Squamous Cell Carcinoma of Head and Neck, Squamous Cell Carcinoma of Head and Neck (SCCHN), HNSCC, Neoplasm Recurrence, Local, Recurrent Head and Neck Squamous Cell Carcinoma
Conditions
Keywords
TMV vaccine, tumor membrane vesicle, personalized cancer vaccine, autologous cancer vaccine, toripalimab-tpzi, LOQTORZI, anti-PD-1, immune checkpoint inhibitor, salvage surgery, adjuvant, neoadjuvant immunotherapy, HNSCC, oral cavity cancer, oropharyngeal cancer, laryngeal cancer, hypopharyngeal cancer, PD-L1, IL-12, B7-1
Brief summary
The goal of this clinical trial is to learn if an experimental, personalized cancer vaccine called TMV vaccine is safe and to find the best dose to study in future trials. The study includes adults with head and neck squamous cell carcinoma that has come back in or near the same area after earlier treatment, and who are planning to have surgery to remove it. The study will also test the vaccine together with toripalimab-tpzi, an approved immunotherapy drug. The TMV vaccine is made from each participant's own tumor tissue. Small particles taken from the surface of the tumor cells have 2 immune-boosting proteins added to them, to help the immune system recognize and attack the cancer. The main questions it aims to answer are: * Is the TMV vaccine safe, and what medical problems do participants have after receiving it? * What is the best dose of the TMV vaccine to use in future studies? * Is the TMV vaccine safe when given together with toripalimab-tpzi before and after surgery? The study has 2 parts. In Part 1 (Phase 1a), participants will: * Have tumor tissue collected during their planned surgery, which is used to make their personal vaccine * Receive the vaccine as small injections into the skin every 2 weeks for 3 doses, starting after they recover from surgery * Visit the clinic about once a week for 8 weeks for checkups, blood tests, and safety monitoring * Have scans every 3 months and be followed for up to 3 years The first participants will receive the lowest dose. Later groups will receive higher doses only if the lower dose is found to be safe. In Part 2 (Phase 1b), participants whose tumors test positive for a marker called PD-L1 will: * Have a biopsy to collect tumor tissue for their personal vaccine * Before surgery, receive 2 doses of the vaccine and up to 2 doses of toripalimab-tpzi through a vein * After surgery, receive 1 more dose of the vaccine and continue toripalimab-tpzi every 3 weeks for up to 1 year * Have regular checkups, blood tests, and scans, and be followed for up to 3 years Researchers will also study blood and tumor samples to learn how the immune system responds to the vaccine.
Detailed description
This is a first-in-human, single-center, open-label Phase 1 study of an autologous tumor membrane vesicle (TMV) vaccine, alone and in combination with toripalimab-tpzi, in adults with loco-regionally recurrent head and neck squamous cell carcinoma (HNSCC) who are candidates for salvage surgery. The TMV vaccine is prepared from each participant's resected or biopsied tumor tissue. Tumor membrane vesicles are modified by protein transfer to display the immunostimulatory molecules IL-12 and B7-1 through glycosylphosphatidylinositol (GPI) anchors, so that tumor antigens and immune-stimulating signals are delivered together at the vaccination site. Phase 1a is a dose escalation of TMV vaccine monotherapy given as adjuvant therapy after salvage surgery. Three dose levels (0.25 mg, 0.5 mg, and 1.0 mg) are administered intradermally every 2 weeks for 3 doses. Up to 6 participants are enrolled at each dose level, and enrollment of the first 2 participants at each dose level is staggered by at least 28 days. Safety and immune stimulating activity are reviewed together to identify the optimal biological dose (OBD). Phase 1b evaluates the TMV vaccine at the OBD in combination with toripalimab-tpzi in participants with PD-L1-positive tumors, using a combined neoadjuvant and post-operative adjuvant approach. Participants receive 2 neoadjuvant vaccine doses (every 2 weeks) and up to 2 doses of toripalimab-tpzi (every 3 weeks) before surgery, followed by 1 adjuvant vaccine dose and toripalimab-tpzi every 3 weeks for up to 1 year or until disease progression. Participants are followed for survival for up to 3 years after treatment initiation.
