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Pembrolizumab and Vorinostat in Treating Patients with Stage IV Non-small Cell Lung Cancer

Trial Status: Active

This phase I / II trial studies the side effects of pembrolizumab when given together with vorinostat and how well they work in treating patients with stage IV non-small cell lung cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab together with vorinostat may kill more tumor cells.

Inclusion Criteria

  • Be willing and able to provide written informed consent/assent for the trial
  • Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Have archival tissue where available; those patients enrolled on the phase 1 escalation trial where archival tissue is not available will undergo a fresh biopsy where clinically feasible after discussion with the sponsor
  • In addition, patients enrolled on the phase 1 dose escalation, phase 1 expansion or phase II trial must be willing and able to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion; newly-obtained is defined as a specimen obtained up to 3 months prior to initiation of treatment on day 1, and must be obtained after most recent treatment; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the sponsor)
  • Randomized phase II: tumor proportional score of PD-L1 >= 1%.
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  • Absolute neutrophil count (ANC) >= 1,500 /mcL (within 10 days of treatment initiation)
  • Platelets >= 100,000/mcL (within 10 days of treatment initiation)
  • Hemoglobin >= 9 g/dL (within 10 days of treatment initiation)
  • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated (creatinine clearance should be calculated per institutional standard) creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or creatinine clearance [CrCl]) >= 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN (within 10 days of treatment initiation)
  • Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN OR =< 5 x ULN for subjects with liver metastases (within 10 days of treatment initiation)
  • Albumin >= 2.5 mg/dL (within 10 days of treatment initiation)
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
  • Left ventricular ejection fraction (LVEF) >= 45% (within 10 days of treatment initiation)
  • Have a histologic or cytologic diagnosis of stage IV NSCLC
  • Phase I/IB (pre-treated): have progression from at least one prior line of therapy; maintenance therapy following platinum doublet-based chemotherapy is not considered as a separate regimen of therapy; subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease within 6 months of completing therapy are eligible for these arms; subjects with recurrent disease >= 6 months after completing a platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a systemic regimen given to treat the recurrence, must have received another treatment in the first-line metastatic setting
  • Randomized phase II: be treatment naive in the stage IV setting, with the exception of patients whose tumors harbor an activating mutation (including but not limited to EGFR, ALK, ROS1) and were previously treated with targeted therapy; subjects who received platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, and developed recurrent (local or metastatic) disease < 6 months of completing therapy are ineligible for this arm; subjects with recurrent disease >= 6 months after completing a platinum-containing adjuvant, neoadjuvant or definitive chemoradiation therapy given for locally advanced disease, who also subsequently progressed during or after a systemic regimen given to treat the recurrence, are eligible for this arm
  • Female subjects of childbearing potential should have a negative urine or serum pregnancy within 72 hours 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 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects 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 barrier contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy

Exclusion Criteria

  • Is currently participating in and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy at doses >= 10 mg prednisone or any other form of systemic immunosuppressive therapy within 7 days prior to the first dose of trial treatment; subjects are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption); physiologic replacement doses of systemic corticosteroids are permitted, even if > 10 mg/day prednisone equivalents; a brief course (=< 28 days) of corticosteroids for prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity reaction caused by contact allergen) is permitted
  • Has a known history of TB disease (Mycobacterium tuberculosis)
  • Hypersensitivity to pembrolizumab, vorinostat or any of its excipients
  • Patients enrolled on the phase II randomized trial, who have had prior treatment with a PD1 or PDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway (i.e. not “immune therapy naive”) * Note: for those enrolled in the phase I dose escalation, prior use of a PD1 or PDL1, anti-CTLA4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway is allowed; for those enrolled in the phase IB, prior use of a PD1 or PDL1, anti-CTLA4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway is required; for all patients in all phases, prior use of a vaccine for treatment of cancer is allowed
  • Patients enrolled in the phase Ib expansion who have never previously been treated with a PD1 or PDL1 inhibitor, anti-CTLA 4 antibody or any other antibody or drug that specifically targets immune checkpoint pathway in the past (i.e. not "pre-treated”)
  • Patients who have received thoracic radiation > 30 gray (Gy) within six months of the first dose of pembrolizumab
  • Patients taking any histone deacetylase inhibitor (HDACi) other than vorinostat
  • Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier
  • Has had prior chemotherapy within 3 weeks, or targeted small molecule therapy or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: subjects with =< grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: subjects with any grade alopecia are an exception to this criterion and may qualify for the study
  • If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
  • Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids in doses greater than 10 mg of prednisone daily (or equivalent) for at least 7 days prior to trial treatment; this exception does not include carcinomatous meningitis which is excluded regardless of clinical stability
  • Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids in doses greater than 10 mg of prednisone daily [or equivalent] or immunosuppressive drugs); replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment; subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
  • Has an active infection requiring systemic therapy
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, that would substantially increase risk of incurring adverse events (AEs) from the study medications, that would 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 known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
  • Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
  • Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
  • Has received a live vaccine within 30 days of planned start of study therapy; * Note: seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
  • Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis
  • Has a history of, or any evidence of activenon-infectious pneumonitis that required or requires steroids
  • Has evidence of interstitial lung disease
  • Has a history of symptomatic (New York Heart Association [NYHA] class II-IV) heart failure

Florida

Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Jhanelle E. Gray
Phone: 813-745-6895

PRIMARY OBJECTIVES:

I. To determine the safety, tolerability and feasibility of concurrent administration of vorinostat and pembrolizumab. (Phase I escalation)

II. To determine whether concurrent administration of vorinostat and pembrolizumab will be effective in non-small cell lung cancer (NSCLC) patients who have been previously exposed to anti-programmed cell death 1 (PD-1) or anti-programmed cell death 1 ligand 1 (PD-L1) therapy. (Phase Ib expansion)

III. To determine whether concurrent administration of vorinostat and pembrolizumab is more effective than pembrolizumab alone. (Phase II)

SECONDARY OBJECTIVES:

I. To determine immunogenicity molecular profiles that correlate with outcome measures. (Phase Ib and Phase II)

II. To determine immunogenicity profiles that correlate with resistance to therapy. (Phase Ib and Phase II)

III. To examine and model the mechanisms of resistance to immunotherapy available to cancer cells and the eco-evolutionary dynamics that govern proliferation of the resistant phenotypes. (Phase Ib and Phase II)

OUTLINE: This is a phase I, dose escalation study of vorinostat followed by a phase II study.

PHASE I: Patients receive vorinostat orally (PO) once daily (QD) on days 1-21 and pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive vorinostat PO QD on days 1-21 and pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 8 weeks for 1 year, and then every 12 weeks thereafter.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Moffitt Cancer Center

Principal Investigator
Jhanelle E. Gray

  • Primary ID MCC-18494
  • Secondary IDs NCI-2016-00309
  • Clinicaltrials.gov ID NCT02638090