A Phase II Single-Arm Study of High-Bioavailability Curcumin as Neoadjuvant Chemoradiotherapy in Mid-to-Low Rectal Cancer: Integrated Clinical and Translational Analysis of Tumor Tissue

A Phase II Single-Arm Study of High-Bioavailability Curcumin as Neoadjuvant Chemoradiotherapy in Mid-to-Low Rectal Cancer: Integrated Clinical and Translational Analysis of Tumor Tissue

This clinical study investigates the anti-inflammatory and anti-cancer properties of a high-bioavailability formulation of curcumin (BCM-95) in patients with mid-to-low rectal cancer receiving neoadjuvant chemoradiotherapy (nCRT). Curcumin, a polyphenolic compound derived from Curcuma longa, has demonstrated potent anti-inflammatory and anti-neoplastic activities through the modulation of multiple molecular signaling pathways. It has been recognized by the U.S. Food and Drug Administration (FDA) as "Generally Recognized as Safe" (GRAS; GRN No. 686), with an excellent safety profile when administered orally. Reported adverse effects are rare and primarily related to interference with bile secretion or iron metabolism.

Despite its biological potential, conventional curcumin exhibits extremely low oral bioavailability due to its lipophilic nature, rapid metabolism, and systemic elimination. Clinical studies have reported that even at an oral dose of 12 grams per day, the maximum plasma concentration reaches only about 0.051 mg/mL, with up to 75% of the administered dose excreted in feces. To overcome this limitation, the current trial utilizes a curcumin formulation with enhanced absorption (BCM-95), which combines curcumin with essential oils of turmeric to improve systemic bioavailability.

The primary objective of this single-arm, phase II trial is to evaluate whether oral curcumin supplementation can mitigate radiation-induced gastrointestinal toxicity-particularly radiation enteritis-during neoadjuvant chemoradiotherapy for rectal cancer. The secondary objectives include assessing its effect on treatment response, such as the pathological complete response (pCR) rate, tumor regression grade, and patient-reported outcomes related to bowel function and quality of life.

In addition, a translational research component is embedded within this study. Serial tumor tissue and blood samples will be collected at predefined time points to explore the molecular and immunological mechanisms underlying curcumin's therapeutic effects. Analyses will include assessments of inflammatory cytokines, oxidative stress markers, and tumor microenvironmental changes using molecular and histopathologic methods.

Overall, this study aims to provide both clinical and mechanistic evidence supporting the potential of high-bioavailability curcumin as a safe, adjunctive therapeutic strategy to improve treatment tolerance and oncologic outcomes in rectal cancer patients undergoing chemoradiotherapy.

This Phase II single-arm clinical trial investigates the safety, tolerability, and therapeutic potential of high-bioavailability curcumin (BCM-95®) administered concurrently with neoadjuvant chemoradiotherapy (nCRT) in patients with mid- to low-rectal adenocarcinoma. The study is designed and conducted at Chang Gung Memorial Hospital, Linkou (Taiwan), under IRB approval and in accordance with Good Clinical Practice (GCP) guidelines.

Scientific Background and Rationale

Curcumin (diferuloylmethane) is a hydrophobic polyphenol extracted from Curcuma longa with extensive anti-inflammatory, antioxidant, and anti-neoplastic properties mediated through suppression of NF-κB, STAT3, COX-2, and multiple cell-signaling pathways. In preclinical models, curcumin inhibits radiation-induced activation of NF-κB and enhances radiosensitivity of colorectal-cancer cell lines, while protecting normal intestinal epithelium from irinotecan-induced mucosal injury by mitigating oxidative and endoplasmic-reticulum stress. Despite its excellent oral safety record (FDA GRAS Notice No. 686), conventional curcumin suffers from extremely low systemic bioavailability due to poor solubility and rapid metabolism.

