| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Stage IV non-small cell lung cancer (NSCLC) |
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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 | 10029522 |
| E.1.2 | Term | Non-small cell lung cancer stage IV |
| 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 1
- To assess the safety of the combination of radium-223 dichloride and pembrolizumab and to determine the recommended Phase 2 dose (RP2D)
Phase 2
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone) |
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| E.2.2 | Secondary objectives of the trial |
Phase 1
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab
Phase 2
- To assess the efficacy of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone)
- To evaluate the safety of the combination of radium-223 dichloride and pembrolizumab (for Cohort 1: compared to pembrolizumab alone) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Participant must be ≥18 yrs (or age of legal maturity) at time of signing ICF
2. Histologically / cytologically confirmed diagnosis of stage IV NSCLC. Phase 1 incl. participants meeting either Cohort 1 / Cohort 2 inclusion criteria as outlined below
a. Phase 2 Cohort 1:
- No EGFR sensitization (activating) mutation or ALK/ROS1 rearrangement
- Treatment naïve (no prior systemic therapy) for their metastatic NSCLC. Completion of treatment with chemotherapy as part of neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at least 6 mths prior to diagnosis of metastatic disease
- PD-L1 TPS ≥50% as per local assessment
b. Phase 2 Cohort 2:
- Progression on prior treatment with immune checkpoint inhibitor
- If no EGFR sensitization (activating) mutation or ALK/ROS1 rearrangement
1. 1 or 2 prior lines of therapies for metastatic NSCLC
- If EGFR sensitization (activating) mutation or ALK/ROS 1 rearrangement
1. Prior treatment with appropriate tyrosine kinase inhibitor
2. At least one & not more than 3 prior lines of therapy for metastatic NSCLC
- Availability of tumor specimen for determination of PD-L1 status
3. Measurable disease per RECIST v1.1 as assessed by local site investigator/radiologist. Lesions situated in previously irradiated area considered measurable if progression has been demonstrated in such lesions.
4. At least 2 skeletal metastases identified at baseline confirmed by MRI / CT
5. ECOG Performance Status of 0/1
6. Adequate bone marrow & organ function as assessed by following lab. tests
a. Hemoglobin ≥9g/dL without transfusion / erythropoietin within last 4 wks
b. ANC ≥1500/mm3
c. Platelet count ≥100000/mm3 without platelet transfusion within last 4 wks
d. ALT & AST ≤2.5 x upper limit of normal (≤5 X ULN in case of liver metastases)
e. Total bilirubin ≤1.5XULN
f. Creatinine ≤1.5XULN or estimated creatinine clearance ≥30 mL/min as calculated using Cockcroft-Gault equation
g. Prothrombin International normalized ratio or PT & aPTT ≤1.5×ULN unless participant receiving anticoagulant therapy (as long as PT/ aPTT within therapeutic range of intended use of anticoagulants)
- Participants being treated with anticoagulant will be allowed to participate provided no prior evidence of underlying abnormality in these parameters exists. Anticoagulants that require monitoring, standards should be considered & controlled by investigator. New oral anticoagulants, individual risk benefit in accordance with the applicable labels &/or local guidelines should be carefully assessed
7. Female participants of child-bearing potential must have negative serum pregnancy test within 7 days before start of study drug administration. Post-menopausal females & surgically sterilized females are exempt from pregnancy test
8. Females of childbearing potential & males must agree to use highly effective methods of birth control (i.e failure rate <1% per yr) from signing ICF until at least 120 days after last administration of pembrolizumab or 6 mths after last administration of radium-223 dichloride, whatever comes later, when sexually active (plus an additional 30 days [a menstruation cycle] for female participants plus an additional 75 days [a spermatogenesis cycle] for male participants who must refrain from donating sperm during this period).
Highly effective methods of contraception for female participants include: (i) combined hormonal contraception associated with inhibition of ovulation; (ii) progestogen-only hormonal contraception associated with inhibition of ovulation; (iii) IUD; IUS; bilateral tubal occlusion; sexual abstinence. Abstinence only considered an effective method if defined & when this is the preferred and usual lifestyle of the participant.
Adequate contraception for male participant is vasectomy, bilateral orchiectomy & continuous androgen deprivation therapy (total serum testosterone should be less than 50 ng/mL / 1.7 nmol/L). Otherwise participant required to use condoms and participants partner an adequate contraception as described above. Male participants with partners who are pregnant must use a condom during sexual intercourse. Male participants should be advised on the conservation of sperm as there is a potential risk that radiation from radium-223 dichloride could cause adverse effects on fertility. The investigator or a designated associate is requested to advise the participants how achieve highly effective birth control.
Contraceptive use by men / women should be consistent with local regulations regarding the methods of contraception for participants in clinical studies.
9. Capable of giving consent which incl. compliance with requirements & restrictions listed in ICF & in protocol before performing any screening assessment.
10. Participants must be on a BHA treatment, such as bisphosphonates / denosumab treatment unless such treatment is contraindicated / not recommended per investigator’s judgement & incl agreed by medical monitor. |
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| E.4 | Principal exclusion criteria |
1. Previous / concurrent cancer within 3 years prior to enrollment except for curatively treated carcinoma in situ (e.g., breast carcinoma, cervical cancer, prostate carcinoma, non-melanoma skin cancer, and superficial bladder tumors).
