A Study to Evaluate the Safety, Tolerability, Preliminary Efficacy of KRC-01

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.

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.