The main purpose of this study is to see whether the combination of two drugs called
pembrolizumab and vorinostat can help people with advanced lung cancer. Researchers also
want to find out if the combination of pembrolizumab and vorinostat is safe and tolerable.
This study will compare the effects of the combination of two drugs called pembrolizumab and
vorinostat with the effects of pembrolizumab alone. The U.S. Food and Drug Administration
(FDA) has approved pembrolizumab for use to treat a deadly skin cancer called melanoma and
lung cancer and vorinostat to treat some forms of blood and lymph node cancers.
A Phase I/Randomized Phase II clinical trial of pembrolizumab and vorinostat in Eastern
Cooperative Oncology Group (ECOG) 0-1 patients with immune therapy naïve and immune therapy
pretreated locally advanced or metastatic NSCLC who have progressed through one prior line
The begins with a phase I dose escalation utilizing the modified continuous reassessment
method (O'Quigley, Pepe, & Fisher, 1990). This would be followed by a phase I expansion at
the maximum tolerated dose (MTD) in 18 NSCLC patients who have been previously treated with
anti-PD-1 or anti-PD-L1 therapy. In parallel, a separate phase II arm will randomize 70
patients to a pembrolizumab alone group and a pembrolizumab plus vorinostat group.
- Willing and able to provide written informed consent/assent for the trial.
- Be ≥ 18 years of age on day of signing informed consent.
- Have measurable disease based on Response Evaluation Criteria in Solid Tumors
- Have archival tissue where available. Those participants 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, participants 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.
- Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
- Demonstrate adequate organ function.
- Have a histologic or cytologic diagnosis of Stage IV non-small cell lung cancer
- Have progression from at least one prior line of therapy, with progression occurring
no more than 6 months after the end of therapy.
- Females of childbearing potential should have a negative urine or serum pregnancy
within 72 hours prior to receiving the first dose of study medication.
- Females 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.
- Males 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
- 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. Participants 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 (e.g., contrast dye allergy) or
for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity
reaction caused by contact allergen) is permitted.
- Has a known history of tuberculosis (TB) Disease (Mycobacterium tuberculosis).
- Hypersensitivity to pembrolizumab, vorinostat or any of its excipients.
- Participants 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 naïve").
-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 all participants in all phases, prior use of a
vaccine for treatment of cancer is allowed.
- Participants 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
- Participants who have received thoracic radiation >30Gy within 6 months of the first
dose of pembrolizumab.
- Patients taking any 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 with 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: Patients with ≤ Grade 2 neuropathy are an exception to this criterion and may
qualify for the study. Note: Patients with any grade alopecia are an exception to
this criterion and may qualify for the study.
- If participant 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. Previously treated brain metastases may be an exception if stable and
specific other criteria are met.
- Has active autoimmune disease that has required systemic treatment in the past 2
years. Replacement therapy 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 known history of, or any evidence of active, non-infectious pneumonitis.
- Has an active infection requiring systemic therapy.
- 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., HBsAg reactive) or Hepatitis C (e.g., HCV 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
- Has evidence of interstitial lung disease