| General information |
| Database: | DB00517 |
| Objective: | Olaparib has singleagent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). they hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity. |
| Authors: | Lee JM, et al |
| Title: | Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutationassociated breast or ovarian cancer with biomarker analyses. |
| Journal: | J Natl Cancer Inst. |
| Year: | 2014 |
| PMID: | 24842883 |
| Trial Design |
| Clinical Trial Id: | NCT01445418 |
| Agent: | olaparib
|
| Target: | Poly [ADPribose] polymerase1
|
| Cancer Type: | breast cancer, ovarian cancer |
| Cancer Subtype: | BRCA1 or BRCA2 MutationAssociated Breast or Ovarian cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 2 |
| Therapeutic Combination Content: | olaparib and carboplatin |
| Study Type: | Phase i/ib Study |
| Key Patients Feature: | Eligibilitycriteria included gBRCAm BrCa/OvCa or BrCa/OvCa with aBRCAPro score of 30% or higher (24); recurrent or refractory disease or locally advanced unresectable BrCa; measureable (biopsiable for expansion cohort) or evaluable disease; ECOG performancestatus of 0 to 2; normal endorgan function except grade 1 anemia, neutropenia, leukopenia, and aspartate aminotransferase/alanineaminotransferase (AST/ALT); no tumorrelated therapy for 4weeks and no platinum for at least 6 months; no NCI CommonTerminology Criteria (CTCAE v3.0) grade 4 platinum allergicreaction; no prior PARPis; no infection requiring antibiotics within7 days; and no brain metastases diagnosed or active within the pastyear. |
| Biomarker: | BRCA1 or BRCA2 mutation |
| Biomark Analysis: | Proteomic analysis suggests high pretreatment pS209eIF4E and FOXO3a correlated with duration of response (twosided P < .001; Pearson's R (2) = 0.94). |
| Control Group Info: | single arm |
| Treatment Info: | A 3 + 3 dose escalation tested daily oral capsule olaparib (100 or 200mg every 12 hours; dose level1 or 2) with carboplatin area under the curve (AUC) on day 8 (AUC3 day 8), then every 21 days. For dose levels 3 to 6, patients were given olaparib days 1 to 7 at 200 and 400 mg every 12 hours, with carboplatin AUC3 to 5 on day 1 or 2 every 21 days; a maximum of eight combination cycles were permitted, after which daily maintenance of olaparib 400mg every12 hours continued until progression. |
| Primary End Point: | safety, tolerability, and activity of olaparib administered with carboplatin;their translational aim was to discover potential predictive biomarkers of response to the carboplatin/PARPi combination |
| Secondary End Point: | NA |
| Patients Number: | 45 |
| Trial Results |
| DLT_MTD: | Doselimiting toxicity was not reached on the intermittent schedule. Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). Olaparib and cisplatin doses were subsequently reduced to 50 mg bid days 1-5 and 60 mg/m2, respectively; no DLTs were reported for patients receiving this regimen. |
| Objective Response Rate: | Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). |
| Disease Control Rate: | 82.3% in ovarian cancer and 100% in breast cancer |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Grade 3/4 adverse events included neutropenia (42.2%), thrombocytopenia (20.0%), and anemia (15.6%). Responses included 1 complete response (1 BrCa; 23 months) and 21 partial responses (50.0%; 15 OvCa; 6 BrCa; median = 16 [4 to >45] in OvCa and 10 [6 to >40] months in BrCa). |
| Conclusions: | Olaparib capsules 400mg every 12 hours on days 1 to 7carboplatin AUC5 is safe and has activity in gBRCAm BrCaOvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation. |