Combining Anti-PD-1 Therapy with Metformin and Rosiglitazone for Cancer Treatment

A Phase II Clinical Trial of Anti-PD-1 mAb Therapy Alone or With Metabolic Modulators to Reverse Tumor Hypoxia and Immune Dysfunction in Solid Tumor Malignancies

This study is testing if combining a cancer treatment called anti-PD-1 therapy with two diabetes medications, Metformin and Rosiglitazone, can help people with advanced solid tumors fight their cancer better.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 72 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of Pittsburgh (Academic / other)
• Drugs / interventions: Pembrolizumab, Nivolumab, immunotherapy
• Locations: 1 site (Pittsburgh, Pennsylvania)
• Trial ID: NCT04114136 on ClinicalTrials.gov

What this trial studies

This clinical trial investigates the effectiveness of combining anti-PD-1 monoclonal antibodies with metabolic modulators Metformin and Rosiglitazone in patients with advanced solid tumors. Eligible participants will undergo a biopsy and be randomized into three treatment groups: anti-PD-1 mAb plus Metformin, anti-PD-1 mAb alone, or anti-PD-1 mAb plus Rosiglitazone. The study aims to assess whether these combinations can enhance the immune response against tumors by reducing tumor hypoxia and improving T cell function. Patients will continue treatment for up to two years or until disease progression or unacceptable toxicity occurs.

Who should consider this trial

Good fit: Ideal candidates include adults with advanced melanoma, NSCLC, renal cell carcinoma, and other specified solid tumors who are eligible for anti-PD-1 therapy.

Not a fit: Patients with tumors that are not accessible for biopsy or those with Child Pugh Class B or C liver disease may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to improved response rates in patients with advanced solid tumors.

How similar studies have performed: While the combination of immunotherapy with metabolic modulators is a novel approach, similar studies have shown promise in enhancing immune responses in cancer treatment.

Eligibility criteria

Inclusion Criteria:

1. Histologically or cytologically confirmed advanced melanoma, renal cell carcinoma, NSCLC, HCC (Child Pugh Class A only), MSI-High solid tumors, Urothelial Cancer, GE junction/Gastric Adenocarcinoma, or HNSCC for which current standard of care treatment for their stage of disease would be with Pembrolizumab or Nivolumab monotherapy.
2. Accessible tumor for pretreatment (baseline) and post treatment biopsy. Tumor must be accessible for core or surgical biopsy (excisional/incisional), FNA is not adequate
3. Age ≥ 18 years
4. Have at least one measurable area of disease (Target Lesion) based on RECIST 1.1.
5. ECOG performance status 0-2
6. Patients must have normal organ and marrow function as defined below:

   absolute neutrophil count ≥1,500/mcL platelets ≥100,000/mcL total bilirubin ≤ institutional upper limit of normal (ULN) AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN Creatinine clearance ≥40 mL/min/1.73 m2
7. Female subjects of childbearing potential should have a negative urine or serum pregnancy within 7 days prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
8. Female subjects of childbearing potential should be willing to use one methods of birth control or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Women of childbearing potential are those who have not been surgically sterilized or have not been free from menses for \> 1 year.
9. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.
10. Ability to understand and the willingness to sign a written informed consent document
11. If known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI/CT evaluation.
12. A type II DM patient who does not currently require prescription medication for diabetes treatment and has not received metformin, insulin, sulfonylureas or thiazolidinediones within 60 days of the start of study treatment can be enrolled on the study.

Exclusion Criteria:

1. Treatment with prior anti-PD-1 or anti-PD-L1 mAb therapy
2. Patients with type I DM or any patient who has received metformin, insulin, sulfonylureas, or thiazolidinediones within 60 days of start of study treatment for any reason.
3. Pregnancy or breastfeeding. Women of childbearing potential (WOCBP) must practice acceptable methods of birth control to prevent pregnancy. Prior to study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during trial participation and the potential risk factors for an unintentional pregnancy. In addition, men enrolled on this study must be informed of the risks to any sexual partner of childbearing potential and should practice an effective method of birth control.
4. All WOCBP MUST have a negative pregnancy test within 7 days prior to first receiving investigational product. If the pregnancy test is positive, the patient must not receive investigational product and must not be enrolled in the study.
5. Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic therapy or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjogren's syndrome will not be excluded from the study.
6. History of uncontrolled cardiac disease (e.g., uncontrolled hypertension, unstable angina, myocardial infarction within prior 6 months)
7. Symptomatic heart failure or New York Heart Association Class III or IV heart failure
8. Psychiatric illness or other social issues limiting compliance
9. Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
10. Treatment with a non-approved or investigational drug within 14 days prior to Day 1 of study treatment.
11. Prior malignancy within 2 years with the exception of adequately treated basal cell or squamous cell skin cancer, carcinoma of the cervix or prostate cancer.
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
13. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Per Medical History Review
14. Hypersensitivity to metformin, rosiglitazone, pembrolizumab or nivolumab
15. Unable to take in pills either orally or via feeding tube
16. History of acidosis of any type or habitual intake of 5 or more alcoholic beverages a day.
17. Patients that require active treatment with Rifampin or Gemfibrozil for other medical conditions.

Where this trial is running

Pittsburgh, Pennsylvania

• UPMC Hillman Cancer Center — Pittsburgh, Pennsylvania, United States (Recruiting)

Study contacts

• Principal investigator: Dan P Zandberg — UPMC Hillman Cancer Center
• Study coordinator: Jennifer Ruth, RN, BSN

Conditions Melanoma; NSCLC; Hepatocellular Carcinoma; Urothelial Cancer; Gastric Adenocarcinoma; HNSCC; Esophageal Adenocarcinoma; Microsatellite Instability-High Solid Malignant Tumor