Phase I Study of the Proteosome Inhibitor CEP 18770 in Patients With Solid Tumours or Non-Hodgkin's Lymphomas

Solid Tumors Clinical Trial

Official title:

An Open-Label, Dose-escalation, Phase I Study to Determine the Maximum Tolerated Dose, Recommended Dose, Pharmacokinetics, and Pharmacodynamics of the Proteosome Inhibitor CEP 18770 Given Intravenously as Single Agent in Patients With Advanced Solid Tumours or Non-Hodgkin's Lymphomas

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00572637
• Other study ID #: E-CEP\I\01
• Status: Completed
• Phase: Phase 1
• First received: December 12, 2007
• Last updated: May 19, 2010
• Start date: November 2007
• Est. completion date: March 2010

Study information

• Verified date: May 2010
• Source: Ethical Oncology Science
• Contact: n/a
• Is FDA regulated: No
• Health authority: Italy: National Institute of HealthSwitzerland: Swissmedic
• Study type: Interventional

Clinical Trial Summary

This Phase 1 escalating-dose study is designed to assess, the safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel proteasome inhibitor CEP 18770, given intravenously as single agent, in patients with advanced, incurable solid tumours or NHL, and to identify the recommended dose of CEP 18770 to be used in Phase 2 studies.

Description:

This is an open-label, multicenter, dose-escalating study to determine the MTD and dose limiting toxicities (DLTs) of CEP 18770, a novel proteasome inhibitor. The study will also characterize the pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of CEP 18770, and assess the safety and tolerability of CEP-18770 treatment as well as any effect on tumour response whenever possible.

Patients will be treated intravenously with CEP 18770 on days 1, 4, 8, and 11 of a 21-day cycle period. Additional cycles may be administered, up to 6, as long as patients are maintaining their performance status and appear to be receiving clinical benefit from the study.

Safety data will be collected for all patients in order to determine the toxicity and reversibility of toxicity of CEP 18770. Formal assessments will be performed throughout the study including at baseline, prior to each dose of study medication every week, and 30 days following the last dose of study drug. Patients with drug-related toxicities will continue to be reviewed until resolution or stabilization of the toxicity. Pharmacokinetic and pharmacodynamic parameters will also be assessed in each cohort of patients during cycle 1. Where applicable, tumour measurements will be documented and any observed anti-tumour activity will be evaluated.

The study will follow a conventional MTD design with patients recruited in cohorts of 3 patients, with criteria to expand to 6 patients. Enrolment for each cohort will begin when the required number of patients in the prior cohort have completed one 21-day cycle of study drug treatment at the current dose level without experiencing a DLT. Once the MTD has been determined, additional 10 patients will be treated at the MTD to further explore the toxicity of this dose, and its suitability for Phase II studies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 55
• Est. completion date: March 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• diagnosis of relapsed or refractory solid tumour or non-Hodgkin's lymphoma

• unresponsive or poorly responsive to accepted treatment modalities

• expected survival of at least 12 weeks

• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

• fully recovered from any prior surgical procedure(s) and from reversible side effects of prior therapy for cancer including radiation therapy, chemotherapy, and immunotherapy (exceptions: alopecia and grade 1 neurotoxicity).

• al least 4 weeks from last cancer therapy (or 6 weeks from previous mitomycin C; 2 weeks from previous biological therapy; 8 weeks from previous bevacizumab)

• no more than 3 previous chemotherapies for advanced disease (excluding TKIs)

• good health as determined by a medical and psychiatric history, medical examination, ECG, serum chemistry, hematology, urinalysis, and serology.

• for women of childbearing potential use of a medically accepted method of contraception for the duration of the study and for 60 days after the last administration of study drug

• for men not surgically sterile use of an accepted method of birth control for the duration of the study and for 60 days after the last administration of study drug

• willingness and ability to comply with study requirements

Exclusion Criteria:

• Any of the following hematologic values: absolute neutrophil count (ANC) less than 1500/mm3, platelet count less than 100,000/mm3, or hemoglobin less than 9 g/dL

• Any of the following hepatic function values: bilirubin greater than 1.5 times the upper limit of normal (ULN) or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.5 times the ULN

• Serum creatinine value greater than 1.5 mg/dL.

• Known cerebral metastases or active CNS disease

• Signs indicating potential major bone marrow involvement

• Significant neurotoxicity (higher than grade 1 as defined by NCI-CTC scale v. 3.0 and/or a TNSc value = 3)

• Any concomitant cancer related treatment. (Continuing endocrine treatment at stable doses is allowed; treatment must be ongoing for at least 4 weeks)

• Concomitant treatment with steroids

• Previous treatment with high-dose chemotherapy with PBSC support

• Any investigational drug within the past 4 weeks

• Any medications which are human cytochrome P450 34A (CYP3A4) substrates within 1 week, or 5 half-lives (whichever is longer) before the first administration of study drug or need for continuous treatment with these medications during the study

• Known hypersensitivity to boronic acid derivatives or excipients in the CEP-18770 formulation.

• Any condition which, in the judgment of the Investigator, would place the subject at undue risk or interfere with the results of the study, or make the subject otherwise unsuitable (e.g., risk factors for neurological toxicities)

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin
• Solid Tumors

Intervention

Drug:
• CEP-18770
Administered as intravenous infusion on days 1, 4, 8, and 11 of a 21-day cycle up to 6 cycles. Starting dose 0,1 mg/sqm

Locations

Country	Name	City	State
Italy	Europen Institute of Oncology	Milano
Switzerland	IOSI - Oncology Institute of Southern Switzerland - Ospedale S. Giovanni	Bellinzona
Switzerland	Kantonsspital St. Gallen	St. Gallen

Sponsors (1)

Lead Sponsor	Collaborator
Ethical Oncology Science

Countries where clinical trial is conducted

Italy,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose Limiting Toxicities (DLT) and Maximum Tolerated Dose (MTD) of CEP 18770		Within the first 21-day cycle	Yes
Secondary	Pharmacokinetics of CEP-18770 following single and multiple dose administration.		Within the first 21-day cycle	No
Secondary	Profile and time course of inhibition and recovery of proteasome activity		Within the first 21-day cycle	No
Secondary	Antineoplastic activity evaluated with internationally accepted response criteria		throughout the study period	No