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.
