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BRIEF TITLE: Anti-PD-1 mAb Therapy Alone or With Metabolic Modulators to Reverse Tumor Hypoxia and Immune Dysfunction 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


  • Org Study ID: HCC 18-190
  • Secondary ID:
  • NCT ID: NCT04114136
  • NCT Alias:
  • Sponsor: Dan Zandberg - Other
  • Source: University of Pittsburgh

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.

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.

Overal Status Start Date Phase Study Type
Recruiting August 18, 2020 Phase 2 Interventional

Primary Outcomes:

Primary Outcome 1 - Measure: Best overall response

Primary Outcome 1 - Time Frame: From start of the treatment until disease progression/recurrence up to 48 months

Condition:

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

Eligibility

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.
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Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

Official Information

Name: Dan P Zandberg

Role: Principal Investigator

Affiliation: UPMC Hillman Cancer Center

Overall Contact

Name: Krystle Eaton, RN, BSN

Phone: 412-623-7957

Email: mientkiewiczk@upmc.edu

Location

Facility Status Contact
UPMC Hillman Cancer Center
Pittsburgh, Pennsylvania 15232
United States
Recruiting Krystle Eaton, RN, BSN
412-623-7957
mientkiewiczk@upmc.edu