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

  • STATUS
    Recruiting
  • End date
    Dec 25, 2023
  • participants needed
    108
  • sponsor
    Dan Zandberg
Updated on 25 January 2021
cancer
monoclonal antibodies
serum pregnancy test
carcinoma
metastasis
progressive disease
gastric adenocarcinoma
neutrophil count
pembrolizumab
brain metastases
sulfonylureas
brain metastasis
nivolumab
metformin
adenocarcinoma
solid tumour
solid tumor
squamous cell carcinoma of head and neck
metastatic cancer
advanced melanoma

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.

Description

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.

Details
Condition Non-Small Cell Lung Cancer, Adenocarcinoma, Malignant neoplasm of kidney, melanoma, Renal Cell Carcinoma, skin cancer, HEPATIC NEOPLASM, HEPATOCELLULAR CARCINOMA, Metastatic Melanoma, Gastric Adenocarcinoma, Squamous Cell Carcinoma of the Head and Neck, Esophageal Adenocarcinoma, Urothelial Cancer, Squamous Cell Carcinoma of Head and Neck, HNSCC, Kidney Cancer, Malignant Melanoma, Liver Cancer, Malignant Adenoma, Renal Cell Cancer, Renal Cancer, Microsatellite Instability-High Solid Malignant Tumor, Microsatellite Instability-High Solid Malignant Tumor, adenocarcinoma of esophagus, clear cell renal cell carcinoma, nsclc, stomach adenocarcinoma, liver cell carcinoma, Microsatellite Instability-High Solid Malignant Tumor
Treatment Metformin, Rosiglitazone, Nivolumab or Pembrolizumab (dependent upon approved indication)
Clinical Study IdentifierNCT04114136
SponsorDan Zandberg
Last Modified on25 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

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

Exclusion Criteria

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 swallow pills
History of acidosis of any type or habitual intake of 5 or more alcoholic beverages a day
Patients that require active treatment with Rifampin or Gemfibrozil for other medical conditions
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