Pembrolizumab and All-Trans Retinoic Acid Combination Treatment of Advanced Melanoma

Primary Objective

- To identify the MTD and RP2D of the combination of pembrolizumab and ATRA.

Secondary Objective:

- Describe the safety and toxicity of combined treatment with pembrolizumab and all-trans
retinoic acid (ATRA) [brand name VESANOID] in melanoma patients.

- To assess the anti-tumor activity in terms of a). The reduction in MDSC
(immunosuppressive myeloid -derived suppressor cells) frequency and suppressive function
(measured as a continuous variable)in peripheral blood of advanced melanoma patients
undergoing pembrolizumab and VESANOID combination therapy. b). progression free
survival.

Exploratory Objective

- To determine the clinical outcomes with tumor-specific T cell responses.

Inclusion Criteria:

1. Diagnosis of advanced melanoma (unresectable Stage III or Stage IV Melanoma).

2. Planned standard treatment with pembrolizumab.

3. Be willing and able to provide written informed consent for the trial.

4. State willingness to comply with all study procedures and be available for the
duration of the trial.

5. Be ≥ 18 years of age on day of signing informed consent.

6. Have a performance status of 0 or 1 on the ECOG Performance Scale.

7. Demonstrate adequate organ function as defined in Table 1 of the protocol.

8. 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.

9. Female subjects of childbearing potential (Section 6.5.2 - Contraception) must be
willing to use an adequate method of contraception as outlined in Section 6.5.2 of the
protocol - 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.

10. Male subjects of childbearing potential (Section 6.5.2- Contraception) must agree to
use an adequate method of contraception as outlined in Section 6.5.2 of the protocol -
Contraception, starting with the first dose of study therapy through 120 days after
the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception
for the subject.

Exclusion Criteria:

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
treatment.

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. Subjects with
chronic conditions such as vision changes from plaque radiation therapy for ocular
melanoma or prior hearing loss that is not reasonably expected to be exacerbated by
the investigational product may be included.

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 therapy.

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 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
form of systemic treatment.

9. Has known history of, or any evidence of active, non-infectious pneumonitis.

10. Has an active infection requiring systemic therapy.

11. 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.

12. Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.

13. 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.

14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.

15. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

16. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).

17. 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.

18. Has known sensitivity to retinoic acid derivatives.

19. Has a medical history of allogenic stem cell transplant or received a solid organ
transplant.