Patient self-reporting of tolerability using PRO-CTCAE: A randomized double-blind placebo controlled phase II trial comparing gemcitabine in combination with adavosertib or placebo in women with platinum resistant epithelial ovarian cancer.
Authors: Madariaga Ainhoa , Mitchell Sandra A. , Pittman Tyler , Wang Lisa , Bowering Valerie , Kavak Nisan , Quintos Judy , Chang Karen , Ramsahai Janelle , Karakasis Katherine , Welch Stephen , Dhani Neesha C. , Lheureux Stephanie , Oza Amit M. 
Published: June 2021

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Background: A 4 month improvement in OS was demonstrated when Wee1 inhibitor adavosertib (Ad) and gemcitabine (G; arm A) was compared to G and placebo (P; arm B) in a phase 2 trial in recurrent ovarian cancer (NCT02151292). The patient reported outcome version of the CTCAE (PRO-CTCAE) was used to capture self-report of the frequency, severity and/or interference (scored 0-4; higher scores indicating worse symptomatic adverse events [syAEs]). Methods: Ad/P was given orally on D1-2, D8-9, D15-16 with G D1, D8, D15 in a 28-day cycle. English speaking pts in 2 centres completed PRO-CTCAE items electronically in clinic at baseline, D1 and D15 of each cycle and off treatment. An exploratory objective was to characterize syAEs in the first 3 months of therapy. We calculated 12-week area under the curve (AUC12w) as a measure of syAE over time and incremental AUC12w (iAUC12w) for adjustment to baseline syAEs and compared arms A and B using an independent samples t-test. We assessed proportion of scores 3-4 at 6 time-points and compared them using Fisher’s Exact Test at each survey. Results: 51 pts were enrolled and completed ≥1 survey, 47 were evaluable for primary outcome (arm A: 28, B: 19). ECOG status was ≤1 in 44/47 pts. Median number of cycles of therapy were 5 (1-16) in arm A, and 2 (1-16) in B. Survey completion rates were high (arm A 93%, B 95%). Mean AUC12w fatigue severity (A 152 [standard error 9] vs B 112 [10]; p = 0.005) and interference (A 144 [11] vs 98 [15]; p = 0.018), diarrhea frequency (A 70 [12] vs B 33 [9]; p = 0.014), mucositis (A 23 [6] vs B 6 [3]; p = 0.012) and difficulty swallowing severity (A 10 [3] vs B 2 [2]; p = 0.023) were higher in arm A (any grade). There were no statistically significant between-arm differences in abdominal pain, bloating, nausea, vomiting and anxiety. The iAUC12w was significantly higher in arm A vs B for difficulty swallowing severity (A 10.1 [3] vs B -2.7 [4.7]; p = 0.02), mucositis severity (A 19.9 [6.6] vs B -3.1 [6.9]; p = 0.02) and fatigue severity (A 35.2 [8.2] vs B -3.1 [9.8]; p = 0.005). Proportions with high scores (3-4) were only significantly higher at C1D15 for fatigue severity in arm A (A 55% vs B 19%, p = 0.044). No significant differences were seen in other 3-4 scores per survey time. Conclusions: This is the first study evaluating pts self-reported toxicity with adavosertib in a randomized setting, allowing pts self-evaluation of toxicity in the context of improved PFS and OS. Greater fatigue, diarrhea, mucositis and difficulty swallowing were experienced by pts receiving adavosertib and gemcitabine, but score 3-4 reached significance on C1D15 fatigue only. No significant differences were detected in syAE profile for nausea, vomiting, abdominal pain, bloating and anxiety. This approach allows objective assessment of pts perception of toxicity with complex therapy. Clinical trial information: NCT02151292.