Carica papaya leaf extract (CPLE) versus placebo to improve chemotherapy induced thrombocytopenia (CIT): Results of a phase III triple blinded, randomized placebo controlled trial (PACT study).

12008 Background: There is a lack of approved therapeutic options to ameliorate CIT in patients with solid tumors receiving chemotherapy. Carica papaya leaf extract (CPLE) is known to increase platelet counts (PC) in certain infections. Methods: The PACT study is a triple blinded randomized phase III study conducted in two academic centres in patients with solid tumors receiving chemotherapy and developing at least grade 2 or grade 3 CIT (platelet counts < 75,000 x 10^9/ liter and > 25,000 x 10^9/liter). Patients were randomized 2:1 to CPLE arm (capsule CPLE per oral 1100mg three times daily) or placebo arm ( capsule per oral three times daily), which was continued till PC improved to greater than > 75,000 x 10^9/ liter, requirement for platelet transfusions or D+10 post intervention. Baseline PC were graded as per the Common Terminology Criteria for Adverse Events (CTCAE) grades. The primary endpoint of the study was to evaluate whether CPLE improves PC significantly faster (as assessed on D+4 of intervention) and above 75,000 x 10e9 /L as compared to placebo (spontaneous recovery of platelets). To achieve 80% power to detect a difference between the group proportions of 0.25 (50% to 75%) with an alpha of 0.05, 219 patients were required (146 in CPLE group and 73 in placebo group), assuming 10% loss to follow-up rates. Results: Between March 2020 and October 2024, 219 patients were randomized, of whom 198 patients (CPLE arm: 129; placebo arm: 69) were analysed for outcomes. All the baseline parameters were equally distributed in both the arms (2:1) except the proportion of patients in the placebo and the experimental arms had equal number of patients with grade 3 thrombocytopenia (17/129 vs 17/69; p = 0.049). The most common chemotherapeutic regimens were oxaliplatin based (37%) and carboplatin based (27%). The primary outcome of increasing PC > 75,000 x 10^9/ liter at D+4 was significantly improved by CPLE (83/129, 64% vs 33/69, 48%; p = 0.034) as compared to placebo. This improvement was significantly quicker in subgroups including three weekly regimen vs weekly/biweekly, palliative intent vs. curative, > 2 cycles of chemotherapy (< = 2 cycles vs. > 2 cycles) and body surface area (BSA) < 1.6 vs. more. There were no grade 3 or grade 4 treatment related adverse events associated with CPLE. Conclusions: CPLE is the first therapeutic intervention that appears to improve grade 2 and grade 3 chemotherapy induced thrombocytopenia faster and to a greater extent than placebo in this phase III randomized trial. It should be used as a secondary prophylaxis to maintain the chemotherapy intesnity. There were no major safety concerns with the use of CPLE. Clinical trial information: CTRI/2019/08/020987 .