| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IIIb or Stage IV Non-Small Cell Lung Cancer (NSCLC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer (NSCLC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
- To evaluate the safety and tolerability of autologous genetically modified T-cells (lete-cel) in human leukocyte antigen (HLA) HLAA*02:01, HLA-A*02:05 and/or HLAA*02:06 positive participants with NY-ESO1 and/or LAGE1a-positive advanced NSCLC alone [Arm A] or lete-cel in combination with pembrolizumab in participants with NSCLC
lacking actionable genetic aberrations [Arm B] and participants with NSCLC with an actionable genetic aberration [Arm C]
-To determine the response to lete-cel alone [Arm A] or lete-cel in combination with pembrolizumab in participants with NSCLC lacking actionable genetic aberrations [Arm B] and participants with NSCLC with actionable genetic aberrations [Arm C]
|
|
| E.2.2 | Secondary objectives of the trial |
Secondary - Efficacy
-To further investigate the anti-tumor activity of lete-cel alone or letecel in combination with pembrolizumab according to RECIST v1.1
criteria
Secondary - Pharmacokinetics
- To characterize in vivo cellular PK profile (levels, expansion,
persistence) of NY-ESO-1 specific (c259) T cells |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion/Exclusion criteria are grouped into 4 parts and eligibility screening will take place in the following 4 steps:
-Target expression screening:
A set of criteria permitting participants’ blood to be screened for HLA-type and tumor sample to be screened for the expression of NYESO-1/LAGE-1A.
-Leukapheresis eligibility screening: To be fulfilled prior to performing leukapheresis procedure.
-Lymphodepletion eligibility screening: To be fulfilled prior to performing lymphodepletion procedure.
-Treatment fitness: To be evaluated prior to commencing lymphodepleting chemotherapy and administration of
lete-cel.
-Pembrolizumab treatment screening (Arm A ONLY, Part 4): To be fulfilled prior to commencing pembrolizumab treatment among patients in Arm A who progress following administration of lete-cel. 5.1.1. Target Expression Screening Participants are eligible to be screened for target expression (HLA-A*02:01, A*02:05, or A*02:06 and NY-ESO-1/LAGE-1a) only if all of the following criteria apply:
1. The participant (or legally acceptable representative if applicable) provides written informed consent for the screening process described as “Target Expression Screening” in the SoA (Section 1.3).
2. Age ≥18 years on the day of signing informed consent.
3. Medical Monitor (or designee) approval has been obtained if participants are enrolled or to be enrolled in other experimental interventional clinical studies during the screening and leukapheresis stages of this study (GSK208471).
4. Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC.
a. Arms A and B: Participants with NSCLC lacking actionable genetic aberrations (i.e., wild type) per NCCN guidelines, based on SoC diagnostic test.
b. Arm C: Participants with NSCLC with actionable genetic aberrations (e.g., sensitizing EGFR mutation ALK translocation, etc.) per NCCN guidelines, based on SoC diagnostic test.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
6. Tumor tissue sample with associated pathology report is available to perform tumor antigen expression analysis (NY-ESO-1 or, if tested, LAGE-1a), in alignment with Section 8.9.2. Note: Participants may not need to repeat certain screening/baseline assessments or procedures if performed as part of other GSK studies (see Section 4.1.1.1).
5.1.2. Leukapheresis Eligibility Screening
All screening criteria described in Section 5.1.1 must be reviewed and fulfilled along
with all the following criteria prior to leukapheresis. Leukapheresis process may not be
necessary for participants for which lete-cel cell product is already manufactured.
Additionally, participants may not need to repeat certain screening/baseline assessments
or procedures if performed as part of other GSK studies (see Section 4.1.1.1).
7. The participant has successfully completed the HLA and target expression evaluations.
a. Participant is positive for any of the following alleles: HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 by a validated test.
b. Participant’s tumor has been reviewed by the GSK-designated laboratory and confirmed as meeting the pre-defined threshold for expression of NY-ESO-1 and/or, if tested, LAGE-1a
After HLA allele genotyping and tumor antigen expression have been found positive, an
eligible participant must fulfill all the following inclusion criteria:
. Participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
9. Participant must have adequate organ function and blood cell counts as indicated by
the laboratory values in Table 11 and within the appropriate time windows per
Schedule of Activities Table 2 (and per Table 3 for Treatment fitness assessment).
10. Predicted life expectancy that is ≥24 weeks from leukapheresis.
11. Participant has left ventricular ejection fraction ≥45%.
12. Participant is fit for leukapheresis and has adequate venous access for leukapheresis.
13. Contraceptive use by men or women should be consistent with local regulations
regarding the methods of contraception for those participating in clinical studies.
