Phase II Study of Intratumoral KRC-01 (hydrogen peroxide) plus Radiotherapy for Clinical Complete Response in Locally Advanced Stage III Rectal Adenocarcinoma (K-BOOST)

Trial ID: 2025-524378-40-00
Protocol: 2025/4237 K-BOOST
Sponsor: Institut Gustave Roussy

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Diseases & Conditions

Rectal adenocarcinoma

Objectives

The primary objective is to evaluate the clinical complete response (cCR) rate following combined radiotherapy and intratumoral KRC‑01 administration in patients with locally advanced high‑risk stage III rectal adenocarcinoma, reflecting the potential for organ preservation without surgical resection.

Secondary objectives include:

Assessment of safety and tolerability by documenting the incidence and severity of KRC‑01‑related adverse events.
Determination of the pathological complete response (pCR) rate in participants undergoing total mesorectal excision.
Estimation of progression‑free survival and overall survival at 1 year and 2 years.
Evaluation of impact on quality of life using the QLQ‑C30 and EQ‑5D‑5L instruments.
Identification of predictive and prognostic biomarkers, including circulating and tumor‑derived markers.
Correlation of radiological response per RECIST with metabolic response on PET imaging.
Characterization of systemic and intratumoral immune modulation induced by KRC‑01 and chemotherapy through flow cytometry, immunohistochemistry, and single‑cell RNA sequencing.
Analysis of circulating biomarkers such as ctDNA and cytokines and their relationship to clinical response.
Investigation of gut microbiome alterations during therapy and association with therapeutic outcomes.
Longitudinal assessment of patient‑reported quality of life and symptom burden throughout treatment and follow‑up.

Participants

The trial enrolled adult patients, both male and female, who were 18 years of age or older and presented with locally advanced high‑risk stage III rectal adenocarcinoma without distant metastases. Eligible individuals were required to have an Eastern Cooperative Oncology Group (ECOG performance status) of 0 or 1, adequate organ function, and a life expectancy greater than six months. Inclusion mandated histopathological confirmation of the disease, tumor location within 15 cm of the anal margin, and accessibility for intratumoral injection, as well as the intention to receive standard chemoradiotherapy followed by CAPOX or FOLFOX. Participants needed to be able to comply with study visits, provide informed consent, and be affiliated with a social security system. Women of child‑bearing potential had to present a negative pregnancy test. The sponsor did not provide the total number of participants enrolled in the study.

Plans and Procedures

The study is a prospective, open‑label Phase II interventional trial evaluating the combination of intratumoral KRC‑01 (hydrogen peroxide) injections and standard radiotherapy in patients with locally advanced high‑risk stage III rectal adenocarcinoma. Eligible participants undergo a screening visit to confirm inclusion criteria, followed by baseline assessments before initiation of 5‑fluorouracil‑based chemoradiotherapy and the first KRC‑01 injection. Intratumoral administrations of 5 ml KRC‑01 are performed according to the protocol schedule during the radiotherapy course, with subsequent follow‑up visits at week 6 and week 24 to assess tumor response, safety, and quality‑of‑life outcomes. The primary endpoint is the clinical complete response (cCR) rate at week 24; secondary endpoints include overall survival, progression‑free survival, pathological response, adverse‑event incidence, patient‑reported outcomes, and biomarker analyses. Participants remain in the study for approximately 24 weeks from the first injection, with additional follow‑up as required for long‑term safety assessments. Study discontinuation may occur if the investigator determines that continued participation is unsafe due to severe adverse events, disease progression, or if the participant withdraws consent.

Treatment

The investigational product KRC-01 is supplied as a sterile injectable solution containing hydrogen peroxide. Each dose consists of 5 ml administered by intratumoral injection directly into the rectal tumor. The formulation is classified as an injectable pharmaceutical form and is delivered using a sterile syringe under aseptic conditions.

All participants receive standard-of-care external beam radiotherapy targeting the primary rectal lesion and regional lymphatics, as defined for locally advanced rectal cancer. Radiotherapy is delivered in accordance with institutional protocols and is intended to be combined with the intratumoral injections of KRC-01.

Dosing of KRC-01 follows the study‑specified schedule, with injections performed at predetermined intervals relative to the radiotherapy course. Administration timing, volume verification, and injection technique are documented for each treatment session. Participant compliance with the injection schedule and radiotherapy regimen is monitored through treatment logs, source documentation, and periodic site audits to ensure adherence to the protocol.

