DRUGOndansetron
Supportive medication for nausea/vomiting/anorexia. Ondansetron 10mg intravenous (IV) every(q) 8 hours(hr) as needed (prn).
DRUGDroperidol
Supportive medication for nausea/vomiting/anorexia. 1mg intravenous (IV) at 4-6 hours(h) as needed (prn).
DRUGProchlorperazine
Supportive medication for nausea/vomiting/anorexia. 25mg per rectum (PR) as needed (prn) or 10mg intravenous (IV) every(q) 6hours(h) prn.
DRUGDiphenoxylate HCL
Supportive medication for diarrhea. 2.5mg by mouth (po) every(q) 3 hours(h) as needed (prn).
DRUGAtropine sulfate
Supportive medication for diarrhea. 25mcg by mouth (po) every(q) 3 hours(h) as needed (prn).
DRUGCodeine sulfate
Supportive medication for diarrhea. 30-60mg by mouth (po) every(q) 4 hours(h) as needed (prn).
DRUGLoperamide
Supportive medication for diarrhea. 2mg by mouth (po) every(q) 3 hours(h) as needed (prn).
DRUGIndomethacin
Supportive medication for fever. 50-75mg by mouth (po) every(q) 8 hours(h).
DRUGAcetaminophen
Supportive medication for fever. 650mg by mouth (po) every 4 hours (q) 4hr.
Supportive medication for pruritis. 25-50mg by mouth (po) every 4 hours (q) 4hr as needed (prn).
DRUGHydroxyzine HCL
Supportive medication for pruritis. 10-20mg by mouth (po) every 6 hours(h), as needed (prn).
DRUGMeperidine
Supportive medication for chills. 25-50mg intravenous (IV) every 1 hour (q1hr), as needed (prn).
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* INCLUSION CRITERIA: 1. Measurable metastatic or refractory/recurrent human papillomavirus (HPV-16+ cancer (determined by in situ hybridization (ISH) or a polymerase chain reaction (PCR)-based test). 2. Patients must be human leukocyte antigen (HLA-A\*02 by low resolution typing, and HLA-A\*02:01 by one of the high-resolution type results. 3. All patients must have received prior first line standard therapy or declined standard therapy. 4. Patients with three or fewer brain metastases that have been treated with surgery or stereotactic radiosurgery are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for one month before protocol treatment. Patients with surgically resected brain metastases are eligible. 5. Greater than or equal to 18 years of age. 6. Able to understand and sign the Informed Consent Document. 7. Clinical performance status of Eastern Cooperative Oncology Group (ECOG) 0 or 1. 8. Individuals must be willing to practice birth control from the time of enrollment on this study up to twelve (12) months after treatment. Individuals must be willing to undergo testing for HPV-16 prior to becoming pregnant after this period. 9. Individuals of childbearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus. Individuals of childbearing potential are defined as all individuals except individuals who are postmenopausal or who have had a hysterectomy. Postmenopausal will be defined as individuals over the age of 55 who have not had a menstrual period in at least one year. Because there is a potential risk for adverse events in nursing infant's secondary to treatment of the mother with E7 T cell receptor (TCR) transduced peripheral blood lymphocytes (PBLs), breastfeeding should be discontinued if the individual is treated with E7 TCR transduced PBL. These potential risks may also apply to other agents used in this study. 10. Serology: * Seronegative for human immunodeficiency virus (HIV) antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus are less responsive to the experimental treatment and more susceptible to its toxicities.) * Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then the patient must be tested for the presence of antigen by reverse transcription-polymerase chain reaction (RT-PCR) and be hepatitis C virus (HCV) ribonucleic acid (RNA) negative. a. Hematology: * Absolute neutrophil count greater than 1000/mm\^3 without the support of filgrastim. * White blood count (WBC) greater than or equal to 3000/mm\^3 * Platelet count greater than or equal to 100,000/mm\^3 * Hemoglobin \> 8.0 g/dL b. Chemistry: * Serum Alanine aminotransferase (ALT)/Aspartate aminotransferase (AST) less than or equal to 2.5 times the upper limit of normal * Calculated creatinine clearance (CCr) greater than or equal to 50 mL/min/1.73\^2 using the Cockcroft-Gault equation * 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 c. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the E7 TCR cells. Note: Patients may have undergone minor surgical procedures within the past three weeks, as long as all toxicities have recovered to Grade 1 or less.
