| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
BRCA1 or -2 mutated breast cancer
Any other cancer type expected to benefit from olaparib-carboplatin |
BRCA1 of -2 gemuteerde borstkanker
Elk ander kankertype waarbij mogelijke baat is van olaparib-carboplatin |
|
| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer with BRCA1 or -2 mutation |
| Borstkanker met BRCA1 of -2 mutatie |
|
| 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 | 17.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10057654 |
| E.1.2 | Term | Breast cancer female |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10072737 |
| E.1.2 | Term | Advanced breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 17.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast 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 |
Part 1: To obtain the recommended phase 2 dose of the combination of carboplatin and olaparib
Part 2: To compare first line treatment of BRCA-mutated HER2-negative advanced breast cancer with two cycles carboplatin-olaparib followed by olaparib monotherapy with capecitabine with progression free survival as endpoint. |
Deel 1: Het bepalen van de dosis carboplatin-olaparib therapie voor deel 2.
Deel 2: Het vergelijken van eerstelijns behandeling van BRCA-gemuteerde borstkanker met 2 kuren carboplatin-olaparib gevolgd door olaparib monotherapie met capecitabine op progressie-vrije overleving. |
|
| E.2.2 | Secondary objectives of the trial |
Part 1: To investigate pharmacokinetics, pharmacodynamics and preliminary efficacy of the regimen
Part 2: To compare first line treatment of BRCA-mutated HER2-negative advanced breast cancer with two cycles carboplatin-olaparib followed by olaparib monotherapy with capecitabine with progression free survival after second line treatment as endpoint.
To determine the safety and efficacy of study treatments used in first line and second line treatment.
To compare objective response rate and overall survival between the treatment arms (ie. strategy with and without carboplatin-olaparib). |
Deel 1: Pharmacokinetiek, pharmacodynamiek en preliminaire werkzaamheid van het therapieschema
Deel 2: Het vergelijken van eerstelijns behandeling van BRCA-gemuteerde borstkanker met 2 kuren carboplatin-olaparib gevolgd door olaparib monotherapie met capecitabine op progressie-vrije overleving.
Het bepalen van veiligheid en werkzaamheid van de verschillende therapieen in eerste en tweede lijn.
Het vergelijken van objectieve respons rate en overleving tussen de therapie-armen (ie. een vergelijking van de strategie met en zonder carboplatin-olaparib)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Part 1:
1. Histological or cytological proof of advanced cancer pre-treated with maximally one line of systemic chemotherapy and any line of hormonal therapy and potentially benefitting from olaparib-carboplatin combination therapy;
2. Age >= 18 years;
3. Able and willing to give written informed consent;
4. WHO performance status of 0, 1 or 2;
5. Able and willing to undergo blood sampling for PK and PD analysis;
6. Life expectancy > 3 months, allowing adequate follow up of toxicity evaluation and antitumor activity;
7. Evaluable disease according to RECIST 1.1 criteria;
8. Minimal acceptable safety laboratory values
a. ANC of > 1.5 x 109 /L
b. Hemoglobin of at least 5.6 mM
c. Platelet count of > 100 x 10^9 /L
d. Hepatic function as defined by serum bilirubin < 1.5 x ULN, ASAT and ALAT <2.5 x ULN
e. Renal function as defined by serum creatinine < 1.5 x ULN or creatinine clearance > 50 mL/min (by Cockcroft-Gault formula);
9. Negative pregnancy test (urine/serum) for female patients with childbearing potential;
Part 2:
1. Histological or cytological proof of advanced BRCA1 or -2 mutated HER2 negative breast cancer, without systemic chemotherapy pre-treatment for advanced disease and with any line of hormonal therapy pre-treatment;
2. Age >= 18 years;
3. Able and willing to give written informed consent;
4. WHO performance status of 0, 1 or 2;
5. Life expectancy > 3 months, allowing adequate follow up of toxicity evaluation and antitumor activity;
6. Measureable disease according to RECIST 1.1 criteria;
7. Minimal acceptable safety laboratory values
a. ANC of > 1.5 x 109 /L
b. Hemoglobin of at least 5.6 mM
c. Platelet count of > 100 x 109 /L
d. Hepatic function as defined by serum bilirubin < 1.5 x ULN, ASAT and ALAT < 2.5 x ULN
e. Renal function as defined by serum creatinine < 1.5 x ULN or creatinine clearance >50 mL/min (by Cockcroft-Gault formula);
8. Negative pregnancy test (urine/serum) for female patients with childbearing potential;
9. Pretreatment containing an anthracycline and/or taxane in the (neo-)adjuvant setting unless these treatments are not indicated.
