Study of Dalpiciclib Isethionate Plus Pyrotinib Maleate in the Treatment of Advanced Esophageal Squamous Cell Carcinoma

The purpose of this study is to observe and evaluate the efficacy and safety of dalpiciclib combined with pyrotinib as second-line therapy in patients with advanced esophageal squamous cell carcinoma.

The incidence of esophageal cancer is ranked seventh in the world, and the mortality rate ranks sixth in the world. At present, the first-line treatment of advanced esophageal cancer is mainly based on the combination of paclitaxel, cisplatin and fluorouracil. After the failure of first-line treatment, there is no standard second-line treatment. The investigators designed a single-arm, phase II clinical trial of dalpiciclib combined with pyrotinib as second-line therapy in patients with advanced esophageal squamous cell carcinoma.

Eligibility Criteria:
Inclusion Criteria:

1. 18\~75 years, both men and women.；
2. Pathologically (histologically or cytologically) confirmed diagnosis of esophageal squamous cell carcinoma (ESCC), and local recurrence or distant metastasis；
3. Patients undergoing first-line systemic chemotherapy progression or intolerance (progress in maintenance therapy after first-line chemotherapy can also be included). Synchronous chemoradiotherapy for postoperative recurrence or metastasis is considered as first-line treatment; For radical concurrent chemoradiotherapy, neoadjuvant/adjuvant therapy (chemotherapy or chemoradiotherapy), if disease progression occurs during treatment or within 6 months after stopping treatment, Count it as a first-line treatment failure.
4. At least one measurable/evaluable lesion by RECIST v1.1. And the measurable lesions should not have received local treatment such as radiotherapy (The lesion located in the previous radiotherapy area, if confirmed to progress, and meets the RECIST 1.1 standard, can also be used as a target lesion).
5. Tissue samples shall be provided for biomarker analysis, preferably newly acquired tissues, and patients who are unable to provide newly acquired tissues may provide 5-8 pieces of 5um thick paraffin sections that are archived and preserved.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
7. Capable of swallowing tablets normally.
8. Life expectancy of ≥ 12 weeks.
9. The main organs function normally, that is, the following criteria are met:

   1. ANC≥1.5×109/L
   2. PLT≥90×109/L；
   3. HB≥90g/L；
   4. ALB≥28g/L；
   5. TBIL≤1.5 × ULN，ALT and AST ≤ 2.5ULN; if there is liver metastasis, ALT and AST ≤ 5ULN
   6. plasma Cr ≤ 1.5ULN or creatinine clearance (CCr) ≥ 60ml / min.
   7. APTT and INR ≤1.5 × ULN
10. Female subjects of childbearing potential must undergo a blood pregnancy test within 72 hours prior to the first administration of the drug and the result must be negative. They must not be breastfeeding and must agree to use effective contraception during the trial period and for at least 7 months after the last use of Dalpiciclib or at least 8 weeks after the last use of Pyrotinib, whichever is longer. Male subjects with partners of childbearing potential must be surgically sterilized or agree to use effective contraception during the trial period and for at least 7 months after the last use of Dalpiciclib or at least 8 weeks after the last use of Pyrotinib, whichever is longer. Sperm donation is not allowed during the study period.
11. Subjects voluntarily joined the study, signed informed consent, and were well-adhered to follow-u.

Exclusion Criteria:

1. Presence of clinically significant symptoms and uncontrollable third-space fluid accumulations, such as large pleural effusions or ascites, that cannot be managed through drainage or other methods.
2. Chronic diarrhea (including but not limited to irritable bowel syndrome, Crohn's disease, ulcerative colitis) and intestinal obstruction, among other factors that may affect medication intake and absorption.
3. Prolonged corticosteroid therapy exceeding 30 days or requiring long-term corticosteroid use.
4. Prior radiotherapy, chemotherapy, hormonal therapy, surgery, or molecular-targeted therapy within 4 weeks of enrollment (eligible for enrollment if the last dose of anti-neoplastic medication was discontinued for ≥5 half-lives before the initial treatment); prior chemotherapy with nitrosoureas or mitomycin within 6 weeks of enrollment.
5. Unresolved adverse events related to prior treatments to less than grade 2 (excluding alopecia, asthenia, and adverse events deemed by the investigator not to affect eligibility).
6. Participation in another clinical trial of a new drug within 4 weeks, unless the trial is observational (non-interventional) or in a follow-up phase.
7. Persistent uncorrectable hypokalemia and hypomagnesemia at the time of enrollment.
8. Symptomatic or untreated brain metastases.
9. History of other malignancies within the past 5 years, excluding cured cervical carcinoma in situ, basal cell carcinoma of the skin, or squamous cell carcinoma of the skin.
10. Concurrent administration of other anti-neoplastic treatments.
11. Individuals with an allergic constitution or known hypersensitivity to any component of the study medication.
12. Patients with a propensity for gastrointestinal bleeding, including but not limited to:

1) Active ulcers with fecal occult blood (++); 2) History of melena or hematemesis within the past 2 months; 3) For fecal occult blood (+) and the primary tumor site not surgically removed, a gastroscopy is required, and patients with visible active bleeding are ineligible.

13. Active infections, including but not limited to tuberculosis. 14. History of immunodeficiency, including positive HIV testing, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation.

15. Severe cardiac conditions within the past 6 months, including but not limited to:

1. Acute coronary syndrome;
2. Clinically significant arrhythmias requiring medication or unable to discontinue medications that may prolong the QT interval during the study;
3. Acute myocardial infarction;
4. Heart failure;
5. Any other cardiac condition deemed unsuitable for trial participation by the investigator.

16. Pregnant or lactating women, or women of childbearing potential with a positive baseline pregnancy test.

17. Serious comorbidities judged by the investigator to endanger patient safety or impede study completion, such as hypertension, severe diabetes, thyroid disorders, etc.

18. Habitual alcohol consumption, smoking (≥5 cigarettes daily), and other detrimental lifestyle habits; heavy episodic drinking is defined as consuming approximately four or more drinks within 2 hours, where one drink is equivalent to 150 mL of wine, 350 mL of beer, or 50 mL of 80-proof spirits.

19. History of definite neurological or psychiatric disorders, including epilepsy or dementia.