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2,4-thiazolidinedione

Rosiglitazone

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

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

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

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)

Nivolumab or Pembrolizumab (dependent upon approved indication)

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.

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).

Jennifer Ruth, RN, BSN

Dan P Zandberg, MD

Dan P Zandberg

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.

The prognosis for patients with metastatic disease remains poor. The use of immunotherapy in the treatment of cancer is based on the premise that tumors evade the endogenous immune response by being recognized as self, and not non-self. The recent success of immune-modulating agents in patients with refractory solid tumors has provided proof-of-concept of the efficacy of immune system activation as a therapeutic modality. Tumors develop immune resistance using different mechanisms; the goal of immunotherapy is to counteract these resistance mechanisms, allowing the endogenous immune system to reject tumors. One of those mechanisms of resistance is tumor hypoxia

This study aims to examine whether Metformin and Rosiglitazone will reduce tumor oxygen consumption, creating a less hypoxic T cell environment, with pharmacologic remodeling of the TME leading to restored anti-tumor T cell effector function and as a result will act synergistically with anti-PD-1 mAb resulting in a higher response rate than with anti-PD-1 mAb alone. The safety and tolerability of if adding metformin or rosiglitazone to anti-PD-1 mAb therapy will assessed.

Eligible patients will undergo pre-treatment biopsy and then will be randomized to one of three arms: 1. Anti-PD-1 mAb + Metformin 500mg PO BID 2. Anti-PD-1 mAb alone or 3. Anti-PD-1 mAb plus Rosiglitazone 4mg po qdaily. Patients will undergo post treatment biopsy after 5 weeks (+/- 7 days) of treatment and then continue treatment for up to 2 years, or until progression of disease or unacceptable toxicity, whichever occurs first.

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

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

Percent of T cell proliferation (increase in number of cells) in peripheral blood prior to treatment compared to post treatment. T cell proliferation is associated with anti-tumor response.

Percent of mitochondrial restoration in nodal infiltrating lymphocytes (located within tumor) prior to treatment compared to post treatment. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents.

Percent of mitochondria restoration in peripheral blood lymphocytes prior to treatment compared to after treatment. Functional mitochondria might ultimately lead to the restoration of apoptosis in cancer cells that are refractory to current anticancer agents.

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).

The length of time after study enrollment that patients lives without experiencing disease progression per RECIST v1.1. Progressive Disease (PD): ≥20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). The sum must also demonstrate an absolute increase of ≥5 mm. The appearance ≥1 new lesion(s) is considered progression.

The length of time after study enrollment that patients remain alive.

Participants experiencing adverse events (per CTCAE v5.0) that are possibly, probably or definitely related to study treatment, will be tabulated by category, grade and relatedness.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Anti-PD-1 mAb Plus Metabolic Modulator in Solid Tumor Malignancies	NCT04114136	Melanoma NSCLC Hepatocellular ... Urothelial Canc... Gastric Adenoca... HNSCC Esophageal Aden... Microsatellite ...	Nivolumab or Pe... Metformin Rosiglitazone	18 Years -	University of Pittsburgh
Anti-PD-1 mAb Plus Metabolic Modulator in Solid Tumor Malignancies	NCT04114136	Melanoma NSCLC Hepatocellular ... Urothelial Canc... Gastric Adenoca... HNSCC Esophageal Aden... Microsatellite ...	Nivolumab or Pe... Metformin Rosiglitazone	18 Years -	University of Pittsburgh

Spots Global Cancer Trial Database for nivolumab or pembrolizumab (dependent upon approved indication)