Efficacy and Safety Evaluation of IBI308 in Patients With Extranodal NK/T Cell Lymphoma Patients

Efficacy and Safety Evaluation of IBI308 in Patients With Relapsed/Refractory Extranodal NK/T Cell Lymphoma, Nasal Type: a Multicenter, Single Arm, Phase 2 Study (ORIENT-4)

This is phase II study. Efficacy and safety evaluation of IBI308 in patients with relapsed/refractory extranodal NK/T cell lymphoma, nasal type: a multicenter, single arm.

Extranodal NK/T cell lymphoma, nasal type(ENKTL) accounts for about 6% of all lymphomas in china. Epstein Barr virus (EBV) infection is found in all cases of ENKTL and maybe plays an important pathogenetic role.

Conventional anthrocycline-based regimens are not preferred to be used in ENKTL because of high p-glycoprotein expression. ORR of L-asparaginase based regimens is about 80% and no salvage regimens are recommended in ENKTL so far after failure of L-asparaginase based regimen.

Recently, a phase II clinical trial result demonstrated high ORR of anti-PD-1 antibody treatment in ENKTL.IBI308, a humanized monoclonal antibody (mAb) directly against PD-1, is investigated in this phase II Chinese ENKTL clinical trial.

Additionally the correlation between PD-L1 expression and the response to IBI308 treatment in Chinese ENKTL subjects will also be assessed.

Inclusion Criteria:

Inclusion Criteria

1. Histologically confirmed ENKL-NT.
2. Relapsed or refractory ENKTL-NT. Being relapsed is defined as presence of new lesions at the primary location or other sites after achieving CR; being refractory is defined as any one of the followings: PD after 2 treatment cycles, PR not achieved after 4 treatment cycles, or CR not achieved after 6 treatment cycles. Patients who do not response or patients with relapsed disease or PD after autologous stem cell transplantation can enroll.
3. Must have been treated with asparaginase-based regimen (radiotherapy must be performed for stage I/II disease).
4. Long axis of a lesion > 15 mm or 18FDG-PET uptake by lesion.
5. Eastern Cooperative Oncology Group Performance Status (ECOG PS) scores of 0-2.
6. Signed the inform consent form (ICF) and able to comply with the scheduled follow-up visits and related procedures required in the protocol.
7. Between the ages of ≥18 to ≤70 years.
8. Life expectancy≥ 12 weeks.
9. Patients (female patients at childbearing age or male patients whose partners are at childbearing age) must take effective contraceptive measures during the entire course of the trial and within 90 days since the last dose of treatment.
10. Adequate organs and bone marrow functions, as defined below: Count of whole blood cells: absolute neutrophil count (ANC) ≥1.0×10^9/L, platelets (PLTs) count ≥ 50×10^9/L, hemoglobin (HGB) ≥ 8.0 g/L; granulocyte colony-stimulating factor, PLT, or red blood cell (RBC) transfusion has not been performed within 7 days prior to the test. Hepatic function: total bilirubin (TBIL) ≤ 1.5×upper limit of normal (ULN), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. Renal function:serum creatinine (Cr) ≤ 1.5 × ULN. Thyroid function: normal thyroid stimulating hormone (TSH) at baseline, or abnormal TSH at baseline with normal thiiodothronine (T3)/thiiodothronine (T4) and no symptoms.

Exclusion Criteria:

1. Patients with aggressive NK cell leukemia.

2. Patients with primary or secondary central nervous system (CNS) lymphoma.

3. Patients with severe hemophagocytic syndrome at initial diagnosis of ENKTL-NT.

4. Patients with pulmonary great vessel invasion.

5. Previous exposure to any anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies.

6. Enrolled in another interventional clinical study, unless only involved in an observational study (non-interventional) or in the follow-up phase of an interventional study.

7. Received any investigational drug within 4 weeks prior to the first dose of study treatment.

8. The last dose of radiation or anti-tumor therapy (chemotherapy, targeted therapy or tumor embolization) was within 3 weeks prior to receiving the first dose of study treatment; the last dose of nitrosourea or mitomycin C treatment was within 6 weeks prior to receiving the first dose of study treatment.

9. Received immunosuppressants within 4 weeks prior to the first dose of study treatment, excluding local glucocorticoids administered by nasal, inhaled, or other topical routes, or systemic glucocorticoids of physiological doses (no more than 10 mg/day of prednisone or equivalents).

10. Received any live attenuated vaccine within 4 weeks prior to the first dose of study treatment, or is scheduled to receive live attenuated vaccine during the study period.

11. Received major surgery (craniotomy, thoracotomy, or laparotomy) within 4 weeks prior to the first dose of study treatment, or has unhealed wounds, ulcers, or fractures.

12. Active, known, or suspected autoimmune disease (see Appendix 6) or previous medical history of these diseases within 2 years (patients with vitiligo, psoriasis, alopecia, or Graves' disease not requiring systemic treatment, hypothyroidism only requiring thyroid replacement, or type I diabetes only requiring insulin can enroll).

13. Known history of primary immunodeficiency diseases.

14. Known active pulmonary tuberculosis.

15. Known history of allogeneic organ transplantation or allogeneic hem atopoietic stem cell transplantation.

16. Known to be allergic to any ingredients of monoclonal antibodies.

17. Uncontrolled concurrent diseases including but not limited to:

    HIV-infected patients (positive anti-HIV antibody). Active or poorly controlled severe infections. Symptomatic congestive heart failure (NYHA Class III-IV) or symptomatic or poorly controlled arrhythmia.

    Uncontrolled hypertension (systolic blood pressure ≥ 160 mmHg or diastolic blood pressure ≥ 100 mmHg) despite of standard treatment.

    Any arterial thromboembolic events occurred within 6 months prior to enrollment, including myocardial infarction, unstable angina, cerebrovascular accident, or transient cerebral ischemic attack.

    Life-threatening hemorrhagic events or grade 3-4 gastrointestinal/variceal hemorrhage requiring blood transfusion, endoscopy, or surgical treatment within 3 months prior to enrollment.

    History of deep venous thrombosis, pulmonary embolism, or other serious thromboembolic events within 3 months prior to enrollment (implantable port or catheter-related thrombosis, or superficial venous thrombosis are not considered as serious thromboembolisms).

    Uncontrolled metabolic disorders, non-malignant organ or systemic diseases, or cancer-related secondary diseases that may lead to higher medical risks and/or survival evaluation uncertainties.

    Hepatic encephalopathy, hepatorenal syndrome, or cirrhosis with Child-Pugh grade B or C.

    Bowel obstruction or history of the following diseases: inflammatory bowel disease or extensive bowel resection (partial colectomy or extensive small bowel resection accompanied with chronic diarrhea), Crohn's disease, and ulcerative colitis.

    Acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that may lead to the following consequences: increased investigational drug-related risks, or interference with interpreting trial results, and considered ineligible for participating in the trial by the investigators.

18. Known acute or chronic active hepatitis B (chronic HBV carriers or inactive HBsAg-positive patients can enroll if the HBV DNA < 1×10^3 copies/mL), or acute or chronic active hepatitis C (patients with negative HCV antibody can enroll; HCV RNA test is required for patients with positive HCV antibody, those test negative can enroll).

19. History of GI perforation and/or fistula without radical treatment within 6 months prior to the enrollment.

20. Known interstitial lung disease.

21. Clinically uncontrollable third spacing, such as pleural effusion and ascites that cannot be controlled by drainage or other methods prior to enrollment.

22. History of other primary malignant tumors, excluding:

    History of radical treatment for malignant tumors with no evidence of tumor recurrence for more than 5 years prior to enrollment and with a very low risk of recurrence.

    Adequately treated nonmelanoma skin cancer or lentigo maligna with no signs of disease recurrence.

    Adequately treated carcinoma in situ with no signs of disease recurrence.

23. Pregnant or breastfeeding female patients.