Immunotherapy With Y90-RadioEmbolization for Metastatic Colorectal Cancer

NCT04108481 | Terminated Phase 1 DMC FDA Drug FDA Device

• 1 other identifier: 201909709
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

This clinical trial will be conducted as a single-center, open-label, Phase I/2 trial to evaluate the feasibility and safety of Yttrium-90 radioembolization (Y90-RE) in combination with a fixed dose of of immunotherapy (durvalumab - 750 mg) in subjects with liver-predominant, metastatic colorectal cancer (mCRC), which is mismatch repair proficient/microsatellite stable (pMMR/MSS).

Conditions

Colorectal Cancer Metastatic; Colon Cancer; Metastatic Colorectal Cancer; Rectal Cancer; Liver Metastasis Colon Cancer; Colo-rectal Cancer; Colorectal Adenocarcinoma; Colorectal Neoplasms; Liver Metastases; Colorectal Carcinoma

Keywords

Y90; Y90-RE; Radioembolization; Y90-Radioembolization; y-90; Yttrium; Yttrium-90; Microsatellite Stable; MSS; CRC; mCRC; Colorectal; Liver Metastases; Liver Metastasis; Durvalumab; Anti-PD1; Anti-PDL1; Immunotherapy; Colorectal Cancer; Mismatch repair proficient; pMMR; KRAS; NRAS; BRAF; BRAF-V600E

Outcome Measures

Primary Outcomes (1)

• Determine the maximum tolerated dose (MTD) of Yttrium-90 radioembolization combined with immunotherapy durvalumab to treat liver-predominant metastatic colorectal cancer (mCRC)

  MTD will be defined as the highest dose level for which at most 1 out of 6 patients experience a dose-limiting toxicity (DLT) using CTCAE version 5.0.

  Initiation of treatment up to 8 weeks and 2 doses ("priming") of immunotherapy prior to Y90-RE.

Secondary Outcomes (7)

• Incidence of adverse events (AE) per CTCAE version 5.0

  Initiation of screening up to 2 years

• Determine overall response rate (ORR)

  Up to 2 months post treatment

• Determine the disease control rate (DCR)

  Up to 2 months post treatment

• Determine liver-specific progression free survival

  Up to 2 months post treatment

• Determine overall progression free survival

  Up to 2 years

Other Outcomes (6)

• Circulating tumor DNA - ctDNA - liquid biopsy correlates

  Up to 2 months post treatment

• Immune correlates - tissue

  Up to 2 months post treatment

• Immune correlates - blood

  Up to 2 months post treatment

Study Arms (1)

Y90-RE in combination with immunotherapy (durvalumab)

EXPERIMENTAL

The treatment phase starts of with the immunotherapy drug (durvalumab) - "priming doses" every 2 weeks prior to patient getting mapped and ready for treatment with Y90-RadioEmbolization. Post-Y90-RE, treatment is approximately 2 months in combination with fixed doses (750 mg) of durvalumab. The number and timing of doses of durvalumab each patient will receive will depend on the dose level the patient is assigned to (range 2-5 doses of immunotherapy). A single patient will be treated per dose level until the first dose limiting toxicity (DLT) is recorded. Once the first DLT is recorded, two additional patients are treated at the same dose level and the trial reverts to a standard 3+3 design. Up to 6 patients will be treated at each dose level. The maximum tolerated dose (MTD) will be defined as the highest dose level for which at most 1 out of 6 patients experience a DLT.

Drug: Durvalumab; Radiation: Yttrium-90 RadioEmbolization

Interventions

Durvalumab DRUG

Immunotherapy

Also known as: IMFINZI, MEDI4736, MEDI-4736, Anti-PDL1

Y90-RE in combination with immunotherapy (durvalumab)

Yttrium-90 RadioEmbolization RADIATION

Microscopic radioactive particles (TheraSphere®) will be used for radioembolization to deliver the Y90 drug to the liver

Also known as: Y90-RE, Y90, Glass Microspheres, yttrium90, Y-90 Glass Microspheres

Y90-RE in combination with immunotherapy (durvalumab)

