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T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers
Phase 1, PHASE2 trial testing Fludarabine in Vaginal Cancer in 12 participants. Completed in 28 June 2016.
| Lead sponsor | National Cancer Institute (NCI) |
|---|---|
| Phase | Phase 1, PHASE2 |
| Status | Completed |
| Study type | INTERVENTIONAL |
| Allocation | na |
| Design | single group |
| Masking | none |
| Primary purpose | treatment |
| Enrollment | 12 |
| Start date | 14 October 2014 |
| Primary completion | 28 June 2016 |
| Estimated completion | 28 June 2016 |
| Sites | 1 location across United States |
National Cancer Institute (NCI)
Adults 18 to 70, any sex, with Vaginal Cancer or Cervical Cancer. Patients with the condition only — healthy volunteers not accepted.
Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.
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.
| Group | Value | 95% CI |
|---|---|---|
| All Treated Subjects | 2 |
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.
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 0 |
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 2 | |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 0 |
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 a
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | NA | NA – NA |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | NA | NA – NA |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | NA | NA – NA |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 1.5 | 0 – 6 |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | NA | NA – NA |
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
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 1 | |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 2 | |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 1 | |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 6 | |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 2 |
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
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 0 | |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 0 |
Detection of E6 TCR T cells in patients peripheral blood leukocytes (PBL)/apheresis samples by flow cytometry.
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | NA | |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | NA | |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | NA | |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 38 | 30.1 – 45.9 |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | NA | NA – NA |
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 30.7 | 30.7 – 30.7 |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 4.4 | 4.4 – 4.4 |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 12.6 | 12.6 – 12.6 |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 29.9 | 10.4 – 44.4 |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 37.1 | 21.7 – 52.5 |
Presence of PD-1 on circulating lymphocytes by flow cytometry one month after treatment.
| Group | Value | 95% CI |
|---|---|---|
| HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2 | 1 | 1 – 1 |
| HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2 | 2 | 2 – 2 |
| HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2 | 3 | 3 – 3 |
| HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2 | 1 | 0 – 3.6 |
| HPV-16 E6 mTCR PBL MTD + HD IL-2 | 2.2 | 0.5 – 3.9 |
Time frame: 19 months and 7 days. Reporting threshold: 0%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.
| Reaction | System | HPV-16 E6 mTCR PBL 1x10^9 … | HPV-16 E6 mTCR PBL 1x10^10… | HPV-16 E6 mTCR PBL 1x10^11… | HPV-16 E6 mTCR PBL >1x10^1… | HPV-16 E6 mTCR PBL MTD + H… | HPV-16 E6 mTCR PBL MTD + H… |
|---|---|---|---|---|---|---|---|
| Infection (documented clinically or microbiologically) | Infections and infestations | — | — | — | — | — | — |
| Febrile neutropenia | Infections and infestations | — | — | — | — | — | — |
| Dyspnea (shortness of breath) | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Hemorrhage, pulmonary/upper respiratory::Bronchopulmonary NOS | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Obstruction/stenosis of airway::Bronchus | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Prolonged intubation after pulmonary resection (>24 hrs after surgery) | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Diarrhea | Gastrointestinal disorders | — | — | — | — | — | — |
| Reaction | System | HPV-16 E6 mTCR PBL 1x10^9 … | HPV-16 E6 mTCR PBL 1x10^10… | HPV-16 E6 mTCR PBL 1x10^11… | HPV-16 E6 mTCR PBL >1x10^1… | HPV-16 E6 mTCR PBL MTD + H… | HPV-16 E6 mTCR PBL MTD + H… |
|---|---|---|---|---|---|---|---|
| Lymphopenia | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Neutrophils/granulocytes (ANC/AGC) | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Platelets | Blood and lymphatic system disorders | — | — | — | — | — | — |
| Hemoglobin | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Febrile neutropenia | Infections and infestations | — | — | — | — | — | — |
| Dyspnea (shortness of breath) | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Hypoxia | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
| Fatigue | General disorders | — | — | — | — | — | — |
| Infection (documented clinically and microbiologically) | Infections and infestations | — | — | — | — | — | — |
| Bilirubin (hyperbilirubinemia) | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Psychosis (hallucinations/delusions) | Nervous system disorders | — | — | — | — | — | — |
| Rash/desquamation | Skin and subcutaneous tissue disorders | — | — | — | — | — | — |
| Hypotension | Cardiac disorders | — | — | — | — | — | — |
| Creatinine | Metabolism and nutrition disorders | — | — | — | — | — | — |
| Supraventricular and nodal arrhythmia::Sinus tachycardia | Cardiac disorders | — | — | — | — | — | — |
| Syncope (fainting) | Nervous system disorders | — | — | — | — | — | — |
| Renal/Genitourinary - Other, Acute renal injury | Renal and urinary disorders | — | — | — | — | — | — |
| Diarrhea | Gastrointestinal disorders | — | — | — | — | — | — |
| Pleural effusion (non-malignant) | Respiratory, thoracic and mediastinal disorders | — | — | — | — | — | — |
Most-reported serious reactions: Infection (documented clinically or microbiologically), Febrile neutropenia, Dyspnea (shortness of breath), Hemorrhage, pulmonary/upper respiratory::Bronchopulmonary NOS, Hypoxia, Obstruction/stenosis of airway::Bronchus, Prolonged intubation after pulmonary resection (>24 hrs after surgery), Diarrhea.
Data from ClinicalTrials.gov NCT02280811 adverse events section.
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.
8 peer-reviewed publications reference this trial (live from Europe PMC):
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