| 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
(GSK3377794) in human leukocyte antigen (HLA) HLA-A*02:01, HLA-A*02:05 and/or
HLA-A*02:06 positive participants with NY-ESO-1 and/or LAGE-1a positive advanced NSCLC alone [Arm A] or GSK3377794 in combination with pembrolizumab in participants with NSCLC with WT EGFR and WT ALK/ROS1 [Arm B] and participants with NSCLC with EGFR or ALK/ROS1 aberration [Arm C]
- To determine the response to GSK3377794 alone [Arm A] or GSK3377794 in combination with pembrolizumab in articipants with NSCLC with WT EGFR and WT ALK/ROS1 [Arm B] and participants with NSCLC with EGFR or ALK/ROS1 aberration [Arm C] |
|
| E.2.2 | Secondary objectives of the trial |
- To further investigate the anti-tumor activity of GSK3377794
- To describe the persistence of GSK3377794 over time |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1 (Screening) begins with HLA allele genotyping and tumor antigen expression for
patients with histologically or cytologically confirmed advanced Stage IIIb or IV or
recurrent NSCLC.
1. The participant (or legally acceptable representative if applicable) provides written
informed consent for the screening process described as “Target Antigen Expression
Screening” in the SoA (Section 1.3).
2. The participant has successfully completed the HLA and target expression evaluations.
- Participant is positive for any of the following alleles: HLA-A*02:01, HLA-A*02:05, and HLA-A*02:06.
- Participant’s tumor (archival specimen) 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 of the following inclusion criteria:
3. The participant (or legally acceptable representative if applicable) provides written
informed consent for the trial.
4. Age ≥18 years on the day of signing informed consent.
5. Pending approval of Medical Monitor (or designee), participants can be enrolled in
other experimental interventional clinical studies during the screening and leukapheresis stages of this study (GSK208471). (refer to exclusion criteria #19, 20, 22)
6. Histologically or cytologically diagnosed unresectable Stage IIIb or Stage IV NSCLC with measurable disease per RECIST v1.1 as assessed by local site investigator/radiology.
Note: Lesions situated in a previously irradiated area are considered measurable if
progression has been demonstrated in such lesions.
a. Arms A and B: Participants with NSCLC with WT EGFR and WT ALK/ROS1 based on SoC diagnostic test.b. Arm C: Participants with NSCLC with EGFR or ALK/ROS1 aberration based on SoC diagnostic test.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
8. Predicted life expectancy that is ≥3 months.
9. Participant has left ventricular ejection fraction ≥50% or as per institution’s
guidelines.
10. Adequate venous access for leukapheresis.
11. In the Investigator’s opinion, the participant is fit for lymphodepleting chemotherapy
and infusion of GSK3377794.
An archived biopsy of the tumor tissue obtained at any time from the initial diagnosis of
NSCLC to time of study entry is mandatory for tumor antigen expression analysis (NY-ESO-1 and, when available, LAGE-1a).
Note: Based upon approval of the Medical Monitor (or designee), participants can be
enrolled in other experimental interventional clinical studies during the screening and
leukapheresis stages of this study.
5.1.2. Leukapheresis (Part 2)
All screening criteria described in Section 5.1.1 must be reviewed and fulfilled along
with all the following criteria prior to leukapheresis.
12. In the Investigator’s opinion, the participant is suitable for leukapheresis, including
the following laboratory parameters being above the thresholds in the table on page 54 of the Protocol.
13. Leukapheresis can be collected as follows:
a. Between lines of therapies.
b. After the first 3 cycles of current systemic chemotherapy
c. During PD-1/PD-L1 checkpoint blockade regimen (alone or in combination with
chemotherapy) after the first 3 cycles of checkpoint blockade therapy. Wash-out for anti-PD-1/ PD-L1 monotherapy is NOT required.
d. After 9 weeks of current TKI therapy
e. After radiotherapy (refer to Section 5.2.2; exclusion criterion #21)
f. Pending approval of Medical Monitor (or designee), if SoC therapy is refused by
the participant (following discussion between participant and Investigator about
benefits and risks)
Note: Based upon approval of Medical Monitor (or designee), participants can be
enrolled in other experimental interventional clinical studies during the screening and
leukapheresis stages of this study.
An intermediate SoC line of therapy between leukapheresis (Part 2) and treatment
(Part 3) at the time of disease progression is allowed if all of the conditions in Section 6.2
are met.
