Metastatic Carcinoma in the LiverPhase 1NCT03005002
Durvalumab and Tremelimumab in Treating Patients With Microsatellite Stable Metastatic Colorectal Cancer to the Liver
A Phase 1 study testing Durvalumab, Laboratory Biomarker Analysis and Tremelimumab in people with Metastatic Carcinoma in the Liver and MLH1 Gene Mutation, run by City of Hope Medical Center at 1 site in United States.
Trial summary
This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread. Read more about this study
- Who is it for?
- Ages 19 years and older
- Conditions the study is for
- Metastatic Carcinoma in the Liver, MLH1 Gene Mutation, MSH6 Gene Mutation
- What is being tested?
- Durvalumab, Laboratory Biomarker Analysis and Tremelimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- 28 Jun 2017to 26 Nov 2019
- 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 19 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Documented informed consent of the subject and/or legally authorized representative
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of > 12 weeks
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 75 x 10^9/L (>= 75,000 per mm^3)
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- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x institutional upper limit of normal given that all patients have liver metastases
- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
- Female subjects must either be of non-reproductive potential (ie, post-menopausal by history: >= 60 years old and no menses for >= 1 year without an alternative medical cause; AND/OR history of hysterectomy, AND/OR history of bilateral tubal ligation, AND/OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
- Subject is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
- Patients must have received at least one prior line of therapy for the treatment of metastatic disease with a fluoropyrimidine in combination with oxaliplatin and/or irinotecan; patients with prior adjuvant therapy who progressed within 6 months of completion of treatment may be eligible
- Patients must have liver-only metastases or predominant liver metastatic disease
- Patients should have microsatellite stable (MSS) tumor by polymerase chain reaction (PCR) assay or mismatch repair protein proficient (MMRP) tumor by immunohistochemistry as confirmed by the presence of MLH1, MSH2, MSH6, and PMS2; the diagnosis of colorectal cancer should be confirmed by pathology either on the primary tumor or from a prior biopsy of a metastatic disease site
- Patients should have been identified by their respective physicians as candidates for radioembolization and scheduled to undergo such a procedure
- Patients should agree to serial liver metastases biopsy pre-treatment, post-radioembolization, and post-combination immunotherapy
- Patients should have measurable metastatic disease in the liver, defined (for the purpose of this study) as at least 1 measurable lesion more than 2 cm in size and readily accessible to ultrasound (US) or computed tomography (CT)-guided biopsy
- Patients should not be deemed candidate for curative hepatic resection
Who cannot join
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) or previous enrollment in the present study
- Participation in another clinical study with an investigational product during the last 4 weeks
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
- 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 study drug and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligns without evidence of disease
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- Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ
- Receipt of the last dose of chemotherapy or tyrosine kinase inhibitors should be at least 3 weeks prior to durvalumab and tremelimumab dosing; monoclonal antibodies such as bevacizumab, ziv-aflibercept, ramucirumab, cetuximab, and panitumumab should be at least 6 weeks prior to durvalumab and tremelimumab therapy
- Clinical ascites
- Liver involvement by > 50% with metastatic disease determined by the investigator
- Complete portal vein thrombosis on CT scans
- Failure to satisfy minimum criteria of lung shunting (> 20%) or presence of extrahepatic gastrointestinal activity on microaggregated albumin (MAA) scan or angiogram that preclude SIR-Spheres
- Prior external beam radiation to the liver
- Mean QT interval corrected for heart rate (QTc) >= 470 ms calculated from 3 electrocardiograms (ECGs) using Fridericia's correction
- Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab or tremelimumab, with the exceptions of intranasal, topical, and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid
- Any unresolved toxicity (> Common Terminology Criteria for Adverse Events [CTCAE] grade 2) from previous anti-cancer therapy; subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripherally neuropathy)
- Any prior systemic anti-cancer immunotherapy treatment
- Active or prior documented autoimmune disease within the past 2 years; NOTE: Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded
- Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
- History of primary immunodeficiency
- History of allogeneic organ transplant
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
- Known history of previous clinical diagnosis of tuberculosis
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or tremelimumab
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids
- Subjects with uncontrolled seizures
- Patients with symptomatic extrahepatic metastases
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period
- Known allergy or hypersensitivity to investigational product (IP) or any excipient
Trial locations and contacts
1 site in 1 country.
