A phase II study of oral chlorophyllin in haemorrhagic cystitis secondary to radiation therapy for pelvic malignancies (CLARITY).

Abstract

48 Background: Chronic hemorrhagic cystitis (cHC) is seen in 5-15% of patients undergoing pelvic radiotherapy (pRT), often after a long cancer free survival. Hyperbaric oxygen therapy, the only modality with benefit proven in a randomized trial has limited utilization due of lack of availability, need of multiple sessions & cost. In this phase II study, we aimed to evaluate the efficacy & safety of Sodium-copper-chlorophyllin (CHL), a semi-synthetic mixture of sodium & copper salts of chlorophyll, in pRT-induced cHC. This study was based on our preclinical findings where CHL offered radioprotection & significantly reduced mortality & morbidity in mice exposed to lethal doses of whole-body radiation.A subsequent phase 1 trial in adult healthy volunteers established the recommended phase 2 dose. Methods: This was a prospective, single centre, single arm, interventional phase II clinical trial (NCT05348239). Adult patients with grades II-IV hematuria (CTCAE v5.0) following pRT received at least 3 months prior were eligible. All patients received oral CHL 750 mg OD for a maximum of 3 months. A Simon two-stage minimax design with a type 1 error of 2.5% & 80% power led to a sample size of 24 patients. The primary objective was the objective response rate (ORR), defined as the proportion of patients with complete response (CR) [resolution of gross hematuria] or partial response (PR) [decrease by at least one CTCAE grade of hematuria, but not complete resolution] from day 30-90 of starting the drug. At least seven objective responses were required to consider the drug for further development. Results: Thirty two patients were screened of whom 24 were enrolled, with median age of 63 (43-86) years. Indications for pRT included cervical (15), rectal (5) & prostate cancer (4). The median time from RT to cHC was 45 (4-216) months. At enrolment, 6 (25%), 17 (70.8%) & 1 (4.1%) patients had CTCAE grades 2, 3 & 4 hematuria respectively, majority being refractory. An objective response occurred in 20 patients (83.3%; 95% CI, 62-95%), (Stable=1, PR=10, & CR=10 as the best response).11 unrelated SAEs were observed in 8 patients. No treatment-related grade 4/5 adverse events were reported.No patient required angioembolisation, vesical artery ligation, or cystectomy.Proteomics studies indicated modulation of coagulation pathways and improved stem cell mediated regeneration and wound healing following chlorophyllin treatment. Conclusions: In this phase II study,oral CHL has shown objective & sustained response in cHC related grade II-IV hematuria following pRT. A randomized, placebo-controlled, phase III trial assessing the efficacy of oral CHL is now planned. Clinical trial information: NCT05348239 .