This trial will study the safety and tolerability and disease survival rates in adultpatients with recurrent/metastatic (R/M) HNSCC when treated with carboplatin orcisplatin, paclitaxel, and toripalimab.
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.
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 Name: 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 Name: 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 Name: Platinol, Platinol-AQ
Drug: Paclitaxel
A chemotherapy drug that works by slowing or stopping cancer cell growth.
Other Name: 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 Name: intensity-modulated radiotherapy (IMRT)
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.
UPMC Hillman Cancer
Pittsburgh, Pennsylvania, United States
Investigator: Jennifer Ruth, RN, BSN
Contact: 412-623-8963
ruthj2@upmc.edu
Investigator: Matthew Spector, MD, FACS
Jennifer Ruth, RN, BSN, CCRP
412-623-8963
ruthj2@upmc.edu
Mel J Mendez, BS
878-261-6071
mendezmj@upmc.edu
Matthew Spector, MD, FACS, Principal Investigator
UPMC Hillman Cancer Center