Efficacy

Efficacy will be evaluated primarily by the Clinical Complete Response (cCR) rate assessed at week 24 after completion of radiotherapy combined with intratumoral KRC‑01 injections. Secondary efficacy assessments include overall survival (OS) and progression‑free survival (PFS), both measured from the date of inclusion until death or disease progression, respectively. Pathologic outcomes will be determined by the proportion of patients achieving pathologic complete response (pCR) or major pathologic response (MPR) in surgical specimens, defined as the complete absence of viable tumor cells or less than 10 % residual tumor cells. Radiological response will be quantified using RECIST criteria, while metabolic response will be evaluated by PET imaging. Circulating tumor DNA (ctDNA) and other biomarkers will be collected for correlation with clinical outcomes.

Patient‑reported outcomes will be captured with the validated EORTC QLQ‑C30 and EQ‑5D‑5L questionnaires at baseline, week 6, and week 24. Immune modulation will be characterized through flow cytometry, immunohistochemistry, and single‑cell RNA sequencing of tumor and peripheral samples. Additional exploratory analyses will include assessment of cytokines, gut microbiome composition, and longitudinal quality‑of‑life measures throughout treatment and follow‑up. All efficacy parameters will be measured according to the predefined schedule, recorded in case report forms, and analyzed using appropriate statistical methods for time‑to‑event and categorical outcomes.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Males and females ≥ 18 years of age
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Histopathologically confirmed locally advanced rectal adenocarcinoma, stage III (high risk)
No evidence of metastatic disease on computed tomography (chest and abdomen), including resectable metastases. (M0, and no oligometastases)
At least one of the following criteria: cT4a, cT4b, presence of extramural invasion (EMVI+), cN2, involvement of the mesorectal fascia (MFI+), involvement of lateral lymph nodes (lat LN+)
Adenocarcinoma located with a lower border less than 15 cm from the anal margin
Primary resection without chemoradiotherapy is unlikely to achieve clear margins.
Tumor lesion must be mesurable by endoscopic visual assessment
Target tumor is accessible for intratumoral injections.
Intention to undergo treatment including 5 Fu based chemoradiotherapy and CAPOX (6 cycles) or FOLFOX (9 cycles)
Life expectancy > 6 months
Acceptable organ functions, as evidenced by the laboratory data described in the protocol
Women of childbearing potential must have a negative serum β-HCG pregnancy test within 7 days prior to the administration of the first study treatment and/or urine pregnancy 12 hours prior to the administration of the first study treatment.
Patients who either do not consent to a tumor biopsy or do not have accessible lesions will not be eligible.
Patients should understand, sign, and date the written informed consent form prior to any protocol-specific procedures performed.
Patient should be able and willing to comply with study visits and procedures as per protocol.
Patient must be affiliated to a social security system or beneficiary of the same.

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Exclusion Criteria

Patients not deemed fit for radiotherapy or preexisting condition which would deter radiotherapy, e.g., fistulas, severe ulcerative colitis (including subjects currently taking sulphasalazine), active Crohn’s disease, prior adhesions.
Concomitant medications/comorbidities that may prevent the patient from receiving study treatments
Contraindication to fluoropyrimidines or oxaliplatin and capecitabin
Yellow fever vaccine and live attenuated vaccines are contraindicated due to the risk of severe vaccine-induced infection. Note: The currently authorized COVID-19 vaccines are not live vaccines and therefore can be safely administered.
Known history of human immunodeficiency virus (HIV) infection or seropositive results consistent with active hepatitis B virus (HBV) or active hepatitis C virus (HCV) infection.
Pregnant or breastfeeding women or intending to become pregnant during the clinical investigation.
Patient under guardianship or deprived of his liberty by a judicial or administrative decision or incapable of giving its consent.
Any Previous radiotherapy in the pelvic region.
contraindications to MRI (e.g., subjects with pacemakers, claustrophobia, excessive weight, etc.).
Participation in another clinical study with an investigational product during the last 3 months.
Prior rectal surgery.
Prior investigational treatment for rectal cancer.
High medical risk because of systemic diseases (e.g., uncontrolled infections, uncontrolled diabetes) in addition to the qualifying disease under study.
Peripheral sensory neuropathy grade ≥2 (for the future administration of oxaliplatin)
Dihydropyrimidine deshydrogenase (DPD) deficiency. DPD status must be assessed prior to inclusion, and uracilemia testing is mandatory before initiation of fluorouracil-based treatment. Patients with unknown DPD status are not eligible.
Patients with hypokalemia below the lower limit of normal, hypomagnesemia, hypocalcemia, or QT/QTc interval >450 msec in males or >470 msec in females at inclusion are not eligible.
Patients with known high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) tumors are not eligible, as these patients may benefit from standard-of-care immunotherapy.
Patients receiving therapeutic anticoagulation are not eligible. Prophylactic anticoagulation at low dose (e.g., thromboprophylaxis) may be allowed at the investigator’s discretion, provided that the bleeding risk is considered minimal.
Patients receiving concomitant treatment with brivudine or who have received brivudine within the previous 4 weeks.