| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic Non-Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 10059515 |
| E.1.2 | Term | Non-small cell lung cancer metastatic |
| 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 |
Phase I (Safety Run-in) The primary objective of the Phase I Safety Run-in part is to investigate the safety of IO102 in combination with either pembrolizumab alone or pembrolizumab and chemotherapy (carboplatin and pemetrexed) in patients with metastatic NSCLC, that are eligible for pembrolizumab treatment as first-line therapy for stage IV disease.
Phase II: To assess the efficacy of IO102 in combination with either pembrolizumab alone or pembrolizumab and chemotherapy versus either pembrolizumab alone or pembrolizumab and chemotherapy as measured by objective response rate (ORR) per investigator assessment in patients with metastatic NSCLC, that are eligible for pembrolizumab treatment as first-line therapy. |
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| E.2.2 | Secondary objectives of the trial |
| To investigate the safety profile and the secondary measures of efficacy including disease control rate (DCR), time to event parameters including duration of objective response (DOR), progression free survival (PFS), overall survival (OS), and tumor shrinkage. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patients with histologically or cytologically confirmed metastatic NSCLC (Cohort A) or non-squamous NSCLC (Cohort B), who have not received prior systemic treatment for their metastatic disease.
a. No known sensitizing EGFR or ALK mutations
b. Solitary metastases must be biopsied to confirm the diagnosis metastasis from NSCLC
2. PD-L1 tumor expression of greater than or equal to 50% (Cohort A) or below 50% (Cohort B). PD-L1 tumour expression should be confirmed prior to randomization using the DAKO 22C3 assay, using local/central services.
3. A male participant able to father a child must agree to use contraception starting with the screening visit and through 120 days after last dose of pembrolizumab or 180 days after last dose of chemotherapy.
4. A female participant is eligible to participate if she is not pregnant not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. A WOCBP who agrees to follow contraceptive guidance starting with the screening visit and through 120 days after last dose of pembrolizumab or 180 days after last dose of chemotherapy.
5. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial in accordance with ICH-GCP and local legislation prior to admission to the trial.
6. Be ³18 years of age on day of signing informed consent.
7. Have measurable disease per RECIST 1.1 as assessed by local site investigator/radiologist. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
8. Have provided a blood sample and archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded tissue blocks are preferred to slides.
Note: If archival tissue is available, it is preferred this is obtained less than or equal to 90 days prior to randomization. If using unstained cut slides, newly cut slides should be used for the testing, within 14 days from the date slides are cut.
9. Have an ECOG performance status of 0 to 1.
10. Have adequate organ function. Specimens must be collected within 10 days prior to the start of trial treatment. |
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| E.4 | Principal exclusion criteria |
1. A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related AE (irAE)
3. Has received prior systemic anti-cancer therapy in the first line setting for the participant's metastatic disease (treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed as long as completed at least 6 months prior to diagnosis of metastatic disease).
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible.
Note: If participant received major surgery, they must have recovered adequately from the adverse events and/or complications from the intervention prior to starting trial treatment.
4. Has received prior radiotherapy to the lung >30 Gy within 6 months of start of trial treatment. Participants must have recovered from all radiation-related adverse events, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
5. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
6. Is currently participating in or has participated in a trial of an investigational agent (e.g. small molecules, immunotherapy, chemotherapy monoclonal antibodies or any other experimental drug in the neoadjuvant or adjuvant setting) or has used an investigational device within 6 months prior to the first dose of trial treatment.
Note: Participants who have entered the follow-up phase of an investigational trial may participate as long as it has been 6 months after the last dose of the previous investigational agent.
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of trial treatment.
8. Has a known additional malignancy that is progressing or has required active treatment within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ that have undergone potentially curative therapy are not excluded.
9. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging, clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of trial treatment.
10. Has severe hypersensitivity (≥Grade 3) to IO102, pembrolizumab, carboplatin, pemetrexed and/or any of its excipients.
11. 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 is not considered a form of systemic treatment and is allowed.
12. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local health authority.
15. Has a known history of Hepatitis B or known active Hepatitis C virus infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the patient's participation for the full duration of the trial, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
17. Has known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the trial.
18. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days for cohort A and 180 days for cohort B after last dose of trial treatment.
19. Has had an allogenic tissue/solid organ transplant. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I (Safety Run-in)
The primary endpoint includes the incidence and severity of AEs and SAEs, including event of clinical interest (ECI), ECOG performance status, physical examination vital signs, electrocardiograms (ECG), and changes in laboratory values (clinical chemistry and hematology). Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be used for grading of events.
Phase II:
Objective response rate (ORR) evaluated by RECIST 1.1. Objective response rate is defined as the rate of complete response [CR] plus partial response [PR]. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary end points will be assessed on an ongoing basis throughout the trial |
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| E.5.2 | Secondary end point(s) |
The secondary objectives of the trial include (based on RECIST 1.1.):
• Objective response rate (ORR) by baseline PD-L1 expression
• Disease control rate (DCR), defined as CR + PR + stable disease (SD for ≥24 weeks
• Time to Event parameters including:
i. Time to response (TTR)
ii. Duration of response (DOR)
iii. Progression Free Survival
iv. Overall survival
v. Time from first treatment administration to the commencement of first subsequent treatment or death if this occurs first (TFST) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary end points 1 and 2 will be assessed on an ongoing basis throughout the trial.
Secondary end point 3 points i-v will be assessed on an ongoing basis throughout trial and until commencement of first subsequent treatment or death if this occurs first (TFST). |
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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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Safety and Efficacy Study |
|
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Phase 2, Arm A2 will be the comparator for arm A1. Phase 2 Arm B2 will be the comparator for Arm B1 |
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| E.8.2.4 | Number of treatment arms in the trial | 6 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| United States |
| Denmark |
| Germany |
| Netherlands |
| Spain |
| United Kingdom |
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| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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