E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small cell lung cancer (NSCLC) |
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E.1.1.1 | Medical condition in easily understood language |
Non-small cell lung cancer |
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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) |
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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 |
Part 1
- To determine safety and tolerability of novel regimen(s)
Part 2
-Determine whether experimental regimen(s) provide evidence for improved survival over SOC therapy
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E.2.2 | Secondary objectives of the trial |
Part 1
-To provide a preliminary evaluation of the efficacy of experimental regimen(s)
-Characterize the pharmacokinetic properties of experimental regimen(s)
Part 2
-Evaluate milestone survival in participants treated with experimental regimen(s) versus SoC therapy for NSCLC
-Evaluate other measures of antitumor activity of the experimental regimen(s) compared with SoC therapy for NSCLC (RECIST 1.1 and iRECIST)
-Evaluate the safety and tolerability of the experimental regimen(s) compared with SoC therapy for NSCLC
-Characterize the pharmacokinetic properties SoC or experimental regimen(s)
-Determine Immunogenicity of experimental regimen(s) |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Substudy 1 is docetaxel versus docetaxel + GSK3359609; date and version are as per the main protocol; objectives are per main protocol.
See Sec 12.1.2 of 205801 protocol. |
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E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent/assent as described in Section 12.4 of protocol which includes compliance with the requirements and restrictions listed in the ICF and in this protocol
2. Male or female, aged 18 years or older at the time consent is obtained
Note: Participants in Korea must be age 19 years or older at the time consent is obtained.
3. Histologically or cytologically confirmed diagnosis of NSCLC (squamous or nonsquamous)
and:
a. Documented disease progression (for example, based on radiographic imaging) during or after a maximum of 2 lines of systemic treatment for locally/regionally advanced recurrent, Stage IIIb/Stage IIIc/Stage IV or metastatic disease:
I. No more than or less than 1 line of platinum-containing chemotherapy regimen and
ii. No more than or less than 1 line of PD(L)1 mAb containing regimen.
Notes:
o PD(L)1 mAb received during a previous clinical trial may meet this requirement upon consultation with study medical monitor.
o Participants who received a regimen similar to the PACIFIC regimen [chemoradiotherapy followed by PD(L)1] as part of SoC AND have relapsed within one year from the first dose of chemoradiotherapy would fulfill the protocol requirement for platinum-based chemotherapy treatment and PD-1/L1 treatment. This would be considered a single line of treatment for the purpose of PD(L)1 line of therapy stratification.
o PD(L)1 mAb can be administered with the platinum-based chemotherapy regimen and this would count as a single line of therapy.
o PD(L)1 mAb may be counted as a prior treatment if the agent is approved in at least 1 country for the treatment of cancer.
o Participants who have completed 2 years of pembrolizumab or another PD(L)1 mAb, discontinue from that therapy, experience disease progression, and are then retreated with PD(L)1, will be considered as
having had one line of PD(L)1 therapy.
o Adjuvant or neo-adjuvant systemic anticancer therapy will not count toward the 2 lines of therapy unless disease recurs during the first year following the start of adjuvant chemotherapy.
b. Participants with known BRAF molecular alterations must have had disease progression after receiving the locally available SoC treatment for the molecular alteration.
c.Participants who received prior anti-PD(L)1 therapy must fulfill the following requirements:
oHave achieved a CR, PR or SD and subsequently had disease progression (per RECIST 1.1 criteria) either on or after completing PD(L)1 therapy
oHave not progressed or recurred within the first 12 weeks of PD(L)1 therapy, either clinically or per RECIST 1.1 criteria
4. Measurable disease, presenting with at least 1 measurable lesion per RECIST 1.1 (see Appendix 12 of protocol for definition of a measurable lesion)
5. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0 or 1
6. A tumor tissue sample obtained at any time from the initial diagnosis of NSCLC to time of study entry is mandatory. Although a fresh tumor tissue sample obtained during screening is preferred, archival tumor specimen is acceptable. See Section 9.9.2 of protocol for further details on tumor tissue requirements.
7. Adequate organ function as defined in Table 2
8. A male participant must agree to use a highly effective contraception as detailed in Appendix 6 of this protocol during the treatment period and for at least 120 days after the last dose of study treatment and refrain from donating sperm during this period.
Note: If the participant is randomized to the SoC regimen only, duration of contraception should be as per local label.
9. A female participant is eligible to participate if she is not pregnant (see Appendix 6 of protocol), not breastfeeding, and at least 1 of the following conditions apply:
i. Not a woman of childbearing potential (WOCBP) as defined in Appendix 6 of protocol
OR
ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 6 of protocol during the treatment period and for at least 120 days after the last dose of study treatment.
Note: If the participant is randomized to the SoC regimen only, duration of contraception is should be as per the local label.
10. Life expectancy of at least 12 weeks |
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
1. Received prior treatment with the following therapies (calculation is based on date of last therapy to date of first dose of study treatment):
a. Docetaxel at any time
b. Any of the investigational agents being tested in the current study, refer to Section 12.1 for additional information
c. Systemic approved or investigational anticancer therapy within 30 days or 5 half-lives of the drug, whichever is shorter. At least 14 days must have elapsed between the last dose of prior anticancer agent and the first dose of study drug is administered.
d. Prior radiation therapy: permissible if at least one non-irradiated measurable lesion is available for assessment per RECIST version 1.1
or if a solitary measurable lesion was irradiated, objective progression is documented. A wash out of at least 2 weeks before start of study drug for radiation of any intended use is required.
