Advanced Non Small Cell Lung Cancer
Conditions
Brief summary
This is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical activity autologous clonal neoantigen reactive T cells (cNeT) administered intravenously in adults with advanced non-small cell lung cancer (NSCLC).
Detailed description
This is a first-in-human, open-label, multi-centre, phase I/IIa study to characterise the safety and clinical activity of autologous clonal neoantigen reactive T cells (cNeT) administered intravenously in adults with advanced non-small cell lung cancer (NSCLC). Patients will initially enter the study for procurement of tumour materials required to manufacture ATL001. Following manufacture of ATL001, the product will be given back to eligible patients following lymphodepletion. Patients will continue to be followed up for a minimum of 5 years, as part of a separate Long Term Follow Up Protocol, or, if the separate protocol is not available at the study site, within this protocol.
Interventions
BIOLOGICALATL001
ATL001 infusion
DRUGPembrolizumab
Checkpoint inhibitor
Sponsors
Achilles Therapeutics UK Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Patient must be at 18-75 years old. 2. Patients must have confirmed diagnosis of non-small cell lung cancer that is considered to be smoking related. 3. Patient is considered medically fit to undergo procurement of starting material and ATL001 administration procedures. 4. ECOG Performance Status 0-1. 5. Adequate organ function per the laboratory parameters defined in the protocol. 6. Anticipated life expectancy ≥ 6 months at the time of tissue procurement. 7. Measurable disease according to RECIST 1.1 criteria. Additional Inclusion Criteria will apply as per the protocol.
Exclusion criteria
1. Patients with untreated, symptomatic or progressing CNS metastases. Lesions should be clinically and radiologically stable for 2 months after treatment and should not require steroids. 2. Patients with hepatitis B or C, human immunodeficiency virus infection (HIV1/2), syphilis or HTLVI/II infection. 3. Patients for whom there is documented evidence of an actionable tumour driver oncogene mutation (EGFR, ALK or ROS-1) at the time of initial screening. Patients who have progressed on standard targeted therapies, or for whom no approved targeted treatments are available, are not excluded. 4. Patients requiring immunosuppressive treatments. 5. Patients requiring regular steroids at dose higher than prednisolone 10mg/day (or equivalent) 6. Patients with superior vena cava syndrome. 7. Patients with clinically significant, progressive, and/or uncontrolled renal, hepatic, haematological, endocrine, pulmonary, cardiac, gastroenterological or neurological disease. 8. Patients with a history of immune mediated central nervous system toxicity, or a history of ≥ Grade 2 diarrhoea/colitis within the past 6 months caused by previous immunotherapy. 9. Patients with an active concurrent cancer or a history of cancer within the past 3 years (except for in situ carcinomas, early prostate cancer with normal Prostate- Specific Antigen (PSA) or non-melanomatous skin cancers) 10. Patients with a history of organ transplantation 11. Patients who have previously received any investigational cell or gene therapies Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | 62 months due to early termination | Evaluate TEAEs and serious AEs, by incidence, severity and relationship to ATL001 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Assessment for Time to Response (TTR) From ATL001 Infusion | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate the endpoint of TTR by the investigator and ICR, per RECIST v1.1 and im-RECIST |
| Disease Assessment for Objective Response Rate (ORR) | Every 6 weeks for 6 months, then every 3 months (up to 62 months due to early termination) | Evaluate the endpoint of overall response rate (ORR), as assessed by investigator and ICR, per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune modified RECIST( im-RECIST). RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) is a standardized system for measuring tumor response to treatment in clinical trials. Tumors are assessed by imaging (e.g., CT or MRI) based on changes in size. Responses are categorized as: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): ≥30% reduction in the sum of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD). Progressive Disease (PD): ≥20% increase in the sum of target lesions, or appearance of new lesions. These criteria help assess the efficacy of treatments in solid tumors supported by im-RECIST in immunotherapy. |
| Disease Assessment for Duration of Response (DoR). The DoR is Defined as the Time From the Date of First Documented Response Until the Date of Documented Disease Progression or Death | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate the endpoint of DOR by the investigator and ICR, per RECIST v1.1 and im-RECIST |
| Disease Assessment for Change From Baseline in Tumour Size | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate the clinical activity of ATL001 in patients with advanced NSCLC using change from baseline in tumour size at week 6 , week 12 and best overall change from baseline, as assessed by investigator and independent central review (ICR) |
| Disease Assessment for Progression-Free Survival (PFS) | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate the efficacy endpoints of PFS as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST |
| Overall Survival (OS) | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate OS by the investigator |
| Disease Assessment for Disease Control Rate (DCR) | Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months | Evaluate the endpoints of DCR as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST |
Countries
France, Germany, Spain, United Kingdom, United States
Participant flow
Pre-assignment details
Please be advised that Cohort B was not formally opened therefore, no patients were enrolled into this arm.
