Study of Pembrolizumab Combined With Decitabine and Pralatrexate in PTCL and CTCL

Inclusion Criteria:

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 as defined by the Lugano Criteria for PTCL and by the GlobalResponse Score for CTCL.

4. Patient must have histologically confirmed relapsed or refractory Peripheral T-celllymphoma (PTCL) or cutaneous T-cell Lymphoma (CTCL) as per WHO criteria and TNMBclassification and staging.

5. There is no upper limit for the number of prior therapies. Patient may have relapsedafter prior autologous stem cell transplant.

6. Patients who had prior treatment for their disease, as long as there is radiographicevidence of refractory or relapsed disease and the patient meets all other clinicaland laboratory criteria for study treatment.

7. Be willing to provide tissue from a newly obtained core or excisional biopsy of atumor lesion. Be willing to provide FNA of a tumor lesion. Newly-obtained is definedas a specimen obtained up to 6 weeks (42 days) prior to initiation of treatment onDay 1. Subjects for whom newly obtained samples cannot be provided (e.g.inaccessible or subject safety concern) may submit an archived specimen only uponagreement from the Sponsor.

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

9. Demonstrate adequate organ function as defined in the protocol, all screening labsshould be performed within 10 days of treatment initiation.

10. Female subjects of childbearing potential should have a negative urine or serumpregnancy within 72 hours prior to receiving the first dose of study medication. Ifthe urine test is positive or cannot be confirmed as negative, a serum pregnancytest will be required.

11. Female subjects of childbearing potential (Section 7.7.9.2) must be willing to usean adequate method of contraception as outlined in Section 7.9.2 - Contraception forthe course of the study through 120 days after the last dose of study medication.

12. Male subjects of childbearing potential (Section 7.9.2) must agree to use anadequate method of contraception as outlined in Section 7.9.2- Contraception,starting with the first dose of study therapy through 120 days after the last doseof study therapy.

Exclusion Criteria:

1. Has lack of resolution of adverse events (AE) due to previously administeredantineoplastic therapy to grade 1 or less according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

2. Had prior therapy with PD-1 inhibitors.

3. Has a diagnosis of immunodeficiency or has been receiving any immunosuppressivetherapy within 7 days prior to the first dose of trial treatment. Use of steroidequivalent to prednisone 10 mg/day does not constitute an exclusion criterion.

4. Has a known history of active TB (Bacillus Tuberculosis)

5. Hypersensitivity to pralatrexate, or decitabine or pembrolizumab or any of itsexcipients.

6. Has received prior allogeneic stem cell transplant.

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 ofthe skin that has undergone potentially curative therapy or in situ cervical cancer.

8. Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided they are stable (without evidence of progression by imaging for at leastfour weeks prior to the first dose of trial treatment and any neurologic symptomshave 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. Thisexception does not include carcinomatous meningitis which is excluded regardless ofclinical stability.

9. Has active autoimmune disease that has required systemic treatment in the past 2years (i.e. with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitaryinsufficiency, etc.) is not considered a form of systemic treatment. The followingare exceptions to this criterion: subjects with vitiligo or alopecia; subjects withhypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement;subjects with psoriasis not requiring systemic treatment; patients with autoimmunephenomena secondary to active lymphoma.

10. Has known history of, or any evidence of non-infectious pneumonitis/interstitiallung disease that required steroids or has current pneumonitis/interstitial lungdisease.

11. Has an active infection requiring systemic therapy.

12. Has a history or current evidence of any condition, therapy, or laboratoryabnormality that might confound the results of the trial, interfere with thesubject's participation for the full duration of the trial, or is not in the bestinterest of the subject to participate, in the opinion of the treating investigator.

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

14. Is pregnant or breastfeeding or expecting to conceive or father children within theprojected duration of the trial, starting with the pre-screening or screening visitthrough 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 or live-attenuated vaccine within 30 days of plannedstart of study therapy. Administration of killed vaccines is allowed.

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