Colorectal AdenocarcinomaPhase 2NCT03800602
Nivolumab and Metformin in Patients With Treatment Refractory MSS Colorectal Cancer
A Phase 2 study testing Metformin and Nivolumab in people with Colorectal Adenocarcinoma and Metastatic Microsatellite Stable Colorectal Carcinoma, run by Emory University at 3 sites in United States.
Trial summary
This phase II trial studies how well nivolumab and metformin work in treating patients with microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous treatment. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Colorectal Adenocarcinoma, Metastatic Microsatellite Stable Colorectal Carcinoma, Refractory Colorectal Carcinoma
- What is being tested?
- Metformin and Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 29 participants
- Where
- 3 sitesUnited States
- Study dates
- 15 Jan 2019to 4 Sep 2021
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
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
- Patients must have histologically or cytologically confirmed stage IV colorectal adenocarcinoma with measurable disease
- Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan containing chemotherapy (needs to be treated with anti-epidermal growth factor receptor (EGFR) agent if extended RAS wild type)
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky ≥ 70%)
- Life expectancy of greater than 3 months
- Absolute neutrophil count ≥ 1,500/µL
Show all 20Show fewer
- Platelets ≥ 100,000/µL
- Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment)
- Serum creatinine ≤ 1.5 x upper limit of normal (ULN) OR creatinine clearance ≥ 60 mL/min/1.73 m² for patients with creatinine levels > 1.5 x ULN. Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin > 1.5 ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT] ≤ 2.5 x institutional upper limit of normal
- Serum albumin ≥ 2.5 mg/dl
- International normalized ratio (INR) or prothrombin time (PT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
- Patients with diabetes mellitus should be on a stable diabetic treatment regimen for at least 1 month prior to trial enrollment and keep a blood glucose level log at home for the first 4 weeks of the trial
- Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication; if the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
- Male subjects of childbearing potential must agree to use an adequate method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 120 days after the last dose of study medication
- Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- Ability to understand and the willingness to sign a written informed consent document
Who cannot join
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study
- Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- Metformin use in the last 3 months
- Patients who are receiving any other investigational agents
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
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- History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and metformin
- Has a known history of active tuberculosis (TB) (Bacillus tuberculosis)
- Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
- Has known history of, or any evidence of active, non-infectious pneumonitis
- Has an active infection requiring systemic therapy
- Has known substance abuse disorders that would interfere with cooperation with the requirements of the trial
- Has received prior therapy with an anti-programmed death (PD)-1, anti-PD-L1, or anti-PD-L2 agent
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days of planned start of study therapy.
- Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris or myocardial infraction within 6 months of study entry, serious cardiac arrhythmia requiring medications, baseline corrected QT (QTc) > 450 msec or previous history of QT prolongation while taking other medications
- Other medications, or severe acute/chronic medical or psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study
- Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer; subjects with prior malignancies are eligible if the subject has been disease free for > 5 years
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Emory University Hospital Midtown
Atlanta, Georgia, 30308
Emory University Hospital/Winship Cancer Institute
Atlanta, Georgia, 30322
Emory Saint Joseph's Hospital
Atlanta, Georgia, 30342
About this study
Official title: Phase II Trial of Nivolumab and Metformin in Patients With Treatment Refractory MSS Metastatic Colorectal Cancer
This phase II trial studies how well nivolumab and metformin work in treating patients with microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Metformin is an antidiabetic drug that and may reduce the risk of colorectal cancer development in patients. Giving nivolumab and metformin may work better in treating patients with refractory microsatellite metastatic colorectal cancer.
Read the detailed description
PRIMARY OBJECTIVE:
- To evaluate the effect of nivolumab and metformin combination on the overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
SECONDARY OBJECTIVES:
- To determine the effect of nivolumab and metformin combination on clinical outcomes, progression free survival and overall survival, and biochemical response (CEA).
II. To compare the effect of nivolumab and metformin combination on immune and metabolic biomarkers in the tumor microenvironment and systemic circulation (pre and post treatment paired biopsies required).
OUTLINE:
Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal
After completion of study treatment, patients are followed up at day 30 and then periodically thereafter.
- Conditions
- Colorectal Adenocarcinoma, Metastatic Microsatellite Stable Colorectal Carcinoma, Refractory Colorectal Carcinoma, Stage IV Colorectal Cancer, Stage IVA Colorectal Cancer, Stage IVB Colorectal Cancer
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MetforminDrug
Also called Glucophage, Glumetza, Fortamet
Given PO
NivolumabBiological
Also called BMS-936558, MDX-1106, NIVO, ONO-4538
Given IV
| Study group | Role | What they receive |
|---|---|---|
| Treatment (nivolumab, metformin) | Experimental | Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal. Receives: Drug: Metformin; Biological: Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Overall Response Rate (ORR)
Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1., and rate will be calculated as a proportion (responders/total patients).
Measured: Up to 1 year after study start
Secondary outcomes (3)
Progression Free Survival (PFS)
For progression free survival, progression or death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
Measured: Assessed up to 2 years after study start
Overall Survival (OS)
For overall survival, death from any cause will be defined as the event. Patients will be censored at time of last follow-up.
Measured: Assessed up to 2 years after study start
Biological Response: Carcinoembryonic Antigen (CEA)
Tumor marker carcinoembryonic antigen (CEA) will be assessed.
Measured: Up to 1 year after study start
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Jan 2019
- Study start15 Jan 2019
- Primary completion4 Sep 2020
- Study completion4 Sep 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Colorectal AdenocarcinomaStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 29 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- Bristol-Myers Squibb, National Cancer Institute (NCI), National Institutes of Health (NIH)
- Responsible party
- Principal investigator, Olumide Gbolahan, Emory University
- Investigators
- Olumide B. Gbolahan, MBBS, MSc, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03800602
- Sponsor's protocol ID
- IRB00106678
- Other IDs
- NCI-2018-02201, Winship4494-18, P30CA138292
- Status last verified
- Sep 2024
- First submitted
- 9 Jan 2019
- Last updated
- 5 Sep 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
Akce M, Farran B, Switchenko JM, Rupji M, Kang S, Khalil L, Ruggieri-Joyce A, Olson B, Shaib WL, Wu C, Alese OB, Diab M, Lesinski GB, El-Rayes BF. Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer. J Immunother Cancer. 2023 Oct;11(10):e007235. doi: 10.1136/jitc-2023-007235.
PubMed 37852737
Study at a glance
From the registry record, last updated by the sponsor on 5 Sep 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase II Trial of Nivolumab and Metformin in Patients With Treatment Refractory MSS Metastatic Colorectal Cancer
- ClinicalTrials.gov ID
- NCT03800602
- Acronym / sponsor ID
- IRB00106678
- Conditions
- Colorectal Adenocarcinoma, Metastatic Microsatellite Stable Colorectal Carcinoma, Refractory Colorectal Carcinoma, Stage IV Colorectal Cancer, Stage IVA Colorectal Cancer, Stage IVB Colorectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 29 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- Bristol-Myers Squibb, National Cancer Institute (NCI), National Institutes of Health (NIH)
- Study start
- 15 Jan 2019 (actual)
- Primary completion
- 4 Sep 2020 (actual)
- Study completion
- 4 Sep 2021 (actual)
- First posted
- 11 Jan 2019 (actual)
- Results
- Posted 5 Sep 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This phase II trial studies how well nivolumab and metformin work in treating patients with microsatellite stable (MSS) stage IV colorectal cancer that has not responded to previous treatment. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Metformin is an antidiabetic drug that and may reduce the risk of colorectal cancer development in patients. Giving nivolumab and metformin may work better in treating patients with refractory microsatellite metastatic colorectal cancer.
Detailed description
PRIMARY OBJECTIVE:
- To evaluate the effect of nivolumab and metformin combination on the overall response rate (ORR) as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
SECONDARY OBJECTIVES:
- To determine the effect of nivolumab and metformin combination on clinical outcomes, progression free survival and overall survival, and biochemical response (CEA).
II. To compare the effect of nivolumab and metformin combination on immune and metabolic biomarkers in the tumor microenvironment and systemic circulation (pre and post treatment paired biopsies required).
OUTLINE:
Patients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal
After completion of study treatment, patients are followed up at day 30 and then periodically thereafter.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Treatment (nivolumab, metformin) | Experimental | Drug: Metformin, Biological: NivolumabPatients receive metformin PO BID starting on day 1. After 14 days of metformin only period patients also receive nivolumab IV every 4 weeks starting on day 15. Courses repeat every 28 days for up to 2 years in the absence of disease progression, unacceptable toxicity or consent withdrawal. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- Patients must have histologically or cytologically confirmed stage IV colorectal adenocarcinoma with measurable disease
- Prior treatment with 5 Fluorouracil (or capecitabine), oxaliplatin and irinotecan containing chemotherapy (needs to be treated with anti-epidermal growth factor receptor (EGFR) agent if extended RAS wild type)
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky ≥ 70%)
- Life expectancy of greater than 3 months
Key exclusion criteria (22 listed)
- Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
- Metformin use in the last 3 months
- Patients who are receiving any other investigational agents
- Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab and metformin
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 |
|---|---|---|
| MetforminAlso: Glucophage, Glumetza, FortametGiven PO | Drug | Treatment (nivolumab, metformin) |
| NivolumabAlso: BMS-936558, MDX-1106, NIVO, ONO-4538Given IV | Biological | Treatment (nivolumab, metformin) |
Primary outcome
Overall Response Rate (ORR)
Time frame: Up to 1 year after study start
Response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1., and rate will be calculated as a proportion (responders/total patients).
3 secondary outcomes
Progression Free Survival (PFS)
Time frame: Assessed up to 2 years after study start
Overall Survival (OS)
Time frame: Assessed up to 2 years after study start
Biological Response: Carcinoembryonic Antigen (CEA)
Time frame: Up to 1 year after study start
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Sep 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 37852737Akce M, Farran B, Switchenko JM, Rupji M, Kang S, Khalil L, Ruggieri-Joyce A, Olson B, Shaib WL, Wu C, Alese OB, Diab M, Lesinski GB, El-Rayes BF. Phase II trial of nivolumab and metformin in patients with treatment-refractory microsatellite stable metastatic colorectal cancer. J Immunother Cancer. 2023 Oct;11(10):e007235. doi: 10.1136/jitc-2023-007235.
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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.
Olumide B. Gbolahan, MBBS, MSc principal investigator
Emory University
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Metformin and Nivolumab in people with Colorectal Adenocarcinoma and Metastatic Microsatellite Stable Colorectal Carcinoma, run by Emory University at 3 sites 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 20 inclusion and 22 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 5 Sep 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites 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 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Sep 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
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?
Overall Response Rate (ORR) (time frame: Up to 1 year after study start). 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 NCT03800602, which also lists 1 linked publication.
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 5 Sep 2024.