Affordable Made-in-India Microspheres for Liver Cancer Therapy

Study Objective: Phase-1 Dose-escalation of 188Re-microspheres with comparator arm (Safety and primary efficacy)

Study Design: This is an open-label, multi-centric, randomized, dose escalation Phase I study with an active comparator arm (90Y-Theraspheres). The study will be initiated at PGIMER, Chandigarh, India and the other participating centres (AIIMS, New Delhi, India and TMH, Mumbai, India) would be added in a phased manner.

Study Settings:

The study will be conducted in the Department of Nuclear Medicine, PGIMER Chandigarh, which will serve as the coordinating and primary executing department, in collaboration with the Departments of Hepatology, Gastroenterology, and Phase I Centre of Clinical Pharmacology Unit, PGIMER Chandigarh, for patient screening, eligibility confirmation, therapeutic drug and dosimetry-related expertise, and overall conduct of Selective Internal Radiation Therapy (SIRT) in patients with hepatocellular carcinoma (HCC).

Study Design:

The study employs a 3+3 dose-escalation design in the investigational (188Re) arm, with parallel randomization to an active comparator (90Y) within each cohort in a 2:1 ratio. Three sequential tumor absorbed-dose cohorts are planned (80-100 Gy, 100-150 Gy, and 150-200 Gy). Dose escalation decisions will be based on the occurrence of dose-limiting toxicities (DLTs) during the predefined 28-day evaluation window and adjudicated by an independent Safety Review Committee (SRC). The total planned sample size is 18 patients (12 in the 188Re arm and 6 in the 90Y arm).

Study Protocol:

All patients will undergo a detailed pre-therapy assessment by the multidisciplinary study team prior to the procedure. This assessment will include a complete medical history, physical examination, review of performance status and laboratory investigations. Patients will be counseled regarding the procedure, expected benefits, and potential risks, and written informed consent will be obtained before any study-specific interventions.

Pre-therapy dosimetry will be performed to determine treatment feasibility and calculate the activity to be administered. In the 188Re arm, a lung shunt study using 99mTc-labelled microspheres will be performed on the day of therapy; in the 90Y arm, a 99mTc-MAA scan will be conducted at least one week prior to therapy so that desired dose may be imported. In both cases, a microcatheter will be placed via femoral artery puncture under digital subtraction angiography (DSA) guidance into the intended hepatic arterial branch. A scout dose of 3-5 mCi (111-185 MBq) of radiolabelled microspheres will be infused. Whole-body planar images will be acquired using a gamma camera equipped with an appropriate collimator, followed by regional SPECT/CT including the liver and tumor. Patient-specific attenuation correction will be performed using attenuation maps derived from the patients CT component. Image interpretation will be performed independently by two nuclear medicine physicians. Regions of interest (ROI) will be drawn on the liver, tumor, and lungs in anterior and posterior projections to calculate geometric mean counts. Lung shunt fraction (LSF) will be computed.

The tumor-to-normal liver ratio (TNR) will be calculated by placing an ROI over the area of maximal tumor uptake and a size-matched ROI over normal liver parenchyma; the count ratio will be recorded as TNR. Based on the CT tumor volume (cc) provided by the interventional radiologist, perfused liver mass (kg) will be obtained by multiplication with the liver tissue density (1.03 g/cc). The therapeutic activity to be administered will be calculated.

The calibration factor is 50 for 90Y and 34 for 188Re. The cohort-specified tumor dose will be delivered while ensuring that the mean absorbed dose to lungs and normal liver does not exceed 30 Gy, and the bone marrow dose does not exceed 2 Gy.

Before the treatment, the microcatheter position will be reconfirmed under DSA, and the calculated activity of 188Re microspheres (or standard-of-care 90Y microspheres) will be slowly infused. Intra-procedural DSA images will be acquired to confirm stasis or near-stasis of flow. The catheter will be flushed with saline after infusion. Residual activity in the vial and delivery set will be measured to determine the net administered dose. Radiation exposure at the hepatic region, injection site, and at one meter will be recorded. Post-SIRT tumor dose will be estimated using the monocompartmental method.

Post-therapy, serial whole-body images will be obtained during the patient's hospital stay, and a SPECT/CT scan will be performed at 24-48 hours to document microsphere biodistribution. Additional imaging may be obtained in selected patients to refine dosimetry, depending on logistical feasibility and radionuclide half-life. Personalized post-therapy dosimetry will be performed by drawing ROIs over the liver, tumor, lungs, and spleen on processed SPECT/CT images and applying the MIRD formula within dosimetry software to compute absorbed doses to each organ and the tumor. During hospitalization, laboratory tests (CBC, LFT, RFT) will be repeated, and any adverse events will be documented. Patients will be discharged after the 48-hour imaging, if clinically stable.

Study Endpoints:

Primary Endpoint:

Dose-Limiting Toxicity (DLT) rate (Day 1-Day 28): Proportion of patients experiencing ≥1 treatment-related DLT within 28 days post-SIRT, adjudicated per CTCAE v5.0 by the Safety Review Committee (SRC).

