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Advanced Hepatocellular CarcinomaPhase 1/2NCT05620004

Safety and Efficacy of Bifidobacterium Therapy in Patients With Advanced Liver Cancer Receiving Immunotherapy

A Phase 1/2 study testing Bifidobacterium Bifidum Oral Product in people with Advanced Hepatocellular Carcinoma, run by Sun Yat-sen University at 1 site in China.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

This study plans to observe the changes of liver cancer and immune cell subsets by replicating the high abundance intestinal flora and liver cancer mouse model, reveal the relationship and mechanism of intestinal flora in the immunotherapy of liver cancer, and study the impact on prognosis by regulating the positive… Read more about this study

Who is it for?
Ages 18 to 65 years
Conditions the study is for
Advanced Hepatocellular Carcinoma
What is being tested?
Bifidobacterium Bifidum Oral Product
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteChina
Study dates
1 Nov 2021to 31 Oct 2024
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 65 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients with HCC diagnosed by pathological histology or cytology or clinically confirmed.
  • Expected survival ≥ 12 weeks.
  • No systemic systemic antitumor therapy against hepatocellular carcinoma prior to the first dose.
  • Child-Pugh liver function rating: Grade A or B (≤7 points).
  • Stage IIIa: regardless of tumor status, with vascular invasion, no extrahepatic metastasis; liver function grade Child-Pugh A/B; PS 0~2, IIIb: regardless of tumor status, regardless of vascular invasion, with extrahepatic metastasis; liver function grade Child-Pugh A/B; PS 0~2. Not Stage B not suitable for radical surgery and/or local treatment.
  • ECOG physical status score ≤2.
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  • At least one measurable lesion according to RECIST v1.1 (measurable lesion spiral CT tracing length ≥ 10 mm or enlarged lymph node short diameter ≥ 15 mm)
  • Routine blood tests: (no blood transfusion, G-CSF medication correction within 14 days prior to screening)
  • Laboratory test values within 7 days prior to enrollment meet the following requirements (no blood components, cell growth factors, albumin, or other corrective therapies are allowed within the first 14 days of obtaining laboratory tests), as follows.
  • ① Blood count: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count (PLT) ≥ 75×109/L; hemoglobin level (HGB) ≥ 9.0 g/dL.
  • ② Liver function: serum total bilirubin (TBIL) ≤2× upper limit of normal (ULN); alanine amino transferase (ALT) and aspartate aminotransferase (ST) ≤5×ULN; serum albumin ≥28 g/L; alkaline phosphatase (ALP) ≤5×ULN.
  • Renal function: serum creatinine (Cr) ≤ 1.5×ULN or creatinine clearance (CCr) ≥ 50 mL/min (Cockcroft-Gault formula); urine routine results show urine protein <2+; for patients with urine protein ≥2+ at baseline, 24-hour urine collection and 24-hour urine protein quantification <1g should be performed.
  • ④ Coagulation: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 times ULN.
  • Female patients of childbearing age or male patients whose sexual partners are women of childbearing age are required to use effective contraception throughout the treatment period and for 6 months after the last dose.
  • Sign a written informed consent form and be able to comply with protocol visits and related procedures.

