T Cell Non-Hodgkin Lymphoma, Peripheral T-Cell Lymphoma, Not Otherwise Specified, Angioimmunoblastic T-cell Lymphoma, Anaplastic Large Cell Lymphoma
Conditions
Keywords
T cell lymphoma, Relapsed T cell Non-Hodgkin Lymphoma, Refractory T cell Non-Hodgkin Lymphoma, AUTO4
Brief summary
The purpose of this study is to test the safety and efficacy of AUTO4 a chimeric antigen receptor (CAR) T cell treatment targeting TRBC1 in patients with relapsed or refractory TRBC1 positive selected T-Non-Hodgkin Lymphoma (NHL).
Detailed description
The study will consist of 2 phases, a Phase I/dose escalation phase and a Phase II/expansion phase. Patients with relapsed or refractory TRBC1 positive selected T-NHL will be enrolled in both phases of the study. Eligible patients will undergo leukapheresis to harvest T cells, the starting material for the manufacture of the autologous CAR-T product AUTO4. Following preconditioning by a chemotherapeutic regimen, the patient will receive AUTO4 intravenously as a single dose following which they will then enter a 24-month follow-up period
Interventions
BIOLOGICALAUTO4
AUTO4 (Ritux-QBEND/10-Ritux-CD8 sort-suicide gene generated as a marker/suicide gene for T cells \[RQR8\]/anti-T cell receptor beta constant \[aTRBC\]1 CAR T cells). Following pre-conditioning with chemotherapy (cyclophosphamide and fludarabine), patients will be treated with doses from 25 to 900 x 10\^6 RQR8/anti-TRBC1 CAR T cells in Phase I. Following dose determination patients will be treated with the selected doses of RQR8/aTRBC1 CAR T cells (AUTO4) in Phase II.
Sponsors
Autolus Limited
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Male or female, aged ≥ 18 years. 2. Willing and able to give written, informed consent to be screened for TRBC1 positive T-NHL and to enter the main study. 3. Confirmed diagnosis of selected T-NHL, including: 1. Peripheral T cell lymphoma not otherwise specified, or 2. Angioimmunoblastic T cell lymphoma, or 3. Anaplastic large cell lymphoma 4. Confirmed TRBC1 positive tumour. 5. Relapsed or refractory disease and have had ≥1 prior lines of therapy. 6. Positron emission tomography (PET)-positive measurable disease per Lugano classification. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1. 8. Adequate bone marrow function without the requirement for ongoing blood products. 9. Adequate renal, hepatic, pulmonary, and cardiac function. 10. For females of childbearing potential (defined as \< 2 years after last menstruation or not surgically sterile), a negative serum or urine pregnancy test must be documented at screening, prior to pre-conditioning and confirmed before receiving the first dose of study treatment. For females who are not postmenopausal (\< 24 months of amenorrhea) or who are not surgically sterile (absence of ovaries and/or uterus), a highly effective method of contraception together with a barrier method must be used from the start of the pre-conditioning stage and for at least 12 months after the last dose of AUTO4 (study treatment). They must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 12 months after receiving the last dose of study drug 11. For males, it must be agreed that 2 acceptable methods of contraception are used. 12. No contra-indications for leukapheresis, or the pre-conditioning regimen.
Exclusion criteria
Patients meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Numbers of Patients With Grade 3 to 5 Toxicity Occurring Within 60 Days of AUTO4 Infusion. | 60 days of AUTO4 infusion | To assess the safety and tolerability of AUTO4 administration. The incidence of Grade 3-5 toxicities occurring within 60 days of AUTO4 infusion. |
| Frequency of Dose-limiting Toxicity (DLT) of AUTO4 Within 28 Days of AUTO4 Infusion. | 28 days of AUTO4 infusion | To identify the recommended Phase II dose and maximum tolerated dose (MTD), if an MTD exists, of AUTO4 by monitoring the frequency of DLT of AUTO4 within 28 days of AUTO4 infusion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency and Severity of All Adverse Events (AEs) and Serious Adverse Events (SAEs). | 24 months post treatment | All AEs/SAEs were recorded from admission for pre-conditioning chemotherapy (Day -6 relative to AUTO4). Due to the long period between consent and AUTO4 treatment, any AEs/SAEs related to bridging chemotherapy not associated with study procedures did not require reporting as study AEs/SAEs. Any significant events were added to the patient's medical history. All AEs/SAEs related to study procedures (leukapheresis, bone marrow assessments) were reported. |
| To Assess the Overall Safety and Tolerability of AUTO4. | 24 months post treatment | Incidence and severity of opportunistic infections following AUTO4 infusion. |
| Feasibility of Generating AUTO4: Number of Patients Whose Cells Achieve Successful AUTO4 Manufacture as a Proportion of the Number of Patients Undergoing Leukapheresis. | Up to 8 weeks post leukapheresis | Feasibility of product generation was examined by assessing the number of AUTO4 successfully manufactured as a fraction of the number of patients undergoing leukapheresis (all patients enrolled). |
| Determine the Complete Response (CR) Rate Following Treatment With AUTO4. | Up to 24 months | Participants achieving CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F (Fluorine isotope 18)-2-fluoro-2-deoxy-D-glucose fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT): 1. no uptake or no residual uptake (when used interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease * complete metabolic response - score of 1, 2 or 3 in nodal or extranodal sites with or without a residual mass * partial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size * stable disease or no metabolic response - score of 4 or 5 with no obvious change in FDG uptake Progressive disease score 4 or 5 in any lesion |
| Evaluate Duration of Response (DOR) Following Treatment With AUTO4. | Up to 24 months | DOR was defined as the time from the first observed CR or partial response (PR) to documented disease progression or death due to any cause, for patients who were considered as responders. Patients who received protocol specified anti-cancer treatment post AUTO4 infusion were ignored in the main analysis. Patients who proceeded to stem cell transplantation (SCT) after AUTO4 infusion were censored at the time of SCT (including the conditioning regimen for SCT). Patients who received new non-protocol anticancer therapies other than SCT were censored at the date of last adequate assessment prior to the new therapy. Patients who experienced event after missing two or more scheduled disease assessments were censored at the date of last adequate assessment prior to the event. Data for DOR were pooled for analysis because the number of patients was \<5 for all of the groups and the intended model cannot be built with such a small sample size. |
| Evaluate Progression-free Survival (PFS) Following Treatment With AUTO4. | Up to 24 months | PFS was defined as the time from the first treatment of AUTO4 to documented disease progression/relapse or death due to any cause. If a patient did not have relapse or death due to any reason prior to data cut-off, PFS was censored at the date of the last adequate assessment by default. Patients who received protocol specified anti-cancer treatment post AUTO4 infusion were ignored in the main analysis. Patients who proceeded to SCT after AUTO4 infusion were censored at the time of SCT (including the conditioning regimen for SCT). Patients who received new non-protocol anticancer therapies other than SCT were censored as the date of last adequate assessment prior to the new therapy. Patients who experienced event after missing two or more scheduled disease assessments were censored at the date of last adequate assessment prior to the event |
| Evaluate Overall Survival (OS) Following Treatment With AUTO4. | Up to 24 months | OS was defined as the time from the first treatment of AUTO4 to death due to any cause. Patients who had not died prior to data cut-off or database finalization were censored at the last contact date. Patients who received SCT after AUTO4 infusion were ignored in the main analysis. |
| Time to Response (PR and CR) | 24 months post treatment | Time taken for participants achieving PR or CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F FDG PET-CT: 1. no uptake or no residual uptake (when used interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease: * Complete metabolic response - score of 1, 2, or 3 in nodal or extranodal sites with or without a residual mass * Partial metabolic response - score of 4 or 5 with reduced uptake compared with baseline and residual mass(es) of any size |
| Evaluate Time to CR Following Treatment With AUTO4. | Up to 24 months | The time taken for participants achieving CR per Lugano criteria based on independent central radiology review. The Lugano classification of response by 18F-2-fluoro-2-deoxy-D-glucose FDG PET-CT: 1. no uptake or no residual uptake (when used interim) 2. slight uptake, but below blood pool (mediastinum) 3. uptake above mediastinal, but below or equal to uptake in the liver 4. uptake slightly to moderately higher than liver 5. markedly increased uptake or any new lesion (on response evaluation) Non-progressive disease: • Complete metabolic response - score of 1, 2, or 3 in nodal or extranodal sites with or without a residual mass |
| To Determine the Expansion and Persistence of AUTO4 Following Infusion. | Up to 24 months | RQR8/aTRBC1-CAR positive T cells as determined by polymerase chain reaction at a range of time points in the peripheral blood. |
| Duration of TRBC1 Positive T Cell Aplasia. | Up to 24 months | Enumeration of circulating T cell receptor beta constant 1 positive T cells assessed by flow cytometry at a range of time points in the peripheral blood. |
Countries
Spain, United Kingdom
Participant flow
Pre-assignment details
Twenty patients were enrolled and AUTO4 was manufactured using leukapheresed autologous peripheral blood mononuclear cells. Five patients did not receive AUTO4 infusion. This was due to death in 2 patients, achieving remission with other chemotherapy (1 patient), central nervous system involvement (1 patient) and proceeding to stem cell transplant (1 patient).
