Breast NeoplasmsPhase 1NCT02145559
A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors
A Phase 1 study testing Metformin XR, Delayed Metformin and Sirolimus in people with Breast Neoplasms and Lung Neoplasms, run by University of Chicago at 1 site in United States.
Trial summary
Given the role of mTOR signaling and probable synergistic activity of combining sirolimus and metformin in patients with advanced solid tumors, the investigators hypothesize that: 1. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Breast Neoplasms, Lung Neoplasms, Cancer of Liver
- What is being tested?
- Metformin XR, Delayed Metformin and Sirolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 24 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2014to Jul 2018
- 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
- Histologically or cytologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
- ECOG performance status 0 or 1 (See Appendix B).
- Age ≥ 18 years.
- Non-pregnant, non-lactating women using adequate contraception.
- Ability to understand and willingness to sign informed consent.
- Adequate hematologic, renal and hepatic function, as defined by each of the following:
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- Absolute neutrophil count (ANC) > l500/μl
- Platelets > 100,000/μl
- Total bilirubin < 1.5 x upper limit of normal
- SGOT and SGPT < 2.5x upper limit of normal for patients without liver metastases or SGOT and
- SGPT < 5 x upper limit of normal for patients with liver metastases.
- Creatinine < 1.4 mg/dl for females or < 1.5 mg/dl for males.
- Prior treatment with mTOR inhibitors will be allowed as long as the patient did not have ≥ Grade 3 toxicity attributed to the mTOR inhibitor with prior therapy.
- Measurable or non-measurable disease will be allowed.
- Patients taking substrates, inhibitors, or inducers of CYP3A4 (See Appendix C) should be encouraged to switch to alternative drugs whenever possible, given the potential for drug-drug interactions with sirolimus.
Who cannot join
- Prior treatment with an mTOR inhibitor (including sirolimus) is allowed; however, patients with ≥ grade 3 toxicities with an mTOR inhibitor are excluded.
- Fasting glucose > 200 mg/dL or fasting triglycerides > 300 mg/dL.
- Patients who have had chemotherapy or immunotherapy within 4 weeks of starting study drug, or radiotherapy within 14 days of starting study drug, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- Patients may not be receiving any other investigational agents or any concomitant antineoplastic therapy, with the exceptions of octreotide LAR (for neuroendocrine tumors) and endocrine therapy (for prostate, breast, or gynecologic malignancies).
- Serious underlying medical (including acute decompensated congestive heart failure) or psychiatric illnesses that would, in the opinion of the treating physician, substantially increase the risk for complications related to treatment. Similarly, any unstable medical condition that, in the opinion of the treating physician or study investigators, would interfere with the study objectives.
- Pregnancy or breastfeeding.
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- Major surgery within 4 weeks.
- Concurrent use of any proton pump inhibitors, as these limit the absorption of metformin30,41.
- History of lactic acidosis as per prior medical records or provided by the patient.
- Metabolic acidosis, acute or chronic. Acidosis will be defined a blood pH < 7.35. Acidosis will be suspected if serum bicarbonate is < 22 mEq/L. In such cases, venous blood pH would be checked to confirm or exclude acidosis.
- Participants with known uncontrolled diabetes, defined as a hemoglobin A1C of > 8%.
- Participants who are already on treatment with metformin, except when metformin can be held for 4 weeks prior to the start of the study.
- History of ongoing alcohol abuse or binge drinking. Alcohol abuse will be defined as a pattern of drinking that results in harm to one's health, interpersonal relationships, and ability to work. Binge drinking will be defined as at least one episode of consuming more than five units in men and four units in women during the previous month. One unit of alcohol can generally said to be a half pint of beer, a single measure (shot glass) of a spirit or a small glass of table wine.
Trial locations and contacts
1 site in 1 country.
About this study
Given the role of mTOR signaling and probable synergistic activity of combining sirolimus and metformin in patients with advanced solid tumors, the investigators hypothesize that:
- The combination of metformin plus sirolimus will result in reduction of p4EBP1, p70S6K and pAKT more than sirolimus alone in peripheral blood T cells (PBTC).
- The combination of metformin plus sirolimus will result in decreased levels of serum biomarkers including fasting insulin, C-peptide, glucose, triglycerides, LDH, IGF-1, IGF-1R, IGF-BP and leptin, but an increase in adiponectin in peripheral blood.
- Expression of active forms of AMPK, mTOR, PI3K, PTEN loss, AKT, LKB1, P62, LC3, and/or ULK1 in the tumor tissue (original pathology) will be predictive of response to combination therapy. This will be an exploratory hypothesis for this study.
- Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be mitigated by combining sirolimus with metformin.
- Metformin plus sirolimus will have promising anti-cancer activity and this activity will correlate with decreases in the above biomarkers. This will be an exploratory hypothesis for this study.
Read the detailed description
Objectives:
This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and metformin therapy.
Primary Objective:
- To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
Secondary Objectives:
- To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone. ii. To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses. iii. To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.
Study Design:
This will be an open-label, randomized study in which all eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days (lead-in period); cycle 1, days 1-8. Before starting the sirolimus the investigators will obtain previous pathology (if available) and collect blood lymphocytes for baseline testing of biomarkers as is shown in study calendar. The pharmacodynamic biomarkers will be collected again on cycle 1, day 8 to assess the effect of sirolimus alone on these biomarkers. In the previous study, the effect of sirolimus on p70S6K was observed within 48 hours of the first dose9. On day 8, patients will be randomized 1:1 to metformin XR (500 mg daily with the evening meal) or no metformin for two weeks (through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. A repeat biomarkers evaluation will be done on cycle 1, day 22 to assess the effect of adding metformin on these pharmacodynamic biomarkers. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. CT scans will be obtained after every 2 cycles to assess the response by RECIST version 1.140. Metformin will be temporarily held on the day of CT scan and resumed 48 hours after CT scan. This is due to increased risk of lactic acidosis with iodinated contrast agent and is a standard procedure for contrast enhanced CT scan at the University of Chicago.
- Conditions
- Breast Neoplasms, Lung Neoplasms, Cancer of Liver, Lymphoma, Cancer of Kidney
- Being tested
- Metformin XR, Delayed Metformin, Sirolimus
- Medical subject headings
- Breast Neoplasms, Lung Neoplasms, Liver Neoplasms, Lymphoma, Kidney Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Metformin XRDrug
Delayed MetforminDrug
SirolimusDrug
| Study group | Role | What they receive |
|---|---|---|
| Metformin XR | Experimental | All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Receives: Drug: Metformin XR; Drug: Sirolimus |
| Delayed Metformin | Active comparator | All eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. Receives: Drug: Delayed Metformin; Drug: Sirolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pharmacodynamic Biomarker p70S6K
To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
Measured: 28 days
Secondary outcomes (3)
Pharmacodynamic Biomarkers p4EBP1 and pAKT
To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone.
Measured: 28 days
Tolerability - Full physical Exam
To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses a full history and physical exam will be conducted on days 1, 8, and 15.
Measured: 28 day cycles
Fasting Serum Glucose and Triglycerides
To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.
Measured: 28 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 May 2014 (estimated)
- Study startApr 2014
- Primary completion15 Nov 2016
- Study completionJul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast NeoplasmsStudies of the same condition, open and under way.
- More trials run by University of ChicagoThe 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
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 24 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Chicago
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Manish Sharma, M.D., Principal investigator, University of Chicago
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02145559
- Sponsor's protocol ID
- IRB13-0614
- Status last verified
- Apr 2019
- First submitted
- 19 May 2014
- Last updated
- 22 Apr 2019
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors
- ClinicalTrials.gov ID
- NCT02145559
- Acronym / sponsor ID
- IRB13-0614
- Conditions
- Breast Neoplasms, Lung Neoplasms, Cancer of Liver, Lymphoma, Cancer of Kidney
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 24 participants (actual)
- Lead sponsor
- University of ChicagoUniversity, hospital or other
- Study start
- Apr 2014
- Primary completion
- 15 Nov 2016 (actual)
- Study completion
- Jul 2018 (actual)
- First posted
- 23 May 2014 (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.
Given the role of mTOR signaling and probable synergistic activity of combining sirolimus and metformin in patients with advanced solid tumors, the investigators hypothesize that:
- The combination of metformin plus sirolimus will result in reduction of p4EBP1, p70S6K and pAKT more than sirolimus alone in peripheral blood T cells (PBTC).
- The combination of metformin plus sirolimus will result in decreased levels of serum biomarkers including fasting insulin, C-peptide, glucose, triglycerides, LDH, IGF-1, IGF-1R, IGF-BP and leptin, but an increase in adiponectin in peripheral blood.
- Expression of active forms of AMPK, mTOR, PI3K, PTEN loss, AKT, LKB1, P62, LC3, and/or ULK1 in the tumor tissue (original pathology) will be predictive of response to combination therapy. This will be an exploratory hypothesis for this study.
- Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be mitigated by combining sirolimus with metformin.
- Metformin plus sirolimus will have promising anti-cancer activity and this activity will correlate with decreases in the above biomarkers. This will be an exploratory hypothesis for this study.
Detailed description
Objectives:
This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and metformin therapy.
