A Phase I Open-Label, Single-Arm, Dose-Escalation Clinical and Pharmacology Study of CCI-001 as Monotherapy and in Combination With Standard Chemotherapy in Patients With Recurrent and/or Metastatic Solid Tumours

Inclusion criteria

Unless otherwise noted, inclusion criteria apply to all Parts of the protocol.

• Subject has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
• Patients must have histologically or cytologically confirmed recurrent or metastatic solid tumours. For Part 1 and Part 2, patients must have disease progression on their last treatment, have exhausted available approved lines of therapy or better-characterized therapies that, at the discretion of the Investigator, are felt to be more appropriate therapy, or have malignancies for which there are no approved therapies. For Part 3, patients must have disease progression on their last treatment and have been treated with up to 3 approved lines of chemotherapy.
• For Part 3, only patients of the following tumour types will be permitted to enroll: gynecologic cancers (ovarian, fallopian tube, cervical, endometrial, vulvar), pancreaticobiliary adenocarcinomas and others (lung adenocarcinoma, head and neck adenocarcinomas, transitional cell bladder cancer, and upper GI tumours [including esophageal, gastroesophageal junction and stomach]).
• For Part 3, patients' tumours must be deemed to be sensitive to the planned chemotherapy regimens (gemcitabine for pancreaticobiliary adenocarcinomas carboplatin for lung adenocarcinomas and gemcitabine or carboplatin for gynecologic cancers) to be allowed to enroll in the study.
• Four weeks must have elapsed since prior chemotherapy, hormonal therapy, targeted therapy, or radiation therapy. There is no restriction in the amount of bone marrow previously radiated.
• Patients must have measurable disease by Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria.
• Recovery to baseline or Grade 1 for all drug-related toxicities due to prior chemotherapy, radiation, hormonal therapy, or molecular targeted therapy, except for alopecia, nausea, diarrhea and constipation.
• Age >18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) <1.
• Life expectancy of greater than 12 weeks.
• Patients must have normal organ and marrow function as defined below:

• absolute neutrophil count ≥ 1.5 x 10˄9/L/L
• hemoglobin ≥ 90 g/L
• platelets ≥ 100 x 10˄9/L/L
• total bilirubin ≤ 1.5 x Upper limit of normal (ULN)
• AST (SGOT) and ALT(SGPT) ≤ 2.5 x ULN (≤ 5 x ULN for liver metastases)
• Creatinine (Cr) ≤ 1.5 x ULN
• All other laboratory assessments must be ≤ Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v5.
• Cardiac ejection fraction by echocardiogram must be >50% for patients at baseline. Any structural changes found must be reviewed by the treating investigator and deemed acceptable and safe prior to study enrolment. Any noted cardiac fibrosis will exclude a patient.
• Baseline ECG with QTc ≤ 470 msec for females and ≤ 450 msec for men.
• Agree to use adequate contraception (see Section 8.7) during the study and for 12 months after receiving the final dose of study drug.
• Ability and willingness to adhere to study-required procedures.

Exclusion criteria

• Patients may not be receiving any other investigational agents, chemotherapy, immunotherapy, radiotherapy, or molecular targeted agents within 28 days prior to enrollment to study.
• Patients previously exposed to CCI-001 are not permitted to re-enroll.
• Patients may not have symptomatic CNS metastasis. Patients with treated CNS metastasis are eligible, provided their disease is radiographically stable over a period of ≥ 8 weeks, asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants for the treatment of the symptoms from their brain metastases. Screening of asymptomatic patients without a history of CNS metastasis is not required.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-001 such as other derivatives of colchicine.
• History of allergic reactions or intolerance to anticipated chemotherapeutic agents.
• The presence of Grade 2 or higher peripheral neuropathy due to a prior medical condition (such as multiple sclerosis), medications, or other etiologies.
• Any psychological, familial, sociological, or geographical conditions that do not permit medical follow-up and compliance with the study protocol.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant or nursing women.
• Human Immunodeficiency Virus (HIV)-positive patients.
• Hepatitis B- and/or C-positive patients. A negative test is required at screening.
• History of other invasive cancer within 2 years of study entry. The exceptions are in situ cervical cancer, basal cell carcinoma or squamous cell carcinoma of the skin, and localized prostate cancer after curative therapy such as surgery, or radiation (Gleason score < 7). For these exceptions, all treatment must have been completed at least 6 months prior to enrollment.
• Patients taking warfarin. Low dose or therapeutic dose of heparin or low molecular weight heparin is allowed.
• Cardiac fibrosis on echocardiogram.

Adherence to all inclusion and exclusion criteria is mandatory; no waivers will be granted.