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Immune Checkpoint Inhibitors

HPV Specific T Cells plus lymphodepletion (Cytoxan and Fludarabine) and nivolumab

Dose escalation study with 5 dose levels: DL1-1×10\^7 cells/m2, DL2-3×10\^7 cells/m2, and DL3-1×10\^8 cells/m2, DL4- 2 to 3×10\^8 cells/m2, DL5- 0.8 to 1×10\^9 cells/m2

Group A -HPVST cells Group B -lymphodepletion \& nivolumab \& HPVST cells.

First, treatment in Group A will be completed for DL1 and DL2. Only if DL2 in Group A proves safe, Group B will be treated on DL2, DL3, DL4, and DL5.

Group A will be treated at DL3, DL4, and DL5 only if there is excessive toxicity in cohorts treated with lymphodepletion.

HPVSTs will be given by IV injection over 1-10 minutes through a peripheral or a central line on day 0.

If patients have clinical benefit (as determined by symptoms, physical exam or radiological studies) \& no significant toxicities, they may get up to 5 repeat infusions (for max total of 6 infusions) of HPVSTs at or below the same dose level.

HPV Specific T Cells

500mg/m\^2/day x 3 days (on days -4, -3 and -2)

Cytoxan

30mg/m\^2/day x 3 days (on days -4, -3, and -2)

240mg every 2 weeks (+/- 3 days) starting on day -1

Carlos Ramos, MD

Subjects have a type of cancer that has been associated with an infection with a virus called human papilloma virus (HPV). The cancer has come back, has not gone away after standard treatment or the subject cannot receive standard treatment.

This is a research study using special immune system cells called HPVST cells, a new experimental treatment.

Investigators want to find out if they can use this type of treatment in patients with HPV-cancers. They have discovered a way to grow large number of HPV-specific T cells from the blood of patients with HPV-cancers. They want to see if these special white blood cells, called HPVST cells, that will have been trained to kill HPV infected cells can survive in the blood and affect the tumor. They will also see if they can make the T cells more active against the HPV-cancers by engineering them to be resistant to the TGF-beta chemical that these HPV-cancers produce. They will grow these HPVST cells from the patient's blood.

The purpose of this study is to find the biggest dose of HPVSTs that is safe, to see how long they last in the body, to learn what the side effects are and to see if the HPVSTs will help people with HPV associated cancers.

If the treatment with HPVST cells alone proves safe (Group A), additional group of patients (Group B) will receive Nivolumab in addition to HPVST cells in a lymphodepleted environment. Nivolumab is an antibody therapy that helps T cells control the tumor and it is FDA approved for the treatment of certain types of cancers, including Hodgkin's lymphoma. Lymphodepletion will decrease the level of circulating T cells prior to infusion of HPVST cells, thereby giving them room to expand. The purpose of this part of the study is to find out if TGF-beta resistant HPVST cells in combination with Nivolumab are safe, how long they last in the body and if they are more effective than HPVST cells alone in controlling the tumor.

HPV is found in the cancer cells of more than half the patients with certain types of cancer, suggesting that it may play a role in causing the cancer. The virus makes proteins in the tumor cells that should allow the diseased cells to be recognized and killed by a part of the body's own immune system called T cells. Unfortunately, tumors are able to avoid being killed by making molecules that turn off these T cells. So, the cancer cells infected by HPV are able to hide from the body's immune system and escape destruction.

The investigators have previously studied cancers caused by a different virus, called Epstein-Barr virus (EBV). These EBV-cancers are like HPV-cancers, since they turn off the T cells that would otherwise destroy them, and so can keep growing. They investigators have found, however, that if they removed the T cells from the blood of patients with EBV-cancers and grew them outside the body, they could increase the number and the activity of T cells directed against the tumors. When these T cells were given back to the patients, the T cells eliminated the cancers in over half the recipients. Investigators also found that they could engineer the T cells to be even more active against the EBV-cancer cells by making them resist an inhibitory chemical called TGF-beta, which is produced by these cancer cells.

Investigators will collect up to 390 mL of blood. Then they will use this blood to grow T cells. First they will grow them in a special type of cell called a dendritic cell, which stimulates the T cells. These dendritic cells will then be loaded with bits of proteins from the HPV virus called E6 and E7. These dendritic cells will be used to stimulate T cells. This stimulation trains the T cells to kill cells with the HPV proteins E6 and E7 on their surface. Next, the investigators will grow these HPV-specific T cells by more stimulation with dendritic cells and HPV proteins, and, when needed, a special type of cell called K562. These K562 cells were treated with radiation so they cannot grow.

To make these T cells resistant to the TGF-beta released by the tumor, investigators will put a new gene in them in the laboratory called a mutant TGF-beta receptor. In cells with this new gene, TGF-beta released by the tumor cells will not be able to bind to the mutant TGF-beta receptor on the T cell. Investigators hope this will improve the chances that after the T cells are injected they will be able to keep working and kill the tumor cells. This gene is added to the cells using a mouse retrovirus that has been changed to stop it from causing infections. Retroviruses enter the cell's DNA (genetic material) to make permanent changes to the cell. After making these cells, they will be frozen.

For treatment, the cells will be thawed and injected in a vein over 1 to 10 minutes. Initially, one dose of T cells will be given (which is considered day 0).

If, after the 1st infusion, there is a reduction in the size of the subject's cancer (or no increase) on CT or MRI scans as assessed by a radiologist, the subject can receive additional doses if it would be to his/her benefit, if s/he would like to receive more doses, and if there is enough product remaining to give any additional injections (at the same or a lower dose).

If treatment with HPVST cells alone proves safe, additional group of patients (Group B) will receive HPVST cells with nivolumab in lymphodepleted environment. One dose of the drug nivolumab is given one day before the HPVST cells are infused and then every 2 weeks for a total of four doses of nivolumab. Lymphodepletion will be given daily starting day -4 prior to administration of HPVSTs.

This is a dose escalation study. The dose the patient will get will depend on how many participants get the agent beforehand and how they react.

Investigators will follow the patient during and after the injections at predetermined time points which may require blood draws and other examinations.

HPV-16/18 E6/E7-Specific T Lymphocytes, Relapsed HPV-Associated Cancers, HESTIA

HPV-16/18 E6/E7-Specific T Lymphocytes in Patients With Relapsed HPV-Associated Cancers

DLT will be defined as any toxicity that is irreversible or life threatening, defined as the following, considered to be possibly, probably, or definitely related to the HPVST injection.

1. Non-hematologic DLT is any grade 3 or grade 4 non-hematologic toxicity.
2. Hematologic DLT is defined as any grade 4 hematologic toxicity.

To measure anti-tumor effects of HPV-specific T lymphocytes

Center for Cell and Gene Therapy, Baylor College of Medicine

The Methodist Hospital Research Institute

Baylor College of Medicine

Assistant Professor

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Nasopharyngeal Carcinoma

Carcinoma, Squamous Cell

Head and Neck Neoplasms

Laryngeal Diseases

Neoplasms, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Hypopharyngeal Neoplasms

Nasopharyngeal Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Nasopharyngeal Diseases

Laryngeal Cancer

Hypopharyngeal Cancer

Cisplatin

* Participants will be enrolled in cohorts of 3- 6 per dose level. Once the MTD is reached, an additional 10 patients will be treated at that dose level and an amendment will be submitted to declare the dose.
* BKM120 will start 2 weeks prior to first dose of cisplatin and radiation start. During the study, BKM120 will be administered orally daily for 45 days. Starting dose 40 mg.
* Cisplatin: Starting Dose 30 mg/m2, given IV, weekly on days: (1, 8, 15, 22, 29, 36 and 43).
* Radiotherapy: All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks.

BKM120 is a potent and highly specific oral pan-class I PI3K inhibitor.

BKM120

IMRT is the medical use of ionizing radiation, generally as part of cancer treatment to control or kill malignant cells

Intensity-modulated radiotherapy (IMRT)

Glenn J. Hanna, MD

This research study is evaluating a drug called buparlisib (BKM120) as a possible treatment for locally advanced head and neck squamous cell cancer.

* This phase Ib study is combining standard chemoradiotherapy with weekly cisplatin and BKM120 to assess tolerability of this combination in high risk patients with locally advanced Squamous Cell Carcinoma of the Head and Neck (SCCHN). The investigators will also obtain preliminary information about the efficacy of this treatment.
* The participant will receive the study drug buparlisib once daily, by mouth, for 45 days. The participant will be given a study drug-dosing diary for each cycle. It will include special instructions for taking the study drug at home.
* The investigators are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects, not everyone who participates in this research study will receive the same dose of the study drug. The dose given will depend on the number of participants who have been enrolled in the study before and how well they have tolerated their doses.
* All participants will receive weekly cisplatin injection. Cisplatin will be given intra-venously (IV) on days: (1, 8, 15, 22, 29, 36 and 43) at DFCI.
* All participants will receive daily radiotherapy with intensity-modulated radiotherapy (IMRT) for 7 weeks, delivered at DFCI. IMRT is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor.
* The investigators would like to keep track of the participant's medical condition. Follow-up will continue every 4 to 12 weeks after the end of treatment for the first year and at the investigator's discretion thereafter.

Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck

A Phase Ib Study of BKM120 With Weekly Cisplatin and Radiotherapy in High Risk Locally Advanced Squamous Cell Cancer of the Head and Neck

There are no plans to share the IPD. Cumulative data will be published however.

Determine Maximum Tolerated Dose (MTD) of BKM120/cisplatin in combination with radiation therapy in patients with locally advanced squamous cell cancer of the head and neck.

Novartis Pharmaceuticals

Dana-Farber Cancer Institute

Principal Investigator

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
HPV-16/18 E6/E7-Specific T Lymphocytes, Relapsed HPV-Associated Cancers, HESTIA	NCT02379520	Human Papilloma... Human Papilloma... Human Papilloma... Human Papilloma... Human Papilloma... Human Papilloma...	HPV Specific T ... Cytoxan Fludarabine Nivolumab	18 Years -	Baylor College of Medicine
Phase Ib Study of BKM120 With Cisplatin and XRT in High Risk Locally Advanced Squamous Cell Cancer of Head and Neck	NCT02113878	Carcinoma, Squa... HPV Positive Or... Hypopharyngeal ... Early Invasive ... Carcinoma of La... Cancer of Nasop...	BKM120 Cisplatin Intensity-modul...	18 Years -	Dana-Farber Cancer Institute

Spots Global Cancer Trial Database for human papillomavirus positive oropharyngeal carcinoma