2.Received >2 prior lines of therapy for NSCLC, including participants with BRAF molecular alterations. (See inclusion criterion #3 for eligible lines of therapy guidance)
Note: Patients with known molecular alterations with therapeutic options available (e.g., EGFR, ALK, ROS1) are excluded from participation in this study unless no other therapeutic options are available locally.
3. Invasive malignancy or history of invasive malignancy other than disease under study within the last 2 years, except as noted below:
- Any other invasive malignancy for which the participant was definitively treated, has been disease-free for at least 2 years and in the opinion of the principal investigator and GSK Medical Monitor will not affect the evaluation of the effects of the study treatment on the currently targeted malignancy, may be included in this clinical trial.
- Curatively treated non-melanoma skin cancer or successfully treated in situ carcinoma of the skin.
4.Carcinomatous meningitis (regardless of clinical status) and uncontrolled or symptomatic central nervous system (CNS) metastases.
Note: Participants with previously treated brain metastases may participate provided they are asymptomatic (any neurologic symptoms have returned to baseline [participants may be receiving stable doses of anticonvulsants]), radiographically stable (without evidence of progression by imaging for at least 4 weeks prior to the first dose of study treatment), have no evidence of new or enlarging brain metastases, and are clinically stable off steroids for at least 2 weeks prior to study treatment.
5. Major surgery ≤28 days of first dose of study treatment.
6. Autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years. Replacement therapies which include physiological doses of corticosteroids for treatment of endocrinopathies (for example, adrenal insufficiency) are not considered systemic treatments.
Note: Participants with controlled Type 1 diabetes mellitus (T1DM) are eligible.
7. Receiving systemic steroids (>10 mg oral prednisone or equivalent) or other immunosuppressive agents within 7 days prior to first dose of study treatment.
Note: Steroids as premedication for hypersensitivity reactions (e.g., computed tomography [CT] scan premedication) are permitted.Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed.
8. Prior allogeneic/autologous bone marrow or solid organ transplantation.
9. Receipt of any live vaccine within 30 days prior to first dose of study treatment. Refer to the SRM for clarity on COVID-19 vaccines.
10. Toxicity from previous anticancer treatment that includes:
a. ≥ Grade 3 toxicity considered related to prior immunotherapy and that led to treatment discontinuation.
b. Toxicity related to prior treatment that has not resolved to ≤Grade 1 (except alopecia, hearing loss, endocrinopathy managed with replacement therapy, and peripheral neuropathy which must be ≤Grade 2).
11. History (current and past) of idiopathic pulmonary fibrosis, pneumonitis (for past pneumonitis exclusion only if steroids were required for treatment), interstitial lung disease, or organizing pneumonia.
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 Medical Monitor.
12. Recent history (within the past 6 months) of uncontrolled symptomatic ascites, pleural or pericardial effusions
13. Recent history (within the past 6 months) of gastrointestinal obstruction that required surgery, acute diverticulitis, inflammatory bowel disease, or intraabdominal abscess
Refer protocol for other exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Part 1 - AEs, SAEs, DLTs, changes in safety/laboratory assessment parameters, dose modifications
Part 2 - Overall survival as measured by time from randomization to death
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Following discontinuation of study treatment, participants will be followed every 12 weeks for disease progression until death or withdrawal from further contact. |
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E.5.2 | Secondary end point(s) |
Part 1:
-Objective Response Rate (ORR); Disease Control Rate (DCR)
-PK parameters that include Cmax and Cmin for experimental regimen(s) (and investigational agent/s included in other arms), as data permit.
Part 2:
-Milestone survival rate at 12 and 18 months;
-CR, PR, SD, PD, PFS, ORR, DOR, DCR; iCR, iPR, iUPD, iCPD, iSD; iPFS; iORR; iDOR;
-Frequency and severity of AEs, AESI; SAEs and AE/SAEs leading to dose modifications/delays/withdrawals; changes in laboratory, vital signs, and safety assessment parameters, including immunogenicity (ADA);
-PK parameters that may include Cmax and Cmin for experimental regimen(s) and for SoC alone, as data permit
-ADA incidence for experimental regimens(where appropriate)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Milestone survival at 12 months and 18 months from study start
2. Time of response (i.e. time of complete or partial response, disease progression, progression free survival, as well as overall response duration).
3. Adverse events (serious and non-serious) and events of special interest reported from start of treatment until 90 days after the last dose of study treatment or, if related to protocol-mandated procedures, from the time of consent until 90 days after the last dose of study treatment. Safety monitoring of by evaluation of dose modification/delays/withdrawals, lab values, vital signs, and other safety assessments including immunogenicity evaluated at time of pre and post-dosing throughout the study, as described in the schedule of activities.
Please Refer Protocol |
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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 | No |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 63 |
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 |
Korea, Republic of |
Russian Federation |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |