Trial Title:
Autologous T Cells Targeting HPV16 HPV18 & Survivin in Patients With R/R HPV-related Oropharyngeal Cancers
NCT ID:
NCT05582590
Condition:
Oropharyngeal Cancer
Human Papilloma Virus
Head and Neck Cancer
Head and Neck Squamous Cell Carcinoma
Oropharyngeal Squamous Cell Carcinoma
Oropharyngeal Cancer, Metastatic
Head and Neck Cancer Metastatic
HPV-Related Squamous Cell Carcinoma
HPV-Related Mucosal Head and Neck Squamous Cell Carcinoma
Relapsed Oropharyngeal SCC
Refractory Oropharyngeal Squamous Cell Carcinoma
Conditions: Official terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Squamous Cell Carcinoma of Head and Neck
Papilloma
Oropharyngeal Neoplasms
Cyclophosphamide
Fludarabine
Conditions: Keywords:
relapsed or refractory HPV-related oropharyngeal cancer
human papilloma virus-related cancer
HPV-related head and neck cancer
HPV-related oropharyngeal cancer
cell therapy
adoptive cell therapy
NEXI-003
Head and neck cancer
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Intervention model description:
Standard 3+3 study design for the Dose Escalation Stage and a Dose Expansion Stage
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Fludarabine
Description:
Lymphodepletion Chemotherapy on Days -5, -4, and -3 before Cycle 1 ONLY
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Arm group label:
Dose Expansion Stage
Other name:
Fludara
Intervention type:
Drug
Intervention name:
Cyclophosphamide
Description:
Lymphodepletion Chemotherapy administered on Days -5, -4, and -3 before Cycle 1 ONLY
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Arm group label:
Dose Expansion Stage
Other name:
Cytoxan
Intervention type:
Biological
Intervention name:
NEXI-003 T cells
Description:
Adoptive Cell Therapy specified dose on specified day(s)
Arm group label:
Cohort 1
Arm group label:
Cohort 2
Arm group label:
Cohort 3
Arm group label:
Cohort 4
Arm group label:
Dose Expansion Stage
Summary:
This is a multicenter, open-label, Phase I, first-in-human trial to characterize the
safety and clinical activity of an antigen-specific CD8+ T-cell product in patients with
relapsed or refractory locally advanced or metastatic HPV-related oropharyngeal cancers.
Patients must have received at least one prior standard treatment regimen consisting of
systemic immunotherapy and/or chemotherapy. The investigative agent is an autologous
adoptive T-cell product derived from the patient's endogenous cytolytic T cells that are
directed toward HPV-16 E6/E7, HPV-18 E6/E7 antigens, and a tumor-associated antigen
(Survivin) by ex vivo exposure to an artificial antigen presenting cell to which HLA-A2
antigen-peptides have been fit within the pocket of an MHC class 1 molecule. Patients
must express HLA-A*0201.
Detailed description:
The primary objective is to assess the safety of NEXI-003 in patients with relapsed or
refractory HPV-related oropharyngeal cancers. The study will consist of two stages: a
Dose-Escalation (Stage 1) and a Dose Expansion (Stage 2).
The first stage of the trial is the Dose-Escalation (Stage 1). A standard dose-escalation
3+3 design will be utilized to identify a safe maximum tolerated dose (MTD) of NEXI-003
in patients with relapsed or refractory HPV-related oropharyngeal cancers. The MTD of
NEXI-003 T cells will be identified during the first 28-day cycle (Cycle 1) of the
Dose-Escalation Stage, which is defined as the DLT period. A total of 4 dosing cohorts
are planned in the Dose Escalation Stage.
Initially 3 patients are enrolled into a dosing cohort. After all 3 patients in a cohort
have been followed for 28 days of Cycle 1 (the DLT Period), the safety information will
be assessed by the Data Review Committee (DRC). If no DLT is reported in the first 3
patients enrolled during the 28-day initial cycle of treatment (the DLT Period),
enrollment into the next higher dose cohort may begin, after safety information is
assessed by the DRC. If 1 of the first 3 patients has a DLT, then 3 more patients will be
enrolled into that cohort. If a DLT occurs in ≥ 2 patients, then the MTD will be judged
to have been exceeded and the next lower cohort dose will be considered the MTD. If a DLT
occurs in ≤ 1 of 6 patients, then patients may be enrolled in the next highest dose
level. The DRC will review eligibility criteria, doses of all study treatments and safety
data and make recommendations as to the further conduct of the study. If ≥ 2 patients in
Cohort 1 experience a DLT, then Cohort -1 (1 x 10^8 NEXI-003 T cells on Day 1 of Cycle 1;
stepdown dose, if needed) will be evaluated using the 3+3 design.
After identification of the MTD, or the finding that the last dosing cohort is tolerated
well (i.e., the maximum practical dose [MPD]), 12 patients will be enrolled to receive
NEXI-003 treatment at the MTD/MPD level in the Dose Expansion Stage to gain additional
safety, clinical activity, and pharmacokinetic data (i.e., persistence and expansion) of
the NEXI-003 antigen specific CD8+ T cell product. Safety, clinical activity, and
pharmacokinetic data from the Dose Escalation and Dose Expansion stages will be assessed
to determine the recommended Phase 2 dose (RP2D).
Patients in both the Dose Escalation and Dose Expansion Stages may receive additional
cycles of NEXI-003 per investigator discretion and if protocol-specified criteria are
met.
Each of the two stages of the study will consist of the following three consecutive study
periods for each patient: Pretreatment Period (consisting of Screening,
Leukapheresis/Manufacturing, and Baseline Re-evaluation), Treatment Period (consisting of
lymphodepletion [LD] chemotherapy and NEXI-003 treatment), and Post-Treatment Period
(consisting of Post-treatment Follow-up and Survival Follow-up). The Pretreatment Period
will be approximately 4 to 6 weeks. The Treatment Period will consist of at least 28-day
cycle (i.e., 4 weeks), and per investigator discretion if the patient meets
protocol-specified criteria, the patient may receive additional 4-week cycles. The
Post-Treatment Follow-up Period will consist of up to 9 months of post-treatment
assessments, and up to 9 months of survival follow-up.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. The patient will be typed for HLA-A*0201 expression as determined by high resolution
sequence-based typing method. If documented HLA results are available from a
previous test, the patient can be enrolled using these results after review and
approval by the sponsor.
2. Patients with cytologically or histologically confirmed locally advanced or
metastatic HPV related oropharyngeal cancers with confirmed detection of HPV-16
and/or HPV-18.
3. Patients with HPV-related oropharyngeal cancers who have received at least 1 prior
line of standard-of-care (SOC) treatment (for example, per the current NCCN
Guidelines for Patients with Oropharyngeal Cancer) consisting of systemic
immunotherapy and/or chemotherapeutic treatment.
1. The last dose of cytotoxic chemotherapy and/or steroids must be administered at
least 28 days prior to the leukapheresis procedure.
2. Any adverse event(s) that the patient may have experienced from prior therapy
must have resolved to ≤ Grade 1 according to NCI CTCAE version 5.0.
4. Measurable disease per RECIST v1.1 criteria (at least 1 lesion that can be measured
accurately in at least 1 dimension with the longest diameter ≥ 10 mm [MRI or CT scan
sliced thickness ≤ 5 mm]).
5. Pulse oximetry ≥ 92% on room air.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy of at least 3 months.
8. Be willing to comply with the study schedule and all other protocol requirements.
9. Women of childbearing potential (WOCBP), defined as a sexually mature woman who has
not undergone a hysterectomy or tubal ligation or who has not been naturally
postmenopausal for at least 24 consecutive months, must have 2 negative pregnancy
tests prior to treatment. All sexually active WOCBP and all sexually active male
patients must agree to use highly effective methods of birth control throughout the
study.
10. Ability of the patient to understand and willingness to sign a written informed
consent form.
Exclusion Criteria:
1. A diagnosis of other malignancies if the malignancy has required therapy within the
last 3 years or is not in complete remission. Exceptions are non-metastatic basal
cell or squamous cell carcinomas of the skin or prostate cancer that does not
require treatment. Patients taking adjuvant hormonal therapy for definitively
treated cancers (e.g., breast cancer, prostate cancer) are eligible.
2. Major surgery within 28 days prior to the first study drug administration (minimally
invasive procedures, such as diagnostic biopsies, are permitted).
3. Known central nervous system involvement.
4. Treatment with an allogeneic hematopoietic stem cell transplantation.
5. Treatment with any investigational agent(s) at the time of informed consent.
6. Left ventricular ejection fraction (LVEF) < 45%, congestive heart failure (as
defined by New York Heart Association Functional Classification III or IV), unstable
angina, serious uncontrolled cardiac arrhythmia, a myocardial infarction within 6
months prior to study entry or a history of myocarditis.
7. The following hematological laboratory results at Screening (these results must be
independent of blood product or hematopoietic growth factor support):
1. Hemoglobin < 9.0 g/dL.
2. Platelet count < 100,000/μL.
3. Absolute neutrophil count (ANC) < 1000/ μL.
8. The following chemistry laboratory results at Screening:
1. Serum creatinine ≥ 1.5 mg/dL or estimated glomerular filtration rate (eGFR) ≤
50 mL/min/1.73 m^2.
2. Serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3x
the upper limit of normal (ULN) or serum total bilirubin > 2 mg/dL (except for
patients in whom hyperbilirubinemia is attributed to Gilbert's Syndrome).
9. International normalized ratio (INR) or activated partial thromboplastin time (aPTT)
> 1.5x ULN within 1 week prior to the start of lymphodepletion chemotherapy, unless
on a stable dose of an anticoagulant.
10. Are pregnant or breastfeeding.
11. Vaccination with any live virus vaccine is not permitted prior to the initiation of
study treatment.
1. Inactivated annual influenza vaccination is allowed.
2. Vaccines such as COVID-19 vaccine, e.g., SARS-CoV-2 vaccine > 7 days before
administration is acceptable. For vaccines requiring more than 1 dose, the full
regimen should be completed prior to Cycle 1 Day 1.
12. Active bacterial, viral, or fungal infection within 72 hours of the start of
lymphodepletion chemotherapy; patients with ongoing use of prophylactic antibiotics,
antifungal agents, or antiviral agents remain eligible as long as there is no
evidence of active infection.
13. Have human immunodeficiency virus (HIV) active infection as indicated by positive
HIV polymerase chain reaction (PCR) test, human T-cell leukemia virus type 1
infection, or hepatitis B virus (HBV) or hepatitis C virus (HCV) viremia or are at
risk for HBV reactivation (at risk for HBV reactivation is defined as being
hepatitis B surface antigen [HbsAg] positive, or anti-HBe-antibody positive), or are
positive for HBV DNA. HCV ribonucleic acid (RNA) must be undetectable by laboratory
test.
14. Any condition including the presence of laboratory abnormalities, that places the
patient at an unacceptable risk if the patient was to participate in the study.
15. Have an active autoimmune disease that has required systemic treatment in past 2
years (i.e., with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs).
Note: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is permitted.
16. Patients who experienced the following immune checkpoint inhibitor-related AEs even
if the AE resolved to ≤ Grade 1 or baseline:
1. ≥ Grade 3 ocular AE
2. Changes in liver function tests that met the criteria for Hy's Law (> 3× ULN of
either ALT/AST with concurrent > 2× ULN of total bilirubin (total and direct)
and without alternate etiology)
3. ≥ Grade 3 neurologic toxicity
4. ≥ Grade 3 colitis
5. ≥ Grade 3 renal toxicity
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Start date:
March 31, 2025
Completion date:
August 25, 2027
Lead sponsor:
Agency:
NexImmune Inc.
Agency class:
Industry
Source:
NexImmune Inc.
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05582590