Interventions
BIOLOGICALTMV Vaccine
Autologous, personalized tumor membrane vesicle (TMV) vaccine prepared from the participant's own tumor tissue, collected at salvage surgery (Phase 1a) or by biopsy (Phase 1b). Tumor membrane vesicles are modified by protein transfer to display the immunostimulatory molecules IL-12 and B7-1 through glycosylphosphatidylinositol (GPI) anchors. Administered by intradermal injection at dose levels of 0.25 mg, 0.5 mg, or 1.0 mg in Phase 1a, and at the optimal biological dose identified in Phase 1a for Phase 1b.
BIOLOGICALToripalimab-tpzi
Anti-PD-1 monoclonal antibody administered at 240 mg by intravenous infusion every 3 weeks, for up to 2 doses before salvage surgery and then for up to 1 year after surgery or until disease progression (Phase 1b only).
Sponsors
Metaclipse Therapeutics Corporation
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age 18 years or older. * Recurrent, histologically proven squamous cell carcinoma of the head and neck (HNSCC), amenable to curative salvage surgery. EBV- and HPV/p16-positive and -negative tumors are allowed. Squamous cell carcinoma of the oral cavity, larynx, hypopharynx, oropharynx, sinonasal carcinoma, and cancer of unknown primary (squamous cell carcinoma only) are allowed. * Oropharyngeal tumors must have EBV and p16 or HPV testing done. * Tumor tissue must be available and banked (below -70°C) at the time of salvage surgery (Phase 1a) or biopsy (Phase 1b), with the tissue collection informed consent signed. * Enough tissue collected at salvage surgery (Phase 1a) or biopsy (Phase 1b) to make at least 3 doses of vaccine: resectable tumor tissue weighing at least 1 gram (approximately 0.5 to 3 cm³) with adequate cellularity (greater than 40% viable tumor cellularity), as assessed by pathology using the corresponding biopsy or surgical specimen. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Phase 1b only: Tumor must be PD-L1 positive (combined positive score \[CPS\] of 1 or higher) by IHC (22C3), performed in the MD Anderson CLIA-certified laboratory. * Phase 1b only: Measurable disease per RECIST 1.1. * Adequate hematologic function: * Absolute neutrophil count ≥ 1,500 cells/µL * Platelets ≥ 100,000/µL * Hemoglobin ≥ 9.0 g/dL (red blood cell transfusion allowed) * Adequate hepatic function: * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) * AST and ALT ≤ 2.5 x ULN * Albumin ≥ 3.0 g/dL * Adequate renal function: * Serum creatinine ≤ 1.5 x ULN * Creatinine clearance ≥ 50 mL/min, calculated using the Cockcroft-Gault formula * INR ≤ 1.5. Anticoagulation is allowed. Patients receiving low molecular weight heparin on a stable therapeutic dose for more than 2 weeks, or with a factor Xa level \< 1.1 U/mL, are allowed. * Willing and able to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures. * Able to understand and willing to sign written informed consent documents. * Females of childbearing potential (FCBP) must agree to use 2 acceptable methods of contraception, 1 from Category A and 1 from Category B, during study treatment and for 3 months after the last dose, or agree to remain abstinent from heterosexual intercourse when this is consistent with their preferred and usual lifestyle. * Category A (highly effective methods): hormonal contraceptives (oral, injectable, transdermal, or implantable); intrauterine device (IUD) or intrauterine hormone-releasing system; vasectomized partner (with confirmed azoospermia) as the sole sexual partner * Category B (barrier methods): male condom; female condom; diaphragm or cervical cap used with spermicide * An FCBP is a sexually mature woman who has not had a hysterectomy or bilateral oophorectomy, or who has not been naturally postmenopausal for at least 24 consecutive months (has had menses during the preceding 24 consecutive months). * Males who are sexually active with an FCBP must agree to use an effective method of contraception (for example, a male condom) during study treatment and for 3 months after the last dose, in addition to their partner's contraception, or agree to remain abstinent from heterosexual intercourse when this is consistent with their preferred and usual lifestyle. * Females of childbearing potential must have a negative serum pregnancy test at study entry.
