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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
Anti-PD-1 mAb (monoclonal antibody)
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).
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania, United States
RECRUITINGBest 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).
Time frame: From start of the treatment until disease progression/recurrence up to 48 months
Progression-free survival (PFS)
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.
Time frame: Up to 48 months
Overall Survival (OS)
The length of time after study enrollment that patients remain alive.
Time frame: Up to 48 months
Number of Participants Experiencing Adverse Events Attributed to Treatment
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.
Time frame: Up to 48 months
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