AZD2281, Cisplatin, and Gemcitabine in Treating Patients With Unresectable or Metastatic Solid Tumors - Full Text View

Sponsored by:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00678132

Purpose

RATIONALE: AZD2281 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Drugs used in chemotherapy, such as cisplatin and gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. AZD2281 may help cisplatin and gemcitabine kill more tumor cells by making tumor cells more sensitive to the drugs.

PURPOSE: This phase I trial is studying the side effects and best dose of AZD2281, cisplatin, and gemcitabine in treating patients with unresectable or metastatic solid tumors.

Condition	Intervention	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: PARP inhibitor AZD2281 Drug: cisplatin Drug: gemcitabine hydrochloride	Phase I

Study Type:	Interventional
Study Design:	Treatment, Non-Randomized, Open Label
Official Title:	A Phase I Combination Study of AZD2281 and Cisplatin Plus Gemcitabine in Adults With Solid Tumors

Resource links provided by NLM:

MedlinePlus related topics: Cancer

Drug Information available for: Cisplatin Gemcitabine Gemcitabine hydrochloride AZD 2281

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Safety and tolerability [ Designated as safety issue: Yes ]
Maximum tolerated dose of PARP inhibitor AZD2281 in combination with cisplatin and gemcitabine hydrochloride [ Designated as safety issue: Yes ]
Effect of treatment on PAR and γ-H2AX levels in tumor biopsies and peripheral blood mononuclear cells pre- and post-treatment [ Designated as safety issue: No ]

Secondary Outcome Measures:

Pharmacokinetics [ Designated as safety issue: No ]

Estimated Enrollment:	55
Study Start Date:	February 2008
Estimated Primary Completion Date:	December 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Group 1: Experimental Patients receive oral PARP inhibitor AZD2281 twice daily on days 1, gemcitabine IV over 1 hour on days 1 and 8, and cisplatin IV over 1 hour on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: PARP inhibitor AZD2281 Given orally Drug: cisplatin Given IV Drug: gemcitabine hydrochloride Given IV
Group 2: Experimental Patients receive gemcitabine IV over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on day 1 during course 1 (closed 3/19/09). For all subsequent courses, patients receive oral PARP inhibitor AZD2281, gemcitabine, and cisplatin as in group 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: PARP inhibitor AZD2281 Given orally Drug: cisplatin Given IV Drug: gemcitabine hydrochloride Given IV

Detailed Description:

OBJECTIVES:

Primary

Establish the safety and tolerability of PARP inhibitor AZD2281 in combination with cisplatin and gemcitabine hydrochloride in patients with unresectable or metastatic solid tumors.
Establish the maximum tolerated dose of this regimen in these patients.
Evaluate the effect of this regimen on PAR and γ-H2AX levels in tumor biopsies and peripheral blood mononuclear cells pre- and post-treatment.

Secondary

Evaluate the pharmacokinetics of PARP inhibitor AZD2281 and gemcitabine to assess a potential drug-drug interaction.

OUTLINE: Patients are assigned to 1 of 2 treatment groups. Patients are assigned to group 1 until the maximum tolerated dose (MTD) is determined. Once the MTD is determined, additional patients are assigned to group 2 and treated at the MTD determined in group 1.

Group 1: Patients receive oral PARP inhibitor AZD2281 twice daily on day 1, gemcitabine hydrochloride IV over

1 hour on days 1 and 8, and cisplatin IV over 1 hour on day 1.
Group 2: Patients receive gemcitabine hydrochloride IV over 1 hour on days 1 and 8 and cisplatin IV over 1 hour on day 1 during course 1 at the MTD determined in group 1 (closed 3/19/09). For all subsequent courses, patients receive oral PARP inhibitor AZD2281, gemcitabine hydrochloride, and cisplatin as in group 1 at the MTD determined in group 1. In both groups, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood and tumor samples are collected periodically for pharmacokinetic and other laboratory studies. Total drug concentration of PARP inhibitor AZD2281 and gemcitabine is measured by liquid chromatography and mass spectrometry. PAR concentration is measured by immunoassay and γ-H2AX levels are measured by western blotting and immunofluorescence assay. PARP polymorphisms (e.g., SNP, PARP1, and Val762Ala) and polymorphisms in the XRCC1 gene are also assessed.

After completion of study treatment, patients are followed for 30 days.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically confirmed solid tumor malignancy
- Unresectable or metastatic disease for which standard curative measures do not exist, or are associated with minimal patient survival benefit
Brain metastases allowed provided the brain metastases were previously treated and have remained stable for
- 3 months AND do not require steroids (except for maintenance replacement doses of steroids) or anti-seizure medications
No lymphomas or primary CNS malignancies
No more than 2 prior severely myelosuppressive cytotoxic chemotherapy regimens

PATIENT CHARACTERISTICS:

ECOG performance status (PS) 0-2 or Karnofsky PS 60-100%
Life expectancy ≥ 3 months
Absolute neutrophil count ≥ 1,500/μL
Platelet count ≥ 100,000/μL
Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST/ALT ≤ 2.5 times ULN
Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
Not pregnant
No nursing during and for 30 days after completion of study treatment
Negative pregnancy test
Fertile patients must use effective contraception before, during, and for 30 days after completion of study treatment
No uncontrolled intercurrent illness including, but not limited to, any of the following:
- Ongoing or active infection
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Cardiac arrhythmia
- Prolonged QTc interval (> 500 msec)
- Psychiatric illness/social situation that would limit compliance with study requirements
No other clinically significant illness that would compromise study participation including, but not limited to, any of the following:
- Immune deficiencies or confirmed diagnosis of HIV infection, hepatitis B, or hepatitis C
- