Holmium-166 TARE in Liver Limited Unresectable Colorectal Cancer Patients (HAITI)

Phase II Study Evaluating Holmium-166 TARE Followed by Maintenance Therapy in Liver Limited Unresectable Colorectal Cancer Patients After First-line Chemotherapy and Target Agents

The aim of this study is to assess the efficacy of 166Ho-TARE followed by maintenance therapy with fluoropyrimidine and anti-EGFR or bevacizumab in liver-limited unresectable colorectal cancer patients, in terms of progression free rate 9- and 8-months for cohort A and B, respectively.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Cancer Metastatic
• Intervention / Treatment: Drug: Capecitabine; Procedure: 166Holmium TARE; Drug: Cetuximab; Drug: Panitumumab; Drug: 5-Fluorouracil; Drug: Bevacizumab

Detailed Description

HAITI is a phase II, single-arm trial of 166Ho-TARE followed by maintenance therapy in liver-limited unresectable colorectal cancer patients, achieving partial response or stable disease according to RECIST 1.1 criteria after 6-12 cycles of induction first-line chemotherapy.

Two cohorts of patients are included:

• left sided RAS/BRAF wild-type (cohort A)
• right-sided and/or RAS mutated (cohort B)

Enrolled patients will be treated with different maintenance therapy according to study cohort (fluoropyrimidine + anti-EGFR or bevacizumab).

• Study Type: Interventional
• Enrollment (Estimated): 46
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Gianluca Masi, MD; Phone Number: +39050992466; Email: gianluca.masi@unipi.it
• Study Contact Backup: Name: Laura Delliponti; Phone Number: +39.050.992192; Email: haiti.trial@gmail.com

Study Locations

• Italy
  • Pisa, Italy, 56126
    • Recruiting
    • Azienda Ospedaliero Universitaria Pisana
    • Principal Investigator: Gianluca Masi, MD
    • Contact: Beatrice Borelli, MD, PhD; Phone Number: +39050992192; Email: b.borelli89@gmail.com
    • Sub-Investigator: Beatrice Borelli, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Written informed consent to study procedures;
• Age ≥18 years;
• Histologically proven diagnosis of colorectal adenocarcinoma, with or without primary tumour in situ;
• Liver-only disease at radiological exams involving less than 50% of liver volume;
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≤2;
• Patients with partial response or stable disease according to RECIST 1.1 criteria deemed unresectable after 6-12 cycles of induction first-line chemotherapy;
• Life expectancy of at least 12 weeks;

• Hematopoietic function: absolute neutrophil count ≥ 1,500/mm3; platelet count

  ≥100,000/mm3; haemoglobin level ≥ 9 g/dL;

• Liver function: total bilirubin ≤ 1.5 times upper limit of normal (ULN); alkaline phosphatase

  ≤ 5 times ULN; AST ≤ 5 times ULN;

• Renal function: creatinine clearance > 50 mL/min or serum creatinine 1.5 x UNL; no renal disease that would preclude study treatment or follow-up;
• Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For this trial, women of childbearing potential are defined as all women after puberty, unless they are postmenopausal for at least 12 months, are surgically sterile, or are sexually inactive. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient;
• Subjects and their partners must be willing to avoid pregnancy during the trial. Male subjects with female partners of childbearing potential and female subjects of childbearing potential must, therefore, be willing to use adequate contraception as outlined in Section 7.5 - Contraception, starting during study screening visit throughout the study period up to 180 days after the last dose of chemotherapy Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject;
• Will and ability to comply with the protocol

Inclusion criteria for Cohort A:

• RAS/BRAF wild-type and left sided primary tumor
• First-line induction chemotherapy regimen permitted up to 6-12 cycles with:

FOLFOX or FOLFIRI + anti-EGFR (cetuximab or panitumumab). Patients who interrupted anti-EGFR target therapy during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy can be enrolled.

Inclusion criteria for Cohort B:

• RAS mutated and/or right-sided primary tumor
• First-line induction chemotherapy regimen admitted up to 6-12 cycles with:

FOLFOX/FOLFIRI/XELOX + bevacizumab or FOLFOXIRI + bevacizumab. Patients who interrupted bevacizumab during induction phase due to toxicity or other reasons, candidate to maintenance with fluoropyridine alone therapy can be enrolled.

Exclusion Criteria:

• Patients with radiological evidence of extra liver distant metastases.
• Evidence of ascites, cirrhosis, portal hypertension, main portal venous tumour involvement or thrombosis, or any other contraindications to radioembolization treatment;
• Previous radiotherapy delivered to the liver;
• Patients with BRAF mutated and/or MSI-high tumours;
• Previous history of malignancy within the last 5 years will be excluded with the exception of localized basal and squamous cell carcinoma or cervical cancer in situ;
• Treatment with any investigational drug within 30 days prior to enrolment or 2 investigational agent half-lives (whichever is longer);
• Active uncontrolled infections or other clinically relevant concomitant illness contraindicating study procedures and treatment administration Clinically significant (e.g. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure (CHF), serious cardiac arrhythmia requiring medication
• Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study and until 180 days after the last trial treatment;
• History of a previous allergic reaction to contrast media that would preclude safe angiography of the hepatic arteries, in the opinion of the treating Interventional Radiologist;
• Known hypersensitivity to fluoropyrimidine, anti-VEGF or anti-EGFR MoAb.
• Psychiatric or addictive disorders, or other conditions that, in the opinion of the investigator, would preclude study participation;
• Withdrawal of the consent to take part to the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: COHORT A/B; Eligible patients will receive Scout dose procedure. After 1-2 weeks, patients eligible for radioembolization will receive 166Ho-TARE and at least after 3 weeks, maintenance treatment with fluoropyrimidine plus target agents (anti-EGFR or bevacizumab) according to the respective study cohort. Maintenance treatment: Cohort A: CETUXIMAB iv day1, over 1 hours, 500 mg/sqm or PANITUMUMAB iv over 1 hours, 6 mg/kg, every 14 days; LED 200 mg/sqm iv over 1 hour, day 1; 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment Cohort B: BEVACIZUMAB 5 mg/kg iv biweekly day1, over 30 minutes; LED 200 mg/sqm iv over 1 hour, day 1; 5-FLUOROURACIL ic 48 h, starting on day 1 every 14 days; 2400 mg/sqm and 400 mg/sqm bolus if FOLFOX/FOLFIRI in the induction treatment CAPECITABINE, 1000 mg/sqm orally twice daily, day 1-14, plus bevacizumab 7,5 mg/kg iv every 21 days is allowed.

Drug: Capecitabine; Chemotherapy; Procedure: 166Holmium TARE; 166Ho-TARE treatment comprises of two hospital visits: one for a work-up procedure and another for the therapy procedure, with usually a 1-2 weeks interval.; Drug: Cetuximab; Target agent; Drug: Panitumumab; Target agent; Drug: 5-Fluorouracil; Chemotherapy; Drug: Bevacizumab; Target agent

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS) Rate	PFS is defined as the time from study enrolment to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis.	36 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Toxicity rate	Overall Toxicity rate is defined as the percentage of patients, relative to the total of enrolled subjects, who receive 166Ho-TARE and at least one cycle of chemotherapy, experiencing any adverse event, according to National Cancer Institute Common Toxicity Criteria (version 5.0) during the study treatment.	36 months
Grade 3/ Grade 4 Toxicity rate	Grade 3/ Grade 4 Toxicity rate is defined as the percentage of patients, relative to the total of enrolled subjects, who receive 166Ho-TARE and at least one cycle of chemotherapy, experiencing a specific adverse event of severity grade 3/ grade 4, according to National Cancer Institute Common Toxicity Criteria (version 5.0) during the study treatment.	36 months
Post-treatment Disease Control Rate (DCR)	Post-treatment DCR, is defined as the percentage of patients, relative to the total of enrolled subjects, achieving a complete (CR), partial (PR) response or stable disease (SD), according to RECIST 1.1 criteria, during the study treatment. The determination of clinical response will be based on investigator reported measurements. Tumor re-assessment with CT scan will be repeated every 8- weeks.	36 months
Progression free survival	Progression free survival (PFS), is defined as the time from study enrolment to the first documentation of objective disease progression or death due to any cause, whichever occurs first. PFS will be censored on the date of the last evaluable on study tumor assessment documenting absence of progressive disease for patients who are alive, on study and progression free at the time of the analysis.	36 months
Overall Survival	Overall Survival (OS), is defined as the time from enrolment to death from any cause. For patients still alive at the time of analysis, the OS time will be censored on the last date the patients were known to be alive.	36 months
Dose-response relationships	Dose-response relationships are defined as the relationships between the tumor-absorbed doses calculated on post-treatment SPECT-CT (dependent variables) and the following independent variables: tumor response (SD, PR, CR according to RECIST CRITERIA v 1.1), progression free survival rate, and Overall Survival.	36 months
Quality of Life (QoL) assessed using the EORTC QLQ-CR29 questionnaire	The EORTC QLQ-CR29 is a patient-reported outcome measure to evaluate health-related quality of life among colorectal cancer patients in research and clinical practice. QoL assessed using the EORTC QLQ-CR29 questionnaire will be evaluate at specific time-points (baseline, tumor reassessment and disease progression) and will be assessed through descriptive summary statistics.	36 months
Quality of Life (QoL) assessed using the EORTC QLQ-CR30 questionnaire	The EORTC QLQ-CR30 is 30-item instrument designed to measure quality of life in all cancer patients. QoL assessed using the EORTC QLQ-CR30 questionnaire will be evaluate at specific time-points (baseline, tumor reassessment and disease progression) and will be assessed through descriptive summary statistics.	36 months
Quality of Life (QoL) assessed using the EuroQol EQ-5D questionnaire	The EuroQol EQ-5D comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. QoL assessed using the EuroQol EQ-5D questionnaire will be evaluate at specific time-points (baseline, tumor reassessment and disease progression) and will be assessed through descriptive summary statistics.	36 months

Collaborators and Investigators

• Sponsor: Gruppo Oncologico del Nord-Ovest
• Investigators: Principal Investigator: Gianluca Masi, MD, Azienda Ospedaliero, Universitaria Pisana

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2024
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: March 8, 2024
• First Submitted That Met QC Criteria: March 25, 2024
• First Posted (Actual): March 27, 2024

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Unresectable colorectal cancer; Maintenance therapy; TARE; HOLMIUM; Liver-limited colorectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Fluorouracil; Capecitabine; Bevacizumab; Panitumumab; Cetuximab
• Other Study ID Numbers: HAITI 2023-505356-22-00

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No