Neoplasms

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Respiratory Tract (Lung and Bronchial) Diseases

Blood and Lymph Conditions

Immune System Diseases

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Rare Diseases

Breast Neoplasms

Carcinoma, Renal Cell

Lung Neoplasms

Lymphoma

Liver Neoplasms

Kidney Neoplasms

Carcinoma

Breast Diseases

Skin Diseases

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

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Digestive System Neoplasms

Gastrointestinal Diseases

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Urologic Neoplasms

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Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Male Urogenital Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Renal Cell Carcinoma

Lymphosarcoma

Hypoglycemic Agents

All Drugs and Chemicals

Anti-Infective Agents

Antineoplastic Agents

Metformin

Sirolimus

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

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.

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.

Metformin XR

Delayed Metformin

Manish Sharma, M.D.

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.

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

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.

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.

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.

To compare fasting serum glucose and triglycerides on sirolimus before and after the addition of metformin XR.

University of Chicago

Spots Global Cancer Trial Database for delayed metformin