Clinical trial NCT05934448: Pembro Plus CAR T-cell Therapy in R/R in PMBCL
Official title: A Phase II Trial of Pembrolizumab in Combination With Chimeric Antigen Receptor Therapy in Patients With Relapsed/Refractory Primary Mediastinal B-cell Lymphoma
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Primary Mediastinal Large B-cell Lymphoma (PMBCL)
Primary Mediastinal Large B Cell Lymphoma
Primary Mediastinal Large B-Cell Lymphoma Refractory
Primary Mediastinal Large B-Cell Lymphoma Recurrent
Epstein-Barr Virus Positive Diffuse Large B-Cell Lymphoma
T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Keywords: Primary Mediastinal Large B-cell Lymphoma (PMBCL)
Primary Mediastinal Large B Cell Lymphoma
Primary Mediastinal Large B-Cell Lymphoma Refractory
Primary Mediastinal Large B-Cell Lymphoma Recurrent
T-Cell/Histiocyte-Rich Large B-Cell Lymphoma
Epstein-Barr virus-positive diffuse large B-cell lymphoma
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2023-07-07
Enrollment: 35
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This research study is evaluating the combination of drugs, pembrolizumab with chimeric antigen receptor (CAR) T-cell therapy, as a possible treatment for primary mediastinal B-cell lymphoma that has recurred after prior treatment.

The names of the study drugs involved in this study are:

- Pembrolizumab

Standard treatment will include:

* CAR T-cell therapy (either axicabtagene-ciloleucel or lisocabtagene maraleucel)
* Cyclophosphamide
* Fludarabine

Detailed description: This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The names of the study drugs involved in this study are:

- Pembrolizumab

Standard treatment will include:

* CAR T-cell therapy (either axicabtagene-ciloleucel or lisocabtagene maraleucel)
* Cyclophosphamide
* Fludarabine Participants will receive study treatment for up to 2 years and will be followed for 5 years. It is expected that about 35 people will take part in this research study.

The U.S. Food and Drug Administration (FDA) has approved pembrolizumab for this specific disease after two or more lines of therapy, but not in combination with CAR T-cell therapy.

The CAR T-cell therapies to be used in this study are axicabtagene-ciloleucel and lisocabtagene maraleucel. The U.S. FDA has approved axicabtageneciloleucel and lisocabtagene maraleucel as treatment options for this disease, but not in combination with pembrolizumab.

A small subset of patients with T-cell histiocyte-rich large B-cell lymphoma and EBV+ large B-cell lymphoma will also be included.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed diagnosis of PMBCL, EBV+ DLBCL or THRLBCL at one of the participating institutions.
* Availability of archival or freshly collected tumor tissue before study enrollment. If archival tissue is unavailable or is determined to be inadequate, tumor tissue must be obtained from a biopsy performed at screening, unless an exception is given after consultation with the sponsor-investigator.
* Eligible for standard of care CAR T-cell therapy with progression after at least two prior lines of therapy OR refractory to initial chemoimmunotherapy OR relapse within 12 months of front-line chemoimmunotherapy OR one prior line of therapy and not fit for HSCT.
* ECOG Performance Status of 0 or 1.
* Left ventricular ejection fraction (LVEF) ≥ 50% on cardiac multiple-gated acquisition (MUGA) scan or cardiac echocardiogram (ECHO).
* Adequate hematologic function (unless due to underlying disease, as established for example, by extensive bone marrow involvement or due to hypersplenism secondary to the involvement of the spleen by lymphoma per the investigator), defined as follows:

  * ANC ≥ 1,000/μL
  * Hemoglobin ≥ 8 g/dL
  * Platelet count ≥ 50,000/μL
* Participants must have adequate organ as defined below:

  * Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN
  * AST(SGOT)/ALT(SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver involvement)
  * Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance (by Cockcroft-Gault) ≥ 40 ml/min for patients with serum creatinine \>1.5 x ULN
* At least one bi-dimensionally FDG-avid measurable lymphoma lesion on PET/CT scan, defined as ≥ 1.5 cm in its longest dimension on CT scan, or ≥ 1 cm if extranodal (and measurable).
* Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 6 months for WOCBP and for men after the last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control, e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, use of two forms of birth control, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile.
* Age ≥18 years.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Patients in urgent need of cytoreductive therapy.
* Participants who are receiving any other investigational agents.
* History of other malignancies, except:

  * Malignancy treated medically or surgically with curative intent and with no known active disease present for ≥2 years before study registration
  * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
  * Adequately treated carcinoma in situ without evidence of disease.
  * Localized prostate cancer and low-risk prostate cancer on active surveillance
  * In the opinion of the treating investigator, there is limited potential to interfere with the safety or efficacy of the investigational regimen. Such exceptions must be approved by the Sponsor-Investigator.
* Has received a live vaccine within 30 days prior to study registration. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
* Less than 6 months of response to prior PD-L1 inhibitor or PD-1 inhibitor or grade 3 or higher immune-related adverse events.
* Prior treatment with CAR T-cell therapy.
* Lactating or pregnant. Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) at screening. WOCBP will require a negative pregnancy test within 72 hours prior to starting treatment, but eligibility for study enrollment may be confirmed based on testing at screening.
* Known active lymphomatous involvement of the central nervous system. History of prior CNS involvement is allowed.
* Recent infection requiring intravenous antibiotics that was completed ≤7 days before the first dose of study drug, or any uncontrolled active systemic infection.
* Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus infection.
* History of Human immunodeficiency virus (HIV)-infection.
* Has received prior radiotherapy within 2 weeks of study registration. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
* Has received prior systemic anti-cancer therapy within 2 weeks or investigational agents within 4 weeks.
* Significant liver disease, such as hepatitis (viral or non-viral) or cirrhosis
* Prior macrophage activation syndrome (MAS) or hemophagocytic lymphohistiocytosis (HLH)
* Uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months of enrollment.
* Known history of central nervous system or neurologic disease including stroke or intracranial hemorrhage within 3 months prior to enrollment or seizure disorder. Prior CNS involvement with lymphoma is allowed if previously treated with no evidence of involvement at study entry.
* Prior solid organ or allogeneic stem cell transplant or within 6 weeks of autologous stem cell transplant.
* 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).
* Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to study registration. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
* Active pneumonitis or interstitial lung disease.
* Severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
* Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant 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.
* Has not met requirements for standard of care CAR-T therapy

Primary outcomes:
measure: Complete Response (CR) Rate at 6 Months
timeFrame: 6 months
Secondary outcomes:
measure: Treatment-Related Grade 3 or Higher Cytokine Release Syndrome (CRS) Rate
timeFrame: 6 months
measure: Treatment-Related Grade 3 or Higher Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Rate
timeFrame: 6 months
measure: Treatment-Related Grade 3 or Higher Prolonged Cytopenia Rate
timeFrame: 6 months
measure: Treatment-Related Grade 3 or Higher Immune-Related Adverse Event (irAE) Rate
timeFrame: 6 months
measure: Complete Response (CR) Rate at 6 Months in patients with EBV+ DLBCL and THRLBCL
timeFrame: 6 months
measure: Partial Response (PR) Rate
timeFrame: baseline, 1 month, 3 month, and every 6 months up to 24 months
measure: Duration of Response (DOR)
timeFrame: baseline, 1 month, 3 month, and every 6 months up to 24 months
measure: Median Progression-free survival (PFS)
timeFrame: Baseline, 1 month, 3 month (if not CR at 1 month) and then every 6 months until 24 months.
measure: Median overall survival (OS)
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Jennifer Crombie, MD
role: PRINCIPAL_INVESTIGATOR
References: