ORIENT-4: Efficacy and Safety Evaluation of IBI308 in Patients With Extranodal NK/T Cell Lymphoma Patients

Sponsor
Innovent Biologics (Suzhou) Co. Ltd. (Industry)
Overall Status
Completed
CT.gov ID
NCT03228836
Collaborator
(none)
28
1
1
30.2
0.9

Study Details

Study Description

Brief Summary

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.

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
28 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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)
Actual Study Start Date :
Aug 23, 2017
Actual Primary Completion Date :
Feb 28, 2020
Actual Study Completion Date :
Feb 28, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: Sintilimab (IBI308)

Drug: Sintilimab
Sintilimab (IBI308) 200mg IV Q3W

Outcome Measures

Primary Outcome Measures

  1. Objective Response Rate (ORR) Before First PD [Up to ~30 months (through database cut-off date of 28-February-2020)]

    The tumor assessment is according to Lugano 2014 Criteria and then International Working Group (IWG) 2007 Criteria after 24 weeks. Objective response is defined as best overall response (CR or PR) across all assessment time points during the period from enrollment to termination of trial treatment (per Lugano 2014 criteria during intial 24 weeks, per IWG 2007 criteria after 24 weeks). The primary efficacy endpoint is ORR evaluated using the 2014 Lugano Criteria before first progression disease (PD).

Secondary Outcome Measures

  1. Progression Free Survival (PFS) [Up to ~30 months (through database cut-off date of 28-February-2020)]

    PFS was defined as the time from the first dose to the first documented progressive disease (PD) per Lugano 2014 or death due to any cause, whichever occurred first. Participates who neither progress nor die were censored at the date of their last tumor imaging evaluation. Participates who did not have any tumor imaging evaluation after baseline were censored on the date of enrollment.

  2. Duration of Response (DOR) [Up to ~30 months (through database cut-off date of 28-February-2020)]

    DOR was defined as the time from first date of response to first PD per Lugano 2014 or death. Subjects who neither progress nor die were censored at the date of their last tumor imaging evaluation.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years to 70 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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) ≥1.0×109/L, platelets (PLTs) count ≥ 50×109/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.

  1. 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).

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

  3. Known interstitial lung disease.

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

  5. 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.

  1. Pregnant or breastfeeding female patients.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Jiangsu Provincial Hospital Nanjing Jiangsu China

Sponsors and Collaborators

  • Innovent Biologics (Suzhou) Co. Ltd.

Investigators

  • Principal Investigator: Jian-yong Li, Master, The First Affiliated Hospital with Nanjing Medical University

Study Documents (Full-Text)

More Information

Publications

None provided.
Responsible Party:
Innovent Biologics (Suzhou) Co. Ltd.
ClinicalTrials.gov Identifier:
NCT03228836
Other Study ID Numbers:
  • CIBI308D201
First Posted:
Jul 25, 2017
Last Update Posted:
Jan 12, 2021
Last Verified:
Dec 1, 2020
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail
Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Participants with relapsed or refractory ENKTL-NT were enrolled to receive sintilimab (IBI308) 200mg intravenous infusion (IV) every 3 weeks (Q3W).
Period Title: Overall Study
STARTED 28
Treated 28
COMPLETED 11
NOT COMPLETED 17

Baseline Characteristics

Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Participants with relapsed or refractory ENKTL-NT were enrolled to receive sintilimab (IBI308) 200mg IV Q3W.
Overall Participants 28
Age (Count of Participants)
<=18 years
0
0%
Between 18 and 65 years
27
96.4%
>=65 years
1
3.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
40.32
(12.67)
Sex: Female, Male (Count of Participants)
Female
11
39.3%
Male
17
60.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
Asian
28
100%
Native Hawaiian or Other Pacific Islander
0
0%
Black or African American
0
0%
White
0
0%
More than one race
0
0%
Unknown or Not Reported
0
0%
Region of Enrollment (Count of Participants)
China
28
100%

Outcome Measures

1. Primary Outcome
Title Objective Response Rate (ORR) Before First PD
Description The tumor assessment is according to Lugano 2014 Criteria and then International Working Group (IWG) 2007 Criteria after 24 weeks. Objective response is defined as best overall response (CR or PR) across all assessment time points during the period from enrollment to termination of trial treatment (per Lugano 2014 criteria during intial 24 weeks, per IWG 2007 criteria after 24 weeks). The primary efficacy endpoint is ORR evaluated using the 2014 Lugano Criteria before first progression disease (PD).
Time Frame Up to ~30 months (through database cut-off date of 28-February-2020)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Participants with relapsed or refractory ENKTL-NT were enrolled to receive sintilimab (IBI308) 200mg IV Q3W.
Measure Participants 28
Number (95% Confidence Interval) [Percentage of Participants]
60.7
216.8%
2. Secondary Outcome
Title Progression Free Survival (PFS)
Description PFS was defined as the time from the first dose to the first documented progressive disease (PD) per Lugano 2014 or death due to any cause, whichever occurred first. Participates who neither progress nor die were censored at the date of their last tumor imaging evaluation. Participates who did not have any tumor imaging evaluation after baseline were censored on the date of enrollment.
Time Frame Up to ~30 months (through database cut-off date of 28-February-2020)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Participants with relapsed or refractory ENKTL-NT were enrolled to receive sintilimab (IBI308) 200mg IV Q3W.
Measure Participants 28
Median (95% Confidence Interval) [Days]
104.0
3. Secondary Outcome
Title Duration of Response (DOR)
Description DOR was defined as the time from first date of response to first PD per Lugano 2014 or death. Subjects who neither progress nor die were censored at the date of their last tumor imaging evaluation.
Time Frame Up to ~30 months (through database cut-off date of 28-February-2020)

