AS703569 and Gemcitabine Combination in Advanced Malignancies

A Phase I, Dose-escalation Study of a Combination AS703569 and Gemcitabine Given to Subjects With Advanced Malignancies

In clinical practice and research, combination of anticancer agents is often used to improve efficacy of treatment. In vitro and in vivo experiments have shown additive-synergistic anti-tumour effects of AS703569 treatment when combined with gemcitabine. Specifically, additive-synergistic anti-tumour effects were noticed when the two agents were given sequentially and not concomitantly i.e. AS703569 given the day before or the day after gemcitabine. This trial was designed to investigate in parallel two regimens testing sequential administration of AS703569 either the day after gemcitabine infusion, (Regimen 1) or the day before (Regimen 2).

Study Overview

• Status: Completed
• Conditions: Pancreatic Cancer
• Intervention / Treatment: Drug: AS703569/gemcitabine; Drug: AS703569/gemcitabine

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1000
    • Institut Jules Bordet
• France
  • Clichy, France, 92118
    • Service Inter-Hospitalier de Canderologie Bichat-Beaujon (SIHC) Hopital Beaujon
  • Paris, France, 75679
    • Unite d'Oncologie Medicale Hopital COCHIN

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Histologically/cytologically confirmed diagnosis of measurable or assessable malignancy, who meets one of the following conditions:

Subject with a tumour for which gemcitabine is approved, Subject with a tumour for which gemcitabine is considered standard of care, Subject with other tumour type either refractory or intolerant to or for whom there is not an accepted standard treatment.

Male or female with at least 18 years of age. Life expectancy of at least 3 months.

Eastern Cooperative Oncology Group (ECOG) Performance Status < 2.

No more than 3 prior chemotherapy regimens for advanced/metastatic disease.

At least 4 weeks since last chemotherapy, hormonal therapy, immunotherapy, biological or any other pharmacological or investigational treatment or radiotherapy (6 weeks wash-out for nitrosoureas and mitomycin C, 5 half-lives for non-cytotoxics). Subjects on chronic hormonal therapy may continue with the same treatment unchanged.

Adequate renal, hepatic and bone marrow functions (assessed 7 days before inclusion in the trial) as defined by:

Serum creatinine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Regimen 1: AS703569/gemcitabine; Gemcitabine on Days 1 and 8, AS703569 on Days 2 and 9, of a 21-day cycle	Drug: AS703569/gemcitabine; Gemcitabine on Days 1 and 8, AS703569 on Days 2 and 9, of a 21-day cycle. The starting dose (DL1) for AS703569 will be 10mg/m2/day. The subsequent dose levels of AS703569 will follow the dose-escalation scheme with an approximate 50% increase from DL1 to DL2, 40% from DL2 to DL3, and thereafter an approximate increase of 33% from one dose level to the next. Gemcitabine will be administered at the dose of 1000mg/m2 once weekly during the first two weeks of each 21-day cycle.; Other Names: Aurora kinase inhibitor; MSC1992371A; Drug: AS703569/gemcitabine; AS703569 on Days 1 and 8, gemcitabine on Days 2 and 9, of a 21-day cycle. The starting dose (DL1) for AS703569 will be 10mg/m2/day. The subsequent dose levels of AS703569 will follow the dose-escalation scheme with an approximate 50% increase from DL1 to DL2, 40% from DL2 to DL3, and thereafter an approximate increase of 33% from one dose level to the next. Gemcitabine will be administered at the dose of 1000mg/m2 once weekly during the first two weeks of each 21-day cycle.; Other Names: Aurora kinase inhibitor; MSC1992371A
Experimental: Regimen 2: AS703569/gemcitabine; AS703569 on Days 1 and 8, gemcitabine on Days 2 and 9, of a 21-day cycle	Drug: AS703569/gemcitabine; Gemcitabine on Days 1 and 8, AS703569 on Days 2 and 9, of a 21-day cycle. The starting dose (DL1) for AS703569 will be 10mg/m2/day. The subsequent dose levels of AS703569 will follow the dose-escalation scheme with an approximate 50% increase from DL1 to DL2, 40% from DL2 to DL3, and thereafter an approximate increase of 33% from one dose level to the next. Gemcitabine will be administered at the dose of 1000mg/m2 once weekly during the first two weeks of each 21-day cycle.; Other Names: Aurora kinase inhibitor; MSC1992371A; Drug: AS703569/gemcitabine; AS703569 on Days 1 and 8, gemcitabine on Days 2 and 9, of a 21-day cycle. The starting dose (DL1) for AS703569 will be 10mg/m2/day. The subsequent dose levels of AS703569 will follow the dose-escalation scheme with an approximate 50% increase from DL1 to DL2, 40% from DL2 to DL3, and thereafter an approximate increase of 33% from one dose level to the next. Gemcitabine will be administered at the dose of 1000mg/m2 once weekly during the first two weeks of each 21-day cycle.; Other Names: Aurora kinase inhibitor; MSC1992371A

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	To determine the maximum tolerated dose (MTD) during a 21-day cycle, for each of the two planned regimens using combination therapy with AS703569 and gemcitabine.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-emergent adverse events (TEAE)	Proportion/number of subjects with TEAE's during the first and subsequent treatment cycles in each cohort for each of the 2 regimens.	Minimum 21 days or 1 cycle
Progression-Free Survival (PFS) time (For subjects with locally advanced /metastatic pancreatic cancer included after completion of the dose escalation part)	PFS time is defined as time (in months) from first drug intake to date of progression as reported and documented by the investigator (i.e. radiological progression per Response Evaluation Criteria in Solid Tumors [RECIST] criteria) or death from any cause.	Variable
Time to Tumor Progression (TTP) time (For subjects with locally advanced /metastatic pancreatic cancer included after completion of the dose escalation part)	TTP time is defined as the time (in months)from first drug intake to the date of progression, as reported and documented by the Investigator (i.e. radiological progression per RECIST).	Variable
Overall Survival (OS) time (For subjects with locally advanced /metastatic pancreatic cancer included after completion of the dose escalation part)	OS time is defined as the time (in months) from first drug intake to any cause of death.	Variable
Progressive disease (PD)	Proportion of patients with progressive disease as assessed at the end of every other cycle according to disease-specific guidelines	Every other cycle
Best overall response (For subjects with locally advanced /metastatic pancreatic cancer included after completion of the dose escalation part)	For subjects with locally advanced /metastatic pancreatic cancer: Best overall response: presence of at least one confirmed Complete Response (CR) or confirmed Partial Response (PR) (using RECIST v1.0) during treatment in the 2 regimens as assessed at the end of every other cycle.	Every other cycle

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Narmyn Rejeb, MD, Merck Serono S.A., Geneva

Publications and helpful links

General Publications

• Raymond E, Alexandre J, Faivre S, Goldwasser F, Besse-Hammer T, Gianella-Borradori A, Jego V, Trandafir L, Rejeb N, Awada A. A phase I schedule dependency study of the aurora kinase inhibitor MSC1992371A in combination with gemcitabine in patients with solid tumors. Invest New Drugs. 2014 Feb;32(1):94-103. doi: 10.1007/s10637-013-9950-y. Epub 2013 Mar 29.

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): February 1, 2011

Study Registration Dates

• First Submitted: March 31, 2010
• First Submitted That Met QC Criteria: March 31, 2010
• First Posted (Estimate): April 1, 2010

Study Record Updates

• Last Update Posted (Estimate): January 30, 2014
• Last Update Submitted That Met QC Criteria: January 29, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Aurora kinase inhibitor; AS703569; MSC1992371A; Cancer treatable with gemcitabine
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Gemcitabine
• Other Study ID Numbers: 27902