A Phase II Trial of Pembrolizumab in Combination With Chimeric Antigen Receptor Therapy in Patients With Relapsed/Refractory Primary Mediastinal B-cell Lymphoma
Overview
- Phase
- Phase 2
- Intervention
- Pembrolizumab
- Conditions
- Primary Mediastinal Large B-cell Lymphoma (PMBCL)
- Sponsor
- Jennifer Crombie, MD
- Enrollment
- 35
- Locations
- 2
- Primary Endpoint
- Complete Response (CR) Rate at 6 Months
- Status
- Recruiting
- Last Updated
- last month
Overview
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.
Investigators
Jennifer Crombie, MD
Sponsor Investigator
Dana-Farber Cancer Institute
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
- •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:
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.
Arms & Interventions
PEMBROLIZUMAB
* Participants will undergo (leukapheresis) for manufacturing of commercial product as per standard of care (SOC) Cycle 1 Day -21or earlier * Pembrolizumab will be administered per protocol on cycle 1 day -20 and on day +1 following Chimeric Antigen Receptor (CAR) Therapy Infusion infusion, every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity. * Upon the completion of successful manufacturing, patients will undergo lymphodepleting chemotherapy (fludarabine, cyclophosphamide) for chimeric antigen receptor (CAR) therapy infusion as per SOC. * Participants will receive Chimeric Antigen Receptor (CAR) Therapy Infusion (SOC) on day 0 in the hospital and will remain in the inpatient setting for observation for a minimum of 7 days or until CAR T-cell toxicities resolve to grade 1 or better. The choice of CAR-T product will be left to the discretion of the treating investigator.
Intervention: Pembrolizumab
PEMBROLIZUMAB
* Participants will undergo (leukapheresis) for manufacturing of commercial product as per standard of care (SOC) Cycle 1 Day -21or earlier * Pembrolizumab will be administered per protocol on cycle 1 day -20 and on day +1 following Chimeric Antigen Receptor (CAR) Therapy Infusion infusion, every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity. * Upon the completion of successful manufacturing, patients will undergo lymphodepleting chemotherapy (fludarabine, cyclophosphamide) for chimeric antigen receptor (CAR) therapy infusion as per SOC. * Participants will receive Chimeric Antigen Receptor (CAR) Therapy Infusion (SOC) on day 0 in the hospital and will remain in the inpatient setting for observation for a minimum of 7 days or until CAR T-cell toxicities resolve to grade 1 or better. The choice of CAR-T product will be left to the discretion of the treating investigator.
Intervention: Lymphodepletion Chemotherapy
PEMBROLIZUMAB
* Participants will undergo (leukapheresis) for manufacturing of commercial product as per standard of care (SOC) Cycle 1 Day -21or earlier * Pembrolizumab will be administered per protocol on cycle 1 day -20 and on day +1 following Chimeric Antigen Receptor (CAR) Therapy Infusion infusion, every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity. * Upon the completion of successful manufacturing, patients will undergo lymphodepleting chemotherapy (fludarabine, cyclophosphamide) for chimeric antigen receptor (CAR) therapy infusion as per SOC. * Participants will receive Chimeric Antigen Receptor (CAR) Therapy Infusion (SOC) on day 0 in the hospital and will remain in the inpatient setting for observation for a minimum of 7 days or until CAR T-cell toxicities resolve to grade 1 or better. The choice of CAR-T product will be left to the discretion of the treating investigator.
Intervention: Chimeric Antigen Receptor (CAR) Therapy Infusion
PEMBROLIZUMAB
* Participants will undergo (leukapheresis) for manufacturing of commercial product as per standard of care (SOC) Cycle 1 Day -21or earlier * Pembrolizumab will be administered per protocol on cycle 1 day -20 and on day +1 following Chimeric Antigen Receptor (CAR) Therapy Infusion infusion, every 3 weeks for up to 2 years, unless there is confirmed progression of disease or unacceptable toxicity. * Upon the completion of successful manufacturing, patients will undergo lymphodepleting chemotherapy (fludarabine, cyclophosphamide) for chimeric antigen receptor (CAR) therapy infusion as per SOC. * Participants will receive Chimeric Antigen Receptor (CAR) Therapy Infusion (SOC) on day 0 in the hospital and will remain in the inpatient setting for observation for a minimum of 7 days or until CAR T-cell toxicities resolve to grade 1 or better. The choice of CAR-T product will be left to the discretion of the treating investigator.
Intervention: Leukapheresis
Outcomes
Primary Outcomes
Complete Response (CR) Rate at 6 Months
Time Frame: 6 months
Per Lugano 2014 criteria, Complete Response (CR) is defined as PET-CT, score 1, 2, or 3\* with or without a residual mass on 5 point scale; or on CT, target nodes/nodal masses must regress to ≤ 1.5 cm in LDi, and no extralymphatic sites of disease.
Secondary Outcomes
- Treatment-Related Grade 3 or Higher Cytokine Release Syndrome (CRS) Rate(6 months)
- Partial Response (PR) Rate(baseline, 1 month, 3 month, and every 6 months up to 24 months)
- Treatment-Related Grade 3 or Higher Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) Rate(6 months)
- Complete Response (CR) Rate at 6 Months in patients with EBV+ DLBCL and THRLBCL(6 months)
- Treatment-Related Grade 3 or Higher Prolonged Cytopenia Rate(6 months)
- Treatment-Related Grade 3 or Higher Immune-Related Adverse Event (irAE) Rate(6 months)
- Duration of Response (DOR)(baseline, 1 month, 3 month, and every 6 months up to 24 months)
- Median Progression-free survival (PFS)(Baseline, 1 month, 3 month (if not CR at 1 month) and then every 6 months until 24 months.)
- Median overall survival (OS)(Up to 5 years)