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
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 (objective response rate and progression-free survival). Expansion cohorts (Parts 2 and 3) will enroll patients with the following tumour types: gynecologic cancers (ovarian \[including fallopian tube and primary peritoneal\], cervical, endometrial, vulvar), pancreaticobiliary adenocarcinomas and others (lung adenocarcinoma, head and neck adenocarcinomas, transitional cell bladder cancer, and upper GI tumours \[including esophageal, gastroesophageal junction and stomach\]). Part 2 Expansion cohorts will be treated at the recommended dose. Part 3 Expansion cohorts will be treated at a CCI-001 dose lower than the recommended dose in combination with either gemcitabine or cisplatin.
• 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.