3.4.1 Pharmaceutical and Therapeutic Background The importance of intact immune surveillance
in controlling outgrowth of neoplastic transformation has been known for decades.
Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in
cancer tissue and favorable prognosis in various malignancies. In particular, the presence of
CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to
correlate with improved prognosis and long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune
control. The normal function of PD-1, expressed on the cell surface of activated T-cells
under healthy conditions, is to down-modulate unwanted or excessive immune responses,
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member
related to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor
signaling upon engagement of its ligands (PD-L1 and/or PD L2). The structure of murine PD-1
has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing
an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail
which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell
stimulation, PD 1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within
its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ,
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which
PD-1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both
molecules regulate an overlapping set of signaling proteins. PD-1 was shown to be expressed
on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and
Natural Killer cells. Expression has also been shown during thymic development on CD4-CD8-
(double negative) T-cells as well as subsets of macrophages and dendritic cells. The ligands
for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of
cell types, including non-hematopoietic tissues as well as in various tumors. Both ligands
are type I transmembrane receptors containing both IgV- and IgC-like domains in the
extracellular region and contain short cytoplasmic regions with no known signaling motifs.
Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell
receptor. PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably
on vascular endothelium, whereas PD-L2 protein is only detectably expressed on
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2
is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to
dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of
this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in
subjects with melanoma (MEL). This suggests that the PD-1/PD-L1 pathway plays a critical role
in tumor immune evasion and should be considered as an attractive target for therapeutic
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands,
PD-L1 and PD-L2. KeytrudaTM (pembrolizumab) has been approved in the United States for the
treatment of patients with unresectable or metastatic melanoma and disease progression
following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. KeytrudaTM
(pembrolizumab) is also a U.A.E. Ministry of Health registered medication.
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.
2. Be 18 years of age on day of signing informed consent.
3. Have measurable disease based on RECIST 1.1.
4. Be willing 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 6 weeks (42 days)
prior to initiation of treatment on Day 1. 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.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
6. Demonstrate adequate organ function as defined in Table 1, all screening labs should
be performed within 10 days of treatment initiation.
Table 1 Adequate Organ Function Laboratory Values System Laboratory Value
Hematological Absolute neutrophil count (ANC) ≥1,500 /mcL Platelets ≥100,000 / mcL
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days
of assessment) Renal Serum creatinine OR Measured or calculated creatinine clearance
(GFR can also be used in place of creatinine or CrCl) ≤1.5 X upper limit of normal
≥60 mL/min for subject with creatinine levels > 1.5 X institutional ULN Hepatic Serum
total bilirubin ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total
bilirubin levels > 1.5 ULN AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases Albumin >2.5 mg/dL Coagulation
International Normalized Ratio (INR) or Prothrombin Time (PT)
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
≤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 aCreatinine clearance
should be calculated per institutional standard.
9. Female subject 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.
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an
adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the
course of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating 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.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
3. Has a known history of active TB (Bacillus Tuberculosis)
4. Hypersensitivity to pembrolizumab or any of its excipients.
5. 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.
6. Has had prior chemotherapy, 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: If subject received major surgery, they must have recovered adequately from
the toxicity and/or complications from the intervention prior to starting
7. 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.
8. 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 for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
9. Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e. with use of disease modifying agents, corticosteroids 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.
10. Has known history of, or any evidence of active, non-infectious pneumonitis.
11. Has an active infection requiring systemic therapy.
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 known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
14. 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.
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
18. 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.