Outcome Measure Data

Analysis Population Description
[Not Specified]
Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Participants with relapsed or refractory ENKTL-NT were enrolled to receive sintilimab (IBI308) 200mg IV Q3W.
Measure Participants 28
Median (95% Confidence Interval) [Days]
126.0

Adverse Events

Time Frame Up to ~30 months (through database cut-off date of 28-February-2020)
Adverse Event Reporting Description Safety Population: all the participants who received at least one dose of the investigational drug.
Arm/Group Title Sintilimab (IBI308)
Arm/Group Description Sintilimab (IBI308) 200mg IV Q3W
All Cause Mortality
Sintilimab (IBI308)
Affected / at Risk (%) # Events
Total 7/28 (25%)
Serious Adverse Events
Sintilimab (IBI308)
Affected / at Risk (%) # Events
Total 7/28 (25%)
Gastrointestinal disorders
Gastrointestinal haemorrhage 1/28 (3.6%)
Pancreatitis acute 1/28 (3.6%)
General disorders
Disease progression 1/28 (3.6%)
Pyrexia 1/28 (3.6%)
Immune system disorders
Anaphylactic shock 1/28 (3.6%)
Infections and infestations
Localised infection 1/28 (3.6%)
Pneumonia 1/28 (3.6%)
Metabolism and nutrition disorders
Diabetic ketoacidosis 1/28 (3.6%)
Musculoskeletal and connective tissue disorders
Intervertebral disc disorder 1/28 (3.6%)
Other (Not Including Serious) Adverse Events
Sintilimab (IBI308)
Affected / at Risk (%) # Events
Total 28/28 (100%)
Blood and lymphatic system disorders
Anaemia 3/28 (10.7%)
Lymphadenitis 2/28 (7.1%)
Cardiac disorders
Myocardial ischaemia 2/28 (7.1%)
Ventricular extrasystoles 3/28 (10.7%)
Endocrine disorders
Autoimmune thyroiditis 2/28 (7.1%)
Hypothyroidism 9/28 (32.1%)
Gastrointestinal disorders
Constipation 2/28 (7.1%)
Gastritis 2/28 (7.1%)
Mouth ulceration 2/28 (7.1%)
General disorders
Face oedema 2/28 (7.1%)
Pain 2/28 (7.1%)
Pyrexia 13/28 (46.4%)
Infections and infestations
Enterovirus infection 2/28 (7.1%)
Gingivitis 2/28 (7.1%)
Pharyngitis 2/28 (7.1%)
Pneumonia 2/28 (7.1%)
Respiratory tract infection 2/28 (7.1%)
Sinusitis 5/28 (17.9%)
Upper respiratory tract infection 7/28 (25%)
Urinary tract infection 5/28 (17.9%)
Investigations
Alanine aminotransferase increased 3/28 (10.7%)
Aspartate aminotransferase increased 5/28 (17.9%)
Blood albumin decreased 5/28 (17.9%)
Blood alkaline phosphatase increased 6/28 (21.4%)
Blood bilirubin increased 5/28 (17.9%)
Blood glucose increased 7/28 (25%)
Blood lactate dehydrogenase increased 6/28 (21.4%)
Blood thyroid stimulating hormone increased 8/28 (28.6%)
C-reactive protein increased 2/28 (7.1%)
Electrocardiogram abnormal 2/28 (7.1%)
Gamma-glutamyltransferase increased 2/28 (7.1%)
Globulins decreased 2/28 (7.1%)
Globulins increased 5/28 (17.9%)
Haemoglobin decreased 9/28 (32.1%)
Haemoglobin urine present 2/28 (7.1%)
Lipase increased 5/28 (17.9%)
Lymphocyte count decreased 17/28 (60.7%)
Neutrophil count decreased 3/28 (10.7%)
Platelet count decreased 6/28 (21.4%)
Protein total decreased 2/28 (7.1%)
Protein urine present 4/28 (14.3%)
Red blood cells urine positive 2/28 (7.1%)
Thyroid function test abnormal 2/28 (7.1%)
Thyroxine free decreased 5/28 (17.9%)
Thyroxine increased 4/28 (14.3%)
Tri-iodothyronine free decreased 2/28 (7.1%)
Urine ketone body present 2/28 (7.1%)
Weight decreased 2/28 (7.1%)
White blood cell count decreased 14/28 (50%)
Metabolism and nutrition disorders
Diabetes mellitus 2/28 (7.1%)
Electrolyte imbalance 2/28 (7.1%)
Hypokalaemia 2/28 (7.1%)
Hypoproteinaemia 2/28 (7.1%)
Musculoskeletal and connective tissue disorders
Myalgia 2/28 (7.1%)
Nervous system disorders
Headache 2/28 (7.1%)
Renal and urinary disorders
Nephrolithiasis 2/28 (7.1%)
Respiratory, thoracic and mediastinal disorders
Cough 2/28 (7.1%)
Nasal obstruction 2/28 (7.1%)
Oropharyngeal pain 2/28 (7.1%)
Skin and subcutaneous tissue disorders
Pruritus 2/28 (7.1%)
Rash 4/28 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

Name/Title Yi Bo
Organization Innovent Biologics (Suzhou) Co., Ltd. (seal)
Phone +8613382419112
Email jessica.yi@innoventbio.com
Responsible Party:
Innovent Biologics (Suzhou) Co. Ltd.
ClinicalTrials.gov Identifier:
NCT03228836
Other Study ID Numbers:
  • CIBI308D201
First Posted:
Jul 25, 2017
Last Update Posted:
Jan 12, 2021
Last Verified:
Dec 1, 2020