Participants by arm
| Arm | Count |
|---|---|
| Cohort A Following lymphodepletion with enhanced host conditioning, infusion of cell therapy product ATL001, followed by a low dose regimen of IL- 2.
ATL001: ATL001 infusion | 22 |
| Cohort B Following lymphodepletion with enhanced host conditioning, infusion of cell therapy product ATL001 in combination with a checkpoint inhibitor, followed by a low dose regimen of IL- 2.
ATL001: ATL001 infusion
Pembrolizumab: Checkpoint inhibitor | 0 |
| Cohort C Following lymphodepletion with enhanced host conditioning, infusion of cell therapy product ATL001, followed by a higher dose regimen of IL-2.
ATL001: ATL001 infusion | 5 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 12 | 0 | 0 |
| Overall Study | Progressive disease | 2 | 0 | 1 |
| Overall Study | Study termination by sponsor | 8 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Cohort A | Cohort C |
|---|---|---|---|
| Age, Customized Age <65 years | 20 Participants | 19 Participants | 1 Participants |
| Age, Customized Age >=65 years | 7 Participants | 3 Participants | 4 Participants |
| Baseline ECOG performance status Grade 0 | 10 Participants | 8 Participants | 2 Participants |
| Baseline ECOG performance status Grade 1 | 17 Participants | 14 Participants | 3 Participants |
| Body mass index (kg/m^2) | 26.81 (kg/m^2) STANDARD_DEVIATION 5.49 | 26.75 (kg/m^2) STANDARD_DEVIATION 5.818 | 27.10 (kg/m^2) STANDARD_DEVIATION 4.256 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 18 Participants | 4 Participants |
| Region of Enrollment France | 3 participants | 3 participants | 0 participants |
| Region of Enrollment Germany | 6 participants | 4 participants | 2 participants |
| Region of Enrollment Spain | 2 participants | 1 participants | 1 participants |
| Region of Enrollment United Kingdom | 12 participants | 11 participants | 1 participants |
| Region of Enrollment United States | 4 participants | 3 participants | 1 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 1 Participants |
| Sex: Female, Male Male | 16 Participants | 12 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 14 / 22 | 1 / 5 |
| other Total, other adverse events | 22 / 22 | 5 / 5 |
| serious Total, serious adverse events | 8 / 22 | 0 / 5 |
Outcome results
Primary
Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability
Evaluate TEAEs and serious AEs, by incidence, severity and relationship to ATL001
Time frame: 62 months due to early termination
Population: Cohort B never opened.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | ATL001 related TEAEs | 16 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs related to any component of study treatment | 19 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious IL-2 related TEAEs | 0 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | IL-2 related TEAEs | 16 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs with CTCAE grade >= 3 | 16 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs | 21 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs with CTCAE grade >= 3 related to any component of study treatment | 14 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious TEAEs | 6 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Lymphodepletion related TEAEs with CTCAE grade >= 3 | 12 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Lymphodepletion related TEAEs | 16 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | ATL001 related TEAEs with CTCAE grade >= 3 | 4 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious TEAEs related to any component of study treatment | 2 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | IL-2 related TEAEs with CTCAE grade >= 3 | 6 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious ATL001 related TEAEs | 1 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs leading to death | 0 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious Lymphodepletion related TEAEs | 1 Participants |
| Cohort A | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | SAEs | 8 Participants |
