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

NCT02145559 | Completed Phase 1 DMC

• 1 other identifier: IRB13-0614
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief 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. 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. 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. 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. 4.Sirolimus induced toxicity, especially hyperglycemia and hypertriglyceridemia, will be mitigated by combining sirolimus with metformin.
5. 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.

Conditions

Breast Neoplasms; Lung Neoplasms; Cancer of Liver; Lymphoma; Cancer of Kidney

Outcome Measures

Primary Outcomes (1)

• 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.

  28 days

Secondary Outcomes (3)

• Pharmacodynamic Biomarkers p4EBP1 and pAKT

  28 days

• Tolerability - Full physical Exam

  28 day cycles

• Fasting Serum Glucose and Triglycerides

  28 days

Study Arms (2)

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.

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.

Drug: Delayed Metformin; Drug: Sirolimus

Interventions

Metformin XR DRUG

Metformin XR

Delayed Metformin DRUG

Delayed Metformin

Sirolimus DRUG

Delayed Metformin; Metformin XR

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• 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.

You may not qualify if:

• 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.
• 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.

Sponsors & Collaborators

• University of Chicago: lead

Study Sites (1)

University of Chicago

Chicago, Illinois, 60637, United States

Location

MeSH Terms

Conditions

Breast Neoplasms; Lung Neoplasms; Liver Neoplasms; Lymphoma; Kidney Neoplasms

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Manish Sharma, M.D.

  University of Chicago

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 19, 2014
• First Posted: May 23, 2014
• Study Start: April 1, 2014
• Primary Completion: November 15, 2016
• Study Completion: July 1, 2018
• Last Updated: April 22, 2019

Record last verified: 2019-04

Locations

US (1)