TBio-4101 and Pembrolizumab With or Without Chemotherapy for the Treatment of Patients With Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma
This phase I trial tests the safety and tolerability of TBio-4101 and pembrolizumab with or without chemotherapy for the treatment of patients with head and neck squamous cell carcinoma that has come back after a period of improvement (recurrent) or that has spread from where it first started (primary site) to other places in the body (metastatic). TBio-4101 is a tumor-infiltrating lymphocyte (TIL) drug that involves the use of special immune cells called T-cells. A T-cell is a type of lymphocyte, or white blood cell. Lymphocytes protect the body from viral infections, help other cells fight bacterial and fungal infections, produce antibodies, fight cancers, and coordinate the activities of other cells in the immune system. A monoclonal antibody such as pembrolizumab is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). Chemotherapy drugs such as cyclophosphamide, fludarabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Interleukin-2 is a drug given after TBio-4101 to boost the immune system. Giving TBio-4101 and pembrolizumab with or without chemotherapy may be safe and tolerable in treating patients with recurrent or metastatic head and neck squamous cell carcinoma.
Inclusion Criteria
- Patients must have pathologically confirmed, recurrent, unresectable or metastatic solid tumors of HNSCC, excluding nasopharyngeal and nasal cavity carcinomas, and must have received no prior treatment for metastatic disease
- Patients must have at least 1 cm^3 (1.1 g) of viable tumor tissue amenable for resection for tumor infiltrating lymphocytes (TIL) generation, and at least one target tumor that can be used for response assessment by Response Evaluation Critiera in Solid Tumors (RECIST) 1.1 and immune mediated Response Evaluation Criteria in Solid Tumors (iRECIST) criteria and for mandatory translational tumor biopsy (where applicable)
- Patients must be willing and able to undergo an apheresis procedure
- Any systemic therapy, including anti-cancer monoclonal antibodies, must have been completed at least 3 weeks prior to TIL harvest or apheresis, whichever is earlier, and any prior therapy-related adverse events (AEs) must have resolved to grade ≤ 1 except for alopecia and vitiligo. Neuropathy and anemia must have resolved to grade ≤ 2
- Age 18-75 years at the time of TIL harvest
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Participants given pembrolizumab monotherapy must have a combined positive score (CPS) ≥ 1
- Absolute neutrophil count (ANC) ≥ 1500/mm^3 (non-growth factor supported)
- Platelet count ≥ 100,000/mm^3
- Hemoglobin ≥ 8.0 g/dL
- Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase [SGOT])/ Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 times the institutional upper limit of normal (ULN)
- Cockcroft-Gault estimated glomerular filtration rate (GFR) ≥ 60 mL/min
- Total bilirubin ≤ 2.0 mg/dL (except in participants with Gilbert’s Syndrome where the bilirubin must be ≤ 3 mg/dL)
- Seronegative for Human immunodeficiency virus (HIV) antibody, hepatitis B surface antigen, and hepatitis C (HCV) antibody (if HCV antibody positive, must be tested for HCV ribonucleic acid [RNA], which must be negative to be eligible)
- The participant (or legally acceptable representative if applicable) provides written informed consent for the trial
- The effects of TBio-4101 on the developing human fetus are unknown. For this reason and because other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration
- INITIATION OF NMA-LD CHEMOTHERAPY: A minimum of 14 days have elapsed since the last dose of platinum therapy and the anticipated start of NMA-LD chemotherapy
- INITIATION OF NMA-LD CHEMOTHERAPY: A CT scan has been performed within 2 weeks of the planned start date of NMA-LD chemotherapy to provide baseline tumor measurements for response assessment. The participant must still have measurable disease
- INITIATION OF NMA-LD CHEMOTHERAPY: Any prior therapy-related adverse events (AEs) must have resolved to Grade =< 1 except for alopecia and vitiligo. Neuropathy, anemia and neutropenia must have resolved to Grade =< 2
- INITIATION OF NMA-LD CHEMOTHERAPY: Left ventricular ejection fraction (LVEF) ≥ 45%
