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

Обзор

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.

Вмешательства

• Препарат CCI-001
  Part 1 Dose Escalation: CCI-001 will be given intravenously starting at 1.2mg/m2 in the first cohort. The dose escalation between cohorts will depend on adverse event grading, as judged by NCI-CTCAE. Part 1 is complete when the maximum tolerated dose and the recommended expansion dose are determined. Part 2 Dose Expansion: cohorts of patients with the following tumour types will be enrolled: gynecologic cancers (ovarian \[including fallopian tube and primary peritoneal\], cervical, endometrial,

Первичные конечные точки

• To determine (Part 1) and confirm (Part 2) the safety of the recommended dose of intravenous CCI-001 monotherapy, and to examine the safety of CCI-001 with gemcitabine or carboplatin (Part 3) for patients with recurrent or metastatic solid tumours. [Срок оценки: Cycle 1 (28 days)]
• To determine, during the Part 1 dose-escalation, the recommended dose of intravenously infused CCI-001 for the dose expansion part of the trial. [Срок оценки: Cycle 1 (28 days)]

Вторичные конечные точки (6)

• To evaluate clinical response (objective response rate and progression-free survival) in patients with recurrent and/or metastatic solid tumours, treated with CCI-001 monotherapy (Parts 1, 2), or combined with gemcitabine or carboplatin (Part 3). [Срок оценки: Patients will have a baseline scan prior to dosing, and re-evaluated with imaging every 8 weeks. To continue from baseline scan to first documented date of disease progression, or date of death from any cause.]
• To evaluate survival in patients treated with CCI-001 with recurrent and/or metastatic solid tumours, with particular attention to those in expansion cohorts [Срок оценки: Start of treatment period (Cycle 1, Day1) to 30 days past the last treatment. Each Cycle is 28 days.]
• To determine the time to maximum plasma level (Tmax) of CCI-001 administered intravenously. [Срок оценки: Measured on Cycle 1 Days 1 and 15, Cycle 2 Day 1. Each cycle is 28 days.]
• To determine the maximum plasma concentration (Cmax) of CCI-001 administered intravenously. [Срок оценки: Measured on Cycle 1 Days 1 and 15, Cycle 2 Day 1. Each cycle is 28 days.]
• To determine the area under the curve (AUC) of CCI-001 administered intravenously. [Срок оценки: Measured on Cycle 1 Days 1 and 15, Cycle 2 Day 1. Each cycle is 28 days.]
• To determine the terminal half life (t1/2) of CCI-001 administered intravenously. [Срок оценки: Measured on Cycle 1 Days 1 and 15, Cycle 2 Day 1. Each cycle is 28 days.]

Критерии участия

Критерии включения

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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Последовательный дизайн

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Канада · 1 центр

• Cross Cancer Institute — Edmonton

Идентификаторы

NCT: NCT04823897 · PMH-001

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