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Study of PD-1 Inhibitors After CD30.CAR T Cell Therapy in Relapsed/Refractory Hodgkin Lymphoma

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ClinicalTrials.gov Identifier: NCT04134325
Recruitment Status : Recruiting
First Posted : October 22, 2019
Last Update Posted : July 15, 2021
Sponsor:
Collaborator:
American Society of Clinical Oncology
Information provided by (Responsible Party):
UNC Lineberger Comprehensive Cancer Center

Brief Summary:
LCCC1852-ATL is a prospective pilot study designed to determine if chimeric antigen receptor T (CAR-T) cells result in immunomodulation which can be subsequently exploited by programmed cell death protein 1 (PD-1) antibodies to achieve clinical responses in subjects with relapsed/refractory (r/r) classical Hodgkin Lymphoma (cHL).

Condition or disease Intervention/treatment Phase
Relapsed Hodgkin Lymphoma Refractory Hodgkin Lymphoma Biological: Nivolumab Biological: Pembrolizumab Early Phase 1

Detailed Description:

In this study, investigators will enroll 10 subjects with relapsed/refractory cHL who have previously been treated with anti-PD-1 therapy, have received a CD30 CAR-T cell therapy and have evidence of progression. Subjects will be offered anti-PD-1 therapy (nivolumab or pembrolizumab, at the discretion of treating oncologist), as per standard of care in r/r HL. Peripheral blood samples will be collected from subjects after consent has been obtained at the time of progression following CD30 CAR-T cell therapy as well as at Day 21 and Day 42 of anti-PD-1 therapy. Investigators will also have access to peripheral blood samples prior to CD30 CAR-T cell therapy, acquired during a prior clinical study. Peripheral blood samples will be immunophenotyped by mass cytometry and T-cell receptor (TCR) sequencing will be pursued to establish expansion of clinically relevant T-cell clones.

The primary objective of this study is to estimate the objective response rate (ORR) of anti-PD-1 therapy after progression on CD30 CAR-T cell therapy in r/r cHL. The secondary objectives will be to measure the change in T-cell receptor clonality during treatment with anti-PD-1 therapy after progression after CD30 CAR-T therapy, the change in peripheral blood immunophenotype during treatment with anti-PD-1 therapy after progression on CD30 CAR-T cell therapy and progression free survival (PFS) of anti-PD-1 therapy after progression on CD30 CAR-T cell therapy.

Preliminary data from subjects treated with anti-PD-1 therapy after progression following CD30 CAR-T cell therapy has suggested surprisingly robust clinical responses to anti-PD-1 therapy. Therefore, this pilot study is an important advancement in our understanding of both immunomodulation after CD30 CAR-T cell therapy as well as clinical response to anti-PD-1 therapy. This study will serve as a baseline for clinical response and immunomodulation for future clinical trials evaluating the combination of anti-PD-1 therapy and CD30 CAR-T cell therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective Pilot Study Assessing the Immunomodulatory Effect and Clinical Activity of Programmed Cell Death Protein 1 Inhibition Following CD30 Directed Chimeric Antigen Receptor T Cell Therapy in Relapsed/Refractory Classical Hodgkin Lymphoma
Actual Study Start Date : September 1, 2019
Estimated Primary Completion Date : December 1, 2021
Estimated Study Completion Date : December 1, 2036

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Single Arm PD-1 Inhibitors after CD30.CAR-T Therapy
Subjects with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) who have previously progressed on anti-PD-1 therapy, have received a CD30 CAR-T cell therapy and have evidence of progression. Subjects will be offered anti-PD-1 therapy (nivolumab or pembrolizumab, at the discretion of treating oncologist), as per standard of care in r/r cHL.
Biological: Nivolumab
Nivolumab administered at 240mg every two weeks or 480 mg every four weeks as per standard of care after treatment with CD30.CAR T cells
Other Name: Opdivo

Biological: Pembrolizumab
Pembrolizumab administered at 200 mg every three weeks or 400 mg every six weeks as per standard of care after treatment with CD30.CAR T cells
Other Name: Keytruda




Primary Outcome Measures :
  1. Objective response, defined as complete response (CR) or partial response (PR) at 12 weeks after initiating anti-PD-1 therapy [ Time Frame: 12 weeks ]
    Response will be determined by the Lymphoma Response to Immunomodulatory Therapy Criteria in order to evaluate the efficacy of anti-PD-1 therapy after progression on CD30 CAR-T cell therapy in relapsed/refractory (r/r) classical Hodgkin Lymphoma (cHL).


Secondary Outcome Measures :
  1. Peripheral T-cell receptor frequency per 100,000 clones on Day 1, Day 21, and Day 42 of anti-PD-1 therapy. [ Time Frame: 42 days ]
    To measure the change in peripheral blood T-cell receptor clonality during treatment with anti-PD-1 therapy after progression on CD30 CAR-T cell therapy.

  2. Percent change in peripheral blood T-cell subsets [ Time Frame: 42 days ]
    Percent change in peripheral blood T-cell subsets will be measured by Fluidigm® based mass cytometry from Day 1 of anti-PD-1 therapy to Day 21 and Day 42 of anti-PD-1 therapy.

  3. Progression free survival [ Time Frame: From first day of anti-PD-1 therapy to clinical progression or death, up to 15 years ]
    Progression free survival of anti-PD-1 therapy after progression on CD30 CAR-T cell therapy will be defined as the duration of time from the first day of anti-PD-1 therapy to clinical progression or death as a result of any cause. Response will be determined by the Lymphoma Response to Immunomodulatory Therapy Criteria.



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

Inclusion Criteria:

  • Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.
  • Age ≥18 years at the time of consent.
  • Subject is planned to start on standard of care anti-PD-1 therapy per community standards of medical care by their treating oncologist.
  • Subject has a diagnosis of relapsed/refractory classical Hodgkin lymphoma after at least three lines of prior therapy with clinical progression after either ATLCAR.CD30 and/or ATLCAR.CD30.CCR4.
  • Subjects with prior allogeneic stem cell transplant will be eligible, but will be counseled during consent regarding possible increased risk of graft versus host disease with anti-PD-1 therapy after allogeneic stem cell transplant.
  • Subjects must have previously been treated with anti-PD-1 therapy prior to receiving autologous CAR-T-cell therapy.
  • Subject is willing to provide blood samples that are clinically necessary during anti-PD-1 therapy administered per community standards of medical care.
  • Female subject of childbearing potential must agree to use adequate contraception during the study. Adequate contraception is defined by the concomitant use of two effective methods of contraception from the time of informed consent until 150 days after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets <1% failure rate for protection from pregnancy in the product label. Female subjects of non-childbearing potential are those who are postmenopausal greater than 1 year or who have had a bilateral tubal ligation or hysterectomy or bilateral oophorectomy. Female subjects must refrain from egg cell donation while on study treatment and for at least 150 days after the last dose of investigational product.
  • Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 150 days after the last dose of study therapy. Male subjects should agree to refrain from sperm donation while receiving study treatment and for at least 150 days after the last dose of study treatment.
  • Subject is willing and able to comply with study procedures based on the judgment of the investigator or protocol designee.
  • Subject is willing to consent to study-required blood draws.

Exclusion Criteria:

  • Subject has history of hypersensitivity reactions to anti-PD-1 therapy.
  • Subject has any contraindication to anti-PD-1 therapy at time of enrollment or inability to be treated with anti-PD-1 therapy for any other reason.
  • Subject 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 corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic replacement.
  • Subject has evidence of interstitial lung disease or a history of (non-infectious) pneumonitis resulting from previous anti-PD-1 treatment that required steroids or current pneumonitis. History of radiation pneumonitis is not considered a form of non-infectious pneumonitis of concern.
  • Subject has received anti-CD30 CAR-T therapy within the previous 6 weeks.
  • Subject is pregnant or breastfeeding (Note: breast milk cannot be stored for future use while the mother is being treated on the study. Subject must abstain from breastfeeding for 150 days after end of treatment).
  • Subject has known active infection with HIV, HTLV, HBV, HCV or any active, uncontrolled infection or sepsis.
  • Subject has received chemotherapy or anti-PD-1 therapy following CD30 CAR-T cell product administration.
  • Subject has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.
  • Subject is currently using systemic corticosteroids at doses ≥10 mg prednisone daily or its equivalent, or other immunosuppressive medications.
  • Subject has received a live attenuated vaccine within 30 days of initiating study treatment (i.e., 30 days prior to the first dose, during treatment, and for 30 days after study treatment discontinuation). Inactivated vaccines, such as the injectable influenza vaccine, are permitted.
  • Subject has received radiation therapy less than 7 days prior to anti-PD-1 therapy initiation
  • Subject has had a major surgery within 28 days prior to anti-PD-1 therapy.
  • Subject is not considered to be an acceptable candidate for anti-PD-1 therapy per the treating oncologist's discretion.

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): NCT04134325


Contacts
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Contact: Catherine Cheng 919-445-4208 catherine_cheng@med.unc.edu
Contact: Spencer Laing 919-962-8618 spencer.laing@med.unc.edu

Locations
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United States, North Carolina
Lineberger Comprehensive Cancer Center at University of North Carolina Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Catherine Cheng    919-445-4208    catherine_cheng@med.unc.edu   
Contact: Spencer Laing    919-962-8618    spencer.laing@med.unc.edu   
Sub-Investigator: Natalie Grover, MD         
Sub-Investigator: Anne Beaven, MD         
Sub-Investigator: Jonathan Serody, MD         
Sub-Investigator: Maurice Alexander, PharmD         
Sub-Investigator: Tatjana Grgic, PharmD         
Sub-Investigator: Jonathan Ptachcinski, PharmD         
Sub-Investigator: James Shaw, PharmD         
Sponsors and Collaborators
UNC Lineberger Comprehensive Cancer Center
American Society of Clinical Oncology
Investigators
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Principal Investigator: Timothy Voorhees, MD Clinical Fellow
Additional Information:
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Responsible Party: UNC Lineberger Comprehensive Cancer Center
ClinicalTrials.gov Identifier: NCT04134325    
Other Study ID Numbers: LCCC1852-ATL
First Posted: October 22, 2019    Key Record Dates
Last Update Posted: July 15, 2021
Last Verified: July 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
Product Manufactured in and Exported from the U.S.: No
Keywords provided by UNC Lineberger Comprehensive Cancer Center:
Classic Hodgkin Lymphoma
Relapsed Hodgkin Lymphoma
Refractory Hodgkin Lymphoma
Relapsed/Refractory Hodgkin Lymphoma
CD30
cell therapy
CAR-T
modified T cells
PD-1
Additional relevant MeSH terms:
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Lymphoma
Hodgkin Disease
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Pembrolizumab
Nivolumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action