Combining Pembrolizumab with Decitabine and Pralatrexate for T-cell Lymphomas

Novel Immuno-epigenetic Based Platform for Patients With Peripheral T-cell Lymphoma (PTCL) and Cutaneous T-cell Lymphoma (CTCL): an International Phase Ib Study of Pembrolizumab Combined With Decitabine and/or Pralatrexate

This study is testing a new combination of three drugs to see if it can help people with tough-to-treat T-cell lymphomas feel better and improve their treatment outcomes.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 37 (estimated)
• Ages: 18 Years to 90 Years
• Sex: All
• Sponsor: University of Virginia (Academic / other)
• Drugs / interventions: pembrolizumab, prednisone
• Locations: 2 sites (Pittsburgh, Pennsylvania and 1 other locations)
• Trial ID: NCT03240211 on ClinicalTrials.gov

What this trial studies

This international, multicenter, phase Ib trial aims to evaluate the safety and efficacy of pembrolizumab in combination with decitabine and pralatrexate for patients with relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL). The study will determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of these combinations while assessing dose-limiting toxicities (DLTs). Utilizing a continual reassessment method for dose allocation, the trial seeks to enhance the antitumor activity of pembrolizumab by priming and modulating malignant cells and their microenvironment. The study will also involve tissue sampling to support the evaluation of treatment effects.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with histologically confirmed relapsed or refractory PTCL or CTCL.

Not a fit: Patients with non-relapsed or non-refractory T-cell lymphomas or those who do not meet the eligibility criteria may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment combination could provide a new therapeutic option for patients with difficult-to-treat T-cell lymphomas.

How similar studies have performed: While this approach is novel in its specific combination, similar studies have shown promise in utilizing immunotherapy and epigenetic modulators for treating lymphomas.

Eligibility criteria

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 Global Response Score for CTCL.
4. Patient must have histologically confirmed relapsed or refractory Peripheral T-cell lymphoma (PTCL) or cutaneous T-cell Lymphoma (CTCL) as per WHO criteria and TNMB classification and staging.
5. There is no upper limit for the number of prior therapies. Patient may have relapsed after prior autologous stem cell transplant.
6. Patients who had prior treatment for their disease, as long as there is radiographic evidence of refractory or relapsed disease and the patient meets all other clinical and laboratory criteria for study treatment.
7. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Be willing to provide FNA 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.
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 labs should be performed within 10 days of treatment initiation.
10. 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.
11. Female subjects of childbearing potential (Section 7.7.9.2) must be willing to use an adequate method of contraception as outlined in Section 7.9.2 - Contraception for the 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 an adequate 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 dose of study therapy.

Exclusion Criteria:

1. Has lack of resolution of adverse events (AE) due to previously administered antineoplastic 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 immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Use of steroid equivalent 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 its excipients.
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 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 (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. The following are exceptions to this criterion: subjects with vitiligo or alopecia; subjects with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement; subjects with psoriasis not requiring systemic treatment; patients with autoimmune phenomena secondary to active lymphoma.
10. Has known history of, or any evidence of non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
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 or live-attenuated vaccine within 30 days of planned start 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

Where this trial is running

Pittsburgh, Pennsylvania and 1 other locations

• Allegheny Health Network — Pittsburgh, Pennsylvania, United States (Recruiting)
• University of Virginia — Charlottesville, Virginia, United States (Recruiting)

Study contacts

• Principal investigator: Enrica Marchi, MD, PhD — University of Virginia
• Study coordinator: Marian Abdelmalek, MSc

Conditions PTCL; CTCL; Pembrolizumab; Decitabine; Pralatrexate; T-cell lymphoma