BCM-95® Curcumin is a patented formulation that combines 95 % curcuminoids with turmeric essential oils, improving absorption approximately seven-fold compared with standard curcumin. Given its dual ability to radiosensitize tumor tissue and protect normal mucosa, BCM-95® Curcumin may attenuate radiation-induced enteritis while enhancing tumor regression and pathological complete-response (pCR) rates following nCRT.

Objectives

Primary Objective: To evaluate whether oral BCM-95® Curcumin can reduce the incidence and severity of radiation-induced gastrointestinal toxicity, particularly grade ≥ 3 proctitis/enteritis, during nCRT.

Secondary Objectives: To assess improvement in treatment response (clinical and pathological CR rates, tumor-regression grade), treatment completion rate, and quality-of-life indices; and to explore anti-cancer and immunomodulatory mechanisms through translational analyses of tumor and blood specimens.

Study Overview

A total of 72 patients with stage II-III (mid- to low-) rectal adenocarcinoma will receive standard long-course nCRT (50.4 Gy in 28 fractions with concurrent fluoropyrimidine-based chemotherapy) or equivalent short-course radiotherapy plus chemotherapy, along with oral BCM-95® Curcumin 3 g per day. Treatment begins concurrently with chemotherapy and continues through the full nCRT period. Follow-up includes surgical resection or a watch-and-wait strategy based on clinical response.

Each participant undergoes serial evaluations:

Baseline: history, colonoscopy, pelvic MRI, CT staging, laboratory profile, and CEA.

During therapy: bi-weekly hematology and biochemistry tests; adverse-event assessment (CTCAE v5.0, RTOG/EORTC criteria).

Post-radiation (2-3 weeks): colonoscopy graded by Vienna Rectoscopy Score to quantify acute proctitis.

At completion of nCRT: pelvic MRI and colonoscopy for clinical response evaluation.

Surgery or watch-and-wait: histopathologic examination for pCR and tumor-regression grade.

Translational research includes multiplex immunohistochemistry on paired tumor and adjacent mucosa (pre-treatment, post-radiation, post-CRT) and peripheral-blood analyses for immune-cell phenotyping (BD FACSymphony panel), cytokine profiling (MILLIPLEX array), and circulating-tumor-DNA (ctDNA) monitoring. These studies aim to correlate molecular and immune alterations with clinical outcomes.

Run-in Cohort (Safety Lead-in)

A run-in phase enrolling 6 patients will precede full recruitment. Dose-limiting toxicities (DLTs) include grade ≥ 3 non-hematologic AEs (except expected nausea/vomiting), ALT/AST > 3×ULN (confirmed) or > 5×ULN any time, bilirubin > 2×ULN with hepatic enzyme elevation, grade 4 hematologic toxicity > 7 days, or any toxicity requiring treatment interruption > 2 weeks. If ≤ 1/6 patients develops a DLT, the study proceeds to full Phase II enrollment (n = 72).

Endpoints

Primary Endpoint: Incidence of grade ≥ 3 gastrointestinal toxicity (enteritis/proctitis) evaluated by NCI CTCAE v5.0 and RTOG/EORTC criteria.

Secondary Endpoints: (1) Vienna Rectoscopy Score; (2) any grade III AEs during therapy; (3) clinical CR rate (RECIST v1.1); (4) pathological CR rate; (5) treatment completion rate.

Exploratory Endpoints: three-year disease-related failure rate, five-year overall survival, and molecular/immunologic correlates.

Statistical Considerations

The sample size (n = 72, 64 evaluable) was calculated by an exact one-proportion test (80 % power, α = 0.05) to detect a 15 % absolute reduction in acute radiation proctitis (30 % → 15 %). Efficacy and safety analyses follow the intent-to-treat principle. Categorical variables will be analyzed by χ² or Fisher's exact test; continuous variables by t or Mann-Whitney U test; survival by Kaplan-Meier and log-rank tests (p < 0.05 two-sided). Analyses will be performed in SPSS v24.

