Pembrolizumab + Decitabine + Pralatrexate for T-Cell Lymphoma

Not currently recruiting at 4 trial locations

Overseen By Marian Abdelmalek, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Owen A, O'Connor, M.D., Ph.D.

Must not be taking: Immunosuppressants, PD-1 inhibitors

Disqualifiers: Active infection, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

Duration: 1-2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores new treatment combinations for T-cell lymphoma, a type of blood cancer. Researchers test different mixes of three drugs—pembrolizumab (an immunotherapy drug), pralatrexate, and decitabine—to find the safest and most effective doses. People with relapsed or hard-to-treat T-cell lymphoma who have already received other treatments might be suitable candidates for this trial. Participants will help scientists understand how these drug combinations work and how well they improve the condition.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on immunosuppressive therapy or have recently received a live vaccine, you may need to stop or adjust these treatments before starting the trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that the combination treatments under study, including pembrolizumab, pralatrexate, and decitabine, have demonstrated promising safety results in past studies. Pembrolizumab, commonly used in cancer treatment, is usually well-tolerated but can sometimes cause immune-related side effects, such as rare conditions like type 1 diabetes, occurring in about 0.2% of patients.

Pralatrexate has been studied in patients with T-cell lymphoma and, while effective, may cause low blood cell counts, mouth sores, and fatigue. Decitabine, often used for blood-related cancers, is generally well-tolerated but can lead to temporary drops in blood cell counts.

When combined, pembrolizumab with either pralatrexate or decitabine has proven safe and effective in patients with heavily treated T-cell lymphoma. These combinations are being tested to determine the best doses that balance effectiveness with minimal side effects. Overall, these treatments show good potential for safety, but patients must be monitored closely for any side effects during the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for T-cell lymphoma because they combine pembrolizumab, a checkpoint inhibitor that unleashes the immune system against cancer, with other drugs like pralatrexate and decitabine, which target cancer cells directly. Unlike standard treatments such as CHOP (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), these combinations aim to enhance the body's natural defenses while simultaneously attacking cancer cells. The unique aspect of these treatments lies in their potential to offer a dual approach: boosting immune response and disrupting cancer cell growth, which could lead to more effective outcomes for patients.

What evidence suggests that this trial's treatments could be effective for T-Cell Lymphoma?

This trial will evaluate the effectiveness of different combinations of pembrolizumab, pralatrexate, and decitabine for treating T-cell lymphoma. Research shows that combining pembrolizumab with other treatments may help treat T-cell lymphoma. In Arm A of this trial, pembrolizumab combines with pralatrexate, which has shown a response rate of about 29% in patients whose T-cell lymphoma has returned or resisted treatment. Pralatrexate alone has a response lasting about 10 months on average in similar cases. In Arm B, pembrolizumab and pralatrexate combine with decitabine, which might enhance effectiveness by altering the tumor environment to improve results. Arm C will test pembrolizumab with decitabine. Early studies suggest these treatments are safe and can lead to positive responses in patients. ^{3 5 6 7 8}

Who Is on the Research Team?

Enrica Marchi, MD

Principal Investigator

University of Virginia

Owen O'Connor, MD, PhD

Principal Investigator

University of Virginia

Are You a Good Fit for This Trial?

Adults with relapsed or refractory Peripheral T-cell lymphoma (PTCL) or Cutaneous T-cell Lymphoma (CTCL), who can provide consent and a recent tumor sample. They must have adequate organ function, no severe unresolved side effects from past cancer treatments, not be on immunosuppressants, and agree to use contraception. Excluded are those with active infections, certain other cancers, CNS metastases, autoimmune diseases requiring treatment in the last 2 years, known allergies to trial drugs or their components.

Inclusion Criteria

I am fully active or restricted in physically strenuous activity but can do light work.

My organ functions are within the required range for the study.

Be willing and able to provide written informed consent/assent for the trial

Exclusion Criteria

I have been treated with PD-1 inhibitors before.

I have not taken immunosuppressive drugs in the last week, except for low-dose steroids.

