T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers

Phase 1

Completed

Conditions: Cervical Cancer
Anal Cancer
Oropharyngeal Cancer
Vaginal Cancer
Penile Cancer

Interventions: Drug: Fludarabine
Drug: Cyclophosphamide
Biological: E6 TCR
Drug: Aldesleukin

Registration Number: NCT02280811

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

The National Cancer Institute (NCI) Surgery Branch has developed an experimental therapy for treating patients with cancer that involves taking white blood cells from the patient, growing them in the laboratory in large numbers, genetically modifying these specific cells with a type of virus (retrovirus) to attack only the tumor cells, and then giving the cells back to the patient. This type of therapy is called gene transfer. Researchers want to test this on human papilloma virus (HPV)-associated cancers.

Objective:

- The purpose of this study is to determine a safe number of these cells to infuse and to see if these particular tumor-fighting cells (Anti-HPV E6) can shrink tumors associated with HPV and test the toxicity of this treatment.

Eligibility:

- Adults age 18-66 with an HPV-16-associated cancer.

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

* Leukapheresis: If the patients meet all of the requirements for the study they will undergo leukapheresis to obtain white blood cells to make the anti HPV E6 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 anti HPV E6 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 take up to 2 days.

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 E6 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.

* T cells genetically engineered with a TCR targeting HPV-16 E6 (E6 TCR) display specific reactivity against human leukocyte antigen serotype within HLA-A A serotype group (HLA-A2+), HPV-16+ target cells.

OBJECTIVES:

Primary Objective

* To determine a safe dose of administration of autologous T cells transduced with an anti-HPV-16 E6 TCR and aldesleukin to patients following a nonmyeloablative but lymphodepleting preparative regimen.

* To determine the objective tumor response rate (Complete or Partial Response) and duration in patients with metastatic or recurrent/refractory HPV-16+ cancers treated with this regimen.

ELIGIBILITY:

* Patients greater than or equal to 18 years old and less than or equal to 70 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:

* Patients will receive a non-myeloablative lymphocyte-depleting preparative regimen of cyclophosphamide and fludarabine

* On day 0 patients will receive transduced lymphocytes and then begin high dose aldesleukin

* The study will begin with a phase I dose escalation. After the maximum tolerated dose (MTD) cell dose has been determined, the patients will be enrolled into the phase II portion of the study.

* Clinical and immunologic response will be evaluated about 4 to 6 weeks after treatment and then about every 1-6 months until disease progression

* Following a dose escalation phase of 9 to 18 patients, initially 21 evaluable patients will be enrolled in the phase II portion of the study. If 0 to 1 of the 21 patients experiences a clinical response, then no further patients will be enrolled. If 2 or more of the first 21 evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled. The accrual ceiling will be set at 61 patients. Provided that about 1 patient every 6 weeks will be enrolled onto this trial, approximately 4 years may be needed to accrue the maximum number of patients.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
T Cell Receptor Immunotherapy	E6 TCR	patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin
T Cell Receptor Immunotherapy	Fludarabine	patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin
T Cell Receptor Immunotherapy	Cyclophosphamide	patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin
T Cell Receptor Immunotherapy	Aldesleukin	patients will receive cyclophosphamide and fludarabine followed by infusion of the human papilloma virus (HPV) E6 T cell receptor (TCR), followed by high dose aldesleukin

Primary Outcome Measures

Name	Time	Method
Duration of Response	up to one year	Duration of response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Response is assessed by the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. 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. Progression is at least a 20% increase in the sum of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Maximum Tolerated Dose (MTD)	participants were followed for the duration of hospital stay, an average of 3 weeks	The MTD is the highest dose at which ≤1 of 6 patients experienced a dose limiting toxicity (DLT) or the highest dose level studied if DLTs are not observed at any of the dose levels.
Objective Tumor Response Rate (Complete or Partial Response)	4 years	Objective tumor response rate is defined as the number of participants with a complete or partial response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Complete response is disappearance of all target lesions. 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.

Secondary Outcome Measures

Name	Time	Method
Expression of Programmed Cell Death 1 (PD-1) by Circulating E6 T-Cell Receptor (TCR) T-Cells	one month after treatment	Presence of PD-1 on circulating lymphocytes by flow cytometry one month after treatment.
Number of Participants With a Dose Limiting Toxicity (DLT)	19 months and 7 days	A dose limiting toxicity is all Grade 3 and greater toxicities with the exception of myelosuppression, defined as lymphopenia, neutropenia, decreased hemoglobin, and thrombocytopenia, due to chemotherapy preparative regimen. Aldesleukin expected toxicities as defined in Appendix 2 and 3 of the protocol. Expected chemotherapy toxicities as defined in the pharmaceutical information section. Immediate hypersensitivity reactions (excluding symptomatic bronchospasm and grade 4 hypotension) occurring within 2 hours of cell infusion (related to cell infusion) that are reversible to a grade 2 or less within 24 hours of cell administration with standard therapy. Grade 3 fever. Events that are clearly related to the patient's disease.
Percentage of Cluster of Differentiation 3 (CD3+) Cells That Are E6 T-Cell Receptor Memory of Circulating T-Cells in Responders and Non-responders	One month after treatment	Detection of E6 TCR T cells in patients peripheral blood leukocytes (PBL)/apheresis samples by flow cytometry.
Number of Participants With Serious and Non-serious Adverse Events	19 months and 7 days	Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in 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.