Window of Opportunity in Preserving Laryngeal Function Trial

Official title

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

Overview

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.

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.

Interventions

• 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.
• 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.
• 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.
• Drug Paclitaxel
  A chemotherapy drug that works by slowing or stopping cancer cell growth.
• 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

Primary outcome measures

• 1-Year Disease-free survival (DFS) [Time frame: At 1 year]

Secondary outcome measures (4)

• Overall Survival (OS) [Time frame: Up to 5 years]
• Larynx preservation rate [Time frame: Up to 5 years]
• Endoscopic evaluation of swallowing (FEES) [Time frame: At Baseline, at 9 weeks, at 6 months after start of treatment, up to 1 year]
• Neck Dissection Impairment Index (NDII) [Time frame: At Baseline, at every (21 day) treatment cycle, up to 1-year ± 14 days]

Eligibility criteria

Inclusion criteria

• Pathologically confirmed and previously untreated squamous cell carcinoma of the larynx or hypopharynx
• AJCC 8th Edition Stage III - IV disease (T1-T2/N1-N3, T3-T4/N0-N3)
• Disease (primary \& nodal) must be potentially surgically resectable and curable with conventional surgery and CRT
• ECOG PS 0 - 2
• 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.
• 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.
• 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
• Must have the ability to understand and the willingness to sign a written informed consent document.

Exclusion criteria

• Prior treatment for head and neck cancer
• Unresectable laryngeal or hypopharyngeal squamous cell carcinoma
• Distant metastatic disease
• 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.
• Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
• Known allergy or hypersensitivity to carboplatin or cisplatin, toripalimab, or paclitaxel.
• Prior malignancy within 2 years that in the investigator's opinion would be likely to affect the outcomes for the patient.
• Peripheral sensory neuropathy > grade 2 by CTCAE v5.0
• 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.
• 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).

• Note: No testing for Hepatitis B, Hepatitis C, or HIV is required unless mandated by local health authority or clinically indicated.
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• UPMC Hillman Cancer — Pittsburgh

Identifiers

NCT: NCT07423078 · HCC 25-126

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