Who cannot join

  • Patients with hepatocellular carcinoma who have received prior treatment with carrilizumab or any other PD-L1 or PD-1 antagonist, or who have participated in a phase III study with apatinib after receiving systemic therapy.
  • Subjects with any active autoimmune disease or history of autoimmune disease, including but not limited to: hepatitis, pneumonia, uveitis, colitis (inflammatory bowel disease), pituitary inflammation, vasculitis, nephritis, hyperthyroidism and hypothyroidism, except vitiligo or resolved childhood asthma/atopic disease. Patients with asthma requiring intermittent use of bronchodilators or other medical interventions should also be excluded.
  • Subjects with systemic or absorbable topical corticosteroids requiring immunosuppressive drugs or immunosuppressive doses. Prednisone or equivalent doses greater than 10 mg/day are contraindicated for 2 weeks prior to dosing. Corticosteroids for intravenous contrast allergy prophylaxis are permitted.
  • Persons with known or suspected allergic reactions to any component of the Karelixu formulation.
  • Central nervous system (CNS) metastases with clinical signs (including cerebral edema, steroid requirements, or progressive disease). Subjects receiving treatment for brain or meningeal metastases must be clinically stable (no evidence of new or enlarged metastases on magnetic resonance imaging [MRI] at least 4 weeks apart) and have discontinued treatment with systemic steroid immunosuppressive doses (>10 mg/day of prednisone or equivalent) at least 2 weeks prior to study drug.
  • Other malignancies (except cured basal cell carcinoma of the skin and cervical cancer)
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  • Clinically significant cardiovascular disease, including but not limited to: severe acute myocardial infarction, unstable or severe angina, coronary artery bypass surgery, congestive heart failure (New York Heart Association (NYHA) class >2), ventricular arrhythmia requiring medical intervention, and left ventricular ejection fraction (LVEF) <50% within 6 months prior to enrollment.
  • Poorly controlled hypertension within 3 months: systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg.
  • Subjects with bleeding tendency or on thrombolytic or anticoagulant therapy.
  • Subjects who have received systemic chemotherapy, radiotherapy, immunotherapy, hormonal therapy, surgery, or targeted therapy within 4 weeks (or equivalent to 5 half-lives, whichever is greater) prior to dosing or have any unresolved adverse event > Common Terminology Criteria for Adverse Events (CTCAE) Level 1 (allowing for unresolved stable chronic toxicity).
  • Subjects with clinically symptomatic ascites or pleural effusion that remains uncontrolled by therapeutic puncture and drainage.
  • History of gastrointestinal bleeding within 3 months or significant tendency to gastrointestinal bleeding such as: esophageal varices, locally active ulcerative lesions, gastric and duodenal ulcers, ulcerative colitis or gastrointestinal diseases such as portal hypertension or tumor resection with risk of bleeding
  • Severe bleeding (bleeding >30 ml within 3 months), hemoptysis (>5 ml within 4 weeks) or thromboembolic events (within 12 months, including stroke events and/or transient ischemic attacks).
  • Active infection or fever of unknown origin >38.5°C during the screening visit or on the first scheduled dosing date (patients with fever due to tumor may be included at the discretion of the investigator)
  • History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, or severely impaired lung function.
  • History of immunodeficiency including human immunodeficiency virus (HIV) positive, or other acquired or congenital immunodeficiency disease, or active hepatitis (transaminases not meeting inclusion criteria, hepatitis B virus (HBV) DNA ≥ 104/ml or hepatitis C virus (HCV) RNA ≥ 103/ml (or higher). Chronic hepatitis B virus carriers with HBV DNA <2000 IU/ml (<104/ml) must receive antiviral therapy throughout the study.
  • Subjects who have participated in other clinical trials or completed other clinical trials within 4 weeks.
  • Subjects who may be receiving other anti-tumor systemic therapy during the study.
  • Subjects who may have received a vaccine during the study period or who have previously received a vaccine within 4 weeks.
  • History of psychiatric disorder or psychotropic substance abuse.
  • Any other medical, psychiatric or social condition that, in the opinion of the investigator, may affect the subject's rights, safety, welfare or ability to sign informed consent, cooperate and participate in the study or interfere with the interpretation of the results.

Trial locations and contacts

1 site in 1 country.

Chan Xie, PhD contact

8602085252372

happyxiechan@hotmail.com

China1 site, 1 recruiting

  • The Third Affiliated Hospital of Sun Yat-Sen University

    Guangzhou, Guangdong, 510630

    Chan Xie, Dr., 8602085252372, happyxiechan@hotmail.com

    Chan Xie, PhD

    Recruiting

Other trials in China

About this study

Official title: Safety and Efficacy of Bifidobacterium Therapy in Patients With Advanced Liver Cancer Receiving Immunotherapy: a Randomized Controlled, Single-center Clinical Trial

This study plans to observe the changes of liver cancer and immune cell subsets by replicating the high abundance intestinal flora and liver cancer mouse model, reveal the relationship and mechanism of intestinal flora in the immunotherapy of liver cancer, and study the impact on prognosis by regulating the positive correlation of lactic acid bacteria and bifidobacteria of rumen coccus in patients with advanced liver cancer receiving immunotherapy

Read the detailed description

Select patients with advanced hepatocellular carcinoma who have been clinically consulted by MDT,those patients will be treated with carrilizumab and apatinib mesylate, and divide them into two groups randomly .Collect the stool specimens and clinical data from those who will be treated with oral bifidobacterium or without bifidobacterium during immunotherapy.; Use 16S sequencing to detect the changes in the composition ratio of intestinal flora and the level of galactose acid, judge the response to clinical treatment and establish the relationship curve with clinical treatment efficacy.

