Dose-escalation, Safety and Pharmacokinetic Study of Briciclib in Advanced Solid Tumors

Study Overview
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Brief Summary
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The main objectives of this study are to determine the safety profile of briciclib, an experimental anti-cancer drug, as it is administered intravenously once weekly as escalating doses in adult patients with advanced cancer and solid tumors, and to determine the highest dose of briciclib that can be safely given. Secondary objectives are to determine how the amount of briciclib in circulation changes over time and how much briciclib gets into the urine for excretion, and to document potential anti-tumor effects of briciclib.

Detailed Description
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This will be a Phase I, 2-stage, open-label, dose-escalating, multicenter study of the 2-hour, once-a-week intravenous (IV) administration of briciclib in 3-week cycles, in up to 54 adult patients with advanced cancer and solid tumors. The study will be conducted in 2 stages: a dose-escalation stage to determine the Maximum Tolerated Dose (MTD) and a Recommended Phase 2 Dose (RPTD) confirmation stage. Patients with stable disease (SD) or response may remain treated on study until progression.

Official Title
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A Phase I, Dose-escalation Study of the Safety, Pharmacokinetics and Efficacy of Weekly Intravenous Briciclib in Patients With Advanced Solid Tumors

Conditions
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Neoplasms, Advanced Solid Tumor

Intervention / Treatment
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* Drug: briciclib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumor (leukemia and lymphoma are excluded) Malignancy that is incurable and for which standard (FDA approved or established standard clinical practice) curative, or palliative measures do not exist or are no longer effective Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. Minimum expected life expectancy > 6 months One or more measurable lesion(s) (target lesion[s]) that can be accurately measured in at least 1 dimension Willing to adhere to the prohibitions and restrictions specified in the protocol The patient must sign an informed consent form (ICF) Exclusion Criteria: Recent major surgery (within the past 14 days) Chemotherapy or dose of other potentially myelosuppressive treatment within 3 weeks prior to Screening (6 weeks for nitrosoureas or mitomycin C) No more than a total cumulative dose of 450 mg/m^2 of prior doxorubicin chemotherapy Definitive radiotherapy (> 10 fractions and maximal area of hematopoietic active Bone Marrow treated greater than 25%) within 4 weeks prior to Screening Palliative radiotherapy (≤ 10 fractions) within 2 weeks prior to Screening Known brain metastases, except brain metastases that have been previously removed or irradiated and currently have no clinical impact Residual adverse events due to previously administered agents (except alopecia, stable residual neuropathy, and residual hand, foot syndrome) that have not recovered to Grade 1 or below in severity level (based on NCI CTCAE) before Screening Ascites requiring active medical management, including paracentesis Pleural effusion requiring active medical management Peripheral bilateral edema requiring active medical management Hyponatremia (serum sodium value less than 130 mEq/L) History of allergic reactions attributed to compounds of similar chemical or biologic composition to briciclib Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, bleeding, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements History of myocardial infarction Any other concurrent investigational agent or chemotherapy, radiotherapy, hormonotherapy, or immunotherapy. Exceptions are long-term hormonals for prostate (eg, goserelin) and octreotide for neuroendocrine malignancies Patients who are positive for human immunodeficiency virus type 1 (HIV-1) and are receiving combination anti-retroviral therapy Hemoglobin (Hgb) < 9 g/dL White Blood Cell count (WBC) < 4,000/µL Absolute Neutrophil Count (ANC) < 1,500/µL Platelet (PLT) count ≤ 100,000/µL Total bilirubin greater than 1.5 x the institutional upper limit of normal (ULN) Aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 2.5 x institutional ULN. If liver function abnormalities are due to metastatic disease, patients are eligible provided the ALT and AST are < 5 x ULN Serum creatinine > 2 x ULN

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: briciclib<br>The starting dose of briciclib in the Escalation Stage will be 17 mg/week, with subsequent dose escalation levels of 35 mg, 70 mg, 140 mg, 280 mg, 560 mg, and 1120 mg. The dose of briciclib in the RPTD Confirmation Stage will be the dose as determined during the escalation stage. At each dose level, briciclib will be administered as a 2-hour intravenous infusion, once-a-week per 3-week cycles. | Drug: briciclib<br> <br> * Other names: ON 013105;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events | Adverse events will be grouped by system organ class (SOC) and preferred term (PT) using the most recent version of the Medical Dictionary for Regulatory Activities (MedDRA), and will be summarized by worst grade according to NCI Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. | Up to 1 year | 
| Number of patients with Dose Limiting Toxicity (DLT) | Dose-limiting toxicity is defined as an adverse event that is considered to be drug-related and meets one of the Protocol definitions. | Up to 3 weeks | 
| Maximum Tolerated Dose | Maximum Tolerated Dose (MTD) will be defined during the Dose Escalation Stage based on evaluation of the number of patients with Dose-limiting Toxicity (DLT). The MTD will be used to determine the Recommended Phase 2 Dose (RPTD). | 3 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of briciclib in the plasma | The amount of briciclib in the plasma of patients in the Recommended Phase 2 Dose (RPTD) Confirmation stage only will be measured by a validated Liquid Chromatography-Mass Spectroscopy (LC-MS) method. Pharmacokinetic parameters will be derived from the concentration versus time values. | 24 hours | 
| Concentration of briciclib in the urine | The amount of briciclib in the urine of patients in the Recommended Phase 2 Dose (RPTD) Confirmation stage only will be measured by a validated Liquid Chromatography-Mass Spectroscopy (LC-MS) method. Pharmacokinetic parameters will be derived from the concentration versus time values. | 24 hours | 
| Change in size of tumors | Change in the overall tumor will be determined from the tumor burden at Baseline following Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. | Up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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briciclib, Dose escalation, Maximum tolerated dose