United States1 site
City of Hope Medical Center
Duarte, California, 91010
About this study
Official title: A Pilot Feasibility Study of Durvalumab (MEDI4736) and Tremelimumab Following Radioembolization in Patients With Metastatic Microsatellite Stable (MSS) Colorectal Cancer to the Liver
This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.
Read the detailed description
PRIMARY OBJECTIVES:
- Establish the safety of durvalumab and tremelimumab following radioembolization with selective internal radiation (SIR)-Spheres in patients with microsatellite stable (MSS) metastatic colorectal cancer to the liver.
II. Determine the hepatic response rate of SIR-Spheres followed by durvalumab and tremelimumab in patients with MSS metastatic colorectal cancer to the liver.
SECONDARY OBJECTIVES:
- Estimate the progression free survival (PFS) and overall survival (OS) of the overall treated population.
II. Describe the overall response rate of the treated population. III. Describe the extra-hepatic response in the treated population (abscopal responses).
TERTIARY OBJECTIVES:
- Describe intra-tumor immune alterations following SIR-Spheres, and following durvalumab plus tremelimumab in comparison to baseline through serial hepatic metastases biopsies.
II. Describe the immune alterations in the blood following SIR-Spheres and following durvalumab plus tremelimumab.
OUTLINE:
Patients receive durvalumab intravenously (IV) over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
- Conditions
- Metastatic Carcinoma in the Liver, MLH1 Gene Mutation, MSH6 Gene Mutation, PMS2 Gene Mutation, Stage IV Colorectal Cancer, Stage IVA Colorectal Cancer
- Being tested
- Durvalumab, Laboratory Biomarker Analysis, Tremelimumab
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabBiological
Also called Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736
Given IV
Laboratory Biomarker AnalysisOther
Correlative studies
TremelimumabBiological
Also called Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Treatment (durvalumab, tremelimumab) | Experimental | Patients receive durvalumab IV over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity. Receives: Biological: Durvalumab; Other: Laboratory Biomarker Analysis; Biological: Tremelimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Hepatic tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Will be summarized using a 90% exact Clopper-Pearson confidence interval
Measured: Up to 1 year
Incidence of adverse events assessed by NCI CTCAE version 4.03
Toxicities observed will be summarized in terms of type and severity.
Measured: Up to 1 year
Secondary outcomes (5)
Extrahepatic disease response assessed by RECIST 1.1
Measured: Up to 1 year
Hepatic PFS
This will be reported for the overall population (safety analysis set) and will be described for liver only (time to hepatic progress or death) and for overall disease burden (progression free survival per se). Progression free survival will be estimated using the product-limit (Kaplan-Meier) method, with any loss to follow-up as censoring.
Measured: From study treatment to first progression in the treated liver or death (whichever occurs first), assessed up to 1 year
OS
Overall survival will be estimated using the product-limit (Kaplan-Meier) method, with any loss to follow-up as censoring.
Measured: From study treatment to death, assessed up to 1 year
Overall PFS
This will be reported for the overall population (safety analysis set) and will be described for liver only (time to hepatic progress or death) and for overall disease burden (progression free survival per se). Progression free survival will be estimated using the product-limit (Kaplan-Meier) method, with any loss to follow-up as censoring.
Measured: From study treatment to progressive disease (hepatic and extrahepatic) and death, assessed up to 1 year
Overall response rate (both hepatic and extrahepatic disease) assessed by RECIST 1.1
Measured: Up to 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Dec 2016 (estimated)
- Study start28 Jun 2017
- Primary completion26 Nov 2019
- Study completion26 Nov 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Metastatic Carcinoma in the LiverStudies of the same condition, open and under way.
- More trials run by City of Hope Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- City of Hope Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Marwan Fakih, MD, Principal investigator, City of Hope Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03005002
- Sponsor's protocol ID
- 16423
- Other IDs
- NCI-2016-02001, 16423
- Status last verified
- Dec 2018
- First submitted
- 23 Dec 2016
- Last updated
- 26 Dec 2019
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 26 Dec 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pilot Feasibility Study of Durvalumab (MEDI4736) and Tremelimumab Following Radioembolization in Patients With Metastatic Microsatellite Stable (MSS) Colorectal Cancer to the Liver
- ClinicalTrials.gov ID
- NCT03005002
- Acronym / sponsor ID
- 16423
- Conditions
- Metastatic Carcinoma in the Liver, MLH1 Gene Mutation, MSH6 Gene Mutation, PMS2 Gene Mutation, Stage IV Colorectal Cancer, Stage IVA Colorectal Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 9 participants (actual)
- Lead sponsor
- City of Hope Medical CenterUniversity, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Study start
- 28 Jun 2017 (actual)
- Primary completion
- 26 Nov 2019 (actual)
- Study completion
- 26 Nov 2019 (actual)
- First posted
- 29 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This pilot clinical trial studies the side effects and how well durvalumab and tremelimumab work in treating patients with microsatellite stable colorectal cancer that has spread to the liver. Monoclonal antibodies, such as durvalumab and tremelimumab, may interfere with the ability of tumor cells to grow and spread.
