FTD-TPI, Bevacizumab, and Radioembolization With 166Ho-microspheres in Refractory Metastatic Colorectal Cancer

Official title

Single-arm, Phase II Trial of Trifluridine/Tipiracil (FTD-TPI), Bevacizumab, and Individualized Radioembolization With 166Ho-microspheres in Refractory Metastatic Colorectal Cancer

Overview

Extrahepatic disease progression limits clinical efficacy of individualized radioembolization for patients with refractory metastatic colorectal cancer (mCRC). In the same patient population, trifluridine/tipiracil (FTD-TPI) and bevacizumab lead to disease control and overall survival benefit and may be a radiosensitizer. The purpose of this study is to determine safety, tolerability, and activity of individualized radioembolization with 166Holmium (166Ho)-microspheres combined with FTD-TPI and bevacizumab.

Interventions

• Drug Systemic treatment (FTD-TPI and bevacizumab)
  Systemic treatment (FTD-TPI and bevacizumab) administration is according to standard clinical practice. Each treatment cycle will be 28 days in duration. One treatment cycle consists of the following: * Days 1-5: oral intake of FTD-TPI and bevacizumab IV infusion on day 1 * Days 8-12: oral intake of FTD-TPI * Day 15: bevacizumab IV infusion Bevacizumab 5.0mg/kg i.v. is repeated every 2 weeks. If toxicity occurs, dose modifications and dose delays should be administered and applied according t
• Device Radioembolization with 166-Ho microspheres
  Individualized 166Ho radioembolization will be performed via a catheter during angiography. Before the treatment, a scout procedure will be performed to determine individualized 166Ho dose of the treatment. Dosimetry-based treatment planning will be individualized using Q- Suite software. In case of bilateral disease, patients will be treated in two procedures to each hemi-liver, separated by 1 month. Before the first procedure, a scout procedure will be performed in which the individualized 16

Primary outcome measures

• Hepatic objective response rate (hORR) (PERCIST 1.0) [Time frame: Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.]

Secondary outcome measures (11)

• Hepatic objective response rate (hORR) (RECIST 1.1) [Time frame: Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.]
• Overall and extra-hepatic ORR (RECIST 1.1) [Time frame: Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.]
• Overall and extra-hepatic ORR (PERCIST 1.0) [Time frame: Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.]
• Serious adverse events (SAE's) [Time frame: Evaluated every 8 weeks after start treatment during the first half year. The collection period will start from the first day of the first treatment cycle until 180 days thereafter.]
• Grade ≥3 adverse events (CTCAE 5.0) [Time frame: Evaluated every 8 weeks after start treatment during the first half year. The collection period will start from the first day of the first treatment cycle until 180 days thereafter.]
• Occurrence of radioembolization-induced liver disease (REILD) [Time frame: Evaluated every 8 weeks after start treatment during the first half year.]
• Radioembolization related vascular events [Time frame: Evaluated every 8 weeks after start treatment during the first half year.]
• Dose reductions, dose delays of FTD-TPI [Time frame: Evaluated during the first two cycles (each cycle is 28 days).]
• Radioembolization completion rate [Time frame: Evaluated immediately after the radioembolization treatment.]
• Progression free survival (PFS) [Time frame: Evaluated every 8 weeks after the start of treatment until 1 year after the start of treatment or until disease progression, whichever comes first.]
• Overall survival (OS) [Time frame: Evaluated once per year until the end of the study (the end of study is defined as six months after the first day of the first treatment cycle (each cycle is 28 days) of the 36th evaluable participant).]

Eligibility criteria

Inclusion criteria

• Unresectable liver dominant mCRC
• Prior therapy with fluoropyrimidine, oxaliplatin, and irinotecan for the treatment of metastatic colorectal cancer and had demonstrated progressive disease or intolerance to their last regimen

• Patients who have withdrawn from standard treatment due to unacceptable toxicity warranting discontinuation of treatment and precluding retreatment with the same agent prior to progression of disease will also be eligible to enter the study.
• Patients who refuse oxaliplatin or irinotecan will also be eligible to enter the study.
• Patients who had received adjuvant chemotherapy and had recurrence during or within 6 months of completion of the adjuvant chemotherapy count the adjuvant therapy as treatment of metastatic colorectal cancer.
• Written informed consent
• Age >=18 years
• Estimated hepatic tumor replacement ≥ 10% and ≤ 50% of total liver volume Eastern Cooperative Oncology Group performance status 0-1
• Adequate organ function as measured by: WBC ≥ 3.0 x 109/L, platelets ≥ 100 x 109/L, absolute neutrophil count > 1.5 x 109/L, Hemoglobin (Hb) > 5 mmol/L (>8.1 g/dL), eGFR ≥ 35 ml/min, Serum transaminases (AST \& ALT) ≤ 5 x upper limit of normal (ULN), Total bilirubin ≤ ULN, Albumin > 3 g/dL
• At least one measurable liver lesion according to the PERCIST 1.0

Exclusion criteria

• Significant extrahepatic disease, defined as symptomatic extrahepatic disease, more than 10 pulmonary nodules (maximum diameter of each lung metastasis <20mm), and/or peritoneal carcinomatosis.
• Eligible for ablative local treatment of liver metastases (e.g. surgical resection, ablation)
• Lung shunt >20 Gy, as calculated using scout dose SPECT/CT
• Absorbed tumor dose <90 Gy when dosing at a maximum average absorbed normal liver dose
• Other malignancy confounding prognosis
• Receipt of chemotherapy within 28 days prior to study treatment
• Previous or current treatment with radioembolization
• Major surgery within 28 days or incompletely healed surgical incision before starting study therapy
• Any serious comorbidity preventing the safe administration of anti-VEGF antibody treatment. This includes uncontrolled hypertension or treatment with ≥3 antihypertensive drugs, arterial (cerebro)vascular event within the past 6 months, history of severe bleeding, history of GI perforation, or presence of fistulae
• Any serious and/or chronic liver disease preventing the safe administration of radio- embolization
• Uncorrectable extrahepatic deposition of scout dose activity; activity in the falciform ligament, portal lymph nodes and gallbladder is accepted
• Pregnancy or breastfeeding
• Body weight over 150 kg (because of maximum table load)
• Known severe allergy for intravenous contrast fluids
• Participation to another investigational study which may compromise any endpoint of the study

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Netherlands · 1 center

• UMC Utrecht — Utrecht

Identifiers

NCT: NCT06563986 · NL85987.041.24

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