2. Condition by Cohort & Phase:
a. Phase 2 Cohort 1 (& participants eligible for 1st line treatment in Phase 1): 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 (e.g., CTLA-4, OX40, cluster of differentiation [CD]137).
b. Phase 2 Cohort 2 (& participants eligible for ≥ 2nd line treatment in Phase 1): 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 (e.g., CTLA-4, OX40, CD137) and was discontinued from that treatment due to a Grade 3 or higher irAE.
3. Known active CNS metastases &/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 wks by repeat imaging) (note that the repeat imaging should be performed during study screening), clinically stable, & without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
4. Active autoimmune disease that has required systemic treatment in the past 2 yrs (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment & is allowed.
5. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
6. Major surgical procedure / significant traumatic injury within last 28 days. Note: If participants received major surgery, they must have recovered adequately from the toxicity &/or complications from the intervention prior to starting therapy. Central line surgery is not considered major surgery.
7. Non-healing wound, non-healing ulcer / non-healing bone fracture.
8. Evidence / history of any bleeding diathesis, irrespective of severity.
9. Known history / presence of osteonecrosis of jaw.
10. Known hypersensitivity to the active substance or to any of the excipients of radium-223 dichloride or pembrolizumab
11. Seizure disorder requiring medication.
12. Ongoing infection >Grade 2 NCI-CTCAE v.5.0 requiring systemic therapy
13. Significant acute GI disorders with diarrhea as major symptom e.g., Crohn’s disease, malabsorption, or ≥ NCI-CTCAE v.5.0 Grade 2 diarrhea of any etiology.
14. Pregnant / breast-feeding participants.
15. CHF ≥ NYHA class 2.
16. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 mths).
17. Myocardial infarction in the last 6 months
18. Uncontrolled cardiac arrhythmias (≥ grade 3 CTC v5.0).
19. History of osteoporotic fracture
20. Known history of Hepatitis B (defined as HBsAg reactive or detectable HBV DNA or known active Hepatitis C virus (defined as HCV RNA is detected) infection. Note: No testing for Hepatitis B & Hepatitis C is required unless mandated by local authority.
21. Known HIV. No HIV testing required unless mandated by local authority.
22. Previous (within the last 4 wks of the planned first dose of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s). 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.
23. Systemic steroid therapy within 3 days of the planned first dose of study treatment or chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent). Participants with asthma that require intermittent use of bronchodilators, inhaled steroids, or local steroid injections would not be excluded from the study.
24. Previous treatment with live vaccine within 30 days of planned start of study treatment
25. Transfusion of blood products (including platelets or red blood cells) or administration of G-CSF, GM-CSF or recombinant erythropoietin) within 4 wks prior to planned start of study treatment.
26. Prior treatment with radium-223 dichloride or any therapeutic radiopharmaceutical.
27. Prior radiotherapy within 21 days of planned start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, & not have had radiation pneumonitis.
28. Prior transplantation of human cells, tissues & organs (e.g., liver transplant) or candidates for any type of transplantation.
29. History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the trial or interfere with the participation for the full duration of the trial
30. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Number of participants with adverse events (AEs) in Phase 1
2. Number of participants with dose limiting toxicities (DLTs) in Phase 1
3. Objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 in Phase 2 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Until 30 days after the last dose of the study intervention (up to 4 years)
2. Up to 6 weeks
3. Up to 36 weeks |
|
| E.5.2 | Secondary end point(s) |
1. ORR per RECIST v1.1 in Phase 1
2. ORR per iRECIST in Phase 1
3. Duration of response (DOR) per RECIST v1.1 in Phase 1
4. DOR per iRECIST in Phase 1
5. Disease control rate (DCR) per RECIST v1.1 in Phase 1
6. DCR per iRECIST in Phase 1
7. ORR per iRECIST in Phase 2
8. DOR per RECIST v1.1 in Phase 2
9. DOR per iRECIST in Phase 2
10. DCR per RECIST v1.1 in Phase 2
11. DCR per iRECIST in Phase 2
12. Progression free survival (PFS) per RECIST in Phase 2
13. PFS per iRECIST in Phase 2
14. Overall survival (OS) in Phase 2
15. Number of participants with AE in Phase 2 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Points 1-14: Up to 5 years
Point 15: Until 30 days after the last dose of the study intervention (up to 5 years) |
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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 | Yes |
| 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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 |
| To determine the Recommended Phase 2 Dose of radium-223 dichloride in combination with pembrolizumab |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| 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 |
| Belgium |
| Germany |
| Israel |
| Italy |
| Japan |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| 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
|
The date when the last participant has been followed for at least 2 years after the last dose of radium-223 dichloride or died or withdrew consent.
In the event participants roll over to a separate study for long-term FU, the present study will end when all participants have transitioned into the rollover-study or discontinued from this study for another reason. Until the transition to the ROS, participants will continue to follow all the procedures & visits required in the current protocol. |
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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 | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| 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 | 21 |
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