Affordable Made-in-India Microspheres for Liver Cancer Therapy

Primary liver tumors, with hepatocellular carcinoma (HCC) accounting for 80%, represent 6% of global cancer incidence and 9% of global cancer-associated mortality.HCC remains the leading causes of cancer-related deaths worldwide, due to late diagnosis. Although local-stage liver tumors are curable with tumor resection or livertransplantation, 65-70% of diagnosed cases are not suitable for resection due to large or multifocal lesions. For these patients, local therapies such as transcatheterarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) are appropriate at intermediate stages. In cases of advanced and metastatic livertumors, systemic therapies like sorafenib are the standard approach. Selective Intra-arterial Radionuclide Therapy (SIRT) offers a promising treatment for inoperableliver tumors by delivering beta-emitting radiolabeled microspheres directly to tumor sites through the liver's dual blood supply. However, the high cost of standard90Y-microspheres has limited accessibility for patients. This current project aims to develop, optimize, and validate the indigenously prepared microspheres forradiolabeling with 188Re from commercially available generator and indigenously produced radionuclide 177Lu (BARC Mumbai) for SIRT in liver cancer. With hightransformational impact, the current multicentric research will lead to a potentially safe, effective, and promising low-cost SIRT solution for low-income settings.Through collaboration across multiple centers, the study will evaluate the efficacy of microspheres labelled with both radionuclides. By establishing these accessibleSIRT options, this project strives to reduce financial barriers to treatment, advancing the goals of "Jai Anusandhan" towards building innovative therapeutics throughcollaborative research project and improving outcomes for patients with limited options.

Sex

All

Minimum age

18 Years

Maximum age

90 Years

Inclusion Criteria:

1. Age greater than or equal to 18 years (male or female)
2. Histologically or radiologically confirmed diagnosis of HCC deemed inoperable
3. Barcelona Clinic Liver Cancer stage B with ECOG performance status between 0 and 2
4. At least one measurable lesion with longest diameter greater than or equal to 5 cm on cross sectional imaging
5. Portal vein thrombosis may be present or absent
6. Laboratory criteria:

   1. Serum creatinine less than or equal to 1.5 mg per dL
   2. Total bilirubin less than or equal to 2.0 mg per dL
   3. AST or ALT less than or equal to 5 times upper limit of normal
   4. Leukocyte count greater than or equal to 1500 per microliter
   5. Platelet count greater than or equal to 50000 per microliter
   6. Prothrombin time less than or equal to 1.3 times control or INR less than or equal to 1.5
7. Karnofsky performance status greater than 70
8. Ability and willingness to provide written informed consent for participation in the IEC approved protocol

Exclusion Criteria:

1. Women of childbearing potential who are unwilling or unable to use effective contraception or who are pregnant or lactating
2. Child Pugh class C liver function
3. Presence of extrahepatic metastases
4. Severe chronic pulmonary disease with hypoxemia or NYHA class three or four heart failure
5. Myocardial infarction within the past six months
6. Unstable arrhythmia or symptomatic cardiac disease
7. Any other serious uncontrolled illness that in the investigator's opinion would compromise study participation
8. History of other malignancy except adequately treated basal cell carcinoma or cervical carcinoma in situ within the last five years
9. Major surgery within four weeks prior to enrolment
10. Active uncontrolled bacterial infection requiring systemic therapy
11. Liver rupture, tumor penetration of the liver capsule, tumor invasion of the biliary system, or biliary obstruction
12. Known allergy or hypersensitivity to any component of the investigational or comparator microspheres
13. Prior treatment with Selective Internal Radiation Therapy (SIRT)
14. Estimated overall survival less than one month

• BACKGROUNDShukla J, Kalra N, Kumar R, Bhusari P, Chhabra A, Parmar M, Vatsa R, Singh H, Duseja A, Mittal BR. Two Cases of 188Re Microspheres for Inoperable Hepatocellular Carcinoma. Clin Nucl Med. 2019 Feb;44(2):e93-e95. doi: 10.1097/RLU.0000000000002373. PMID 30418210
• BACKGROUNDAggarwal A, Kaur G, Jassal RS, Medhi B, Mittal BR, Shukla J. Unraveling Interaction of Rhenium-188 Microspheres with Primary Hepatic Cancer Cell: A Breakthrough Study. Cancer Biother Radiopharm. 2024 Apr;39(3):188-195. doi: 10.1089/cbr.2023.0146. Epub 2024 Jan 19. PMID 38241504
• BACKGROUNDShukla J, Goyal A, Chhabra A, Rathore Y, Bansal K, Pandey S, Parmar M, Singhal S, Kalra N, Duseja A, Mittal BR. Cold kit for Rhenium-188 microspheres based selective intra-arterial therapy (SIRT): Preparation, characterization and feasibility study. Appl Radiat Isot. 2022 Dec;190:110423. doi: 10.1016/j.apradiso.2022.110423. Epub 2022 Aug 28. PMID 36183659
• BACKGROUNDShukla J, Kalra N, Mittal BR, Duseja A, Kumar R, Singh H, Chaluvashetty SB, Parmar M, Krishnan S, Kumar G, Vatsa R, Chhabra A, Bansal K, Rathore Y, Pandey S. Freeze-dried microspheres for selective intra-arterial radionuclide therapy: an affordable solution. Nucl Med Commun. 2020 Aug;41(8):817-823. doi: 10.1097/MNM.0000000000001225. PMID 32516242
• BACKGROUNDShukla J, Chopra S, Kaur K, Chakraborty S, Singh H, Duseja A, Kalra N, Mittal BR. 177 Lu-Microspheres Selective Intra-arterial Radionuclide Therapy : A Facile and Biocompatible Permanent Micro-Seed Implants for Unresectable Hepatocellular Carcinoma. Clin Nucl Med. 2024 Apr 1;49(4):e170-e171. doi: 10.1097/RLU.0000000000005101. Epub 2024 Feb 6. PMID 38377367