I have a history of active tuberculosis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab, pralatrexate, and/or decitabine in various combinations to determine the maximum tolerated dose and evaluate clinical efficacy

1-2 years

Multiple visits based on treatment schedule (e.g., day 1, 8, 15)

Follow-up

Participants are monitored for safety, efficacy, and duration of response after treatment

1-2 years

What Are the Treatments Tested in This Trial?

Interventions

• Decitabine
• Pembrolizumab
• Pralatrexate

Trial Overview The study is testing combinations of Pembrolizumab with Decitabine and Pralatrexate in patients with PTCL and CTCL. It aims to find the highest dose patients can tolerate without serious side effects (MTD), recommend doses for future phases (RP2D), identify dose-limiting toxicities (DLTs), and assess how well these drug combos work at MTD.

How Is the Trial Designed?

Group I: Arm C: Pembrolizumab plus Decitabine Experimental Treatment 2 Interventions

Subjects will receive pembrolizumab 200 mg IV and decitabine 20 mg/m2 from day 1 to 5 (or day 1 to 3, depending on dose level).

Group II: Arm B: Pembrolizumab plus Pralatrexate plus Decitabine Experimental Treatment 3 Interventions

Subjects will receive pembrolizumab 200 mg IV day 8 with pralatrexate 20 mg/m2 IV day 1, 8, and 15 and decitabine 10 mg/m2 from day 1 to 5 ( or day 1 to 3, depending on dose level).

Group III: Arm A: Pembrolizumab plus Pralatrexate Experimental Treatment 2 Interventions

Subjects will receive pembrolizumab 200 mg IV day 1 with pralatrexate 30 mg/m2 IV day 1, 8, and 15.

Decitabine is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Dacogen for:

• Acute myeloid leukemia
• Myelodysplastic syndromes

Approved in United States as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Canada as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Dacogen for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

Owen A, O'Connor, M.D., Ph.D.

Lead Sponsor

Trials

1

Recruited

40+

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Otsuka Pharmaceutical Development & Commercialization, Inc.

Industry Sponsor

Trials

271

Recruited

170,000+

John Kraus

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Medical Officer since 2023

MD, PhD

Tarek Rabah

Otsuka Pharmaceutical Development & Commercialization, Inc.

Chief Executive Officer since 2022

BS in Biology and BA in Business from the American University of Beirut, MBA from McGill University

Published Research Related to This Trial

Pembrolizumab (Keytruda) is approved for treating advanced endometrial carcinoma that is microsatellite instability-high or mismatch repair deficient, specifically for patients whose disease has progressed after previous treatments.

This approval is significant for patients who are not candidates for curative surgery or radiation, providing a new therapeutic option for a challenging stage of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. Aschenbrenner, DS.[2022]

In the KEYNOTE-189 study involving 616 patients with metastatic non-squamous non-small-cell lung cancer, the combination of pembrolizumab and pemetrexed-platinum significantly maintained quality of life (GHS/QOL) scores compared to placebo, with a notable improvement at week 21.

Patients receiving pembrolizumab also experienced a longer median time to deterioration in symptoms like cough and chest pain, although this result was not statistically significant, indicating potential benefits in symptom management with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Garassino, MC., Gadgeel, S., Esteban, E., et al.[2020]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

Pralatrexate (PDX) shows selective effectiveness against T-cell lymphoma, but resistance can develop through mechanisms like increased dihydrofolate reductase (DHFR) expression and reduced folate carrier1 levels, as seen in resistant cell lines with significantly higher IC50 values.

Combining PDX with hypomethylating agents can reverse resistance, suggesting a potential strategy to enhance treatment efficacy, while DUSP4 and STAT5 may serve as biomarkers for PDX activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of pralatrexate resistant T-cell lymphoma lines reveals two patterns of acquired drug resistance that is overcome with epigenetic modifiers. Scotto, L., Kinahan, C., Casadei, B., et al.[2021]

Pralatrexate is a promising new antifolate drug that shows significant activity against aggressive T-cell lymphomas, particularly in patients with recurrent or refractory disease, which typically have poor treatment options.

The main side effect of pralatrexate is mucositis, but this can be managed with folic acid and vitamin B12 supplementation, making it a safer option for patients undergoing treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pralatrexate, a new hope for aggressive T-cell lymphomas? Rueda, A., Casanova, M., Quero, C., et al.[2022]

Pralatrexate is an effective treatment for relapsed or refractory peripheral T cell lymphoma, achieving an overall response rate of 29% and a median response duration of 10.1 months, making it the first single agent approved for this condition.

