Advanced Cancer, Breast Cancer, Ovarian Cancer
Conditions
Keywords
breast cancer 1, early onset (BRCA1), breast cancer 2, early onset (BRCA2), homologous recombination deficiency, carboplatin, olaparib
Brief summary
A phase I trial to determine the recommended phase two dose of the combination of carboplatin and olaparib.
Detailed description
A 3+3 dose escalation trial of 2 cycles (21 days) carboplatin and olaparib combination therapy, followed by olaparib monotherapy until progression or unacceptable toxicity in patients with advanced cancer.
Interventions
DRUGcarboplatin, olaparib
2 cycles of carboplatin and olaparib combination therapy followed by olaparib monotherapy.
Sponsors
The Netherlands Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histological or cytological proof of advanced cancer pre-treated with maximally one line of systemic chemotherapy in the advanced setting and any line of hormonal therapy for advanced disease, and potentially benefitting from olaparib-carboplatin combination therapy (prior (neo-)adjuvant chemotherapy is accepted and does not count as one line, since administered in early stage disease); 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 1. ANC of ≥ 1.5 x 10\^9 /L 2. Hemoglobin of at least 6.2 mM and no transfusions in the last 28 days. 3. Platelet count of ≥ 100 x 10\^9 /L 4. Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN (or \< 3 x ULN in case of known Gilbert syndrome), ASAT and ALAT 2.5 x ULN (or \<5 x ULN in case of liver metastasis) 5. 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;
Exclusion criteria
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 high dose alkylating agents, a PARP1 inhibitor or carboplatin pretreatment; unless no progression on carboplatin had been observed during earlier treatment and the last carboplatin administration had been longer than 6 months ago; 3. Any current treatment with drugs that induce or inhibit the CYP3A4 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose | per doselevel of 3 to 6 patients (when 3-6 patients have completed DLT period of 3 weeks) | The dose level at which more than 1/6 patients develop a dose limiting toxicity |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics (area under time-concentration curve (AUC)) | 1 year | Pharmacokinetics (PK) measurements of olaparib alone and olaparib in combination with carboplatin |
| Pharmacodynamics (PAR (Poly(ADP) ribose) activation measured with the PAR assay) | 1 year | PAR (Poly(ADP) ribose) activation measured with the PAR assay |
| Objective Response Rate | 1 year | Objective Response Rate according to Response Evaluation Criteria in Solid Tumors (RECIST) |
Countries
Netherlands
Outcome results
None listed