Note: Participation in experimental interventional clinical studies is not allowed between
leukapheresis and study treatment.
5.1.3. Lymphodepletion / Treatment (Part 3)
Participants must meet the following criteria to be eligible for lymphodepleting
chemotherapy and subsequent GSK3377794 treatment.
14. Prior to lymphodepleting chemotherapy, participants must meet all the criteria
described in Section 5.1.1 and Section 5.1.2. This must be confirmed within 2 weeks
before lymphodepletion (see Table 3 within the protocol).
15. Prior therapies
a. All participants with NSCLC with WT EGFR and WT ALK/ROS1 (Arms A and B) should have received and failed at least one line of PD-1/PD-L1 checkpoint blockade therapy (alone or in combination with systemic chemotherapy).
Please refer to the protocol for remainder of the Inclusion criteria P53-P57 |
|
| E.4 | Principal exclusion criteria |
1. NSCLC with BRAF, HER2, and/or any other actionable genetic aberration that can be treated with targeted standard of care (NCCN recommended) therapy.
2. Prior therapies:
a. Arm A and B: Has received and failed ≥3 lines of systemic therapy. Participants who are receiving a second line of systemic therapy during the study screening period can be eligible if they have an expected time to progression of at least four months per investigator assessment, a positive benefit-risk evaluation is provided by the investigator, and there is agreement with the Sponsor Medical Monitor or designee (all parameters are necessary).
b. Arm C: Has received ≥4 lines of systemic therapy (except for the below exclusion criterion #2c).
c. Arm C: Participants with NSCLC with EGFR or ALK/ROS1 aberration who are receiving a fourth line of systemic therapy during the study screening period can be eligible if all the following parameters apply:
- Have an expected time to progression of at least four months per
investigator assessment
- A positive benefit-risk evaluation is provided by the investigator
- In agreement with the Sponsor Medical Monitor (or designee)
3. Prior treatment:
a. Any prior treatment with oncology cell therapy (TCR T-cell therapy or CAR-T therapy)
b. Prior gene therapy using an integrating vector
c. Docetaxel therapy after having failed either doublet platinum-based chemotherapy or PD-1/PD-L1 checkpoint blockade therapy
4. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. Prior malignancy other than NSCLC, with the following exceptions:
a. Participants with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.
b. Participants with malignancies that have been definitively treated may be eligible for the study based on consultation between the Investigator and Sponsor Medical Monitor (or designee).
6. Participant has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to cyclophosphamide, fludarabine, or other agents
used in the study (participants with vitiligo or resolved childhood asthma/atopy are
an exception to this rule).
7. Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its
excipients.
8. 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.
9. 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.
10. Prior allogeneic/autologous bone marrow or solid organ transplantation (participants
who have had a transplant 5 or more years ago, are eligible as long as there are no
symptoms of GVHD) or prior allogeneic hematopoietic stem cell transplantation within the last 5 years.
11. Uncontrolled intercurrent illness including, but not limited to:
a. Ongoing or active infection
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])
g. Interstitial lung disease (participants with existing pneumonitis as a result of
radiation are not excluded; however, participants cannot be oxygen dependent) Note: Post-radiation changes in the lung related to prior radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment may be permitted if agreed upon by the Investigator and Sponsor’s Medical Monitor (or designee).
h. Prior or active demyelinating disease
12. Current unstable liver or biliary disease per Investigator assessment defined by the
presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal
or gastric varices, persistent jaundice, or cirrhosis.
For remainder of the Exclusion criteria's please refer the Protocol P59-P66 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Frequency and severity of AEs
- SAEs and AE/SAEs leading to dose delays and/or withdrawals in participants who received GSK3377794 alone or in combination with pembrolizumab
- Laboratory parameters
- Vital signs
- Eastern Co-operative Oncology Group performance status (ECOG PS)
- Electrocardiograms (ECGs)
- Overall Response Rate (ORR) (investigator assessed according to RECIST 1.1) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Progression-Free Survival (PFS)
- Disease Control Rate (DCR)
- Duration of Response (DoR)
- Time to Response (TTR)
- Maximum persistence (Cmax), time to Cmax (Tmax), and 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 | Yes |
| 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 | 2 |
| 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 |
| Netherlands |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
The end of the study is defined as the date of (whichever occurs later): When all participants have had at least 2 post-baseline disease assessments
or
At least 70% of all participants have progressed or died. |
|
| 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
