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Colorectal CancerPhase 1NCT03802747

Immunotherapy Combined With Y-90 and SBRT for Colorectal Liver Metastases

A Phase 1 study testing Durvalumab, Durvalumab and Tremelimumab and Y-90 Selective Internal Radiation Therapy (SIRT) in people with Colorectal Cancer, run by University of Colorado, Denver.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
Search all trials

Trial summary

This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver metastases for patients with microsatellite stable colorectal cancer. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Colorectal Cancer
What is being tested?
Durvalumab, Durvalumab and Tremelimumab and Y-90 Selective Internal Radiation Therapy (SIRT)
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
Aug 2019to Dec 2024
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologic or cytologic confirmation of metastatic microsatellite stable colorectal cancer
  • Liver metastases not amenable to resection for which palliative Y-90 and SBRT is considered appropriate standard therapy
  • Patients should have received at least one prior standard therapy for metastatic disease. Prior therapies should include regimens containing oxaliplatin and irinotecan in combination with a fluoropyrimidine if appropriate (e.g., FOLFOX and FOLFIRI or their variants) unless contraindicated, not tolerated, or declined.
  • Male or female, age 18 or older
  • ECOG performance status of 0 or 1
  • Body weight >30 kg
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  • Life expectancy of greater than 6 months
  • Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:
  • Women <50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
  • Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
  • Patients must have acceptable organ and marrow function as defined below:
  • Hemoglobin ≥9.0 g/dL
  • Absolute neutrophil count (ANC ≥1.0 x (> 1000 per mm3))
  • Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
  • Total bilirubin : < 2x upper limit of normal
  • AST (SGOT)/ALT (SGPT): <2.5x institutional upper limit of normal
  • Creatinine: <1.5x upper limit of normal OR Creatinine clearance >40mL/min for patients with creatinine levels above institutional normal
  • Ability to understand and willingness to sign a written informed consent document
  • Residual or on-going ≥ Grade 3 treatment-related toxicity from previous chemotherapy should be resolved.

Who cannot join

  • Participation in another clinical study with an investigational drug during the last 4 weeks.
  • Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study
  • Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
  • Patients with Grade >2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
  • Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included only after consultation with the Study Physician.
  • Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
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  • Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
  • History of allogenic organ transplantation.
  • Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
  • Patients with vitiligo or alopecia
  • Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
  • Any chronic skin condition that does not require systemic therapy
  • Patients without active disease in the last 5 years may be included but only after consultation with the study physician
  • Patients with celiac disease controlled by diet alone
  • Prior therapy with an anti-PD-1 or anti-PD-L1, including durvalumab antibody within 6 months prior to enrollment and anti-CTLA4 (including tremelimumab)
  • Prior abdominal radiotherapy
  • Child-Pugh class B or higher
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, uncontrolled hypertension, insterstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent
  • History of another primary malignancy except for:
  • Malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of IP and of low potential risk for recurrence
  • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  • Adequately treated carcinoma in situ without evidence of disease
  • History of leptomeningeal carcinomatosis
  • History of active primary immunodeficiency
  • Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA.
  • Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
  • Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
  • Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP.
  • Contraindication to IV contrast
  • Pregnant and breastfeeding women are excluded. Women of child-bearing potential who are unwilling or unable to use an acceptable method of birth control to avoid pregnancy from screening to 90 days after the last dose of durvalumab monotherapy or 180 days after the last dose of durvalumab + tremelimumab combination therapy are excluded. This applies to any woman who has experienced menarche and who has not undergone successful surgical sterilization or is not postmenopausal (defined as amenorrhea for at least 12 consecutive months, or women on hormone replacement therapy with serum FSH levels greater than 35 mIU/mL). A negative urine or serum pregnancy test must be obtained within 14 days prior to the start of study therapy in all women of child-bearing potential. Male subjects must also agree to use effective contraception for the same time period as above.
  • Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
  • Use of any prohibited concomitant medications, including:
  • Traditional herbal medicines, as their use may result in unanticipated drug-drug interactions that may cause or confound assessment of toxicity.
  • Any live, attenuated vaccine (e.g., FluMist) within 4 weeks prior to Cycle 1 Day 1 or at any time during the study and for at least 5 months after the last dose of durvalumab.
  • Use of steroids to premedicate patients for whom MRI scans with contrast are contraindicated (i.e., patients with contrast allergy or impaired renal clearance)
  • Immunomodulatory agents, including but not limited to interferons or interleukin-2, during the entire study; these agents could potentially increase the risk for autoimmune conditions when administered with durvalumab.
  • Immunosuppressive medications, including but not limited to cyclophosphamide, azathioprine, methotrexate, and thalidomide; these agents could potentially alter the activity and the safety of durvalumab
  • Systemic corticosteroids and tumor necrosis factor-α (TNF-α) inhibitors may attenuate potential beneficial immunologic effects of treatment with durvalumab. Therefore, in situations where systemic corticosteroids or TNF-α inhibitors would be routinely administered, alternatives, including antihistamines, should be considered first by the treating physician. If the alternatives are not feasible, systemic corticosteroids and TNF-α inhibitors may be administered at the discretion of the treating physician (see Section 4.4.2)
  • Initiation or increased dose of granulocyte colony-stimulating factors (e.g., granulocyte colony stimulating factor, granulocyte/macrophage colony-stimulating factor, and/or pegfilgrastim) is prohibited.
  • Shunt Fraction greater than 20% (Requires more than 30gy dose to the lungs in order receive therapeutic dose of Y-90).

About this study

Official title: Phase I Study of Dual Immune Checkpoint Blockade (Anti-PD-L1 (Durvalumab) (MEDI4736) and Anti-CTLA4 (Tremelimumab) Plus Yttrium-90 (Y-90) Radioembolization & Stereotactic Body Radiation Therapy (SBRT) in Refractory Metastatic MSS (Microsatellite Stable) Colorectal Cancer With Liver Metastases

This study is evaluating the combination of Y-90 radioembolization followed by SBRT with the immunotherapy drugs, durvalumab and tremelimumab, to improve disease control of liver metastases for patients with microsatellite stable colorectal cancer.

Being tested
Durvalumab, Durvalumab and Tremelimumab, Y-90 Selective Internal Radiation Therapy (SIRT), Stereotactic Body Radiation Therapy (SBRT)
Keywords
Liver Metastases, Phase 1, Durvalumab, Tremelimumab, Yttrium-90, Radioembolization, Stereotactic Body Radiation Therapy
Medical subject headings
Colorectal Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DurvalumabDrug

    Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity.

  • Durvalumab and TremelimumabDrug

    Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses.

  • Y-90 Selective Internal Radiation Therapy (SIRT)Drug

    Yttrium-90 microsphere therapy consists of resin beads loaded with Yttrium, a pure beta emitter with a 64.2 hour half-life. Radioembolization will be performed as standard of care therapy per current NCCN guidelines.

  • Stereotactic Body Radiation Therapy (SBRT)Drug

    High-dose hypofractionated conformal external beam radiation therapy that is considered a standard of care. SBRT will also be considered for metastases that are persistent and/or progressive after Y-90 based on MR imaging and pathology from tissue biopsies.

Study groups in NCT03802747
Study groupRoleWhat they receive
Y-90, SBRT, and Durvalumab AloneExperimentalSix patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab.
Receives: Drug: Durvalumab; Drug: Y-90 Selective Internal Radiation Therapy (SIRT); Drug: Stereotactic Body Radiation Therapy (SBRT)
Y-90, SBRT, and Durvalumab + TremelimumabExperimentalSix patients will be enrolled in cohorts of three to be administered Y-90, SBRT, and Druvalumab + Tremelimumab.
Receives: Drug: Durvalumab and Tremelimumab; Drug: Y-90 Selective Internal Radiation Therapy (SIRT); Drug: Stereotactic Body Radiation Therapy (SBRT)

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of Treatment Related Adverse Events

    Adverse events related to Y-90, SBRT, and durvalumab plus tremelimumab will be summarized by dose and severity as assessed by the Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0.

    Measured: Start of study to 3 months post treatment completion, up to 5 years

  2. Dose-Limiting Toxicity of Y-90+SBRT in Combination with Dual Immune Checkpoint Blockade

    Defined as the rate of >Grade 3 treatment-related adverse events during treatment or within 3 months of treatment completion.

    Measured: Start of study to 3 months post treatment completion, up to 5 years

Secondary outcomes (7)

  1. Duration of Response (DoR)

    The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  2. Progression Free Survival for Three Months (PFS)

    The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  3. Overall Response Rate (ORR)

    The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  4. Overall Survival for Two Years (OS)

    Measure of overall survival rate by examining the incidence of death over a two year period.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  5. Liver Progression Free Survival for One Year (L-PFS)

    The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  6. Pathological Response Rates (PRR)

    Measured by the percentage of viable tumor throughout and post treatment

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

  7. Time to Tumor Progression (TTP)

    The determination of antitumor activity will be based on objective response assessments as defined by RECIST version 1.1 and immune RECIST.

    Measured: Landmark time of initiation of tremelimumab, about 18 weeks after the start of treatment, to end of follow up, up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Jan 2019
  2. Study startAug 2019 (estimated)
  3. Primary completionDec 2023 (estimated)
  4. Study completionDec 2024 (estimated)

Why it stopped: PI left the institution

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Model description
The first 6 patients will receive durvalumab alone with Y-90 and SBRT followed by 4 months of durvalumab. The next 6 patients will received durvalumab with Y-90 and SBRT followed by 4 months of durvalumab + tremelimumab.Durvalumab will be dosed at 1500 mg fixed dosing every 4 weeks and continued at this interval until progression or dose-limiting toxicity. There will be no dose escalation. For patients who will receive both Durvalumab and Tremelimumab, the Tremelimumab will be dosed at 75 mg every 4 weeks (same day as durvalumab infusion) for a maximum of 4 doses. There will be no dose escalation.
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03802747
Sponsor's protocol ID
18-0710.cc
Other IDs
ESR-17-13132
Status last verified
Dec 2024
First submitted
8 Jan 2019
Last updated
9 Dec 2024
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Durvalumab, Durvalumab and Tremelimumab and Y-90 Selective Internal Radiation Therapy (SIRT) in people with Colorectal Cancer, run by University of Colorado, Denver.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 42 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: withdrawn, as of the sponsor's last update on 9 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was withdrawn before enrolling participants, so there are no results.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of Treatment Related Adverse Events (time frame: Start of study to 3 months post treatment completion, up to 5 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03802747.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Dec 2024.

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