Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Digestive System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Rare Diseases

Uterine Cervical Neoplasms

Adenoma

Vaginal Neoplasms

Anus Neoplasms

Oropharyngeal Neoplasms

Penile Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Intestinal Diseases

Anus Diseases

Rectal Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Vaginal Diseases

Genital Neoplasms, Male

Genital Diseases, Male

Penile Diseases

Male Urogenital Diseases

Vaginal Cancer

Penile Cancer

Anal Cancer

Antineoplastic Agents

Antirheumatic Agents

All Drugs and Chemicals

Anti-Infective Agents

Cyclophosphamide

Fludarabine

Fludarabine phosphate

Aldesleukin

Immunomodulating Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-HIV Agents

Anti-Retroviral Agents

Antiviral Agents

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

Patients will receive Fludarabine 25 mg/m\^2/day for 5 days.

Patients will receive Cyclophosphamide 60 mg/kg/day x 2 days

On day 0, cells will be infused intravenously (IV) over 20-30 minute (between 1 and 4 days after the last dose of fludarabine)

E6 TCR

Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Christian S Hinrichs, M.D.

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.

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.

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

A Phase I/II Study of T Cell Receptor Gene Therapy Targeting HPV-16 E6 for HPV-Associated Cancers

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 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.

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.

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.

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.

Detection of E6 TCR T cells in patients peripheral blood leukocytes (PBL)/apheresis samples by flow cytometry.

Presence of PD-1 on circulating lymphocytes by flow cytometry one month after treatment.

National Cancer Institute (NCI)

Principal Investigator

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

Fludarabine: Patients will receive Fludarabine 25 mg/m\^2/day for 5 days.

Cyclophosphamide: Patients will receive Cyclophosphamide 60 mg/kg/day x 2 days

E6 TCR: On day 0, cells will be infused intravenously (IV) over 20-30 minute (between 1 and 4 days after the last dose of fludarabine)

Aldesleukin: Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

HPV-16 E6 mTCR PBL 1x10^9 + HD IL-2

HPV-16 E6 mTCR PBL 1x10^10 + HD IL-2

HPV-16 E6 mTCR PBL 1x10^11 + HD IL-2

HPV-16 E6 mTCR PBL >1x10^11 up to 2x10^11 + HD IL-2

HPV-16 E6 mTCR PBL MTD + HD IL-2

HPV-16 E6 mTCR PBL MTD + HD IL-2-Retreatment

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Baseline Cancer Types

Dr. Christian Hinrichs

All treated subjects who received at least one dose of human papilloma virus (HPV)-16 E6 monoclonal T cell receptor (mTCR) peripheral blood lymphocytes (PBL) 1x10\^9, 1x10\^10,1x10\^11, \>1x10\^11 up to 2x10\^11 + high-dose (HD) interleukin 2 (IL-2) were included.

All Treated Subjects

Maximum Tolerated Dose (MTD)

Complete Response (CR)

Partial Response (PR)

Objective Tumor Response Rate (Complete or Partial Response)

Duration of Response

Number of Participants With Serious and Non-serious Adverse Events

Number of Participants With a Dose Limiting Toxicity (DLT)

Responders

Non-responders

One patient in group HPV-16 E6 mTCR PBL 1x10\^10 + HD IL-2 did not have research blood collected at one month post infusion, and thus could not examine the cells for that patient at that time point.

Percentage of Cluster of Differentiation 3 (CD3+) Cells That Are E6 T-Cell Receptor Memory of Circulating T-Cells in Responders and Non-responders

Expression of Programmed Cell Death 1 (PD-1) by Circulating E6 T-Cell Receptor (TCR) T-Cells

This is the phase 2 arm that was treated at the MTD determined in the phase 1 portion.

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

Fludarabine: Patients will receive Fludarabine 25 mg/m\^2/day for 5 days.

Cyclophosphamide: Patients will receive Cyclophosphamide 60 mg/kg/day x 2 days

E6 TCR: On day 0, cells will be infused intravenously (IV) over 20-30 minute (between 1 and 4 days after the last dose of fludarabine)

Aldesleukin: Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 5 days (maximum of 15 doses).

Drug Administration

Retreated at the MTD

Carcinoma

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Patients enrolled in Arm A will receive IPI-549 40 mg by mouth daily for at least 14 days

40mg by mouth (PO) every day (QD) for at least 14 days

IPI-549

Debanjali Ghosh, MA

Elaine Eng

Ezra Cohen, MD

The purpose of this study is to investigate how effective the study drug IPI-549 is against types of cancers. IPI-549 is considered experimental because it is not approved by the US Food and Drug Administration (FDA) for the treatment of cancer.

Patients will be treated with 2 weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be obtained prior to initiation of IPI-549 and at surgery.

This is a phase 2 window of opportunity trial in patients with locally advanced head and neck cancer. A key objective is to provide the first proof that macrophage phenotype switching can be accomplished in humans and lay the groundwork for future trials of this novel approach to immune therapy. Patients who are candidates for surgical resection will be enrolled and treated with 2 weeks of IPI-549, a specific PI3Kγ inhibitor. Tumor tissue for research purposes through core biopsies will be obtained prior to initiation of IPI-549 and at surgery.

The study team hypothesizes that mRNA signatures of immune response will be increased in IPI-549-treated patients. For the efficacy endpoints, RECISTv1.1 will be used.

Window of Opportunity Study of IPI-549 in Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma

Phase 2 Window of Opportunity Study of IPI-549 in Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma

To detect IPI-549-induced changes in PI3Kγ-regulated signatures of immune suppression.

Compare pre- vs. post-treatment tumor tissue

T cell receptor (TCR) sequencing at baseline, surgery, end of treatment or at time of disease progression.

To determine safety and tolerability of IPI-549 and change in tumor size in patients with locally advanced HNSCC

The V Foundation for Cancer Research

Ezra Cohen

Professor of Medicine

Cisplatin

Baseline plasma and saliva tests for future translational analysis

Baseline planning FDG PET CT scan

Patients will start their 6 weeks of CCRT within two to three weeks following the planning scans. Cisplatin chemotherapy will be administered. 33 daily fractions of radiotherapy will be delivered over 6 weeks.

A second FDG-PET-CT scan (iPET) and repeat plasma and saliva tests will be carried out after 2 weeks of CCRT (on RT days 9 - 12) and the iPET assessed for residual FDG-avid disease. The biological GTV will be re-outlined based on the residual avid region of the tumour on the second PET-CT (bGTV_iP)

At the end of treatment, plasma and saliva tests will be carried out at 4 weeks post treatment and again at the 3 month post-treatment PET-CT

Swallowing and QoL assessments will be repeated 4 weeks (+/- 2 weeks) after treatment and will be repeated at 6, 12 and 24 months post-treatment. The plasma and saliva samples will be repeated at 12 and 24 months

Patients will have three scans during the trial.

* The 1st scan (prePET) is a baseline diagnostic scan. The patient is in a thermoplastic shell and PET CT will be used by to define a bGTV_P. bGTV_P will then be used as an adjunct to help us delineate the GTV_P.
* The 2nd scan (iPET) takes place following 2 weeks (10 fractions) of chemo-radiotherapy. The patient is in a thermoplastic shell and the PET CT will be used to delineate the remaining avid disease (bGTV_iP).
* The 3rd scan takes place 3 months following the last dose of radiotherapy. It will be used to ascertain whether any avid disease remains and may inform the need for further treatment.

PET-CT scans

The biological GTVs (bGTV_P and bGTV_iP) will be automatically delineated by ATLAAS and verified manually by a nuclear medicine physician and a clinical oncologist. It will consist of the high FDG uptake volume based on visual assessment whilst using suitable windowing levels. Any differences in contouring will be settled either by the two doctors reaching a consensus or by a third doctor if differences between the first two cannot be resolved.

Outlining the biological GTVs (bGTV_P and bGTV_iP)

In order to contribute to our understanding of how disease processes may be monitored in a less invasive and less morbid manner, we will be collecting blood and saliva samples prior to, during, and after the radical treatment of OPSCC in PEARL, to see if there is correlation with disease status and FDG-PET-CT response.

Blood samples for cell-free DNA analysis

Salivary samples for cell-free DNA analysis

Martina Svobodova

Lisette Nixon

Mererid Evans

The PEARL study will recruit approximately 50 patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) who are about to undergo primary treatment with concurrent chemo-radiation from South Wales (Velindre Cancer Centre and Singleton Hospital, Swansea) and Bristol. The main aim is to see whether it is feasible to preform a positron emission tomography-computed tomography (PET-CT) scan after 2 weeks of radiotherapy and re-plan the radiotherapy based on this PET-CT scan, to re-distribute the dose of radiotherapy being delivered, so that a smaller area of normal tissues in the mouth and throat are treated to a high dose of radiotherapy.

PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) caused by Human Papillomavirus (HPV) infection (HPV-positive OPSCC) is increasing in the United Kingdom. It tends to affect younger patients and has a better outcome than most other head and neck cancers.

A large proportion of patients diagnosed with HPV-positive OPSCC will undergo non-surgical treatment. This usually involves 6 to 7 weeks of chemo-radiotherapy, with chemotherapy being given weekly or during the first and fourth week of the radiotherapy course (CCRT). Many patients with HPV-positive OPSCC are cured of their disease but often have to live for several decades with the side effects of their treatment. Side effects from radiotherapy are usually caused because normal tissues surrounding the cancer receive radiation whilst the cancer itself is being treated.

Positron emission tomography-computed tomography (PET-CT) scans are able to look at the metabolic (or biological) activity of cells and are currently recommended in the UK for response assessment after a patient has completed radiotherapy for a head and neck cancer but, as far as we know, have not yet been used routinely to adapt radiotherapy according to the individual patient's response during radiotherapy.

PEARL will explore the feasibility of individually adapting the radiotherapy plan for each patient after 2 weeks of radical CCRT, based on biological changes in tumour activity seen on an interim FDG-PET-CT scan, carried out early on during a course of treatment. The aim is to reduce the dose of radiotherapy received by surrounding normal tissues to ultimately reduce toxicity.

The study will establish the progression free survival rate (PFS) in patients who receive biologically adapted radiotherapy. Furthermore, it will also explore whether changes seen on PET-CT scan during treatment correlate with outcome and with changes in potential blood-based biomarkers of response. Toxicity rates will be assessed, particularly the effect of treatment on swallowing function.

PEARL is a prospective, interventional, non-randomised, phase II feasibility study for patients with good prognosis Human Papillomavirus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) who are suitable for treatment with concurrent chemo-radiotherapy (CCRT).

PEARL PET-based Adaptive Radiotherapy Clinical Trial

PEARL: PET-based Adaptive Radiotherapy Clinical Trial

To maintain a high progression free survival rate with biologically adapted radiotherapy in patients with good prognosis HPV positive OPSCC. To be certain that we are not having a negative impact on PFS by adapting the RT plan we will ensure that PFS is at least as high as expected after treatment with chemo-radiotherapy in patients with similarly staged HPV-positive OPSCC.

As this is a feasibility study, recruitment will be monitored and monthly recruitment rate over 2 years will be presented.

Percentage reduction in mean dose to OAR (superior pharyngeal constrictor muscles, contralateral parotids, contralateral submandibular gland, salivary glands) as a result of PET-CT during treatment. Percentage change to PTV will also be presented.

The proportion of patients who are complete metabolic responders at 3 months as per PERCIST criteria will be presented.

Cumulative acute CTCAE toxicity score percentages during and up to 3 months after treatment will be presented.

Water swallow test will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

MDADI will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

QoL scores will be plotted over time, scores will be presented at 6, 12, 18 and 24 months.

Water swallow test scores will be plotted over time.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers	NCT02280811	Vaginal Cancer Cervical Cancer Anal Cancer Penile Cancer Oropharyngeal C...	Fludarabine Cyclophosphamid... E6 TCR Aldesleukin	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)
Window of Opportunity Study of IPI-549 in Patients With Locally Advanced HPV+ and HPV- Head and Neck Squamous Cell Carcinoma	NCT03795610	Head and Neck S... Head and Neck C... Head and Neck C... Head and Neck C... Head and Neck C... HPV-Related Car... HPV-Related Mal... HPV-Related Squ...	IPI-549	18 Years -	University of California, San Diego
PEARL PET-based Adaptive Radiotherapy Clinical Trial	NCT03935672	Oropharyngeal C...	PET-CT scans Outlining the b... Blood samples f... Salivary sample...	18 Years -	Velindre NHS Trust
T Cell Receptor Immunotherapy Targeting HPV-16 E6 for HPV-Associated Cancers	NCT02280811	Vaginal Cancer Cervical Cancer Anal Cancer Penile Cancer Oropharyngeal C...	Fludarabine Cyclophosphamid... E6 TCR Aldesleukin	18 Years - 70 Years	National Institutes of Health Clinical Center (CC)

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