Detailed description
PRIMARY OBJECTIVES:
- Establish the safety of durvalumab and tremelimumab following radioembolization with selective internal radiation (SIR)-Spheres in patients with microsatellite stable (MSS) metastatic colorectal cancer to the liver.
II. Determine the hepatic response rate of SIR-Spheres followed by durvalumab and tremelimumab in patients with MSS metastatic colorectal cancer to the liver.
SECONDARY OBJECTIVES:
- Estimate the progression free survival (PFS) and overall survival (OS) of the overall treated population.
II. Describe the overall response rate of the treated population. III. Describe the extra-hepatic response in the treated population (abscopal responses).
TERTIARY OBJECTIVES:
- Describe intra-tumor immune alterations following SIR-Spheres, and following durvalumab plus tremelimumab in comparison to baseline through serial hepatic metastases biopsies.
II. Describe the immune alterations in the blood following SIR-Spheres and following durvalumab plus tremelimumab.
OUTLINE:
Patients receive durvalumab intravenously (IV) over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up periodically.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (durvalumab, tremelimumab) | Experimental | Biological: Durvalumab, Other: Laboratory Biomarker Analysis, Biological: TremelimumabPatients receive durvalumab IV over 60 minutes and tremelimumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 4 courses in the absence of disease progression or unacceptable toxicity. Beginning at week 17, patients receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 9 courses in the absence of disease progression or unacceptable toxicity. |
Who may qualify
- Ages
- 19 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (18 listed)
- Documented informed consent of the subject and/or legally authorized representative
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of > 12 weeks
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
Key exclusion criteria (31 listed)
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site) or previous enrollment in the present study
- Participation in another clinical study with an investigational product during the last 4 weeks
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab or an anti-CTLA4, including tremelimumab
- History of another primary malignancy except for:
- Receipt of the last dose of chemotherapy or tyrosine kinase inhibitors should be at least 3 weeks prior to durvalumab and tremelimumab dosing; monoclonal antibodies such as bevacizumab, ziv-aflibercept, ramucirumab, cetuximab, and panitumumab should be at least 6 weeks prior to durvalumab and tremelimumab therapy
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DurvalumabAlso: Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Given IV | Biological | Treatment (durvalumab, tremelimumab) |
| Laboratory Biomarker AnalysisCorrelative studies | Other | Treatment (durvalumab, tremelimumab) |
| TremelimumabAlso: Anti-CTLA4 Human Monoclonal Antibody CP-675,206, CP-675, CP-675,206, CP-675206Given IV | Biological | Treatment (durvalumab, tremelimumab) |
Primary outcome
Hepatic tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
Time frame: Up to 1 year
Will be summarized using a 90% exact Clopper-Pearson confidence interval
Incidence of adverse events assessed by NCI CTCAE version 4.03
Time frame: Up to 1 year
Toxicities observed will be summarized in terms of type and severity.
5 secondary outcomes
Extrahepatic disease response assessed by RECIST 1.1
Time frame: Up to 1 year
Hepatic PFS
Time frame: From study treatment to first progression in the treated liver or death (whichever occurs first), assessed up to 1 year
OS
Time frame: From study treatment to death, assessed up to 1 year
Overall PFS
Time frame: From study treatment to progressive disease (hepatic and extrahepatic) and death, assessed up to 1 year
Overall response rate (both hepatic and extrahepatic disease) assessed by RECIST 1.1
Time frame: Up to 1 year
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 26 Dec 2019.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Marwan Fakih, MD principal investigator
City of Hope Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Durvalumab, Laboratory Biomarker Analysis and Tremelimumab in people with Metastatic Carcinoma in the Liver and MLH1 Gene Mutation, run by City of Hope Medical Center at 1 site in United States.
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 18 inclusion and 31 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: finished, as of the sponsor's last update on 26 Dec 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
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 is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Hepatic tumor response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 (time frame: Up to 1 year). 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?
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 26 Dec 2019.