Exclusion criteria
* Nasopharyngeal carcinoma, salivary gland tumors, or non-squamous cell histology of the head and neck. * Other malignancies within the past 5 years, other than those specified in the inclusion criteria. Patients with prior malignancies, including pelvic cancer, are eligible if disease free for more than 5 years. Patients with prior in situ carcinomas are eligible if there was complete removal. * Not enough tissue collected at surgery (Phase 1a) or biopsy (Phase 1b) for the planned 3 doses (resectable tumor tissue weighing less than 1.0 gram). * Treatment with chronic immunosuppressants (for example, cyclosporine following transplantation). * Prior organ allograft or allogeneic bone marrow transplantation. * Active, known, or suspected autoimmune disease. Patients with vitiligo, psoriasis not requiring systemic treatment, alopecia, resolved childhood asthma/atopy, type I diabetes mellitus, residual hypothyroidism due to an autoimmune condition requiring only hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted. * A condition requiring systemic treatment with corticosteroids (\> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalent are permitted in the absence of active autoimmune disease. * Uncontrolled intercurrent illness including, but not limited to, HIV-positive patients receiving combination antiretroviral therapy, ongoing or active infection, symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris, ventricular arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. * Other medications, severe acute or chronic medical or psychiatric conditions, or laboratory abnormalities that may increase the risk of study participation or study drug administration, or may interfere with interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for the study. * Clinical evidence of bleeding diathesis or coagulopathy. * Active bacterial or fungal infection requiring systemic treatment within 7 days of treatment. * Use of other investigational drugs within 28 days or at least 5 half-lives (whichever is longer) before study drug administration. * Non-oncology vaccines within 28 days before planned treatment. * Failure to recover from Grade 3 or 4 toxicity from previous treatment. * Prior immuno-oncology therapy within 6 months of study enrollment, including experimental anti-tumor vaccines; any agent targeting T cell co-stimulation or checkpoint pathways, such as anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibodies (including ipilimumab); or other medicines specifically targeting T cell co-stimulation or checkpoint pathways. * Ongoing or planned systemic anti-cancer therapy or radiation therapy. The last cycle of cytotoxic therapy must be at least 21 days, and the last dose of radiotherapy at least 14 days, before the first dose of TMV vaccine. * Pregnant or breastfeeding. * Positive pregnancy test at enrollment or before study drug administration. * Prisoners as defined by 45 CFR 46.303(c). * Phase 1b only: History of severe hypersensitivity reaction to any monoclonal antibody. * Phase 1b only: History of hypersensitivity to toripalimab-tpzi (LOQTORZI) or any of its excipients. * Phase 1b only: Prior Grade 4 immune-related adverse events (irAEs) from previous immune checkpoint inhibitor therapy. Patients with Grade 2 or 3 toxicity from prior checkpoint inhibitor therapy may enroll if the toxicity has resolved to Grade 1 or lower.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicities (DLTs) in Phase 1a | From first dose through 3 weeks after the last vaccine dose (7 weeks) | A DLT is a TMV vaccine-related adverse event that is Grade 4 hematologic or Grade 3 or higher non-hematologic per NCI CTCAE v6.0, except Grade 3 injection site reactions adequately controlled with medical treatment. Reported by dose level. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Phase 1a | Frame: From first dose through 30 days after the last vaccine dose (approximately 8 weeks) | TEAEs and SAEs graded by severity per NCI CTCAE v6.0, reported by dose level. |
| Recommended Phase 2 Dose (RP2D) of TMV Vaccine Alone | From first dose through 3 weeks after the last vaccine dose (7 weeks) | RP2D of TMV vaccine monotherapy, selected based on the totality of safety, tolerability, and immunogenicity data across Phase 1a dose levels. |