| Cohort B | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | SAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | SAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs | 5 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs related to any component of study treatment | 5 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Lymphodepletion related TEAEs | 4 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | ATL001 related TEAEs | 4 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | IL-2 related TEAEs | 5 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious TEAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious TEAEs related to any component of study treatment | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious Lymphodepletion related TEAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious ATL001 related TEAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Serious IL-2 related TEAEs | 0 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs with CTCAE grade >= 3 | 5 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs with CTCAE grade >= 3 related to any component of study treatment | 4 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | Lymphodepletion related TEAEs with CTCAE grade >= 3 | 4 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | ATL001 related TEAEs with CTCAE grade >= 3 | 2 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | IL-2 related TEAEs with CTCAE grade >= 3 | 3 Participants |
| Cohort C | Assessment of Treatment Emergent Adverse Events (TEAEs) to Evaluate Safety and Tolerability | TEAEs leading to death | 0 Participants |
Secondary
Disease Assessment for Change From Baseline in Tumour Size
Evaluate the clinical activity of ATL001 in patients with advanced NSCLC using change from baseline in tumour size at week 6 , week 12 and best overall change from baseline, as assessed by investigator and independent central review (ICR)
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months
Secondary
Disease Assessment for Disease Control Rate (DCR)
Evaluate the endpoints of DCR as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months
Secondary
Disease Assessment for Duration of Response (DoR). The DoR is Defined as the Time From the Date of First Documented Response Until the Date of Documented Disease Progression or Death
Evaluate the endpoint of DOR by the investigator and ICR, per RECIST v1.1 and im-RECIST
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months
Secondary
Disease Assessment for Objective Response Rate (ORR)
Evaluate the endpoint of overall response rate (ORR), as assessed by investigator and ICR, per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and immune modified RECIST( im-RECIST). RECIST v1.1 (Response Evaluation Criteria in Solid Tumors) is a standardized system for measuring tumor response to treatment in clinical trials. Tumors are assessed by imaging (e.g., CT or MRI) based on changes in size. Responses are categorized as: Complete Response (CR): Disappearance of all target lesions. Partial Response (PR): ≥30% reduction in the sum of target lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD). Progressive Disease (PD): ≥20% increase in the sum of target lesions, or appearance of new lesions. These criteria help assess the efficacy of treatments in solid tumors supported by im-RECIST in immunotherapy.
Time frame: Every 6 weeks for 6 months, then every 3 months (up to 62 months due to early termination)
Population: No patients treated in Cohort B
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort A | Disease Assessment for Objective Response Rate (ORR) | Non-Responders | 20 Participants |
| Cohort A | Disease Assessment for Objective Response Rate (ORR) | Responders | 2 Participants |
| Cohort B | Disease Assessment for Objective Response Rate (ORR) | Responders | 0 Participants |
| Cohort B | Disease Assessment for Objective Response Rate (ORR) | Non-Responders | 0 Participants |
| Cohort C | Disease Assessment for Objective Response Rate (ORR) | Responders | 0 Participants |
| Cohort C | Disease Assessment for Objective Response Rate (ORR) | Non-Responders | 5 Participants |
Secondary
Disease Assessment for Progression-Free Survival (PFS)
Evaluate the efficacy endpoints of PFS as assessed by the investigator and ICR per RECIST v1.1 and im-RECIST
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months
Secondary
Disease Assessment for Time to Response (TTR) From ATL001 Infusion
Evaluate the endpoint of TTR by the investigator and ICR, per RECIST v1.1 and im-RECIST
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months
Secondary
Overall Survival (OS)
Evaluate OS by the investigator
Time frame: Every 6 weeks for 6 months, then every 3 months for a maximum of 84 months