Lymphoma Clinical Trial
Official title:
A Pharmacodynamic Study of Sirolimus and Metformin in Patients With Advanced Solid Tumors
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.
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.
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