Exclusion criteria
1. Active systemic infections (for e.g.: requiring anti-infective treatment), 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, severe obstructive or restrictive pulmonary disease. Patients with abnormal pulmonary function tests but stable obstructive or restrictive pulmonary disease may be eligible. 2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease). 3. Concurrent 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). 4. Patients with autoimmune diseases such as Crohn's disease, ulcerative colitis, rheumatoid arthritis, autoimmune hepatitis or pancreatitis, and systemic lupus erythematosus. Hypothyroidism, vitiligo and other minor autoimmune disorders are not exclusionary. 5. Patients on immunosuppressive drugs including corticosteroids. With the exception of: intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) -Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; or, -Steroids as premedication for hypersensitivity reactions (e.g., computed tomography (CT) scan premedication) 6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine or aldesleukin. 7. Patients with a history of coronary revascularization or ischemic symptoms unless patient has a normal cardiac stress test. 8. Documented left ventricular ejection fraction (LVEF) of less than or equal to 45% tested. The following patients will undergo cardiac evaluations 1. Clinically significant atrial and/or ventricular arrhythmias including but not limited to: atrial fibrillation, ventricular tachycardia, second or third degree heart block or 2. Age greater than or equal to 50 years old 9. Any other condition, which would, in the opinion of the Principal Investigator, indicate that the subject is a poor candidate for the clinical trial or would jeopardize the subject or the integrity of the data obtained. 10. Subjects with baseline screening pulse oxygen level of \< 95% on room air will not be eligible. If the underlying cause of hypoxia improves, then they may be reevaluated
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Overall Response Rate Partial Response + Complete Response (PR +CR) | At 12 weeks, every 3 months x 3, and every 6 months for approximately 5 years | Response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Compete Response is disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. |
| Phase I: Number of Dose Limiting Toxicities (DLT) | From the day of cell infusion (Day 0) to Day +30 | Adverse events were assessed by the Common Terminology Criteria for Adverse Events v4.0. Grade 3 is serious. Grade 4 is life-threatening. Grade 5 is death related to adverse event. A DLT is defined as all Grade 3 and greater toxicities occurring within 30 days of the cell infusion with the exception of: Cytokine Release Syndrome (CRS) that resolves ≤ grade 2 within 14 days of the last dose of aldesleukin. Autoimmune toxicity that resolves to ≤ grade 2 within 14 days for starting symptom treatment (e.g. steroids). Cardiac, gastrointestinal, dermatological, hepatic, pulmonary, renal, hematologic, neurologic toxicity, or toxicity in Appendix C of the protocol attributable to aldesleukin that resolves to ≤ grade 2 within 14 days of the last dose of aldesleukin. Transient grade 3 hypoxia associated with cell infusion that corrects to ≤ grade 2 with supplemental oxygen and/or that resolves to ≤ grade 2 within 24 hours or before starting aldesleukin. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | From the time of cell infusion (Day 0) until documented progressive disease; a maximum of 12 months | Progression-free survival is the time from start of treatment to disease progression or death from any cause. Disease progression was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Disease progression is at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progressions. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORScott M Norberg, D.O.
National Cancer Institute (NCI)
Participant flow
Pre-assignment details
All enrolled participants are counted. Participants enrolled and not treated are included in the table.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 20 Participants |
| Age, Categorical Between 18 and 65 years | 204 Participants |
| Age, Continuous | 52.32 years STANDARD_DEVIATION 10.5 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 177 Participants |
| Race/Ethnicity, Customized Ethnicity: Unknown or Not Reported | 0 Participants |
| Race/Ethnicity, Customized Race: American Indian or Alaska Native | 1 Participants |
| Race/Ethnicity, Customized Race: Asian | 6 Participants |
| Race/Ethnicity, Customized Race: Asian White | 1 Participants |
| Race/Ethnicity, Customized Race: Black or African American | 0 Participants |
| Race/Ethnicity, Customized Race: Black/White | 0 Participants |
| Race/Ethnicity, Customized Race: Indian or Alaska Native White | 0 Participants |
| Race/Ethnicity, Customized Race: More than one race | 0 Participants |
| Race/Ethnicity, Customized Race: Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Race: Other | 1 Participants |
| Race/Ethnicity, Customized Race: Unknown or Not Reported | 8 Participants |
| Race/Ethnicity, Customized Race: White | 164 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 111 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 18 | 5 / 194 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 6 / 6 | 18 / 18 | 0 / 0 |
| serious Total, serious adverse events | 3 / 3 | 3 / 3 | 5 / 6 | 5 / 18 | 0 / 0 |
Outcome results
None listed