a study to evaluate the safety, tolerability, preliminary efficacy of krc-01

Conditions: Cervical Cancer

Summary: this is a seamless phase 1/2 study consisting of two components. phase 1 component is a dose-escalation, single arm, open label study in 10 patients to evaluate the safety and tolerability of krc 01. phase 2 component is a randomized, open label, controlled, multi-center study in 60 patients to evaluate the preliminary antitumor effect of krc-01 in combination with crt.

this is a seamless phase 1/2 study consisting of two components. phase 1 component is a dose-escalation, single arm, open label study in 10 patients to evaluate the safety and tolerability of krc 01. phase 2 component is a randomized, open label, controlled, multi-center study in 60 patients to evaluate the preliminary antitumor effect of krc-01 in combination with crt. phase 1 component (n=10) phase 1 component is a dose-escalation single arm, open label study. all eligible subjects will receive external beam radiotherapy (ebrt) with cisplatin (40 mg/m2) intravenously (iv) once weekly for 5 weeks (sixth dose optional) followed by image-guided brachytherapy (bt). krc-01 will be dosed intratumorally within 2 hours prior to ebrt starting from second week of ebrt. there are two cohorts (n=5 per cohort) cohort 1: once-a-week between monday to thursday (not necessarily the same day every week) cohort 2: twice-a-week with a 1- or 2- day interval (either mon+wed, mon+thu, or tue+thu) after 5 subjects of cohort 1 have completed crt+bt, the safety review committee (src) will evaluate the safety and tolerability of krc-01 once-a-week dosing and determine go/ no go decision to cohort 2 (twice-a-week dosing). after all 10 subjects have completed crt+bt, the src will evaluate the safety and tolerability of krc 01 and determine go/ no go decision to phase 2 component with optimal dosing regimen. phase 2 component (n=60) phase 2 component is a randomized, open label study. all eligible subjects will be randomized to standard of care (soc) group or soc with krc-01 group. all subjects will receive ebrt with cisplatin (40 mg/m2) iv once-a-week for 5 weeks (sixth dose optional) followed by image-guided bt. only for krc-01 group, krc-01 will be dosed intratumorally at the optimal dosing schedule selected in phase 1 component within 2 hours prior to ebrt starting from second week of ebrt.

Eligibility criteria:
inclusion criteria: * provide written informed consent before participation. * female subjects age 18 years or older. * histologically diagnosed squamous cell carcinoma, adenocarcinoma or adeno-squamous cell carcinoma of the uterine cervix. * figo stage ii and iii locally advanced cervical cancer. * no evidence of metastatic disease. * at least one tumor that qualifies as a response evaluation criteria in solid tumors (recist) v1.1 tumor with tumor size \>5 cm diameter, not previously irradiated, at baseline assessed \[by magnetic resonance imaging (mri)\] within 28 days before day 1. * no prior chemotherapy or radiotherapy for cervical cancer. * intention to undergo treatment including ebrt with 5 cycles of cisplatin followed by bt; to be completed within 8 weeks of its initiation. * patients with predicted life expectancy of 3 months or more. * target tumor is accessible for intratumoral injection. * eastern cooperative oncology group (ecog) performance status of 0 or 1. * negative pregnancy test before start of crt in women of childbearing potential and an ability/willingness to protect against pregnancy from consent and for 3 months post-rt. exclusion criteria: * other primary malignancies except basal cell carcinoma of the skin. * histologically diagnosed small cell (neuroendocrine), melanoma, clear cell and other rare variants of the classical adenocarcinoma at cervices. * previous pelvic or abdominal radiotherapy. * previous total or partial hysterectomy. * combination of preoperative radiotherapy with surgery. * patients receiving neo-adjuvant chemotherapy or non-protocol antineoplastic treatment apart from weekly cisplatin (40 mg/m2). * anatomical location and/or extent of disease difficult to access for safe intratumoral drug injections. * contraindications to the pelvic radiation such as inflammatory bowel disease and collagen vascular disease. * contraindications to mri. * patients on anticoagulants or deranged coagulation profile. * pregnancy or nursing. * high medical risks because of non-malignant systemic disease or with active uncontrolled infection. * participation in another clinical trial with an investigational drug, device or biologic within the preceding 3 months, except an observational study.