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Clinical Trial
. 2014 May 19;106(6):dju089.
doi: 10.1093/jnci/dju089. Print 2014 Jun.

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses

Jung-Min Lee  1 , John L Hays  2 , Christina M Annunziata  2 , Anne M Noonan  2 , Lori Minasian  2 , Jo Anne Zujewski  2 , Minshu Yu  2 , Nicolas Gordon  2 , Jiuping Ji  2 , Tristan M Sissung  2 , William D Figg  2 , Nilofer Azad  2 , Bradford J Wood  2 , James Doroshow  2 , Elise C Kohn  2
Affiliations
Clinical Trial

Phase I/Ib study of olaparib and carboplatin in BRCA1 or BRCA2 mutation-associated breast or ovarian cancer with biomarker analyses

Jung-Min Lee et al. J Natl Cancer Inst. .

Abstract

Background: Olaparib has single-agent activity against breast/ovarian cancer (BrCa/OvCa) in germline BRCA1 or BRCA2 mutation carriers (gBRCAm). We hypothesized addition of olaparib to carboplatin can be administered safely and yield preliminary clinical activity.

Methods: Eligible patients had measurable or evaluable disease, gBRCAm, and good end-organ function. 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. Dose-limiting toxicity was defined in the first two cycles. Peripheral blood mononuclear cells were collected for polymorphism analysis and polyADP-ribose incorporation. Paired tumor biopsies (before/after cycle 1) were obtained for biomarker proteomics and apoptosis endpoints.

Results: Forty-five women (37 OvCa/8 BrCa) were treated. Dose-limiting toxicity was not reached on the intermittent schedule. Expansion proceeded with olaparib 400mg every 12 hours on days 1 to 7/carboplatin AUC5. 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). Proteomic analysis suggests high pretreatment pS209-eIF4E and FOXO3a correlated with duration of response (two-sided P < .001; Pearson's R (2) = 0.94).

Conclusions: Olaparib capsules 400mg every 12 hours on days 1 to 7/carboplatin AUC5 is safe and has activity in gBRCAm BrCa/OvCa patients. Exploratory translational studies indicate pretreatment tissue FOXO3a expression may be predictive for response to therapy, requiring prospective validation.

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Figures

Figure 1.
Figure 1.
Study schema (A) and CONSORT diagram (B). This shows the treatment schedule and timing of the blood and research biopsies collection. BID = twice a day, PBMCs = peripheral blood mononuclear cells.
Figure 2.
Figure 2.
Waterfall plot. Best RECIST response (A) and duration of response (B) are graphed for each patient. Color code defines dose level (DL) of treatment, and the number is an arbitrary patient assignment. The asterisk (*) represents breast cancer patients, and the dagger (†) indicates the one patient with BRCAPro score 68%. The double dagger (‡) identifies patients still receiving therapy at the time data were locked for analysis. Patient 9 was not censored for the response analysis because study treatment was discontinued after one cycle because of intercurrent illness, although computed tomography assessment at 6 weeks showed stable disease.
Figure 3.
Figure 3.
The relationship between pretreatment biopsy protein expression and response duration. A cutoff of R 2 of 0.8 was used to select the top potential predictive biomarkers. A–H) Eight proteins were statistically significantly correlated with progression-free survival (PFS) of 6 or more months. I) pS209-eIF4E and FOXO3a were isolated as drivers for the PFS outcome (P < .001; R 2 = 0.94; root mean square error [RMSE] = 2.41). Reverse-phase protein arrays (RPPAs) were analyzed for correlations between pretreatment protein levels and duration of response with a two-tailed analysis of variance and controlled for false discovery rate of 0.05.
Figure 4.
Figure 4.
Validation of FOXO3a using immunohistochemistry. A) Example of paired FOXO3a stained biopsy set (×400 magnification). Left: pretreatment biopsy. Right: after cycle 1 (C1). Arrowheads: negatively stained nuclei, note similar intensity in pre– and post–cycle 1 samples. Short arrow: tumor cells with positively stained nuclei. Long arrow: tumor cell with positively stained cytosol. Scale bar = 50 μm. B) FOXO3a-positive tumor cell nuclei are reduced after one cycle of treatment. Paired samples sets for five patients were available for enumeration. The mean of FOXO3a-positive cells at baseline vs post-cycle 1 treatment: 427.73 (range = 181–758; standard deviation (SD) = 198.96; 95% confidence interval [CI] = 229.77 to 625.69) vs 112 (range = 19–358; SD = 90.89; 95% CI = 20.78 to 202.58; P < .0001). C) Tumor cells are the source of the FOXO3a signal (P < .001). Tumor and stromal cells with positively stained nuclei were counted per five high-power fields. The median of immunohistochemistry results between tumor and stromal cells were compared using a two-tailed paired Student t test.
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