The main side effect of pralatrexate is mucositis, but this can be managed with folic acid and vitamin B12 supplementation, highlighting the importance of supportive care in enhancing treatment safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Critical appraisal of pralatrexate in the management of difficult-to-treat peripheral T cell lymphoma. Casanova, M., Medina-Pérez, A., Moreno-Beltran, M., et al.[2021]

Pralatrexate is an FDA-approved chemotherapy specifically for relapsed and refractory peripheral T-cell lymphomas, showing promising activity in treating T-cell lymphomas and non-small cell lung cancer.

This drug is designed to have a high affinity for the reduced folate carrier (RFC-1), which enhances its cellular uptake and leads to a stronger antitumor effect compared to traditional antifolates like methotrexate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pralatrexate - from bench to bedside. Zain, JM., Marchi, E.[2017]

In a phase 1 study involving patients with advanced cancer, the combination of pralatrexate and docetaxel, along with vitamin B12 and folic acid supplementation, was found to be well tolerated at a maximum dose of pralatrexate 120 mg/m² and docetaxel 35 mg/m².

This combination showed significant antitumor activity in patients with non-small-cell lung cancer, indicating its potential for further testing in phase 2 trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase 1 study of pralatrexate in combination with paclitaxel or docetaxel in patients with advanced solid tumors. Azzoli, CG., Krug, LM., Gomez, J., et al.[2018]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pralatrexate, an antifolate drug, shows improved effectiveness against T-cell lymphomas when combined with bortezomib, demonstrating synergistic cytotoxicity in various T-lymphoma cell lines.

The combination of pralatrexate and bortezomib did not increase toxicity to normal cells compared to using each drug alone, suggesting a safer treatment option for patients with T-cell malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pralatrexate is synergistic with the proteasome inhibitor bortezomib in in vitro and in vivo models of T-cell lymphoid malignancies. Marchi, E., Paoluzzi, L., Scotto, L., et al.[2015]

Citations

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Pembrolizumab and decitabine for refractory or relapsed ... These data emphasize the importance of acquired T cell number in scRNA-seq experiments as well as the need for statistical definitions of T cell expansions ...

2. ashpublications.org ashpublications.org/blood/article/144/18/1936/517268/Epigenetic-agents-plus-anti-PD-1-reprogram-the

Epigenetic agents plus anti-PD-1 reprogram the tumor ... Key PointsAmong patients relapsed or progressed after DP, CDP combination therapy is tolerable and highly effective.

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Efficacy of Decitabine plus Anti-PD-1 Camrelizumab in ... The median progression-free survival (PFS) of nivolumab or pembrolizumab monotherapy in relapsed/refractory cHL was reported to about 1 year, and long-lasting ...

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PD-1 blockade combined with decitabine to treat refractory... We report a case of refractory PTCL-NOS, which had poor efficacy in the six-line treatments and even suffered disease progression.

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Pembrolizumab + Decitabine + Pralatrexate for T-Cell ... Pralatrexate has shown significant activity against T-cell lymphomas, with an overall response rate of 29% and a median duration of response of 10.1 months in ...

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Study of Pembrolizumab Combined With Decitabine and ... The primary objectives of the study in each arm is to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), dose limiting toxicities ( ...

7. ashpublications.org ashpublications.org/blood/article/140/Supplement%201/9425/487984/Pembrolizumab-in-Combination-with-Epigenetic

Pembrolizumab in Combination with Epigenetic Therapy Is ... Pembrolizumab in combination with epigenetic therapy is safe and active in heavily treated patients with peripheral T-cell lymphoma (PTCL) and cutaneous T-cell ...

8. es.aetna.com es.aetna.com/cpb/medical/data/800_899/0890.html

Pembrolizumab (Keytruda) - Medical Clinical Policy Bulletins It is indicated for multiple types of cancers, including certain types of melanoma, non-small cell lung cancer (NSCLC), gastric cancer, Hodgkin lymphoma, head ...