Primary Objective:
- To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
Secondary Objectives:
- To compare the changes in pharmacodynamic biomarkers p4EBP1 and pAKT in peripheral blood T cells with the combination of metformin XR and sirolimus to those with sirolimus alone. ii. To assess the tolerability of the combination of metformin XR plus sirolimus at the selected doses. iii. To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.
Study Design:
This will be an open-label, randomized study in which all eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days (lead-in period); cycle 1, days 1-8. Before starting the sirolimus the investigators will obtain previous pathology (if available) and collect blood lymphocytes for baseline testing of biomarkers as is shown in study calendar. The pharmacodynamic biomarkers will be collected again on cycle 1, day 8 to assess the effect of sirolimus alone on these biomarkers. In the previous study, the effect of sirolimus on p70S6K was observed within 48 hours of the first dose9. On day 8, patients will be randomized 1:1 to metformin XR (500 mg daily with the evening meal) or no metformin for two weeks (through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. A repeat biomarkers evaluation will be done on cycle 1, day 22 to assess the effect of adding metformin on these pharmacodynamic biomarkers. From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. CT scans will be obtained after every 2 cycles to assess the response by RECIST version 1.140. Metformin will be temporarily held on the day of CT scan and resumed 48 hours after CT scan. This is due to increased risk of lactic acidosis with iodinated contrast agent and is a standard procedure for contrast enhanced CT scan at the University of Chicago.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin XR | Experimental | Drug: Metformin XR, Drug: SirolimusAll eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will recieve metformin XR (500 mg daily with the evening meal)(through day 21). On day 15, patients randomized to metformin XR will have their dose increased to 1000 mg daily if there is no grade ≥ 2 toxicity due to metformin XR. Patients who develop grade 2 toxicity due to metformin will be maintained on metformin XR 500 mg daily for the rest of the study, while patients who develop > grade 2 toxicity will be taken off study. From day 22 onwards, all patients will be on combination of sirolimus and metformin. |
| Delayed Metformin | Active comparator | Drug: Delayed Metformin, Drug: SirolimusAll eligible patients with histologically-confirmed advanced solid tumors will be started on sirolimus (3 mg daily) alone for the first 7 days. On day 8, patients will be randomized to receive no metformin for two weeks (through day 21). From day 22 onwards, all patients will be on combination of sirolimus and metformin. Patients who were initially not randomized to metformin XR will begin taking it at 500 mg daily with an evening meal and titrated up to 1000 mg daily after one week, as above. Each cycle will be 4 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- Histologically or cytologically confirmed solid tumor that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective.
- ECOG performance status 0 or 1 (See Appendix B).
- Age ≥ 18 years.
- Non-pregnant, non-lactating women using adequate contraception.
- Ability to understand and willingness to sign informed consent.
Key exclusion criteria (13 listed)
- Prior treatment with an mTOR inhibitor (including sirolimus) is allowed; however, patients with ≥ grade 3 toxicities with an mTOR inhibitor are excluded.
- Fasting glucose > 200 mg/dL or fasting triglycerides > 300 mg/dL.
- Patients who have had chemotherapy or immunotherapy within 4 weeks of starting study drug, or radiotherapy within 14 days of starting study drug, or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
- Patients may not be receiving any other investigational agents or any concomitant antineoplastic therapy, with the exceptions of octreotide LAR (for neuroendocrine tumors) and endocrine therapy (for prostate, breast, or gynecologic malignancies).
- Serious underlying medical (including acute decompensated congestive heart failure) or psychiatric illnesses that would, in the opinion of the treating physician, substantially increase the risk for complications related to treatment. Similarly, any unstable medical condition that, in the opinion of the treating physician or study investigators, would interfere with the study objectives.
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 |
|---|---|---|
| Metformin XR | Drug | Metformin XR |
| Delayed Metformin | Drug | Delayed Metformin |
| Sirolimus | Drug | Delayed Metformin, Metformin XR |
Primary outcome
Pharmacodynamic Biomarker p70S6K
Time frame: 28 days
To compare the change in the pharmacodynamic biomarker p70S6K in peripheral blood T cells with the combination of metformin XR and sirolimus to that with sirolimus alone.
3 secondary outcomes
Pharmacodynamic Biomarkers p4EBP1 and pAKT
Time frame: 28 days
Tolerability - Full physical Exam
Time frame: 28 day cycles
Fasting Serum Glucose and Triglycerides
Time frame: 28 days
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 22 Apr 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.
Manish Sharma, M.D. principal investigator
University of Chicago
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 Metformin XR, Delayed Metformin and Sirolimus in people with Breast Neoplasms and Lung Neoplasms, run by University of Chicago 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 15 inclusion and 13 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 22 Apr 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?
Pharmacodynamic Biomarker p70S6K (time frame: 28 days). 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 22 Apr 2019.