PhII Study of Toripalimab Followed by Definitive CRT & Adjuvant Toripalimab in Locally Advanced ESCC

Intravenous (IV) toripalimab infusions on Day 1 of each 21-day treatment cycle for 2 doses prior to dCRT followed by adjuvant toripalimab for up to 1 year. No toripalimab will be given during SOC dCRT.

After dCRT, all patients can progress to adjuvant toripalimab or resection followed by adjuvant toripalimab. After adjuvant toripalimab, routine surveillance will involve serial esophagogastroduodenoscopies (EGDs) and imaging.

Treatment will continue for up to an additional year with adjuvant toripalimab infusions, until disease progression, or intolerable toxicity. Patients will be followed for OS and subsequent anticancer therapy for up to 3 years after ending study treatment.

Note: Toripalimab will be provided to the study by Coherus. Each site will obtain carboplatin and paclitaxel from commercial supply to administer as standard of care.

• Toripalimab (Drug), also known as Loqtorzi, toripalimab-tpzi: Injection Q3W at 240mg doses
• Carboplatin + Paclitaxel (Drug), also known as CarboTaxol, PC: Carboplatin AUC 2 Q1W Infusion, Paclitaxel Q1W Infusion 50mg/m2

Primary outcomes

• To determine the clinical complete response rate to proportion of patients with complete clinical response (cCR) 4-12 weeks after completion of standard-of-care (SOC) dCRT. [4-11 weeks after completion of standard-of-care (SOC) dCRT.]: Determine cCR score by achieving all of these:1 * No lesion, budding, or ulceration identified on esophagogastroduodenoscopy (EGD). * Bite-on-bite biopsies with no residual tumor. * EGD with endoscopic ultrasound (EUS) and fine needle aspiration (FNA) of suspicious lymph nodes (LNs) shows no residual tumor. If patients have suspicious LNs unable to be reached by FNA, they will not be classified as clinical complete responders.

Secondary outcomes

• To determine Disease-free survival (DFS [from start of treatment until 1, 2, and 3yrs post treatment]: 1, 2, and 3-year disease free survival rates defined as time from the start of treatment until disease recurrence, death from any cause, or the end of the study period if the patient does not experience recurrence.
• To determine Overall survival (OS) [from start of treatment until 2 and 3yrs post treatment]: 2 and 3-year overall survival rates defined as the time from start of treatment until death from any cause, or the end of the study period/last follow up.
• To determine frequency of Adverse Events (AEs) [through study completion, an average of 1 year]: AEs will be determined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v6).
• To determine Quality of life (QOL) measurements [(during screening), after induction (post-induction assessment), after dCRT (post-CRT assessment), at EOT visit, and then at coinciding follow-up visits for up to 3 years]: The EORTC-QLQ-C30 questionnaire will be administered prior to toripalimab induction (during screening), after induction (post-induction assessment), after dCRT (post-CRT assessment), at EOT visit, and then at coinciding follow-up visits for up to 3 years. Uses scores from 0 to 100 for each part; High functional score means good health; High symptom score means high pain or trouble

Sex: All, ages: 18 Years to 100 Years

Inclusion Criteria:

1. Signed and dated written informed consent.
2. Age ≥ 18 years the day of signing informed consent.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.
4. Previously untreated, resectable, histologically confirmed stage II-IVA esophageal squamous cell carcinoma according to the 8th TNM staging system of the American Joint Committee on Cancer.
5. Has provided archival or newly obtained core or excisional biopsy tissue (fine needle aspirate \[FNA\] is not adequate) of a tumor lesion for local standard of care biomarker analysis. Repeat samples may be required if adequate tissue is not provided. Note: Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
6. Adequate organ and bone marrow function resulted ≤ 28 days prior to first dose of protocol-indicated treatment:

   * Absolute neutrophil count (ANC) ≥ 1500/µL.
   * Platelets ≥ 100,000/µL.
   * Hemoglobin ≥ 7.0 g/dL
   * Estimated glomerular filtration rate (eGFR) ≥ 60 mL/min (as calculated by the Cockcroft-Gault Formula or calculated/measured by an alternative established institutional standard consistently applied across participants at the site) or serum creatinine ≤ 1.5x upper limit of normal (ULN)
   * Total bilirubin ≤ 1.5 times institutional ULN
   * AST (SGOT) and ALT (SGPT) ≤ 2.5 times institutional ULN.
   * Serum albumin ≥ 2.8 g/dL

Exclusion Criteria:

1. Locally advanced and incurable or metastatic disease is deemed incurable.
2. History of another malignancy within 3 years prior to screening, except for non-melanoma skin carcinoma, low-grade localized prostate cancer, superficial bladder cancer, ductal carcinoma in situ (CIS) of the breast, CIS of the cervix, or stage I uterine cancer.
3. Multiple primary esophageal cancers.
4. Previous radiotherapy of the thorax.
5. Previous immune checkpoint inhibitor therapy (including agents targeting PD-1, PD-L1/PD-L2, CTLA-4, LAG-3, TIGIT).
6. Active autoimmune disease, solid organ transplant recipient, or prednisone dose (or a steroid equivalent) of more than 10mg daily.
7. Previous non-infectious pneumonitis or interstitial lung disease.
8. Any severe comorbidity (e.g. uncontrolled diabetes or decompensated heart failure) which in the determination of the treating physician would preclude the patient from receiving this experimental treatment regimen.
9. Contraindication to ICI or suspected allergy/hypersensitivity to monoclonal antibodies or any ingredients of toripalimab.
10. Known allergy/hypersensitivity to carboplatin or paclitaxel.
11. Inability to provide informed consent due to psychological, familial, social, or other factors.
12. Presence of CTCAEv6 grade ≥ 2 neuropathy.
13. Pregnant or breastfeeding.

• Michael Gibson, Principal investigator, Vanderbilt-Ingram Cancer Center