A Phase III Study to Evaluate the Efficacy and Safety of Penpulimab in the Relapsed and Refractory Classical Hodgkin's Lymphoma

Inclusion Criteria:

1. Signed written informed consent form (ICF).
2. Age of ≥ 18 years at the time of enrollment, male or female.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
4. Life expectancy of ≥ 3 months.
5. Histologically confirmed classic Hodgkin's lymphoma (cHL).
6. Relapsed (disease progression during or after most recent therapy) or refractory (failure to achieve CR or PR after most recent therapy) cHL and meet any of thefollowing criterions:
7. Subjects who have received autologous hematopoietic stem cell transplantation (ASCT) after salvage chemotherapy, followed by relapse or progression.
8. For subjects who have not received ASCT, it is required at least 2 lines of priorsystemic chemotherapy. Refractory subjects are defined as failure to achieve PRafter at least 2 cycles of chemotherapy, or failure to achieve CR after at least 4 cycles of chemotherapy. If the best response to treatment is PD or the reasonfor ending the treatment is PD, the subject is considered as refractory withoutrequirement on the number of cycles of treatment received.
9. Have at least one measurable lesion according to Lugano classification 2014.
10. Have adequate hematologic and organ function as defined below:
11. Hematology (supportive treatment with ang blood components or cell growth factorsis not allowed within 7 days prior to enrollment laboratory test): Absoluteneutrophil count (ANC) ≥ 1.0x109/L, platelet count ≥ 75 x109/L, hemoglobin ≥ 80g/L.
12. Kidney: Serum creatinine ≤ 1.5 X ULN and estimated GFR (by Cockroft-Gaultequation) ≥ 50ml/min.
13. Liver: Total bilirubin ≤ 1.5 X ULN, AST/ALT ≤ 2.5 X ULN.
14. Coagulation: International normalized ratio (INR) and activated partialthromboplastin time (APTT) ≤ 1.5 × ULN.
15. Women of childbearing potential (WOCBP) must be tested for serum or urine pregnancynegative within 3 days prior to the first dose of study treatment. WOCBP will beinstructed to adhere to contraception while on treatment and for at least 150 daysafter the last dose of study treatment. Male subjects who are sexually active withWOCBP will be instructed to adhere to contraception while on treatment and for atleast 150 days after receiving the last dose of study treatment.

Exclusion Criteria:

1. Nodular lymphocytes are non-Hodgkin's lymphoma or gray area lymphoma.
2. Central nervous system lymphoma invasion.
3. Have received any investigational treatment or investigational device within 4 weeksprior to the first dose of study treatment.
4. Enrolled in another clinical study at the same time, unless it is an observational (non-interventional) clinical study or in follow-up period for interventional studies.
5. The last radiotherapy or last anti-tumor therapy (chemotherapy, tumor embolization,etc.) has been given within 4 weeks prior to the first dose of study treatment.
6. Prior exposure to any anti-PD-1, anti-PD-L1, anti-CTLA-4 antibody, or any otherantibody or drug target for T cell co-stimulatory or checkpoint pathways, such as ICOSor agonists (e.g., CD40, CD137, GITR and OX40, etc.).
7. Subjects with other malignancy within 5 years prior to the first dose of studytreatment, except for locally curable cancers that have been apparently cured, such asbasal or skin squamous cell carcinoma, superficial bladder cancer, cervix or breastcarcinoma in situ.
8. Active, known or suspected autoimmune disease, or medical history of autoimmunedisease in the past 2 years, with the exceptions of vitiligo, alopecia, graves'disease, psoriasis or eczema not requiring systemic treatment within the last 2 years,asymptomatic but only steady doses of hormone replacement therapy are required forhypothyroidism (caused by autoimmune thyroiditis) or type I diabetes requiring only asteady dose of insulin replacement therapy, or that the primary disease does notrelapse without external triggering factors
9. Systemic glucocorticoids or other immunosuppressive drugs used within 7 days prior tothe first dose of study treatment. It is allowed to use nasal spray, inhaled, or othertopical application of glucocorticoids, and a physiological dose of systemicglucocorticoids does not exceed 10 mg/ day or the equivalent. Glucocorticoids are alsoallowed to temporary use for the treatment of dyspnea symptoms of chronic obstructivepulmonary disease (COPD), or as a prophylactic agent for hypersensitivity reactions.
10. Known active human immunodeficiency virus (HIV) positive.
11. Known history of primary immunodeficiency.
12. Known active tuberculosis.
13. Prior solid organ transplantation, allogeneic hematopoietic stem cell transplantation (HSCT).
14. ASCT within 90 days prior to the first dose of study treatment.
15. History of gastrointestinal perforation and/ or fistula (patients can be enrolled ifthe gastrointestinal perforation or fistula has been surgically removed), ileus (including incomplete ileus requiring parenteral nutrition), extensive bowel resection (partial colectomy or extensive small bowel resection with chronic diarrhea), Crohn'sdisease, ulcerative colitis or chronic diarrhea within 6 months prior to the firstdose of study treatment.
16. Known history of or active interstitial lung disease (ILD) or ILD needs to usecorticosteroids.
17. Patients with untreated chronic hepatitis B virus (HBV) infection or chronic HBVcarriers with HBV DNA exceeding 500 IU/ mL, or hepatitis C virus (HCV) infection.Patients with non-active HBsAg carriers, treated and stable (HBV DNA <500 IU/ mL), andcured HCV infection can be enrolled. Patients with HCV seropositivity are eligibleonly if the HCV RNA test negative.
18. Major surgery (craniotomy, thoracotomy, or laparotomy) performed within 30 days priorto the first dose of study treatment, or not fully recovered from previous surgery.Local procedures (such as systemic placement of ports, prostate biopsy) are allowed,provided that which are completed at least 24 hours prior to the first dose of studytreatment.
19. Subjects with uncontrolled pleural effusion or ascites.
20. Active infection requiring systemic treatment.
21. Uncontrolled concurrent conditions, including but not limited to persistent or activeinfection, symptomatic congestive heart failure (NYHA grade 3 or 4), uncontrolledhypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100mmHg), unstable angina, arrhythmia, or other mental illness/social conditions maylimit the subject's compliance with the study requirements or impair the ability ofthe subject to provide written informed consent.
22. Known history of arterial or venous thrombosis events within 6 months prior to thefirst dose of study treatment, including myocardial infarction, unstable angina, andcerebrovascular accident or transient ischemic attack, pulmonary embolism, deep veinthrombosis, or any other severe thromboembolism. Except for infusion port orcatheter-derived thrombosis, or superficial venous thrombosis, or thrombosis that keepstable after conventional anticoagulant therapy.
23. Unresolved toxicities from prior anti-tumor treatment, defined as toxicity that hasnot recovered to NCI CTCAE V5.0 Grade 0 or 1, or to levels specified in inclusion/exclusion criteria, except for alopecia. Subjects with irreversible toxicity that willnot worsen after administration of study drugs as evaluated by investigator (e.g.,hearing loss) may be eligible after discussion with Sponsor.
24. Have received live or attenuated vaccine(s) within 30 days prior to the first dose ofstudy treatment, or plan to receive live or attenuated vaccine(s) during the study.
25. Known allergy to any components or any ingredients of penpulimab and chemotherapyagents selected by investigator.
26. Pregnant or lactating women.
27. Subjects with NCI CTCAE v5.0 Grade ≥2 peripheral neuropathy.
28. Any conditions that evaluated by investigator may affect subjects' safety, or mayinterfere with the evaluation of study drug, or may confound the interpretation ofstudy results.
29. Uncontrolled metabolic disorders, local or systemic manifestations either due toconcomitant disease or the primary tumor, with high risk and/or uncertainty insurvival evaluation, such as tumor leukemoid reaction (white blood cell count > 20×109/L), cachexia (known weight loss of more than 10% in the 3 months beforescreening), etc.