| Number of Participants With Dose-Limiting Toxicities (DLTs) in Phase 1b | From first dose through 3 weeks after the last TMV vaccine dose or last toripalimab-tpzi dose, whichever is later (up to approximately 15 months) | A DLT is a TMV vaccine-related adverse event that is Grade 4 hematologic or Grade 3 or higher non-hematologic per NCI CTCAE v6.0, in participants receiving TMV vaccine plus toripalimab-tpzi. |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) in Phase 1b | From first dose through 30 days after the last dose of study treatment (up to approximately 15 months) | TEAEs and SAEs graded by severity per NCI CTCAE v5.0. |
| Number of Participants With Immune-Related Adverse Events (irAEs) Attributable to Toripalimab-tpzi in Phase 1b | From first dose through 30 days after the last dose of study treatment (up to approximately 15 months) | Immune-related adverse events attributed to toripalimab-tpzi, graded by severity per NCI CTCAE v5.0. |
| Recommended Phase 2 Dose (RP2D) of TMV Vaccine Plus Toripalimab-tpzi | From first dose through 3 weeks after the last TMV vaccine dose or last toripalimab-tpzi dose, whichever is later (up to approximately 15 months) | RP2D of TMV vaccine in combination with toripalimab-tpzi, selected based on the totality of safety, tolerability, and immunogenicity data. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in T Cell Activation and Phenotype in Peripheral Blood | Before each TMV vaccine dose, and 24 hours and 7 to 9 days after each dose; also 2 weeks after the final dose in Phase 1a (Week 6) | Activation status and phenotype of T cell subsets in peripheral blood mononuclear cells (PBMCs), measured by flow cytometry, in participants receiving TMV vaccine alone (Phase 1a) or TMV vaccine plus toripalimab-tpzi (Phase 1b). |
| Change From Baseline in Plasma Cytokine and Chemokine Levels | Before each TMV vaccine dose, and 24 hours and 7 to 9 days after each dose; also 2 weeks after the final dose in Phase 1a (Week 6) | Plasma cytokine and chemokine biomarkers measured in peripheral blood in participants receiving TMV vaccine alone (Phase 1a) or TMV vaccine plus toripalimab-tpzi (Phase 1b). |
| Change in Percentage of Viable Tumor Cells From Baseline Biopsy to Surgical Resection in Phase 1b | From pre-treatment biopsy to surgical resection (approximately 10 weeks) | Pathologic response to neoadjuvant TMV vaccine plus toripalimab-tpzi, measured as the change in viable tumor cell percentage from the pre-treatment biopsy to the resected specimen. |
| Major Pathologic Response (MPR) Rate in Phase 1b | At surgical resection (approximately 10 weeks after biopsy) | Percentage of participants with 10% or fewer viable tumor cells in the resected specimen after neoadjuvant TMV vaccine plus toripalimab-tpzi. |
| Pathologic Complete Response (pCR) Rate in Phase 1b | At surgical resection (approximately 10 weeks after biopsy) | Percentage of participants with no viable tumor cells (0%) in the resected specimen after neoadjuvant TMV vaccine plus toripalimab-tpzi. |
| Objective Response Rate (ORR) per RECIST v1.1 in Phase 1b | At pre-surgical restaging after neoadjuvant treatment (approximately 6 weeks after first dose) | Percentage of participants with a complete or partial response per RECIST v1.1 on the restaging scan before surgery. |
| Disease Control Rate (DCR) per RECIST v1.1 in Phase 1b | At pre-surgical restaging after neoadjuvant treatment (approximately 6 weeks after first dose) | Percentage of participants with a complete response, partial response, or stable disease per RECIST v1.1 on the restaging scan before surgery. |
| Progression-Free Survival (PFS) | Up to 3 years | Time from treatment initiation to first documented disease recurrence or death from any cause, in participants receiving TMV vaccine alone (Phase 1a) or TMV vaccine plus toripalimab-tpzi (Phase 1b). |
| Overall Survival (OS) | Up to 3 years | Time from treatment initiation to death from any cause, in participants receiving TMV vaccine alone (Phase 1a) or TMV vaccine plus toripalimab-tpzi (Phase 1b). |
Countries
United States
Contacts
CONTACTAnthony Lazaro Manliguez, BS
CONTACTRaja Nicholas, PhD
STUDY_DIRECTORPeriasamy Selvaraj, PhD
Metaclipse Therapeutics
STUDY_DIRECTORMichael Coleman, PhD
Metaclipse Therapeutics
STUDY_DIRECTORChristopher Pack, PhD
Metaclipse Therapeutics
STUDY_DIRECTORKristen Jacobsen, PhD
Metaclipse Therapeutics
Outcome results
None listed