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

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ClinicalTrials.gov Identifier: NCT03240211
Recruitment Status : Not yet recruiting
First Posted : August 7, 2017
Last Update Posted : October 6, 2021
Sponsor:
Collaborators:
Merck Sharp & Dohme Corp.
Otsuka Pharmaceutical Development & Commercialization, Inc.
Information provided by (Responsible Party):
Enrica Marchi, MD, University of Virginia

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
PTCL CTCL Drug: Pembrolizumab Drug: Pralatrexate Drug: Decitabine Phase 1

Detailed Description:

The peripheral T-cell lymphomas (PTCLs) are rare subtypes of Non-Hodgkin lymphoma (NHL) with unique clinicopathologic features and very unfavorable prognosis. Recently it has been demonstrated that PTCLs are characterized by recurrent mutations in epigenetic operators (e.g. TET2, DNMT3A, and IDH2) and escape from immune surveillance.

The safety and toxicity of these combinations will be evaluated throughout the entire study. Dose allocation in Arms A and C will be based upon a continual reassessment method (CRM), and combination allocation in Arm B will be conducted using a DLT-adapted partial order continual reassessment method (POCRM) for dose-finding with combinations of agents.

Study Hypothesis: If pralatrexate and/or decitabine functions in an immunomodulatory fashion then priming and modulating the malignant cells and the microenvironment will enhance the antitumor activity of pembrolizumab in patients with PTCLs and CTCLs.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 42 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This is an international, multicenter, multi-arm, phase Ib, model-based dose-escalation study.

There will be 3 treatment arms in this study.

Masking: None (Open Label)
Primary Purpose: Other
Official Title: 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.
Estimated Study Start Date : October 15, 2021
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2024


Arm Intervention/treatment
Experimental: Pembrolizumab plus Pralatrexate
Subjects will receive pembrolizumab 200 mg IV day 1 with pralatrexate 30 mg/m2 IV day 1, 8, and 15.
Drug: Pembrolizumab
Pembrolizumab 200 mg IV

Drug: Pralatrexate
Pralatrexate 20 or 30 mg/m2 IV push

Experimental: Pembrolizumab plus Pralatrexate plus Decitabine
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.
Drug: Pembrolizumab
Pembrolizumab 200 mg IV

Drug: Pralatrexate
Pralatrexate 20 or 30 mg/m2 IV push

Drug: Decitabine
Decitabine 10 mg/m2

Experimental: Pembrolizumab plus Decitabine
Subjects will receive pembrolizumab 200 mg IV and decitabine 20 mg/m2 from day 1 to 5.
Drug: Pembrolizumab
Pembrolizumab 200 mg IV

Drug: Decitabine
Decitabine 10 mg/m2




Primary Outcome Measures :
  1. Estimated maximum Tolerated Dose (MTD) [ Time Frame: 1 year ]
    If 0 out of 3 patients will experience a DLT, 3 more patients will be enter at the next dose level. If 1 patient will experience a DLT, 3 more patients will be treated at the same dose level. If >1 patient will experience a DLT, then the dose escalation is stopped and this dose is declared MTD. The estimated MTD would be the highest dose at which 0/3 or 1/6 subjects experience a DLT, i.e. dose with an observed DLT rate of less than 0.33.

  2. Recommended Phase 2 Dose [ Time Frame: 1 year ]
    Determine the recommended dose for the Phase 2 portion of the study based on the estimated MTD.


Other Outcome Measures:
  1. Overall Response Rate (ORR) [ Time Frame: 1 year ]
    (ORR) (complete + partial response) will be evaluated using clinical parameters, computerized tomography (CT) scan (PET/CT scan is optional) and bone marrow biopsy, as outlined by the 2007 International Harmonization Project criteria and revised criteria (Lugano).

  2. Progression free survival (PFS) [ Time Frame: 1 year ]
    The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.

  3. Duration of response (DOR) [ Time Frame: 1 year ]
    The time between the initial response to therapy and subsequent disease progression or relapse.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Be willing and able to provide written informed consent/assent for the trial.
  • Be 18 years of age on day of signing informed consent.
  • Have measurable disease based on the Lugano Criteria for PTCL and by the Global Response Score for CTCL.
  • Patient must have histologically confirmed relapsed or refractory Peripheral T-cell lymphoma (PTCL) or cutaneous T-cell Lymphoma (PTCL) as per World Health Organization (WHO) criteria and TNMB classification and staging.
  • There is no upper limit for the number of prior therapies. Patient may have relapsed after prior autologous stem cell transplant.
  • 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.
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. Be willing to provide fine needle aspiration (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.
  • Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale.
  • Demonstrate adequate organ function, all screening labs should be performed within 10 days of treatment initiation.
  • 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.
  • Female subjects of childbearing potential must be willing to use an adequate method of contraception - 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.
  • Male subjects of childbearing potential must agree to use an adequate method of contraception - 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:

  • 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 4.0.
  • Had prior therapy with PD-1 inhibitors.
  • 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.
  • 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. Use of steroid equivalent to prednisone 10 mg/day does not constitute an exclusion criterion.
  • Has a known history of active Bacillus Tuberculosis (TB)
  • Hypersensitivity to pralatrexate, or decitabine or pembrolizumab or any of its excipients.
  • Has received prior allogeneic stem cell transplant.
  • 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.
  • 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.
  • 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.
  • Has known history of, or any evidence of active, non-infectious pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
  • Has an active infection requiring systemic therapy.
  • 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.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • 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.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03240211


Contacts
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Contact: Marian Abdelmalek 434-924-8827 mka6s@virginia.edu
Contact: Justin Alicea 434-243-5350 xzy7tw@virginia.edu

Sponsors and Collaborators
University of Virginia
Merck Sharp & Dohme Corp.
Otsuka Pharmaceutical Development & Commercialization, Inc.
Investigators
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Study Chair: Owen O'Connor, MD, PhD University of Virginia
Principal Investigator: Enrica Marchi, MD, PhD University of Virginia
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Responsible Party: Enrica Marchi, MD, Professor of Medicine, University of Virginia
ClinicalTrials.gov Identifier: NCT03240211    
Other Study ID Numbers: PTCL-002
First Posted: August 7, 2017    Key Record Dates
Last Update Posted: October 6, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Enrica Marchi, MD, University of Virginia:
Pembrolizumab
Decitabine
Pralatrexate
T-cell lymphoma
Additional relevant MeSH terms:
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Lymphoma, T-Cell
Lymphoma, Non-Hodgkin
Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Decitabine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors