A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors

Objectives:

This is a descriptive study to evaluate the pharmacodynamic markers of dual sirolimus and
metformin therapy.

Primary Objective:

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.

Secondary Objectives:

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
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.

Inclusion Criteria

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 following:

- 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.

Exclusion Criteria

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
metformin30,41.

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.