Pre-specified Dose-Limiting Toxicities (DLTs):

DLTs are defined as any of the following treatment-related toxicities occurring within Day 1 to Day 28 post-SIRT, meeting CTCAE v5.0 grade thresholds and judged by the Safety Review Committee (SRC) to be attributable to the investigational product or comparator.

i. Hepatic Toxicities: Radiation-Induced Liver Disease (RILD): Development of jaundice and/or ascites with a disproportionate rise in alkaline phosphatase, in the absence of tumor progression, biliary obstruction, or viral hepatitis flare.

ii. Radiation hepatitis: Defined as an elevation in AST, ALT, ALP or bilirubin in association with clinical features of hepatitis, attributable to SIRT. Radiation hepatitis will be considered when toxicity is Grade III or higher.

iii. Gastrointestinal Toxicities: Gastroduodenal ulcer or gastrointestinal bleeding: Confirmed by endoscopy or imaging, grade ≥ 3 severity, attributable to non-target deposition of microspheres.

iv. Biliary toxicity: Grade ≥ 3 events such as biliary stricture, cholangitis, or bile duct injury.

v. Pulmonary Toxicity:

1. Radiation pneumonitis: Clinical and radiological evidence of pneumonitis with CTCAE v5.0 grade ≥ 3, attributable to microsphere shunting to the lungs.

Constitutional / Post-embolization Syndrome: 2. Post-radioembolization syndrome meeting grade ' ≥ 3 for any of the following:

Nausea/vomiting Abdominal pain Fatigue Loss of appetite or weight loss (\>10% from baseline)

Other Serious Toxicities:

vi. Any other treatment-related grade ≥ 3 non-haematological toxicity considered clinically significant by the SRC.

vii. Grade ≥ 4 haematological toxicity persisting \>7 days, attributable to study treatment.

DLT Characterization Parameters:

For each DLT, the following details must be systematically documented in the case report form (CRF) and reviewed by the SRC:

1. Type of toxicity: precise medical term per CTCAE v5.0 2. Grade: maximum severity reached 3. Time-to-onset: Interval from end of microsphere infusion to first documentation of toxicity 4. Duration: number of days from onset to resolution or stabilization 5. Action taken: treatment modification, hospitalization, dose interruption, or supportive care measures 6. Outcome: recovered/resolved, ongoing, recovered with sequelae, death, or unknown

Treatment-Emergent Adverse Events (TEAEs/SAEs):

Incidence, nature, and severity of TEAEs/SAEs from end-of-procedure through 12 weeks (timepoints: end-of-procedure, 12 h, 24 h, Day 7, Day 14, Weeks 4, 8, 12), graded by CTCAE v5.0, causality by WHO-UMC. All SAE will be reported and compensated as per NDCT 2019, through insurance bought for the purpose.

Serious Adverse Event:

Serious adverse events (SAEs) are those that result in death, are life-threatening, require hospitalization or prolong an existing hospital stay, lead to significant disability, cause congenital anomalies, or necessitate urgent intervention to prevent permanent harm. SAEs will be recorded and reported in accordance with the Third Schedule of the New Drugs and Clinical Trials Rules, 2019.

SAE Reporting Timeline:

1. Initial IEC/IRB notification: Any SAE will be reported to the Institute Ethics Committee (IEC) within 24 hours of its occurrence with a covering letter from the Principal Investigator (PI). 2. Follow-up IEC/IRB report: A detailed follow-up SAE report will be submitted within 14 calendar days of occurrence. 3. Format and mode: The SAE report package will be sent as both hard copy and soft copy (MS Word format) to the IEC office. 4. IEC will send its opinion/recommendation (including causality and compensation, if applicable) to CDSCO/DCGI, with copy to the Sponsor, within 30 days of IEC receipt of the SAE dossier.

• Change From Baseline in Blood Pressure [Срок оценки: Five time-points: Baseline and Week 2, 4, 8, 12 post-SIRT]
• Change From Baseline in Body Temperature [Срок оценки: Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT]
• Change From Baseline in Heart Rate [Срок оценки: Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT]
• Incidence of Clinically Significant ECG Rhythm Abnormalities [Срок оценки: Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT]
• Change From Baseline in ECG Interval Parameters [Срок оценки: Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT]
• Change From Baseline in ECOG Performance Status Score [Срок оценки: Baseline and Weeks 2, 4, 8, 12 post-SIRT]
• Number of Participants With Grade ≥3 Laboratory Abnormalities as Assessed by CTCAE v5.0 [Срок оценки: Five time-points: Baseline and Week 2, 4, 8, 12 post-SIRT]
• Systemic Exposure to Radioactivity [Срок оценки: Five time-points: Hour 0, 2, 12, 24, and 48]
• Quantitative Estimation of Post-therapy Biodistribution and Absorbed Dose Using SPECT/CT [Срок оценки: Day 0, Day 1, Day 2]
• Evaluation of Preliminary Therapeutic Efficacy of 188Re-SIRT via Radiologic Response [Срок оценки: Single time-point: Week 8 post-SIRT]
• Evaluation of Preliminary Therapeutic Efficacy of 188Re-SIRT via Biochemical Response [Срок оценки: Three time-points: Baseline, Week 8 and Week 12 post-SIRT]
• Proportion of Participants Meeting Composite Procedural Safety Criteria for SIRT [Срок оценки: Single time-point: Immediately after performing SIRT]