A Study of CCI-001 in Patients With Recurrent and/or Metastatic Solid Tumours

CCI-001 is a novel colchicine derivative that is being developed by PharmaMatrix Holdings Ltd. (PharmaMatrix). The drug binds to tubulin, a component of the microtubule polymers which are required for a wide range of cellular processes, perhaps most importantly, cell division and mitosis. CCI-001 has been shown to bind more strongly to β-III tubulin, a tubulin subtype which is overexpressed in many cancers.

This trial is being undertaken as a first-in-human, Phase I trial in patients with recurrent and/or metastatic solid tumours. Primary Objectives are to examine the compound's safety profile, and to determine the recommended dose. Secondary Objectives are to determine the compound's pharmacokinetic parameters and to evaluate the clinical response rate and survival. Expansion cohorts in in tumour types known to be sensitive to other approved agents with similar mechanism of action will be treated at the recommended dose: transitional cell bladder cancer, pancreaticobiliary adenocarcinomas, gynecologic cancers (ovarian, cervical, endometrial), and lung adenocarcinoma.


Eligibility Criteria:
Inclusion Criteria:

1. Subject has provided informed consent/assent prior to initiation of any study-specific activities/procedures.
2. Dose escalation phase: Patients must have histologically or cytologically confirmed recurrent or metastatic solid tumours. Patients must have disease progression on the last treatment exposed to, have exhausted available approved lines of therapy or better-characterized therapies that, at the discretion of the investigator, is felt to be more appropriate therapy, or have malignancies for which there are no approved therapies.

   Dose expansion phase: patients with the following tumour types will be permitted to enroll: transitional cell bladder cancer, pancreaticobiliary adenocarcinomas, gynecologic cancers (ovarian, cervical, endometrial), and lung adenocarcinoma.
3. 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.
4. 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.
5. Age ≥18 years.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1.
7. Life expectancy of greater than 12 weeks.
8. Patients must have normal organ and marrow function as defined below:

   * absolute neutrophil count ≥ 1.5 x 10\^9/L
   * hemoglobin ≥ 90 g/L
   * platelets ≥ 100 x 10\^9/L
   * total bilirubin ≤ 1.5 X upper limit of normal (ULN)
   * AST(SGOT) and ALT(SGPT) ≤ 2.5 X ULN (≤ 5 X ULN in the presence of liver metastases)
   * Creatinine (Cr) ≤ 1.5 X ULN
9. Cardiac ejection fraction by echocardiogram must be \>50% 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.
10. Baseline ECG with QTc ≤ 470msec for females and ≤ 450msec for males.
11. Agree to use adequate contraception for the duration of study participation and for 12 months after receiving the final dose of study drug.
12. Ability and willingness to adhere to study required procedures.
13. Patient must have measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 criteria.

Exclusion Criteria:

1. Patients may not be receiving any other investigational agents, chemotherapy, immunotherapy, radiotherapy, or molecular targeted agents within 28 days prior to enrollment to study unless discussed with the Principal Investigator.
2. Patients may not have symptomatic central nervous system (CNS) metastases. Patients with treated CNS metastases 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 metastases is not required.
3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to CCI-001 such as derivatives of colchicine.
4. The presence of grade 2 or higher peripheral neuropathy due to prior medical condition (such as multiple sclerosis), medications, or other etiologies.
5. Any psychological, familial, sociological, or geographical conditions that do not permit medical follow-up and compliance with the study protocol.
6. 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.
7. Pregnant or nursing women.
8. Human Immunodeficiency Virus (HIV)-positive patients.
9. Hepatitis B- and/or C-positive patients. A negative test is required at screening.
10. 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 6 months prior to enrollment.
11. Patients taking warfarin. Low-dose or therapeutic dose of heparin or low-molecular weight heparin are allowed.
12. Cardiac fibrosis on echocardiogram. Adherence to all inclusion and exclusion criteria is mandatory; no waivers will be granted.