Description:
This is a Phase I, open-label multi-site trial designed to evaluate the safety and
feasibility of administering rapidly-generated Tumor associated antigen specific T cells
(TAA-T) with the Programmed Death1 (PD-1) inhibitor Nivolumab, in relapsed/refractory
lymphoma (rel/ref) patients with measurable disease (group A) or as adjunctive therapy
following autologous hematopoeitic stem cell transplant(HSCT) for patients at high risk of
relapse (group B).
The purpose of this study is to find out if the tumor specific T cells given with Nivolumab
are safe and to learn what the side effects are and if the combination can help patients with
relapsed lymphomas.
Title
- Brief Title: Tumor Associated Antigen Specific T Cells (TAA-T) With PD1 Inhibitor for Lymphoma
- Official Title: Phase I Study Utilizing Tumor Associated Antigen Specific T Cells (TAA-T) With PD1 Inhibitor Nivolumab for Relapsed/Refractory Lymphoma
Clinical Trial IDs
- ORG STUDY ID:
SUSTAIN
- NCT ID:
NCT03843294
Conditions
- Hodgkin Lymphoma
- Diffuse Large B Cell Lymphoma
Interventions
| Drug | Synonyms | Arms |
|---|
| TAA-T cells | | TAA-T with Nivolumab |
Purpose
This is a Phase I, open-label multi-site trial designed to evaluate the safety and
feasibility of administering rapidly-generated Tumor associated antigen specific T cells
(TAA-T) with the Programmed Death1 (PD-1) inhibitor Nivolumab, in relapsed/refractory
lymphoma (rel/ref) patients with measurable disease (group A) or as adjunctive therapy
following autologous hematopoeitic stem cell transplant(HSCT) for patients at high risk of
relapse (group B).
The purpose of this study is to find out if the tumor specific T cells given with Nivolumab
are safe and to learn what the side effects are and if the combination can help patients with
relapsed lymphomas.
Detailed Description
The investigators will collect blood from the patients to isolate peripheral blood
mononuclear cells. The investigators will then make special cells called dendritic cells to
stimulate the T cells. Then they will add special mixtures of tumor proteins WT1, PRAME and
Survivin and provide a cytokine milieu favorable to T cell expansion/activation, inducing
selective expansion of T cells targeted to kill tumor cells. This process trains the T cells
to recognize the tumor proteins and become specialized TAA-T cells. The cells will be grown
and frozen until ready for us.
While the T cells are growing, the patients will receive 4 doses of Nivolumab given every 2
weeks. Patients will then receive two infusions of the TAA-T cells every two weeks and
monitored for side effects. Patients will not receive any Nivolumab during the 45 days safety
monitoring period from the first infusion. They will then receive additional two doses of
Nivolumab following second TAA-T cell infusion on Days 108 and 122 from starting treatment.
Only group A patients are eligible for additional doses (3 to 8) if they have stable disease
or response, do not have ≥ grade 3 toxicity attributed to TAA-T cells and do not have
clinical evidence of rapidly progressing disease requiring urgent therapy.
This study will first enroll 6 patients total (Groups A and B) in the initial safety
monitoring or DLT group prior to the expansion phase (additional 12 patients in the expansion
cohort). After the initial safety phase is complete, additional 12 patients will be enrolled
to maximum 18 patients.
For Group B Patients (post auto-HSCT): Study treatment will begin any time after neutrophil
engraftment or Day 30 post auto-HSCT whichever comes first.
Both TAA-T cells and Nivolumab will be given at fixed dose with allowed dose de-escalation of
both agents as follows:
TAA-T cell dose: 2 x 107 cells/m2 Nivolumab 3 mg/kg/dose every 2 weeks
From the first 2 enrolled patients, if at least one patient meets dose limiting toxicity
criteria at the above mentioned combination dose level, then the next 2 patients will receive
TAA-T cells at 1 x 107 cells/m2 without a change in nivolumab dose. If toxicity criteria are
met by at least one patient from these 2 patients, then the dose of Nivolumab will be reduced
to 1mg/kg/dose for patients <18 years or 100 mg for adults <18 years for next 2 patients and
T cells will be given at the same de-escalated dose of 1x 107 cells/m2.
If patient meets eligibility criteria for TAA-T cell infusion, the patient (Group A or Group
B) will receive two TAA-T cell infusions given 2 weeks apart, where the expected volume of
infusion is 1 to 10 cc.
In case the patient experiences toxicity from nivolumab prior to the first TAA-T cell
infusion, they can receive the TAA-T cells after resolution of the Nivolumab toxicities and
steroid dosing has been reduced less than 0.5mg/kg/day.
Trial Arms
| Name | Type | Description | Interventions |
|---|
| TAA-T with Nivolumab | Experimental | All patients will receive Nivolumab(3mg/kg) starting on Day 0 every 2 weeks for 4 doses followed by two infusions of Tumor Associated Antigen Specific T cells (TAA-T) given 2 weeks apart. Patients will receive two additional doses of Nivolumab(Day 108 and Day 122) after the safety monitoring period is complete. Patients can continue Nivolumab after Day 136 at the discretion of the referring/treating physician. | |
Eligibility Criteria
Group A (patients with measurable disease) Relapsed/Refractory Hodgkin Lymphoma (HL) and
Diffuse Large B cell Lymphoma (DLBCL) DLBCL
- Patients with Primary Treatment Failure (PTF) and one or more Ultra-high risk (UHR)
features, no prior salvage treatment required. Please refer to Appendix A for
definitions of PTF and UHR
- Rel/ref DLBCL failing 1st salvage treatment (Progressive disease (PD)/ Stable Disease
(SD)/Partial Response (PR))
- Rel/ref DLBCL without acceptable treatment options in the opinion of the treating
physician HL
- Rel/ref HL failing ≥ 1 salvage regimens, including prior Brentuximab Vedotin (BV)
- Rel/ref after autologous HSCT
Group B (consolidation after auto-HSCT for patients at high risk for relapse) DLBCL
- Patients with < CMR/CR (by PET/CT) with initial treatment regimen
- Patients with relapse <12 months from diagnosis or <6 months from completion of
initial therapy
- Patients with <CMR/CR (by PET/CT) prior to autologous HSCT
- Patients requiring >1 salvage regimen prior to autologous HSCT HL Patients not
eligible for post auto-HSCT consolidation with Brentuximab AND
- Relapsed <12 months from diagnosis or <6 months from completion of initial therapy
- Patients with <CMR/CR (by PET/CT) prior to autologous HSCT
- Patients requiring >1 salvage regimen prior to autologous HSCT
Recipient Procurement (TAA-T Cell Generation) Inclusion Criteria
- Age 12 years to 80 years
- Karnofsky/Lansky score of ≥ 50 (see appendix C).
- Agree to use contraceptive measures during study protocol participation (when age
appropriate)
- Patient or parent/guardian capable of providing informed consent
Recipient Procurement (TAA-T Cell Generation) Exclusion Criteria
- Prior allogeneic BMT
- Prior solid organ transplant
- Patient who has received ATG, Campath or other immunosuppressive T cell monoclonal
antibodies within 28 days of screening for enrollment
- Patient with uncontrolled infections
- Patient with active HIV
- Pregnancy or lactating
- Failure to meet institutional guidelines for treatment with Nivolumab
Recipient Inclusion Criteria for Initial and Subsequent TAA-T Cell Infusion
- Age 12 years to 80 years
- Patient has received at least 4 doses of Nivolumab
- All toxicities attributed to Nivolumab have resolved Steroids less than 0.5 mg/kg/day
prednisone or equivalent
- Karnofsky/Lansky score of ≥ 50
- Pulse oximetry of > 90% on room air
- Bilirubin ≤ 2.5 mg/dL, AST/ALT ≤ 5x upper limit of normal, serum creatinine < 1.0 or
2x the upper limit of normal (whichever is higher)
- Absolute neutrophil count > 250/µL (may be supported with GCSF)
- Agree to use contraceptive measures during study protocol participation (when age
appropriate)
- Patient or parent/guardian capable of providing informed consent
Recipient Exclusion Criteria for Initial and Subsequent TAA-T Cell Infusion
- Investigational therapies within the last 28 days
- Uncontrolled infections
| Maximum Eligible Age: | 80 Years |
| Minimum Eligible Age: | 12 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Incidence of Product-Emergent Adverse Events |
| Time Frame: | 45 days from the first TAA-T cell administrations |
| Safety Issue: | |
| Description: | Number of participants with grades 3-5 infusion-related and grades 4-5 non-hematological adverse events that are not due to the original malignancy, or pre-existing co-morbidities within 45 days of the first dose of TAA-T infusion as defined by the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03, change from baseline at day 45. |
Secondary Outcome Measures
| Measure: | Tumor response to combination immunotherapy |
| Time Frame: | 1 year |
| Safety Issue: | |
| Description: | Number of patients with tumor associated antigen lymphocytes (TAA-T) with Nivolumab response, change from baseline at year one. Response will be assessed by imaging using the Lugano criteria. Response is defined as any patient who does not progress on this study, including patients with active disease who achieve Complete Metabolic Response (CMR)/Complete Response (CR), Partial Metabolic Response (PMR)/ Partial Response (PR), or No Metabolic Response(NMR)/Stable Disease (SD) by PET/CT. |
Details
| Phase: | Phase 1 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Catherine Bollard |
Last Updated
September 19, 2019
