Window of Opportunity in Preserving Laryngeal Function Trial (WOLF)

A Phase II Window of Opportunity in Preserving Laryngeal Function (WOLF) Trial

This trial will study the safety and tolerability and disease survival rates in adult patients with recurrent/metastatic (R/M) HNSCC when treated with carboplatin or cisplatin, paclitaxel, and toripalimab.

Study Overview

• Status: Recruiting
• Conditions: Hypopharyngeal Squamous Cell Carcinoma; Locally Advanced Laryngeal Squamous Cell Carcinoma; Head and Neck Squamous Cell Carcinoma (HNSCC) - Recurrent/Metastatic (R/M)
• Intervention / Treatment: Drug: Toripalimab; Drug: Carboplatin; Drug: Cisplatin; Drug: Paclitaxel; Radiation: Radiation Therapy

Detailed Description

Currently, for patients with locally advanced laryngeal or hypopharyngeal squamous cell carcinoma (SCC), there is the option of total laryngectomy (TL) followed by adjuvant pathology driven therapy (RT or CRT) or an organ preservation approach. Total laryngectomy is a particularly morbid surgery, leaving a patient breathing through the neck for the rest of their life. In recent years however, upfront total laryngectomy with adjuvant RT has been in focus to growing concern of reduced overall survival rates in advanced laryngeal and hypopharyngeal SCC, particularly in patients with T4 disease. As such, upfront TL with adjuvant RT or CRT is typical, with organ preservation protocols more controversial, for T4 LSCC specifically. This trial provides neoadjuvant (chemo)immunotherapy (induction regimen of platinum (carboplatin or cisplatin), paclitaxel, and toripalimab) allowing for a novel approach to patient bioselection for the treatment of laryngeal cancer. Toripalimab is approved in combination with cisplatin and gemcitabine for the first-line treatment of patients with recurrent and/or metastatic nasopharyngeal carcinoma and has shown to significantly improved PFS and OS when combined with cisplatin and gemcitabine. Patients who show response to neoadjuvant therapy in laryngeal cancer have been shown to have 1) a better survival than patients who do not respond and 2) respond better to nonsurgical therapy. The addition of immunotherapy to chemotherapy has the potential to improve the response rate to neoadjuvant therapy, decrease the number of patients who require total laryngectomy as their primary treatment, and to improve the survival of patients with this highly morbid disease.

• Study Type: Interventional
• Enrollment (Estimated): 87
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jennifer Ruth, RN, BSN, CCRP; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu
• Study Contact Backup: Name: Mel J Mendez, BS; Phone Number: 878-261-6071; Email: mendezmj@upmc.edu

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Recruiting
      • UPMC Hillman Cancer
      • Contact: Jennifer Ruth, RN, BSN; Phone Number: 412-623-8963; Email: ruthj2@upmc.edu
      • Contact: Mel J Mendez, BS; Phone Number: 878-261-6071; Email: mendezmj@upmc.edu
      • Principal Investigator: Matthew Spector, MD, FACS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Pathologically confirmed and previously untreated squamous cell carcinoma of the larynx or hypopharynx
2. AJCC 8th Edition Stage III - IV disease (T1-T2/N1-N3, T3-T4/N0-N3)
3. Disease (primary & nodal) must be potentially surgically resectable and curable with conventional surgery and CRT
4. ECOG PS 0 - 2
5. Sexually active fertile subjects and their partners must agree to use highly effective method of contraception prior to study entry, during the course of the study, and for 1 year after the last dose of treatment (whichever is later). An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
6. Female subjects of childbearing potential must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met: Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

7. Must have normal organ and marrow function as defined below:

   • Hemoglobin ≥ 9.0 g/dL
   • Absolute neutrophil count ≥ 1,500/mcL
   • Platelet count ≥ 100,000/mcL
   • Total bilirubin ≤ 1.5 X the institutional upper limit of normal (ULN)
   • AST (SGOT) ≤ 2.5 X institutional upper limit of normal (ULN)
   • ALT (SGPT) ≤ 2.5 X institutional ULN
   • Creatinine clearance ≥ 40 mL/min/1.73 m2 for patients with a creatinine level above institutional normal
8. Must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

1. Prior treatment for head and neck cancer
2. Unresectable laryngeal or hypopharyngeal squamous cell carcinoma
3. Distant metastatic disease
4. Has an active autoimmune disease requiring systemic treatment within the past 3 months, or a syndrome that requires ongoing systemic steroids or immunosuppressive agents. Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic therapy or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism or Sjogren's syndrome will not be excluded from the study.
5. Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
6. Known allergy or hypersensitivity to carboplatin or cisplatin, toripalimab, or paclitaxel.
7. Prior malignancy within 2 years that in the investigator's opinion would be likely to affect the outcomes for the patient.
8. Peripheral sensory neuropathy > grade 2 by CTCAE v5.0
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.

10. Has acute or chronic active hepatitis B and C virus infection or known history of untreated hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (HCV) (defined as HCV RNA [qualitative]) or HIV infection (see note).

    1. Note: No testing for Hepatitis B, Hepatitis C, or HIV is required unless mandated by local health authority or clinically indicated.
    2. Note: Participants with a history of HIV infection are considered eligible if CD4+ T cell counts are ≥350 cells/µL and the patient has had no opportunistic infections in the last 12 months.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: toripalimab + carboplatin + paclitaxel; Prior to treatment: Assessments include laryngoscopy and anatomic imaging studies Treatment: toripalimab 240mg IV with carboplatin (AUC 5) and paclitaxel (175 mg/m^2) IV every 3 weeks for two cycles. (Cisplatin 75mg/m^2 can be used in place of carboplatin at the investigator's discretion.) After 2 Cycles of Treatment: Repeat laryngoscopy and anatomic imaging studies. Undergo swallowing function and extranodal extension status assessment.	Drug: Toripalimab; A monoclonal antibody (recombinant humanized programmed cell death protein 1 (PD-1) monoclonal antibody that acts as a checkpoint inhibitor) used for the treatment of melanoma and nasopharyngeal carcinoma.; Other Names: Loqtorzi; Drug: Carboplatin; A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Paraplatin; Drug: Cisplatin; *Can be used in place of carboplatin at the investigator's discretion. A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Platinol, Platinol-AQ; Drug: Paclitaxel; A chemotherapy drug that works by slowing or stopping cancer cell growth.; Other Names: Taxol; Abraxane
Experimental: Post-bioselection: Chemoradiation + toripalimab monotherapy; Patients with PR ≥50% (not CR) with preserved swallowing function or CR, with preoperative N+ disease and extranodal extension upon neck dissection. Induction Treatment: toripalimab 240mg IV+carboplatin (AUC 5)+paclitaxel (175 mg/m^2) IV Q Continuation Treatment: toripalimab 240mg IV + carboplatin (AUC 5) + paclitaxel (175 mg/m^2) IV Q + Radiation therapy as per the Intervention Description + toripalimab 240mg IV monotherapy for 8 cycles	Drug: Toripalimab; A monoclonal antibody (recombinant humanized programmed cell death protein 1 (PD-1) monoclonal antibody that acts as a checkpoint inhibitor) used for the treatment of melanoma and nasopharyngeal carcinoma.; Other Names: Loqtorzi; Drug: Carboplatin; A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Paraplatin; Drug: Cisplatin; *Can be used in place of carboplatin at the investigator's discretion. A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Platinol, Platinol-AQ; Drug: Paclitaxel; A chemotherapy drug that works by slowing or stopping cancer cell growth.; Other Names: Taxol; Abraxane; Radiation: Radiation Therapy; Megavoltage energy photon beam irradiation. Any treatment planning and delivery system that has been credentialed for head and neck intensity-modulated radiotherapy (IMRT). Simultaneous integrated boost and sequential boost techniques (discretion of treating physician). Total doses delivered to each Planning Target Volume (PTV) (in 33-35 fractions): High: 70 Gy, Boost (if applicable): 66 Gy, Intermediate: 60-63 Gy, Elective: 56-57 Gy A sequential boost will consist of treatment of the combined PTVs 25 fractions followed by three sequential cone-downs targeting (Intermediate + Boost + High); (Boost + High); and High. Total doses for the PTVs: High: 70 Gy, Boost (if applicable): 66 Gy, Intermediate: 60 Gy, Elective: 50 Gy.; Other Names: intensity-modulated radiotherapy (IMRT)
Experimental: Post-bioselection: Radiation + toripalimab monotherapy; Patients with CR, with preoperative N0 disease or N+ disease with no extranodal extension upon neck dissection. Induction Treatment: toripalimab 240mg IV+carboplatin (AUC 5)+paclitaxel (175 mg/m^2) IV Q Continuation Treatment: Radiation therapy as per the Intervention Description + toripalimab 240mg IV monotherapy for 8 cycles	Drug: Toripalimab; A monoclonal antibody (recombinant humanized programmed cell death protein 1 (PD-1) monoclonal antibody that acts as a checkpoint inhibitor) used for the treatment of melanoma and nasopharyngeal carcinoma.; Other Names: Loqtorzi; Drug: Carboplatin; A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Paraplatin; Drug: Cisplatin; *Can be used in place of carboplatin at the investigator's discretion. A chemotherapy medication classified as an alkylating agent. It contains the metal platinum, which binds to DNA in cancer cells, preventing their replication and leading to cell death. This mechanism makes it effective against rapidly dividing cells, such as cancer cells.; Other Names: Platinol, Platinol-AQ; Drug: Paclitaxel; A chemotherapy drug that works by slowing or stopping cancer cell growth.; Other Names: Taxol; Abraxane; Radiation: Radiation Therapy; Megavoltage energy photon beam irradiation. Any treatment planning and delivery system that has been credentialed for head and neck intensity-modulated radiotherapy (IMRT). Simultaneous integrated boost and sequential boost techniques (discretion of treating physician). Total doses delivered to each Planning Target Volume (PTV) (in 33-35 fractions): High: 70 Gy, Boost (if applicable): 66 Gy, Intermediate: 60-63 Gy, Elective: 56-57 Gy A sequential boost will consist of treatment of the combined PTVs 25 fractions followed by three sequential cone-downs targeting (Intermediate + Boost + High); (Boost + High); and High. Total doses for the PTVs: High: 70 Gy, Boost (if applicable): 66 Gy, Intermediate: 60 Gy, Elective: 50 Gy.; Other Names: intensity-modulated radiotherapy (IMRT)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-Year Disease-free survival (DFS)	Proportion of patients who have not experienced disease recurrence/progression or death from any cause at 1 year from start of treatment. Radiologic (CT or MRI) imaging as well as direct visualization by laryngoscopy will be used to assess disease with recurrence requiring a biopsy to be considered positive.	At 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Median time from initiation of study therapy to death from any cause.	Up to 5 years
Larynx preservation rate	The proportion of responding patients (without disease recurrence/progression or death from any cause) who do not undergo laryngectomy during the study period. Radiologic (CT or MRI) imaging as well as direct visualization by laryngoscopy will be used to assess disease with recurrence requiring a biopsy to be considered positive.	Up to 5 years
Endoscopic evaluation of swallowing (FEES)	A portable procedure in which a thin, flexible endoscope is passed through the nose to view the pharynx and larynx during swallowing, allowing the physician to directly observe and assess the patient's swallowing mechanics. The physician will indicate the presence or absence of impairment of the pharynx and/or larynx that effects swallowing.	At Baseline, at 9 weeks, at 6 months after start of treatment, up to 1 year
Neck Dissection Impairment Index (NDII)	Patient Reported Outcome Measure (PROM) is a 10-item, self-report instrument. A 5-level Likert scale is used for responses ranging from 'not at all' = 10 to 'a lot' = 0 related to pain/discomfort and limitation of movement as a result of cancer treatment. The NDII scores range from 0 to 100, with higher scores indicating better shoulder functioning and quality of life (QOL). Factors such as age, weight, radiation treatment, and neck dissection type significantly affect the QOL score.	At Baseline, at every (21 day) treatment cycle, up to 1-year ± 14 days

Collaborators and Investigators

• Sponsor: Matthew Spector
• Collaborators: Coherus Oncology, Inc.
• Investigators: Principal Investigator: Matthew Spector, MD, FACS, UPMC Hillman Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): April 6, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2031

Study Registration Dates

• First Submitted: February 6, 2026
• First Submitted That Met QC Criteria: February 12, 2026
• First Posted (Actual): February 20, 2026

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 6, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: neoadjuvant; immunotherapy; laryngectomy
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Neoplastic Processes; Carcinoma; Carcinoma, Squamous Cell; Pathological Conditions, Signs and Symptoms; Squamous Cell Carcinoma of Head and Neck; Recurrence; Neoplasm Metastasis; Amino Acids, Peptides, and Proteins; Proteins; Organic Chemicals; Therapeutics; Hydrocarbons; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Terpenes; Inorganic Chemicals; Chlorine Compounds; Nitrogen Compounds; Coordination Complexes; Taxoids; Cyclodecanes; Diterpenes; Platinum Compounds; Albumins; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Albumin-Bound Paclitaxel; Carboplatin; Paclitaxel; Cisplatin; Radiotherapy; toripalimab; Radiotherapy, Intensity-Modulated
• Other Study ID Numbers: HCC 25-126

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No