|
|
| E.4 | Principal exclusion criteria |
Part 1:
1. Any treatment with investigational drugs within 28 days prior to receiving the first dose of investigational treatment; or 21 days for standard (neo-)adjuvant chemotherapy, hormonal and immunotherapy;
2. Patients who have received previous treatment with platinum compounds or high dose alkylating agents or a PARP1 inhibitor;
3. Any current treatment with drugs that induce or inhibit the CYP450 system : http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#inVivo or APPENDIX IX
4. Women who have a positive pregnancy test (urine/serum) and/or who are breast feeding;
5. Unreliable contraceptive methods. Women and men enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: oral, injected or implanted hormonal methods, intra-uterine devices or systems, condom or other barrier contraceptive measures, sterilization and true abstinence)
6. Radiotherapy within the last four weeks prior to receiving the first dose of investigational treatment; except 1x8 Gy for pain palliation then a seven days interval should be maintained;
7. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
8. Patients with known active hepatitis B or C;
9. Recent myocardial infarction (< six months) or unstable angina;
10. Symptomatic brain metastases. If adequately treated with resection and/or irradiation and patients are at least four weeks completely free of symptoms of these metastases and without medication related to these metastases patients could be eligible if all other in- and exclusion criteria are obeyed.
11. Known leptomeningeal metastases.
12. Any medical condition not yet specified above that is considered to possibly, probably or definitely interfere with study procedures, including adequate follow-up and compliance and/or would jeopardize safe treatment.
Part 2:
1. Any treatment with investigational drugs within 28 days prior to receiving the first dose of investigational treatment; or 21 days for standard (neo-)adjuvant chemotherapy, hormonal and immunotherapy;
2. Patients who have had previous treatment with PARP1-inhibitors, capecitabine, platinum compounds or high dose alkylating agents;
3. Treatment of advanced disease with non-hormonal therapy;
4. More than two lines of endocrine therapy for advanced disease;
5. Pretreatment not containing an anthracycline and/or taxane in the (neo-)adjuvant setting unless these treatments are not indicated
6. Any current treatment with drugs that induce or inhibit the CYP 450 system : http://www.fda.gov/drugs/developmentapprovalprocess/developmentresources/druginteractionslabeling/ucm093664.htm#inVivo or APPENDIX IX
7. DPD deficiency (determined by the DYPD*2A and 2846A>T genotype) if randomized to capecitabine
8. Women who have a positive pregnancy test (urine/serum) and/or who are breast feeding;
9. Unreliable contraceptive methods. Women and men enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: oral, injected or implanted hormonal methods, intra-uterine devices or systems, condom or other barrier contraceptive measures, sterilization and true abstinence)
10. Radiotherapy within the last four weeks prior to receiving the first dose of investigational treatment; except 1x8 Gy for pain palliation then a seven days interval should be maintained;
11. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
12. Patients with known active hepatitis B or C;
13. Recent myocardial infarction (< six months) or unstable angina;
14. Symptomatic brain metastases. If adequately treated with resection and/or irradiation and patients are at least four weeks completely free of symptoms of these metastases and without medication related to these metastases patients could be eligible if all other in- and exclusion criteria are obeyed.
15. Known leptomeningeal metastases.
16. Any medical condition not yet specified above that is considered to possibly, probably or definitely interfere with study procedures, including adequate follow-up and compliance and/or would jeopardize safe treatment.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: Recommended Phase II dose
Part 2: Progression Free Survival 1
Measured per RECIST version 1.1 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Safety: continuous
Tumor measurements: every 6 weeks |
|
| E.5.2 | Secondary end point(s) |
Part 1:
List of DLTs
Part 2:
Progression Free Survival 2 (on second line treatment)
Objective Response Rate
Overall Survival
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety: continuous
Tumor measurements: every 6 weeks while on study. |
|
| 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 | 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) | 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 |
| Bioequivalence with historic control study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| 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 | 10 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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