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

• ClinicalTrials.gov Identifier: NCT04114136
• Recruitment Status: Recruiting
• First Posted: October 3, 2019
• Last Update Posted: October 8, 2020
• Sponsor: Dan Zandberg
• Information provided by (Responsible Party): Dan Zandberg, University of Pittsburgh

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Melanoma; Renal Cell Carcinoma; NSCLC; Hepatocellular Carcinoma; Urothelial Cancer; Gastric Adenocarcinoma; HNSCC; Esophageal Adenocarcinoma; Microsatellite Instability-High Solid Malignant Tumor	Drug: Nivolumab or Pembrolizumab (dependent upon approved indication); Drug: Metformin; Drug: Rosiglitazone	Phase 2

Detailed 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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 108 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: August 18, 2020
• Estimated Primary Completion Date: December 2022
• Estimated Study Completion Date: December 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Metformin; 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); Anti-PD-1 mAb (monoclonal antibody); Other Name: Opdivo (nivolumab) or Keytruda (pembrolizumab); Drug: Metformin; 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.; Other Name: Glucophage, Glucophage XR, Fortamet, and Glumetza
Experimental: Anti-PD-1 mAb (nivolumab or pembrozilumab) plus Rosiglitazone; 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); Anti-PD-1 mAb (monoclonal antibody); Other Name: Opdivo (nivolumab) or Keytruda (pembrolizumab); Drug: Rosiglitazone; 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).; Other Name: Avandia
Active Comparator: Anti-PD-1 mAb (nivolumab or pembrozilumab); 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); Anti-PD-1 mAb (monoclonal antibody); Other Name: Opdivo (nivolumab) or Keytruda (pembrolizumab)

Outcome Measures

Primary Outcome Measures :

1. Best overall response [ Time Frame: From start of the treatment until disease progression/recurrence up to 48 months ]
   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).

Secondary Outcome Measures :

1. Progression-free survival (PFS) [ Time Frame: Up to 48 months ]
   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.
2. Overall Survival (OS) [ Time Frame: Up to 48 months ]
   The length of time after study enrollment that patients remain alive.
3. Number of Participants Experiencing Adverse Events Attributed to Treatment [ Time Frame: Up to 48 months ]
   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.

Other Outcome Measures:

1. Change in Lymphocyte Cell Status [ Time Frame: Up to 48 months ]
   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.
2. Restoration (change) of Mitochondrial Function in Nodal Infiltrating Lymphocytes [ Time Frame: Up to 48 months ]
   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.
3. Restoration (change) of Mitochondrial Function in Peripheral Blood Lymphocytes [ Time Frame: Up to 48 months ]
   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.
4. Oral and Stool Microbiome [ Time Frame: Up to 48 months ]
   Differences in the composition of the oral and stool microbiomes between responders and non-responders (to treatment) will be characterized using the ANCOM method. ANCOM accounts for the underlying structure in the data and can be used for comparing the composition of microbiomes in two or more populations of people.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 swallow pills
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.

Contacts and Locations

Contacts

Contact: Krystle Eaton, RN, BSN; 412-623-7957; mientkiewiczk@upmc.edu

Contact: Amy Rose, RN, BSN; 412-647-8587; kennaj@UPMC.EDU

Locations

United States, Pennsylvania

UPMC Hillman Cancer Center; Recruiting

Pittsburgh, Pennsylvania, United States, 15232

Contact: Krystle Eaton, RN, BSN 412-623-7957 mientkiewiczk@upmc.edu

Sponsors and Collaborators

Dan Zandberg

Investigators

• Principal Investigator: Dan P Zandberg; UPMC Hillman Cancer Center

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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). pii: e002088. doi: 10.1136/jitc-2020-002088.

• Responsible Party: Dan Zandberg, Associate Professor of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04114136
• Other Study ID Numbers: HCC 18-190
• First Posted: October 3, 2019
• Last Update Posted: October 8, 2020
• Last Verified: October 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Dan Zandberg, University of Pittsburgh:

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

Additional relevant MeSH terms:

Carcinoma; Neoplasms; Adenocarcinoma; Carcinoma, Renal Cell; Microsatellite Instability; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms by Site; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Kidney Diseases; Urologic Diseases; Genomic Instability; Pathologic Processes; Metformin; Rosiglitazone; Pembrolizumab; Nivolumab; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action