Pembrolizumab + Decitabine + Pralatrexate for T-Cell Lymphoma

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

37 Participants Needed

Trial Summary

What is the purpose of this trial?

This is an international, multicenter, multi-arm, phase Ib, model-based dose-escalation study. 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 (DLTs) and to evaluate the clinical efficacy at the MTD of various combinations of pembrolizumab, pralatrexate and decitabine.

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.

What data supports the effectiveness of the drug pralatrexate for T-cell lymphoma?

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 clinical studies. It is the first single agent approved for relapsed or refractory peripheral T-cell lymphoma, indicating its potential effectiveness in treating this condition. ^{1 2 3 4 5}

Is the combination of Pembrolizumab, Decitabine, and Pralatrexate generally safe for humans?

Pembrolizumab, used in cancer treatment, can cause immune-related side effects, including a rare risk of developing type 1 diabetes in 0.2% of cases. Safety data from other studies involving Pembrolizumab show it is generally safe, but it can cause various side effects, some of which may be serious. ^{6 7 8 9 10}

What makes the drug combination of Pembrolizumab, Decitabine, and Pralatrexate unique for T-cell lymphoma?

This drug combination is unique because it includes Pralatrexate, a novel antifolate specifically designed to improve drug uptake and retention in cells, which has shown significant activity against aggressive T-cell lymphomas, a condition with limited treatment options. Pralatrexate is the first single agent approved for relapsed or refractory peripheral T-cell lymphoma, and its combination with Pembrolizumab and Decitabine may offer a new approach to enhance treatment efficacy. ^{1 2 3 4 11}

Research Team

Enrica Marchi, MD

Principal Investigator

University of Virginia

Owen O'Connor, MD, PhD

Principal Investigator

University of Virginia

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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]

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 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]

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]

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]

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 (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]

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]

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]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Critical appraisal of pralatrexate in the management of difficult-to-treat peripheral T cell lymphoma. [2021]

2. United States 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. [2015]

3. Italy pubmed.ncbi.nlm.nih.gov

Pralatrexate, a new hope for aggressive T-cell lymphomas? [2022]

4. Spain pubmed.ncbi.nlm.nih.gov

Pralatrexate - from bench to bedside. [2017]

5. United States 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. [2021]

6. Ireland 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. [2023]

7. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]

8. England 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. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

New Approved Use for Keytruda. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

A phase 1 study of pralatrexate in combination with paclitaxel or docetaxel in patients with advanced solid tumors. [2018]