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥18 years
• Histological or cytological confirmation of colorectal cancer with metastasis to the liver. Mismatch repair or microsatellite instability status of the tumor needs to be known. Tumors need to be mismatch repair proficient (for mismatch repair deficient tumors immunotherapy is already approved).
• Patient must have at least 1 liver lesion measurable as defined in the protocol
• Must have liver metastases and be appropriate for treatment with Y-90 radioembolization therapy as determined by the treating medical oncologist and interventional radiologist/oncologist, and nuclear medicine physician(s). NOTE: the goal of therapy is safety and parenchymal sparing. Typically, since the treatment is personalized, the goal is to have at least 30% liver parenchymal sparing post treatment.
• Must have a metastatic focus amendable to biopsy. It is permissible to use same or alternative lesion for biopsy for assessment for tumor response and changes in microenvironment (mandatory pre- and post-Y90-RE biopsy).
• At least 2 but no more than 3 lines of therapy allowed in metastatic setting. These include at least treatment with a fluoropyrimidine, oxaliplatin, and/or irinotecan-based therapy, an anti-VEGF therapy and, if RAS wild-type, an anti-EGFR therapy, unless deemed intolerant or not suitable by the treating oncologist. NOTE: adjuvant and/or maintenance chemotherapy does not count as an additional line of therapy. (Patients with more than 3 lines of therapy are at risk for liver disease from prior systemic therapies and would not be reasonable candidates for Y90-RE).
• ECOG Performance Status (PS) 0 or 1.
• Negative serum pregnancy test done ≤7 days prior to registration, for persons of childbearing potential only.
• Females of childbearing potential (FOCBP), must use appropriate method(s) of contraception. FOCBP are defined as those who are not surgically sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause). Additionally, FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with durvalumab plus 5 half-lives of durvalumab (13 weeks) plus 30 days (duration of ovulatory cycle) for a total of 17 weeks post-treatment completion (details in appendix).
• Men who are sexually active with FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with durvalumab plus 5 half-lives of durvalumab plus 90 days (duration of sperm turnover) for a total of 25 weeks post-treatment completion (details in appendix).
• Provide written informed consent.
• Ability to complete questionnaire(s) by themselves or with assistance.
• Willingness to provide mandatory blood specimens for correlative research (detailed in protocol).
• Willingness to provide mandatory tissue specimens for correlative research (detailed in protocol). NOTE: If tissue is deemed inaccessible, patient cannot participate in study.
• Willingness to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study).

You may not qualify if:

• Any of the following laboratory abnormalities:
• Hemoglobin \<8.0 g/dL
• Absolute neutrophil count (ANC) \<1500/mm3
• Platelet count \<100,000/mm3
• Total bilirubin \>1.5 x ULN (except in subjects with Gilbert Syndrome, who cannot have a total bilirubin \> 3.0 mg/dL)
• Alanine aminotransferase (ALT) and Aspartate transaminase (AST) \>2.5 x ULN
• Serum creatinine \> 1.5 x ULN OR
• Calculated creatinine clearance \<30 ml/min using the Cockcroft-Gault formula
• Any of the following because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects:
• Pregnant persons
• Nursing persons
• Persons of childbearing potential who are unwilling to employ adequate contraception
• Co-morbid systemic infections, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
• Untreated central nervous system (CNS) metastatic disease (including spinal cord and leptomeningeal disease). NOTE: Patients with previously treated CNS metastases that are radiographically and neurologically stable for ≥ 6 weeks are permitted.
• Uncontrolled intercurrent illness including, but not limited to, autoimmune disease, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. EXCEPTION: Patients who have adequately controlled autoimmune disease with or without medications are permitted as long as deemed reasonable by treating physician.

Sponsors & Collaborators

• University of Iowa: lead
• Biocompatibles UK Ltd: collaborator
• AstraZeneca: collaborator

Study Sites (1)

University of Iowa Hospitals and Clinics

Iowa City, Iowa, 52242, United States

Location

MeSH Terms

Conditions

Colonic Neoplasms; Colorectal Neoplasms; Rectal Neoplasms

Interventions

durvalumab; atezolizumab; Yttrium-90

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Study Officials

• Chandrikha Chandrasekharan, MD

  University of Iowa

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Accelerated titration design with an expansion phase once MTD is determined to treat up to a total of 18 patients.

Study Record Dates

• First Submitted: September 25, 2019
• First Posted: September 30, 2019
• Study Start: October 5, 2020
• Primary Completion: November 17, 2023
• Study Completion: November 17, 2023
• Last Updated: March 28, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)