Anti-PD-1 mAb Plus Metabolic Modulator in Solid Tumor Malignancies

NCT04114136 | Recruiting Phase 2 DMC FDA Drug

• 1 other identifier: HCC 18-190
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with 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, who meet eligibility criteria will undergo a biopsy (core or excisional/incisional; FNA not adequate) for baseline tissue. Patients will then be randomized to one of 3 arms: Anti-PD-1 mAb plus Metformin 500mg po BID, Anti-PD-1 mAb alone, Anti-PD-1 mAb plus Rosiglitazone 4mg po qdaily. Five weeks (+/- 7 days) after initiation of therapy a patient will undergo a repeat biopsy (core or excisional/incisional; FNA not adequate) for correlative analysis. The patient will then continue on study therapy for up to 2 years, or until progression of disease or unacceptable toxicity, whichever occurs first. RECIST 1.1 with modifications, to allow for continued therapy until progressive disease is confirmed if the patient is clinically stable, will be used in the trial.

Conditions

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

Keywords

Anti-PD-1 monoclonal antibody (mAb); tumor infiltrating lymphocytes (TIL)

Outcome Measures

Primary Outcomes (1)

• Best overall response

  Best overall response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1), by tumor type, recorded from the start of the treatment until disease progression/recurrence. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (target or non-target) with reduction in short axis to \<10 mm. Partial Response (PR): ≥ 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters. Incomplete Response/Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, (reference smallest sum diameters). Progressive Disease (PD): ≥ 20% increase in the sum of diameters of target lesions (reference smallest sum diameters); the sum must also demonstrate an absolute increase of at least 5 mm; (appearance ≥ 1 new lesions is considered progression).

  From start of the treatment until disease progression/recurrence up to 48 months

Secondary Outcomes (3)

• Progression-free survival (PFS)

  Up to 48 months

• Overall Survival (OS)

  Up to 48 months

• Number of Participants Experiencing Adverse Events Attributed to Treatment

  Up to 48 months

Other Outcomes (3)

• Change in Lymphocyte Cell Status

  Up to 48 months

• Restoration (change) of Mitochondrial Function in Nodal Infiltrating Lymphocytes

  Up to 48 months

• Restoration (change) of Mitochondrial Function in Peripheral Blood Lymphocytes

  Up to 48 months

Study Arms (3)

Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Metformin

EXPERIMENTAL

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator) Metformin - 500 mg by mouth twice daily

Drug: Nivolumab or Pembrolizumab (dependent upon approved indication); Drug: Metformin

Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Rosiglitazone

EXPERIMENTAL

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator) Rosiglitazone - 4 mg by mouth once daily

Drug: Nivolumab or Pembrolizumab (dependent upon approved indication); Drug: Rosiglitazone

Anti-PD-1 mAb (nivolumab or pembrozilumab)

ACTIVE COMPARATOR

nivolumab (480mg IV q 4 weeks) or pembrozilumab (200mg IV q 3 weeks) - dependent upon approved indication. (If both agents are approved for the disease indication, selection is at the discretion of the investigator)

Drug: Nivolumab or Pembrolizumab (dependent upon approved indication)

Interventions

Nivolumab or Pembrolizumab (dependent upon approved indication) DRUG

Anti-PD-1 mAb (monoclonal antibody)

Also known as: Opdivo (nivolumab) or Keytruda (pembrolizumab)

Anti-PD-1 mAb (nivolumab or pembrozilumab); Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Metformin; Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Rosiglitazone

Metformin DRUG

Acts directly or indirectly on the liver to lower glucose production, and acts on the gut to increase glucose utilisation, increase GLP-1 and alter the microbiome.

Also known as: Glucophage, Glucophage XR, Fortamet, and Glumetza

Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Metformin

Rosiglitazone DRUG

A member of the thiazolidinedione class of antidiabetic agents, improves glycemic control by improving insulin sensitivity. Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPARγ).

Also known as: Avandia

Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Rosiglitazone

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 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.
• Accessible tumor for pretreatment (baseline) and post treatment biopsy. Tumor must be accessible for core or surgical biopsy (excisional/incisional), FNA is not adequate
• Age ≥ 18 years
• Have at least one measurable area of disease (Target Lesion) based on RECIST 1.1.
• ECOG performance status 0-2
• 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
• 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.
• 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.
• 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.
• Ability to understand and the willingness to sign a written informed consent document
• If known to have prior brain metastases, must not have evidence of active (enlarging and/or symptomatic lesions) brain disease on MRI/CT evaluation.
• 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.

You may not qualify if:

• Treatment with prior anti-PD-1 or anti-PD-L1 mAb therapy
• 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.
• 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.
• 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.
• 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.
• History of uncontrolled cardiac disease (e.g., uncontrolled hypertension, unstable angina, myocardial infarction within prior 6 months)
• Symptomatic heart failure or New York Heart Association Class III or IV heart failure
• Psychiatric illness or other social issues limiting compliance
• Has a history of non-infectious pneumonitis that required steroids, evidence of interstitial lung disease, or currently active non-infectious pneumonitis.
• Treatment with a non-approved or investigational drug within 14 days prior to Day 1 of study treatment.
• 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.
• 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.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Per Medical History Review
• Hypersensitivity to metformin, rosiglitazone, pembrolizumab or nivolumab
• Unable to take in pills either orally or via feeding tube

Sponsors & Collaborators

• Dan Zandberg: lead

Study Sites (1)

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

RECRUITING

Related Publications (1)

• Zandberg DP, Menk AV, Velez M, Normolle D, DePeaux K, Liu A, Ferris RL, Delgoffe GM. Tumor hypoxia is associated with resistance to PD-1 blockade in squamous cell carcinoma of the head and neck. J Immunother Cancer. 2021 May;9(5):e002088. doi: 10.1136/jitc-2020-002088.

  PMID: 33986123 DERIVED

MeSH Terms

Conditions

Melanoma; Carcinoma, Hepatocellular; Squamous Cell Carcinoma of Head and Neck; Adenocarcinoma Of Esophagus

Interventions

Nivolumab; pembrolizumab; Metformin; Rosiglitazone

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Liver Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Carcinoma, Squamous Cell; Head and Neck Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Biguanides; Guanidines; Amidines; Organic Chemicals; Thiazolidinediones; Thiazoles; Sulfur Compounds; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Dan P Zandberg

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Jennifer Ruth, RN, BSN

CONTACT

412-623-8963; ruthj2@upmc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: September 26, 2019
• First Posted: October 3, 2019
• Study Start: September 14, 2020
• Primary Completion: August 8, 2025
• Study Completion (Estimated): October 2, 2027
• Last Updated: April 24, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)