A Study of Tislelizumab as Monotherapy in Relapsed or Refractory Classical Hodgkin Lymphoma

A Single Arm, Multicenter, Phase 2 Study of BGB-A317 as Monotherapy in Relapsed or Refractory Classical Hodgkin Lymphoma

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03209973

Enrollment

Registered

2017-07-06

Start date

2017-04-21

Completion date

2020-11-02

Last updated

2025-02-05

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Classical Hodgkin Lymphoma

Brief summary

The primary objective of this study was to evaluate the efficacy of tislelizumab assessed by Independent Review Committee (IRC) in participants with relapsed or refractory classical Hodgkin lymphoma (cHL), as measured by Overall Response Rate (ORR) per the Lugano Classification

Detailed description

This was an open-label, single-arm, multi-center Phase 2 study. Response was to be assessed by PET(positron emission tomography) and computed tomography (CT) scan per the Lugano Classification. CT scan with contrast and Positron emission tomography (PET)/CT was used as required by protocol, until progressive disease (PD), new anti-cancer therapy, withdrawal of consent, death, lost to follow-up, or end of study (EOS), whichever occurred first. Total body magnetic resonance imaging (MRI) was allowed if CT with contrast is contraindicated. During treatment with immune checkpoint inhibitor such as with tislelizumab, pseudo-progression may occur due to immune cell infiltration and other mechanisms as manifested by apparent increase of existing tumor masses or appearance of new tumor lesions. Participants were allowed to continue study treatment if there is suspicion of pseudo-progression, provided they are asymptomatic and have radiographic progression only, until a second consecutive CT scan demonstrates PD at which time study treatment was discontinued permanently. Participants were evaluated for Adverse Events (AEs) (all Grades per National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.03 \[NCI CTCAE v. 4.03\]), serious AEs (SAEs), and any AEs requiring study drug interruption or discontinuation.

Interventions

DRUGTislelizumab

Administered as specified in the treatment arm

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

Key Inclusion Criteria: 1. Histologically confirmed relapsed or refractory cHL (biopsy from diagnosis or at any relapse is acceptable). 2. Participants must have relapsed (disease progression after most recent therapy) or refractory (failure to achieve complete Response (CR) /complete metabolic response \[CMR\] or partial response (PR) to most recent therapy) cHL and and failed to achieve a response or progressed after auto-SCT or meet the criteria of ineligible for auto-SCT. 3. Participants must have measurable disease defined as ≥ 1 nodal lesion that is \> 1.5 cm in the longest diameter, or ≥ 1 extra-nodal lesion (e.g. hepatic nodules) that is \> 1 cm in the longest diameter. 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 5. Life expectancy ≥ 12 weeks. 6. participants must have adequate organ functions as indicated by the following laboratory values: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, independent of growth factor support within 7 days of first dose. 2. Platelet ≥ 75 x 109/L, independent of growth factor support or transfusion within 7 days of first dose. 3. Hemoglobin (Hgb) ≥ 8 g/dL or ≥ 5 mmol/L. 4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN). 5. Aspartate aminotransferase (AST)/glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT)/glutamic-pyruvic transaminase (SGPT) ≤ 2.5 x upper limit of normal (ULN), or ≤ 5X ULN if liver metastases are present. 6. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin level \< 4 x ULN for participants with Gilbert's syndrome). 7. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless participant is receiving anticoagulant therapy and coagulation parameters (prothrombin time \[PT/INR\] and aPTT) are within intended therapeutic range of intended use of the anticoagulant at time of Screening. Participants with factor inhibitors prolonging PT or INR may be included after discussion with the medical monitor. 8. Participants must have no evidence of dyspnea at rest and a pulse oximetry of \> 92% while breathing room air. 9. Participants must have forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) \> 60% by pulmonary function test (PFT); carbon monoxide diffusion capacity (DLCO), FEV1 and FVC all \> 50 % predicted value; all PFTs must be obtained within 4 weeks prior to the first dose of tislelizumab. 10. Prior chemotherapy, radiotherapy, immunotherapy or investigational therapy (including Chinese herbal medicine and Chinese patent medicine) used to control cancer including locoregional treatment must have been completed ≥ 4 weeks before the first dose of tislelizumab, and all treatment-related adverse events are stable and have either returned to baseline or Grade 0/1 (except for alopecia and hemoglobin. For hemoglobin, please follow inclusion criteria #8c \[hemoglobin\]). Key

Exclusion criteria

1. Nodular lymphocyte-predominant Hodgkin lymphoma or gray zone lymphoma. 2. Prior allogeneic hematopoietic stem cell transplant. 3. History of severe hypersensitivity reaction to monoclonal antibodies. 4. New York Heart Association (NYHA) class III or IV heart failure, unstable angina, severe uncontrolled ventricular arrhythmia, electrocardiographic evidence of acute ischemia, or myocardial infarction within 6 months of first day of Screening. 5. Prior malignancy within the past 3 years except for curatively treated basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast. 6. Prior therapy targeting PD-1 or PD-L1. 7. Participants with active autoimmune disease or history of autoimmune disease with high risk of recurrence including but not limited to history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barrè syndrome, myasthenia gravis, systemic lupus erythematosus (SLE), connective tissue disease, scleroderma, inflammatory bowel disease including Crohn's disease and ulcerative colitis, autoimmune hepatitis, toxic epidermal necrolysis (TEN), or Stevens-Johnson syndrome. Note: Participants is permitted to enroll if he/she has vitiligo, eczema, type I diabetes mellitus, endocrine deficiencies including thyroiditis managed with replacement hormone and/or physiologic corticosteroid. Participants with rheumatoid arthritis and/or other arthropathies, Sjögren's syndrome or psoriasis controlled with topical medication, and participants with positive serology such as positive antinuclear antibody (ANA) or anti-thyroid antibody should be evaluated for presence of target organ involvement and potential need for systemic treatment but should otherwise be eligible. 8. Conditions requiring systemic treatment with either corticosteroids (\> 10 mg daily Prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of tislelizumab. Note: Adrenal replacement doses of ≤ 10 mg daily Prednisone are permitted in the absence of active autoimmune disease. Topical, ocular, intra-articular, intra-nasal and inhalational corticosteroid (with minimal systemic absorption), a brief course of corticosteroid for prophylaxis (e.g. contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-type hypersensitivity reaction caused by contact allergen) are allowed. 9. Has history of interstitial lung disease or non-infectious pneumonitis or has evidence of interstitial lung disease or non infectious pneumonitis currently. 10. QT Interval Corrected by the Fridericia Correction Formula (QTcF)interval \> 480 msec, unless secondary to bundle branch block. 11. Serious acute or chronic infection requiring systemic therapy. 12. Known central nervous system (CNS) lymphoma. 13. Underlying medical conditions that, in the Investigator's opinion, will render the administration of study drug hazardous or obscure the interpretation of toxicity or adverse events. 14. Autologous hematopoietic stem cell transplant within 100 days of first dose of tislelizumab. 15. Use of any live vaccine against infectious diseases (e.g. influenza, varicella, etc.) within 4 weeks (28 days) of the first dose of tislelizumab, and any intended use within 60 days after the last dose of tislelizumab. NOTE: Other protocol defined Inclusion/

Design outcomes

Primary

Measure	Time frame	Description
Overall Response Rate (ORR)	From the date of first dose Up to approximately 3 year and 7 months	ORR is defined as the proportion of participants who achieve a best response of Complete Response (CR) or Partial Response (PR), as assessed by Independent Review committee (IRC) per the Lugano Classification

Secondary

Measure	Time frame	Description
Duration of Response (DOR)	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	DOR is defined as the time from the date that response criteria are first met to the date that PD is objectively documented or death, whichever occurs first, assessed by IRC per the Lugano Classification
Rate of Complete Response (CRR)	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	CRR is defined as the percentage of participants who achieve a best response of CR, assessed by IRC per the Lugano Classification
Time to Response (TTR)	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	TTR is defined as the time from the date of the first dose of tislelizumab to the time the response criteria are first met, assessed by IRC per the Lugano Classification
Progression-free Survival (PFS)	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	PFS is defined as the time from the first dose of tislelizumab to the date of Progressive Disease (PD) or death, whichever occurs first, assessed by IRC per the Lugano Classification
Number of Participants With Significant Changes in Clinical Laboratory Results	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	Clinical laboratory (e.g. hematology, serum chemistry, urinalysis) values were evaluated for each laboratory parameter and participants with clinically significant changes are summarized.
Number of Participants With Significant Changes in Electrocardiograms	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	—
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)	From the date of first dose until end of study (Up to approximately 3 years and 7 months)	An adverse event (AE) is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study drug, whether considered related to study drug or not. An SAE is any untoward medical occurrence that, at any dose: * Results in death. * Is life-threatening. * Requires hospitalization or prolongation of existing hospitalization * Results in disability/incapacity * Is a congenital anomaly/birth defect * Is considered a significant medical AE by the investigator based on medical judgement

Countries

China

Participant flow

Recruitment details

70 participants were enrolled at 11 sites in China. The first participant dose date was on 21 April 2017. The study was completed on 02 November 2020.

Participants by arm

Arm	Count
Tislelizumab Tislelizumab 200 mg administered IV Q3W until PD, unacceptable toxicity, death, or study withdrawal by the participant.	70
Total	70

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Death	8
Overall Study	Lost to Follow-up	2
Overall Study	Participant Refused to Return to Treatment	2
Overall Study	Participant Withdrew Due to Higher Risk than Benefit of Treatment	1
Overall Study	Sponsor Decision	18
Overall Study	Transferred to Long Term Extension (LTE) study	32
Overall Study	Withdrawal by Subject	7

Baseline characteristics

Characteristic	Tislelizumab
Age, Continuous	36.2 years STANDARD_DEVIATION 12.73
Age, Customized <65	66 Participants
Age, Customized ≥ 65 and < 75 years	4 Participants
Age, Customized ≥ 75	0 Participants
Race/Ethnicity, Customized Chinese	70 Participants
Region of Enrollment China	70 Participants
Sex: Female, Male Female	30 Participants
Sex: Female, Male Male	40 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	8 / 70
other Total, other adverse events	68 / 70
serious Total, serious adverse events	18 / 70

Outcome results

Primary

Overall Response Rate (ORR)

ORR is defined as the proportion of participants who achieve a best response of Complete Response (CR) or Partial Response (PR), as assessed by Independent Review committee (IRC) per the Lugano Classification

Time frame: From the date of first dose Up to approximately 3 year and 7 months

Population: Modified Safety Analysis Set: All participants in the safety analysis set who had confirmed classical Hodgkin lymphoma.

Arm	Measure	Value (NUMBER)
Tislelizumab	Overall Response Rate (ORR)	87.1 Percentage of Participants

p-value: <0.0001Exact Binomial Test

Secondary

Duration of Response (DOR)

DOR is defined as the time from the date that response criteria are first met to the date that PD is objectively documented or death, whichever occurs first, assessed by IRC per the Lugano Classification