Please refer to the protocol for remainder of the Inclusion criteria P60-P67.
|
|
| E.4 | Principal exclusion criteria |
5.2.1. Target Expression Screening
Participants are not eligible to be screened for target expression if any of the following criteria apply:
1. Prior treatment:
a. Previous treatment with genetically engineered NY-ESO-1-specific T-cells.
b. Previous NY-ESO-1 vaccine or NY-ESO-1 targeting antibody.
c. Prior gene therapy using an integrating vector.
d. Previous allogeneic hematopoietic stem cell transplant.
2. Prior malignancy other than NSCLC, with the following exceptions:
a. Participants with a history of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or has undergone potentially curative therapy with no evidence of that disease
recurrence for 5 years since initiation of that therapy.
3. Participant has undergone prior allogeneic/autologous bone marrow or solid organ
transplantation.
5.2.2. Leukapheresis Eligibility Screening
Participants are not eligible for leukapharesis if any of the Exclusion criteria in Section 5.2.1 apply. Please note that mandatory washout period restrictions must be respected (Table 12) before starting leukapheresis. In addition, participants are not eligible for leukapheresis if any of the following criteria apply:
4.Participant has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to cyclophosphamide, fludarabine, dimethylsulfoxide (DMSO) or other agents used in the study (participants
with vitiligo or resolved childhood asthma/atopy are an exception to this rule)
5. Participant has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of
its excipients.
6. Participant has an active autoimmune disease that has required systemic treatment in
past 2 years (i.e., with use of disease modifying agents, corticosteroids or
immunosuppressive drugs). Replacement therapy (e.g., physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency) is not considered a form
of systemic treatment and is allowed.
7. Participant has a history of chronic or recurrent (within the last year prior to
enrollment) severe autoimmune or active immune-mediated disease requiring
steroids or other immunosuppressive treatments.
8. Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection (including but not limited to systemic fungal
infections)
b. Clinically significant cardiac disease defined by congestive heart failure New
York Heart Association (NYHA) Class >1
c. Uncontrolled clinically significant arrhythmia in last 6 months
d. Acute coronary syndrome (angina or myocardial infarction) in last 6 months
e. Severe aortic stenosis, symptomatic mitral stenosis
f. Inadequate pulmonary function with mechanical parameters <40% predicted
(forced expiratory volume in 1 second [FEV1], forced vital capacity [FVC],
total lung capacity [TLC], pulmonary diffusing capacity for carbon monoxide
[DLCO])
9. Participant has active infection with HIV, HBV, HCV, EBV, CMV, syphilis, or
HTLV as defined below:
a. Positive serology for human immunodeficiency virus (HIV).
b. Active hepatitis B infection as demonstrated by test for hepatitis B surface
antigen. Participants who are hepatitis B surface antigen negative but are
hepatitis B core antibody positive must have undetectable hepatitis B DNA and
receive prophylaxis against viral reactivation.
c. Active hepatitis C infection as demonstrated by hepatitis C RNA test.
Participants who are HCV antibody positive will be screened for HCV RNA
by any RT PCR or bDNA assay. If HCV antibody is positive, eligibility will
be determined based on a negative Screening RNA value.
d. Positive serology for human T lymphotropic virus 1 or 2 (HTLV-1 or -2).
e. Positive serology for Epstein-Barr virus (EBV). Participants with positive EBV
serology will undergo additional tests/assessments in order to rule out active
infection.
f. Active CMV infection. Participants with positive CMV serology need to
undergo additional tests/assessments in order to rule out active infection
g. Positive test for syphilis (spirochete bacterium).
10. Participant is pregnant or breastfeeding.
11. Participant 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 and
in agreement with the Sponsor’s Medical Monitor (or designee).
12. Participant has known psychiatric or substance abuse disorders that would interfere
with cooperating with the requirements of the study
13. QTc >480 msec.
For remainder of the Exclusion criteria's please refer the Protocol P67-P72.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Frequency and severity of AEs, serious adverse events (SAEs) and AEs
of special interest (AESIs; as defined in
protocol)
- AE/SAEs leading to dose delays and/or withdrawals in participants
who received lete-cel alone or in combination with pembrolizumab
- Overall Response Rate (ORR) (investigator assessed according to
RECIST v1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary - Efficacy
-Progression-Free Survival (PFS)
- Disease Control Rate (DCR)
- Duration of Response (DoR)
- Time to Response (TTR)
Secondary - Pharmacokinetics
- Maximum persistence (Cmax),
-Time to Cmax (Tmax),
-Area under the time curve from zero to time t AUC(0-t), as data permit |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| United States |
| Netherlands |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
Print
