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

• ClinicalTrials.gov Identifier: NCT03209973
• Recruitment Status: Active, not recruiting
• First Posted: July 6, 2017
• Results First Posted: October 12, 2020
• Last Update Posted: October 12, 2020
• Sponsor: BeiGene
• Information provided by (Responsible Party): BeiGene

Study Description

Brief Summary:

The primary objective of this study is 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

Condition or disease	Intervention/treatment	Phase
Classical Hodgkin Lymphoma	Drug: Tislelizumab	Phase 2

Detailed Description:

This is an open-label, single-arm, multi-center and multi-national Phase 2 study. Approximately 68 with confirmed cHL would be enrolled. Response will 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 will occur 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 occurs first. PET/CT should be performed at PD suspected clinically or by CT, and CR suspected clinically or by CT. Total body magnetic resonance imaging (MRI) is allowed if CT with contrast is contraindicated. Positron emission tomography (PET)/CT may be used in lieu of a CT with contrast only if the CT of the PET/CT has been performed with diagnostic quality and contrast is administered. 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 are 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 will be discontinued permanently. participants will be 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. The Safety Population includes all participants who received any dose of tislelizumab.

This will be the population for the safety analyses. The modified Safety Population includes all participants in the Safety Population who had centrally confirmed cHL. This will be the population for the efficacy analyses.

The Per-protocol Population (PP) includes participants who received any dose of tislelizumab and had no major protocol deviations. Criteria for exclusion from the PP will be determined and documented before the database lock for the primary analysis. This will be the secondary analysis population for efficacy analysis. The pharmacokinetics (PK) population includes all participants who whom valid tislelizumab PK parameters can be estimated.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 70 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Single Arm, Multicenter, Phase 2 Study of BGB-A317 as Monotherapy in Relapsed or Refractory Classical Hodgkin Lymphoma
• Actual Study Start Date: April 21, 2017
• Actual Primary Completion Date: July 23, 2018
• Estimated Study Completion Date: December 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tislelizumab; Tislelizumab 200 mg administered intravenously (IV) every-3-weeks (Q3W)	Drug: Tislelizumab; Administered as specified in the treatment arm; Other Name: BGB-A317

Outcome Measures

Primary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: Up to 1 year ]
   ORR is defined as the proportion of participants who achieve a best response of Complete Response (CR) or Partial Response (PR), as assessed by IRC per the Lugano Classification

Secondary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: Up to 2years ]
   From the first dose of BGB-A317 to the date of progressive disease (PD) or death, whichever occurs first
2. Duration of Response (DOR) [ Time Frame: Up to 2 years ]
   From the date that response criteria are first met to the date that PD is objectively documented or death, whichever occurs first
3. Rate of Complete Response Rate (CRR) [ Time Frame: Up to 2 years ]
4. Time to Response (TTR) [ Time Frame: Up to 2years ]
   From the date of the first dose of BGB-A317 to the time the response criteria are first met

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 CR/complete metabolic response [CMR] or partial response [PR] to most recent therapy) cHL and meets either one of the following criteria:

   1. Has failed to achieve a response or progressed after autologous hematopoietic stem cell transplant (auto-SCT).
   2. Has received at least two prior systemic chemotherapy regimens for cHL and is not an auto-SCT candidate due to: chemo-resistant disease (unable to achieve CR or partial response [PR] to salvage chemotherapy), advanced age (≥ 65 years of age), failure to collect stem cells or unable to perform stem cell collection as assessed by the Investigator, or any significant co-existing medical conditions.
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. Availability of archival or fresh tumor tissue sample from an evaluable core or excisional biopsy (10-15 unstained formalin fixed paraffin embedded [FFPE] slides). Otherwise, participants may be permitted to enroll on a case-by-case basis after discussion with the Sponsor's medical monitors, provided cHL diagnosis can be confirmed by a central laboratory.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
6. Life expectancy ≥ 12 weeks.

7. 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).
8. 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.
9. Participants must have no evidence of dyspnea at rest and a pulse oximetry of > 92% while breathing room air.
10. 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.
11. 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. Known human immunodeficiency virus (HIV), or active hepatitis B (HBV) or hepatitis C (HCV) infection (detected positive by polymerase chain reaction [PCR]) Inclusion Exclusion HIV Antibody (-) Antibody (+) HBV HBsAg (-) and HBcAb (-) HBsAg (+) HBsAg (-) AND HBcAb (+) HBV DNA < 1000 IU/ml. After enrollment, monthly monitoring for HBV DNA or anti-viral therapy should be given to prevent HBV reactivation HBsAg (-) AND HBcAb (+) HBV DNA ≥ 1000 IU/ml HCV HCV Ab (-) HCV Ab (+) HCV RNA ≥ 1 (log10IU/ml) HCV Ab (+) HCV RNA<1 (log10IU/ml) HBsAg: Hepatitis B surface antigen; HBcAb: Hepatitis B core antibody; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HCV Ab: Hepatitis C antibody; HIV: human immunodeficiency virus; DNA: deoxyribonucleic acid; RNA: ribonucleic acid
15. Autologous hematopoietic stem cell transplant within 100 days of first dose of tislelizumab.
16. 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/Exclusion criteria may apply.

Contacts and Locations

Locations

China, Beijing

Beijing Cancer Hospital

Beijing, Beijing, China, 100142

301 Hospital

Beijing, Beijing, China, 100853

China, Henan

Henan Cancer Province

Zhengzhou, Henan, China

China, Hubei

Tongji Hospital, Tongji Medical College Huazhong University of Science and Technology

Wuhan, Hubei, China

China, Jiangsu

Jiangsu Province Hospital

Nanjing, Jiangsu, China

China, Jilin

The First Affilliated Hospital of Jilin University

Changchun, Jilin, China

China, Shanghai

Fudan University Shanghai Cancer Center

Shanghai, Shanghai, China

China, Sichuan

West China Hospital of Sichuan University

Chengdu, Sichuan, China

China, Tianjin

Institute of Hematology and Blood disease hospital,Chinese Academy of Medical Science

Tianjin, Tianjin, China, 300020

Tianjin Medical Universtity Cancer Institute and Hospital

Tianjin, Tianjin, China, 300060

China, Zhejiang

Zhejiang Cancer Hospital

Hangzhou, Zhejiang, China

Sponsors and Collaborators

BeiGene

Investigators

• Principal Investigator: Jun Zhu, PhD; Beijing Cancer Hospital

  Study Documents (Full-Text)

Documents provided by BeiGene:

Statistical Analysis Plan  [PDF] July 17, 2018

Study Protocol  [PDF] July 15, 2019

More Information

Publications of Results:

Song Y, Gao Q, Zhang H, Fan L, Zhou J, Zou D, Li W, Yang H, Liu T, Wang Q, Lv F, Guo H, Yang L, Elstrom R, Huang J, Novotny W, Wei V, Zhu J. Treatment of relapsed or refractory classical Hodgkin lymphoma with the anti-PD-1, tislelizumab: results of a phase 2, single-arm, multicenter study. Leukemia. 2020 Feb;34(2):533-542. doi: 10.1038/s41375-019-0545-2. Epub 2019 Sep 13.

• Responsible Party: BeiGene
• ClinicalTrials.gov Identifier: NCT03209973
• Other Study ID Numbers: BGB-A317-203; CTR20170119 ( Registry Identifier: Center for drug evaluation, CFDA )
• First Posted: July 6, 2017
• Results First Posted: October 12, 2020
• Last Update Posted: October 12, 2020
• Last Verified: September 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Lymphoma; Hodgkin Disease; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases