Phase I of Carboplatin-Olaparib Followed by Olaparib Monotherapy in Advanced Cancer

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.

Inclusion criteria

• 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);
• Age ≥ 18 years;
• Able and willing to give written informed consent;
• WHO performance status of 0, 1 or 2;
• Able and willing to undergo blood sampling for PK and PD analysis;
• Life expectancy ≥ 3 months, allowing adequate follow up of toxicity evaluation and antitumor activity;
• Evaluable disease according to RECIST 1.1 criteria;
• Minimal acceptable safety laboratory values

• ANC of ≥ 1.5 x 10^9 /L
• Hemoglobin of at least 6.2 mM and no transfusions in the last 28 days.
• Platelet count of ≥ 100 x 10^9 /L
• 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)
• Renal function as defined by serum creatinine ≤1.5 x ULN or creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula);
• Negative pregnancy test (urine/serum) for female patients with childbearing potential;

Exclusion criteria

• 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;
• 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;
• 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
• Women who have a positive pregnancy test (urine/serum) and/or who are breast feeding;
• 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)
• 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;
• Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
• Patients with known active hepatitis B or C;
• Recent myocardial infarction (< six months) or unstable angina;
• 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.
• Known leptomeningeal metastases.
• Patients with myelodysplastic syndrome or acute myeloid leukemia
• 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.