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. 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).
2. 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.
3. 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.
4. Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be
mitigated by combining sirolimus with metformin.
5. 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.
This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and
i. 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.
i. 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
iii. To compare fasting serum glucose and triglycerides on sirolimus before and after the
addition of metformin XR.
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.
1. 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.
2. ECOG performance status 0 or 1 (See Appendix B).
3. Age ≥ 18 years.
4. Non-pregnant, non-lactating women using adequate contraception.
5. Ability to understand and willingness to sign informed consent.
6. Adequate hematologic, renal and hepatic function, as defined by each of the
- 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.
7. 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.
8. Measurable or non-measurable disease will be allowed.
9. 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.
1. Prior treatment with an mTOR inhibitor (including sirolimus) is allowed; however,
patients with ≥ grade 3 toxicities with an mTOR inhibitor are excluded.
2. Fasting glucose > 200 mg/dL or fasting triglycerides > 300 mg/dL.
3. 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.
4. 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).
5. 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.
6. Pregnancy or breastfeeding.
7. Major surgery within 4 weeks.
8. Concurrent use of any proton pump inhibitors, as these limit the absorption of
9. History of lactic acidosis as per prior medical records or provided by the patient.
10. 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.
11. Participants with known uncontrolled diabetes, defined as a hemoglobin A1C of > 8%.
12. Participants who are already on treatment with metformin, except when metformin can
be held for 4 weeks prior to the start of the study.
13. 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.