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 44.0 years |
| Current Lymphoma Subtype Anaplastic large cell lymphoma kinase-negative | 0 Participants |
| Current Lymphoma Subtype Angioimmunoblastic T cell lymphoma | 1 Participants |
| Current Lymphoma Subtype Peripheral T-cell lymphoma | 8 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 0 (FULLY ACTIVE) | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Score 1 (RESTRICTED) | 1 Participants |
| Immunophenotype for T-Cell NHL (CD30) Negative | 0 Participants |
| Immunophenotype for T-Cell NHL (CD30) Not done | 0 Participants |
| Immunophenotype for T-Cell NHL (CD30) Positive | 1 Participants |
| Immunophenotype for T-Cell non-Hodgkin lymphoma (NHL) (cluster of differentiation [CD]5) Negative | 0 Participants |
| Immunophenotype for T-Cell non-Hodgkin lymphoma (NHL) (cluster of differentiation [CD]5) Not done | 0 Participants |
| Immunophenotype for T-Cell non-Hodgkin lymphoma (NHL) (cluster of differentiation [CD]5) Positive | 3 Participants |
| International Prognostic Index High-Intermediate Risk | 0 Participants |
| International Prognostic Index High Risk | 0 Participants |
| International Prognostic Index Low-Intermediate Risk | 0 Participants |
| International Prognostic Index Low Risk | 7 Participants |
| International Prognostic Index Not done | 1 Participants |
| Lactate Dehydrogenase prior to pre-conditioning | 213.0 U/L |
| Prior lines of Lymphoma therapy prior to screening | 2.0 Lines of therapy |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Received Autologous Stem Cell Transplant prior to screening No | 11 Participants |
| Received Autologous Stem Cell Transplant prior to screening Yes | 1 Participants |
| Region of Enrollment Spain | 1 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Relapse and/or Refractory Disease Status Refractory | 2 Participants |
| Relapse and/or Refractory Disease Status Relapsed | 5 Participants |
| Relapse and/or Refractory Disease Status Relapsed and Refractory | 0 Participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 1 Participants |
| Stage of Lymphoma at screening Stage 1 | 0 Participants |
| Stage of Lymphoma at screening Stage 2 | 0 Participants |
| Stage of Lymphoma at screening Stage 3 | 1 Participants |
| Stage of Lymphoma at screening Stage 4 | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 1 / 2 | 0 / 1 | 1 / 4 | 0 / 1 | 2 / 3 | 1 / 1 | 2 / 5 |
| other Total, other adverse events | 3 / 3 | 2 / 2 | 1 / 1 | 4 / 4 | 1 / 1 | 2 / 3 | 1 / 1 | 0 / 5 |
| serious Total, serious adverse events | 2 / 3 | 1 / 2 | 0 / 1 | 2 / 4 | 0 / 1 | 2 / 3 | 1 / 1 | 1 / 5 |
Outcome results
None listed