Safety Monitoring and Ethics

Safety is assessed continuously through bi-weekly labs and AE documentation. Curcumin is paused if ALT/AST > 3×ULN until recovery. Serious adverse events (SAEs) are reported to the Chang Gung IRB per institutional policy. The study follows the Declaration of Helsinki and GCP standards. All participants provide written informed consent. Confidentiality is maintained via coded identifiers; data access is restricted to authorized investigators.

Data and Safety Monitoring Plan (DSMP)

Enrollment review every 3 months by PI.

SAE review quarterly by Safety Officer.

Protocol deviation audit monthly by Clinical Research Coordinator.

Data integrity checked continuously by Data Manager. All findings are reported to the sponsor and IRB.

Anticipated Impact

This study will provide clinical and molecular evidence for the potential of high-bioavailability curcumin as a safe adjunct to neoadjuvant chemoradiotherapy in rectal cancer, with the dual goals of reducing treatment-related toxicity and enhancing tumor response and long-term oncologic outcomes. If proven beneficial, curcumin could be a cost-effective, natural, and readily implementable adjuvant strategy for improving tolerance and quality of life in rectal cancer patients undergoing multimodality therapy.

Inclusion Criteria:

(A) Males and females more than 20 years of age (B) Signed informed consent (C) Patients with a pathologically proven rectal adenocarcinoma located less than 10 cm to the anus.

(D) Clinical staging (AJCC 8th ed.): T2-4 N0 M0 or T any N1-2 M0 (E) Distal metastasis has been excluded by imaging study: by chest-to-pelvic computed tomography or Positron Emission Tomography (F) Preoperative pelvic staging by pelvic Magnetic Resonance Imaging (preferred) or trans-rectal ultrasound (G) Patients with WHO/ECOG performance scale 0 or 1

Exclusion Criteria:

(A) Refuse to sign the informed consent (B) Distal metastasis revealed by the imaging study (C) Patients does not receive radiotherapy (D) Unable to receive further curative resection (E) Patients receive tumor resection before the neoadjuvant treatment (F) Patients have history of more than 5 Gy of pelvic radiation (G) Patients in pregnancy or lactation status (H) Patients have allergic history to curcumin, 5-fluouracil or oxaliplatin (I) Patients of childbearing potential can not cooperate with appropriate contraceptive method (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) (J) Patients with any concurrent malignancy; patients with history of malignancy should be cancer-free for more than 5 years (K) Patients with New York Heart Association (NYHA) class III or IV heart failure, unstable angina pectoris, unstable cardiac arrhythmia or tachycardia (heart rate > 100 beats/minute) (L) Patients have concurrent uncontrolled medical conditions, such as illness ongoing or requiring IV antibiotics, severe chronic renal failure (eGFR <30 mL/min/1.73m2) or severe active hepatitis(AST/ALT>3x upper normal limit)、Total Bilirubin>2 mg/dl (M) Patients with previous or current drug abuse (N) Patients underwent major surgery within 28 days of study enrollment (except diverting colostomy) (O) Patients have Familial Adenomatosis Polyposis Coli (FAP), Hereditary Non-Polyposis Colorectal Cancer (HNPCC), active Crohn's disease or active ulcerative Colitis (P) Patients have known dipyrimidine dehydrogenase deficiency (DPD) (Q) Patients with congenital iron metabolic or hematopoietic diseases (R) Patients with synchronous colon cancer (S) The Patients with hematologic abnormalities (INR > 1.5, white blood cell (WBC) count < 3,000/μL, absolute neutrophil count (ANC) < 1,500/μL, platelet count < 100,000/μL, hemoglobin < 9.0 g/dL not caused by tumor treatment) or known hematologic diseases (aplastic anemia, myelodysplastic syndrome (MDS), leukemia, malignant lymphoma, multiple myeloma, hereditary hematologic diseases such as thalassemia, sickle cell anemia, etc.).

(T) The patient has diabetes mellitus (U) The patient is taking the immunosuppressants Cyclosporine, Tacrolimus, Sirolimus, and Everolimus and antigoagulants (warfarin、NOACs、aspirin) (V) Patients with The medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements