E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Non-small Cell Lung Cancer |
|
E.1.1.1 | Medical condition in easily understood language |
Non-small Cell Lung Cancer |
|
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 | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025054 |
E.1.2 | Term | Lung cancer non-small cell stage IIIB |
E.1.2 | System Organ Class | 100000004864 |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025055 |
E.1.2 | Term | Lung cancer non-small cell stage IV |
E.1.2 | System Organ Class | 100000004864 |
|
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 A :To determine the MTD of Debio 0932 in combination with cisplatin/pemetrexed and cisplatin/gemcitabine in treatment-naïve patients with Stage IIIb or IV NSCLC and with docetaxel in previously treated patients with Stage IIIb or IV NSCLC.
Part B : To compare the effect of adding Debio 0932 to combination chemotherapy with cisplatin/pemetrexed and cisplatin/gemcitabine on the rate of PFS at 6 months in first-line therapy of patients with Stage IIIb or IV NSCLC.
Part C : To compare the effect of adding Debio 0932 to docetaxel on the change in tumour size in second-line therapy of patients with Stage IIIb or IV NSCLC.
|
|
E.2.2 | Secondary objectives of the trial |
Part A: Investigate for Debio 0932, in combination with cisplatin/pemetrexed, cisplatin/gemcitabine, and docetaxel:1. RD
2. Safety;3. PK & potential for drug-drug interactions;4. Anti-tumour activity;5. PD biomarkers of activity
Part B:Compare between treatment arms:1. Best overall response rate;2. Duration of objective response;3. Change in tumour size from baseline until 6 months;4. Overall survival;5. Incidence of new symptomatic brain metastases. Investigate for Debio 0932, in combination with cisplatin/pemetrexed and cisplatin/gemcitabine: 6. Safety; 7. PK and PD profile
Part C: To compare between treatment arms:1. Best overall response rate; 2. Duration of objective response;3. PFS at 6 Months;4. Overall survival;5. Incidence of new symptomatic brain metastases. To investigate for Debio 0932, in combination with docetaxel: 6. Safety;7. PK and PD profile. Parts A, B & C:
Pharmacogenomic, tumour pharmacogenetic, proteomic, & pharmacogenetic factors predictive of response. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Part A :
1. Age ≥ 18 years;
2. Diagnosis of NSCLC with confirmed squamous or non-squamous tumour histology, without known EGFR mutation;
3. Archived tumour sample available;
4. Advanced or metastatic disease (Stage IIIb or IV) ;
5. Patients to be treated with cisplatin/gemcitabine or cisplatin/pemetrexed: No previous systemic treatment with chemotherapy, targeted therapy or investigational agents (except adjuvant therapy if > 6 months ago); Patients to be treated with docetaxel: ≥ 1 previous treatment with chemotherapy.
6. Candidate for treatment with cisplatin/pemetrexed or cisplatin/gemcitabine or docetaxel as determined by the Investigator;
7. Measurable disease by the RECIST criteria;
8. ECOG performance score 0 - 1;
9. Life expectancy ≥ 3 months;
10. ANC ≥ 1 500/μL;
11. Platelets ≥ 100 000/μL;
12. Creatinine clearance ≥ 60 mL/minutes (Cockroft – Gault formula);
13. AST and ALT ≤ 2.5 x ULN; in case of documented liver metastases, AST and ALT ≤ 3.5 x ULN;
14. LVEF ≥ 55% on cardiac ultrasound;
15. If female, neither pregnant nor lactating;
16. Women of child-bearing potential:
a. Negative pregnancy test at screening;
b. Agreement to use appropriate contraception methods from study entry to 6 months after the last day of treatment;
17. Male patients agree to use contraception methods from study entry to 6 months after the last day of treatment;
18. Provide written informed consent;
19. Ability to comply with study procedures.
Part B :
1. Age ≥ 18 years;
2. Diagnosis of NSCLC with confirmed squamous or non-squamous tumour histology, without known EGFR mutation and with known KRAS status;
3. Archived tumour sample available;
4. Advanced or metastatic disease (Stage IIIb or IV) ;
5. No previous systemic treatment with chemotherapy, targeted therapy or investigational agents (except adjuvant therapy if > 6 months ago) ;
6. Candidate for treatment with cisplatin/pemetrexed or cisplatin/gemcitabine as determined by the Investigator;
7. Measurable disease by the RECIST criteria;
8. ECOG performance score 0 - 1;
9. Life expectancy ≥ 3 months;
10. Absolute neutrophil count ≥ 1 500/μL;
11. Platelets ≥ 100 000/μL;
12. Creatinine clearance ≥ 60 mL/minutes (Cockroft – Gault formula);
13. AST and ALT ≤ 2.5 x ULN; in case of documented liver metastases, AST and ALT ≤ 3.5 x ULN;
14. LVEF ≥ 55% on cardiac ultrasound;
15. If female, neither pregnant nor lactating;
16. Women of child-bearing potential:
a. Negative pregnancy test at screening;
b. Agreement to use appropriate contraception methods from study entry to 6 months after the last day of treatment.
17. Male patients agree to use contraception methods from study entry to 6 months after the last day of treatment;
18. Provide written informed consent;
19. Ability to comply with study procedures.
Part C :
1. Age ≥ 18 years;
2. Diagnosis of NSCLC with confirmed squamous or non-squamous tumour histology, without known EGFR mutation and with known KRAS status;
3. Archived tumour sample available unless previous participant in Part B;
4. Advanced or metastatic disease (Stage IIIb or IV) ;
5. One of these two criteria should be fulfilled:
a) Previous participant of Part B with PD under study treatment or
b) New patient in case of futility of the interim analysis of Part B or in case of an insufficient number of patients enrolling from Part B with PD after dual chemotherapy with cisplatin/pemetrexed or cisplatin/gemcitabine or for any other reason.
6. New patients in case of futility of the interim analysis of Part B or in case of an insufficient number of patients enrolling from Part B: PD after dual chemotherapy with cisplatin/pemetrexed or cisplatin/gemcitabine.
7. Candidate for treatment with docetaxel as determined by the Investigator;
8. Measurable disease by the RECIST criteria;
9. ECOG performance score 0 - 1;
10. Life expectancy ≥ 3 months;
11. Absolute neutrophil count ≥ 1 500/μL;
12. Platelets ≥ 100 000/μL;
13. Creatinine clearance ≥ 60 mL/minutes (Cockroft – Gault formula);
14. AST and ALT ≤ 2.5 x ULN; in case of documented liver metastases, AST and ALT ≤ 3.5 x ULN;
15. LVEF ≥ 55% on cardiac ultrasound;
16. If female, neither pregnant nor lactating;
17. Women of child-bearing potential:
a. Negative pregnancy test at screening;
b. Agreement to use appropriate contraception methods from study entry to 6 months after the last day of treatment.
18. Male patients agree to use contraception methods from study entry to 6 months after the last day of treatment;
19. Provide written informed consent;
20. Ability to comply with study procedures. |
|
E.4 | Principal exclusion criteria |
Part A :
1. Unresolved toxicity from previous treatment;
2. Symptomatic brain metastases;
3. For patients on docetaxel: Serum bilirubin levels > ULN associated with serum ALP levels > 6 times ULN;
4. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, major abdominal surgery, significant bowel obstruction, ulcerative colitis, Crohn’s disease);
5. Concurrent treatment with any other systemic anti-cancer therapy;
6. Concomitant treatment with any drug on the prohibited medication list (provided separately);
7. Serious concomitant uncontrolled medical conditions.
Part B :
1. Unresolved toxicity from previous treatment;
2. Symptomatic brain metastases;
3. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, major abdominal surgery, significant bowel obstruction, ulcerative colitis, Crohn’s disease);
4. Concurrent treatment with any other systemic anti-cancer therapy;
5. Concomitant treatment with any drug on the prohibited medication list (provided separately);
6. Serious concomitant uncontrolled medical conditions.
Part C :
1. Unresolved toxicity from previous treatment;
2. Symptomatic brain metastases;
3. Serum bilirubin levels > ULN associated with serum ALP levels > 6 times ULN;
4. Gastro-intestinal disorders that could affect drug absorption (including, but not limited to, major abdominal surgery, significant bowel obstruction, ulcerative colitis, Crohn’s disease) ;
5. Concurrent treatment with any other systemic anti-cancer therapy;
6. Concomitant treatment with any drug on the prohibited medication list (provided separately);
7. Serious concomitant uncontrolled medical conditions.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Part A : Occurrence of DLTs.
Part B : Percentage of patients with PFS at 6 months.
Part C : Change in tumour size from baseline until 6 months.
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At end of each (Parts A, B and C) study treatment phase. |
|
E.5.2 | Secondary end point(s) |
Part A :
1. Change in vital signs, ECG and ECOG PS.
2. Incidence of AEs and SAEs according to NCI-CTCAE criteria.
3. Incidence of laboratory abnormalities according to NCI-CTCAE criteria.
4. Incidence of treatment discontinuations due to AEs and SAEs.
5. Change in LVEF.
6. Pharmacokinetic parameters of Debio 0932 and its metabolite Debio 0932-MET1 in plasma at steady state alone (on Day 21) and in combination with cisplatin/pemetrexed, cisplatin/gemcitabine, and docetaxel (on Day 22): C0h, Cmax, tmax, AUC0-tlast, AUC0-τ, Css av, FI, λz, t1/2, CL/F, and Vz/F calculated for all patients using non-compartmental analysis.
7. Pharmacokinetic parameters of cisplatin (total and unbound)/pemetrexed, cisplatin (total and unbound)/gemcitabine, and docetaxel in plasma after single infusion alone (on Day 1) and in combination with Debio 0932 at steady-state (on Day 22): Cmax, AUC0-tlast, AUC0-∞, λz, t1/2, MRT, CL, Vss, and Vz calculated for all patients using non-compartmental analysis.
8. Best overall response, i.e., best response recorded from start of study treatment until study end.
9. Optional exploration of pharmacodynamic biomarkers in plasma and PBMCs.
10. Pharmacogenomic, tumour pharmacogenetic, proteomic, and pharmacogenetic factors predictive of response to Debio 0932.
Part B :
1. Best overall response, i.e. best response recorded from start of study treatment until study end.
2. Duration of objective response.
3. Change in tumour size from baseline until 6 months.
4. Overall survival.
5. In patients without brain metastases at baseline: incidence of new symptomatic brain metastases.
6. Safety and tolerability (vital signs, ECG, ECOG PS, LVEF and AEs, SAEs, and laboratory abnormalities according to NCI-CTCAE criteria).
7. Optional exploration of pharmacodynamic biomarkers in plasma and PBMCs.
8. Pharmacogenomic, tumour pharmacogenetic, proteomic, and pharmacogenetic factors predictive of response to Debio 0932.
9. If applicable, plasma PK parameters of Debio 0932 and its main metabolite Debio 0932-MET1 derived from a compartmental population PK data analysis (including covariates such as demographic characteristics and pharmacogenetics).
Part C :
1. Best overall response, i.e. best response recorded from start of study treatment until study end.
2. Duration of objective response.
3. Percentage of patients with PFS at 6 Months.
4. Overall survival.
5. In patients without brain metastases at baseline: incidence of new symptomatic brain metastases.
6. Safety and tolerability (vital signs, ECG, ECOG PS, LVEF and AEs, SAEs and laboratory abnormalities according to NCI-CTCAE criteria).
7. Optional exploration of pharmacodynamic biomarkers in plasma and PBMCs.
8. Pharmacogenomic, tumour pharmacogenetic, proteomic, and pharmacogenetic factors predictive of response to Debio 0932.
9. If applicable, plasma PK parameters of Debio 0932 and its main metabolite Debio 0932-MET1 derived from a compartmental population PK data analysis (including covariates such as demographic characteristics and pharmacogenetics) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At end of each (Parts A, B and C) study treatment phase. |
|
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 | Yes |
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 | 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 | 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 | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open-label, non randomised, dose escalation |
|
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 |
Dose-escalation study to determine the maximum tolerated dose of Debio 0932 |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 46 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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
|
Study will be considered as completed when all patients have withdrawn from the study (last visit of last subject in Part C of the study). |
|
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 | 8 |
E.8.9.1 | In the Member State concerned days | 15 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 15 |