A Study of BGB-A317 as Monotherapy in Relapsed or Refractory Classical Hodgkin Lymphoma

Study Description

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Brief Summary:

The study is to evaluate the efficacy of BGB-A317 assessed by Independent Review Committee (IRC) in subjects 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 (BGB-A317)	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 BGB-A317, 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. Subjects 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. Subjects will be evaluated for 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 subjects who received any dose of BGBA317. This will be the population for the safety analyses. The modified Safety Population includes all subjects in the Safety Population who had centrally confirmed cHL. This will be the population for the efficacy analyses.

The Per-protocol Population (PP) includes subjects who received any dose of BGB-A317 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 PK population includes all subjects who whom valid BGB-A317 PK parameters can be estimated.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	70 participants
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 :	June 2019

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Tislelizumab (BGB-A317); Tislelizumab (BGB-A317) 200 mg intravenously (IV) every-3-weeks (Q3W)	Drug: Tislelizumab (BGB-A317); Tislelizumab (BGB-A317) 200 mg intravenously (IV) every-3-weeks (Q3W)

Outcome Measures

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Primary Outcome Measures :

1. Overall Response Rate (ORR) [ Time Frame: Up to 2 years ]
   Overall Response Rate (ORR) defined as the proportion of subjects who achieves a best response of CR or PR, 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 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 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

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

Criteria

Inclusion Criteria:

1. ≥ 18 years of age at time of informed consent.
2. Histologically confirmed relapsed or refractory cHL (biopsy from diagnosis or at any relapse is acceptable).

3. Subject 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.
4. Subject 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.
5. 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, subjects 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.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Life expectancy ≥ 12 weeks.

8. Subject 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 subjects with Gilbert's syndrome).
9. International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless patient 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. Patients with factor inhibitors prolonging PT or INR may be included after discussion with the medical monitor.
10. Subject must have no evidence of dyspnea at rest and a pulse oximetry of > 92% while breathing room air.
11. Subject 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.

12. Female subject is eligible to enter and participate in the study if she is of:

    a. Non-childbearing potential (i.e. physiologically incapable of becoming pregnant) including any female who: i. Has had a hysterectomy. ii. Has had a bilateral oophorectomy (ovariectomy). iii. Has had a bilateral tubal ligation. iv. Is post menopausal (total cessation of menses for ≥ 1 year). b. Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and for at least 120 days after the last dose of tislelizumab, and have a negative urine or serum pregnancy test within 7 days of the first dose of study drug. Adequate contraception, when used consistently and in accordance with both the product label and instructions of the physician, are defined as: i. Vasectomized partner who is sterile prior to the female subject's study entry and is the sole sexual partner for that female.

    ii. Any intrauterine device with a documented failure rate of < 1% per year. iii. Double barrier contraception defined as condom with spermicidal jelly, foam, suppository, or film; OR diaphragm with spermicide; OR male condom and diaphragm.

13. Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for at least 120 days after the last dose of tislelizumab.
14. 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]).
15. Subject has voluntarily agreed to participate by giving written informed consent.

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. Subject 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: Subject 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. Subject with rheumatoid arthritis and/or other arthropathies, Sjögren's syndrome or psoriasis controlled with topical medication, and subject 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. 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.
17. Major surgery within 4 weeks of the first dose of tislelizumab.
18. Pregnant or lactating women.

Contacts and Locations

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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

More Information

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Responsible Party:	BeiGene
ClinicalTrials.gov Identifier:	NCT03209973 History of Changes
Other Study ID Numbers:	BGB-A317-203
First Posted:	July 6, 2017
Last Update Posted:	December 13, 2018
Last Verified:	December 2018

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