Being tested
Bifidobacterium Bifidum Oral Product
Keywords
Advanced Hepatocellular Carcinoma, Immunotherapy, Bifidobacterium

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Bifidobacterium Bifidum Oral ProductDrug

    Also called LiveCombinedBifidobacterium,LactobacillusandStreptococcusthermophilusTablets,Oral

    experimental group use Bifidobacterium Bifidum Oral Product and control group without Bifidobacterium Bifidum Oral Product

Study groups in NCT05620004
Study groupRoleWhat they receive
Bifidobacterium Bifidum Oral ProductExperimentalpatients with advanced hepatocellular carcinoma who will be treate with carrilizumab and apatinib mesylate plus Bifidobacterium Bifidum Oral Product daily
Receives: Drug: Bifidobacterium Bifidum Oral Product
without Bifidobacterium Bifidum Oral ProductNo interventionpatients with advanced hepatocellular carcinoma who will be treate with carrilizumab and apatinib mesylate without Bifidobacterium Bifidum Oral Product daily

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. objective response rate(ORR)

    The proportion of patients with tumor volume reduction up to a pre-specified value and able to maintain the minimum time requirement is the sum of the proportion in complete and partial remission

    Measured: 1 year

  2. disease control rate(DCR)

    The number of cases with remission and stable lesions after treatment as a percentage of evaluable cases that were maintained for at least 4 weeks.

    Measured: 1 year

  3. overall survival(OS)

    The time interval from the start of treatment until the patient's death (from any cause)

    Measured: 1 year

  4. progression-free survival(PFS)

    Time interval from the start of treatment until disease progression (including death)

    Measured: 1 year

  5. Number of participants with treatment-related adverse events as assessed by NCI-CTCAE 5.0."

    Side effects due to immunotherapy

    Measured: 1 year

Secondary outcomes (1)

  1. Change in tumor volume before and after treatment

    The efficacy of the study will be evaluated based on the imaging results and evaluation criteria for efficacy of solid tumorssolid tumors (RECISTv1.1).

    Measured: 24 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted17 Nov 2022
  2. Study start1 Nov 2021
  3. Primary completion31 Dec 2023 (estimated)
  4. Study completion31 Oct 2024 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Select patients with advanced hepatocellular carcinoma who have been clinically consulted by MDT ,those patients will be treated with carrilizumab and apatinib mesylate,and divide them into two groups randomly .Collect the stool specimens and clinical data from those who will be treated with oral bifidobacterium or without bifidobacterium during immunotherapy.
Masking
None (open label)
Enrolment
30 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05620004
Sponsor's protocol ID
XC4
Status last verified
Nov 2022
First submitted
2 Nov 2022
Last updated
17 Nov 2022
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • Meng X, Liu X, Guo X, Jiang S, Chen T, Hu Z, Liu H, Bai Y, Xue M, Hu R, Sun SC, Liu X, Zhou P, Huang X, Wei L, Yang W, Xu C. FBXO38 mediates PD-1 ubiquitination and regulates anti-tumour immunity of T cells. Nature. 2018 Dec;564(7734):130-135. doi: 10.1038/s41586-018-0756-0. Epub 2018 Nov 28.

    PubMed 30487606

  • Ruiz de Galarreta M, Bresnahan E, Molina-Sanchez P, Lindblad KE, Maier B, Sia D, Puigvehi M, Miguela V, Casanova-Acebes M, Dhainaut M, Villacorta-Martin C, Singhi AD, Moghe A, von Felden J, Tal Grinspan L, Wang S, Kamphorst AO, Monga SP, Brown BD, Villanueva A, Llovet JM, Merad M, Lujambio A. beta-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma. Cancer Discov. 2019 Aug;9(8):1124-1141. doi: 10.1158/2159-8290.CD-19-0074. Epub 2019 Jun 11.

    PubMed 31186238

  • Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol. 2004 Jul 15;173(2):945-54. doi: 10.4049/jimmunol.173.2.945.

    PubMed 15240681

  • Riley JL. PD-1 signaling in primary T cells. Immunol Rev. 2009 May;229(1):114-25. doi: 10.1111/j.1600-065X.2009.00767.x.

    PubMed 19426218

  • Janney A, Powrie F, Mann EH. Host-microbiota maladaptation in colorectal cancer. Nature. 2020 Sep;585(7826):509-517. doi: 10.1038/s41586-020-2729-3. Epub 2020 Sep 23.

    PubMed 32968260

  • Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, Agdashian D, Terabe M, Berzofsky JA, Fako V, Ritz T, Longerich T, Theriot CM, McCulloch JA, Roy S, Yuan W, Thovarai V, Sen SK, Ruchirawat M, Korangy F, Wang XW, Trinchieri G, Greten TF. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018 May 25;360(6391):eaan5931. doi: 10.1126/science.aan5931.

    PubMed 29798856

  • Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R, Fluckiger A, Messaoudene M, Rauber C, Roberti MP, Fidelle M, Flament C, Poirier-Colame V, Opolon P, Klein C, Iribarren K, Mondragon L, Jacquelot N, Qu B, Ferrere G, Clemenson C, Mezquita L, Masip JR, Naltet C, Brosseau S, Kaderbhai C, Richard C, Rizvi H, Levenez F, Galleron N, Quinquis B, Pons N, Ryffel B, Minard-Colin V, Gonin P, Soria JC, Deutsch E, Loriot Y, Ghiringhelli F, Zalcman G, Goldwasser F, Escudier B, Hellmann MD, Eggermont A, Raoult D, Albiges L, Kroemer G, Zitvogel L. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018 Jan 5;359(6371):91-97. doi: 10.1126/science.aan3706. Epub 2017 Nov 2.

    PubMed 29097494

  • Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC, Cogdill AP, Zhao L, Hudgens CW, Hutchinson DS, Manzo T, Petaccia de Macedo M, Cotechini T, Kumar T, Chen WS, Reddy SM, Szczepaniak Sloane R, Galloway-Pena J, Jiang H, Chen PL, Shpall EJ, Rezvani K, Alousi AM, Chemaly RF, Shelburne S, Vence LM, Okhuysen PC, Jensen VB, Swennes AG, McAllister F, Marcelo Riquelme Sanchez E, Zhang Y, Le Chatelier E, Zitvogel L, Pons N, Austin-Breneman JL, Haydu LE, Burton EM, Gardner JM, Sirmans E, Hu J, Lazar AJ, Tsujikawa T, Diab A, Tawbi H, Glitza IC, Hwu WJ, Patel SP, Woodman SE, Amaria RN, Davies MA, Gershenwald JE, Hwu P, Lee JE, Zhang J, Coussens LM, Cooper ZA, Futreal PA, Daniel CR, Ajami NJ, Petrosino JF, Tetzlaff MT, Sharma P, Allison JP, Jenq RR, Wargo JA. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. doi: 10.1126/science.aan4236. Epub 2017 Nov 2.

    PubMed 29097493

  • Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018 Jan 5;359(6371):104-108. doi: 10.1126/science.aao3290.

    PubMed 29302014

  • Mager LF, Burkhard R, Pett N, Cooke NCA, Brown K, Ramay H, Paik S, Stagg J, Groves RA, Gallo M, Lewis IA, Geuking MB, McCoy KD. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020 Sep 18;369(6510):1481-1489. doi: 10.1126/science.abc3421. Epub 2020 Aug 13.

    PubMed 32792462

  • Zheng Y, Wang T, Tu X, Huang Y, Zhang H, Tan D, Jiang W, Cai S, Zhao P, Song R, Li P, Qin N, Fang W. Gut microbiome affects the response to anti-PD-1 immunotherapy in patients with hepatocellular carcinoma. J Immunother Cancer. 2019 Jul 23;7(1):193. doi: 10.1186/s40425-019-0650-9.

    PubMed 31337439

  • Jiang Y, Han QJ, Zhang J. Hepatocellular carcinoma: Mechanisms of progression and immunotherapy. World J Gastroenterol. 2019 Jul 7;25(25):3151-3167. doi: 10.3748/wjg.v25.i25.3151.

    PubMed 31333308

  • Schwabe RF, Greten TF. Gut microbiome in HCC - Mechanisms, diagnosis and therapy. J Hepatol. 2020 Feb;72(2):230-238. doi: 10.1016/j.jhep.2019.08.016.

    PubMed 31954488

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Bifidobacterium Bifidum Oral Product in people with Advanced Hepatocellular Carcinoma, run by Sun Yat-sen University at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 15 inclusion and 21 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 17 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Chan Xie, PhD (8602085252372, happyxiechan@hotmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

objective response rate(ORR) (time frame: 1 year). The study lists 5 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05620004, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Nov 2022.

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