- INITIATION OF NMA-LD CHEMOTHERAPY: Participants who are > 60 years of age must undergo cardiology clearance exam and cardiac stress test, unless performed within the last 6 months and there has been no clinical change with respect to heart function. CT coronary angiography is allowed as a substitute for cardiac stress test per recommendation of Moffitt Cardio-Oncologist Dr. Alomar and supported by publication: Sharma et al. J Am Coll Cardiol 2019; 73:893-902. Referral to cardiology for significantly abnormal results per institutional standard of care
- INITIATION OF NMA-LD CHEMOTHERAPY: Participants must have a forced expiratory volume (FEV1) > 60% of predicted value and diffusing capacity of the lung for carbon monoxide (DLCO) (corrected) ≥ 60% of predicted value
- INITIATION OF NMA-LD CHEMOTHERAPY: Participants do not need to repeat infectious disease testing
- INITIATION OF NMA-LD CHEMOTHERAPY: ECOG 0 to 1
- INITIATION OF NMA-LD CHEMOTHERAPY: Participants must continue to demonstrate adequate organ function as defined above. ANC must remain >= 1000/mm^3 (non-growth factor supported)
Exclusion Criteria
- Participants with a known additional malignancy that is progressing or has required active treatment within the past 3 years * Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, that have undergone potentially curative therapy are not excluded
- Participants who have received prior cell therapy or prior organ transplant
- Participants who have received any previous treatment with a PD-1 or PD-L1 inhibitor, including but not limited to: nivolumab, atezolizumab, pembrolizumab, avelumab, or durvalumab. Patients who start pembrolizumab prior to TIL harvest and apheresis may have received one dose of pembrolizumab
- Participants who are receiving any other investigational agents
- Participants who have a history of severe immediate hypersensitivity reaction to the study agents or any of their constituents
- Participants who have a severe allergy to gentamicin (used in the manufacturing of TBio-4101)
- Participants who have received a live or live-attenuated vaccine within 30 days prior to TIL harvest or apheresis, whichever is earlier. Note: Administration of killed vaccines is allowed
- Participants who require chronic anti-coagulant therapy that cannot either be discontinued or changed to an anti-coagulant with a relatively short half-life, such as a low molecular weight heparin
- Participants with either a primary immunodeficiency disorder (i.e., severe combined immunodeficiency syndrome) or acquired immunodeficiency disorders (such as HIV/AIDS)
- Participants with a diagnosis of immunodeficiency or receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to TIL harvest or apheresis, whichever is earlier
- Participants with a serious cardiac condition, such as uncontrolled hypertension, concurrent congestive heart failure, prior history of class III/IV cardiac disease (New York Heart Association [NYHA]), history of cardiac ischemia within the past 6 months, or prior history of cardiac arrhythmia requiring treatment, unless approved by the sponsor Moffitt Cancer Center (MCC)
- Participants with known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to TIL harvest/ apheresis
- Participants with active infections requiring parenteral antibiotics that, in the opinion of the Investigator, would increase the risk of adverse events during TIL harvest or apheresis or start of non-myeloablative lymphodepletion (NMA-LD) chemotherapy
- Participants with a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant’s participation for the full duration of the study, such that it is not in the best interest of the patient to participate, in the opinion of the treating investigator
- Pregnant women are excluded from this study because the effects of TBio-4101 on the developing human fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with TBio-4101, breastfeeding should be discontinued
- INITIATION OF NMA-LD CHEMOTHERAPY: All exclusion criteria defined above apply with the following exceptions * Participants may have received prior pembrolizumab * Participants who develop brain metastases may receive TIL per principal investigator’s discretion
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT06236425.
PRIMARY OBJECTIVE:
I. Define the safety and tolerability of non-myeloablative lymphodepletion (NMA-LD) chemotherapy, autologous tumor infiltrating lymphocytes TBio-4101 (TBio-4101), aldesleukin (IL-2), and pembrolizumab administered following initial progression on pembrolizumab or pembrolizumab/platinum therapy in patients with head and neck squamous cell carcinoma (HNSCC).
SECONDARY OBJECTIVES:
I. Determine the overall response rate (ORR) of TBio-4101 administered in combination with pembrolizumab.
II. Determine the durable response rate (DRR).
III. Determine the duration of response (DoR) and disease control rate (DCR).
IV. Assess the feasibility of TBio-4101.
EXPLORATORY OBJECTIVES:
I. Evaluate time to progression (TTP), and progression-free survival (PFS).
II. Evaluate overall survival (OS).
III. Explore potential significance of T cell phenotype including TCR clonality and diversity and tumor antigen reactivity of TBio-4101 as they correlate with clinical outcome.
IV. Evaluate TBio-4101 engraftment, persistence, activation, phenotype, transcriptome profile and tumor infiltration and correlate these findings with clinical outcome.
V. Compare baseline and on treatment determinants in the tumor by pathology and genomic analysis of pre- and on-treatment biopsies with clinical response.
OUTLINE: Patients are assigned to 1 of 3 arms.
ARM I: Patients undergo tumor resection followed by apheresis and then receive pembrolizumab intravenously (IV) either every 3 weeks (Q3W) or every 6 weeks (Q6W) in the absence of unacceptable toxicity for 2 to 3 cycles. Patients undergo disease assessment and patients with a partial or complete response with continue with treatment with pembrolizumab per their physician. Patients without a partial or complete response may undergo radiation or additional chemotherapy per their physician. Patients then receive cyclophosphamide IV over 1 hour on day -7 and -6, fludarabine IV over 30 minutes on day -7 to -3, TBio-4101 IV over 20-30 minutes on day 0 and interleukin-2 IV over 15 minutes every 8 hours for up to 6 doses starting 2-3 hours after TBio-4101. Patients receive pembrolizumab IV on days 14, 35, 56 and then every 6 weeks, starting on week 12, for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, computed tomography (CT) scan, magnetic resonance imaging (MRI), x-ray imaging, echocardiogram, and blood sample collection and may undergo bone biopsy throughout the study.
ARM II: Patients undergo tumor resection followed by apheresis and then receive pembrolizumab IV and cisplatin IV Q3W in the absence of unacceptable toxicity for 2 to 3 cycles. Patients undergo disease assessment and patients with a partial or complete response with continue with treatment with pembrolizumab per their physician. Patients without a partial or complete response may undergo radiation or additional chemotherapy per their physician. Patients then receive cyclophosphamide IV over 1 hour on day -7 and -6, fludarabine IV over 30 minutes on day -7 to -3, TBio-4101 IV over 20-30 minutes on day 0 and interleukin-2 IV over 15 minutes every 8 hours for up to 6 doses starting 2-3 hours after TBio-4101. Patients receive pembrolizumab IV on days 14, 35, 56 and then every 6 weeks, starting on week 12, for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, x-ray imaging, echocardiogram, and blood sample collection and may undergo bone biopsy throughout the study.
ARM III: Patients undergo tumor resection followed by apheresis and then receive pembrolizumab IV, carboplatin IV and fluorouracil IV, over 4 days, Q3W in the absence of unacceptable toxicity for 2 to 3 cycles. Patients undergo disease assessment and patients with a partial or complete response with continue with treatment with pembrolizumab per their physician. Patients without a partial or complete response may undergo radiation or additional chemotherapy per their physician. Patients then receive cyclophosphamide IV over 1 hour on day -7 and -6, fludarabine IV over 30 minutes on day -7 to -3, TBio-4101 IV over 20-30 minutes on day 0 and interleukin-2 IV over 15 minutes every 8 hours for up to 6 doses starting 2-3 hours after TBio-4101. Patients receive pembrolizumab IV on days 14, 35, 56 and then every 6 weeks, starting on week 12, for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo tumor biopsy, CT scan, MRI, x-ray imaging, echocardiogram, and blood sample collection and may undergo bone biopsy throughout the study.
After completion of study treatment, patients are followed up at 60 days and then every 3 months for the first 2 years, every 6 months for the next 2 years and then yearly thereafter.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationMoffitt Cancer Center
Principal InvestigatorKedar Kirtane
- Primary IDMCC-23098
- Secondary IDsNCI-2024-01144
- ClinicalTrials.gov IDNCT06236425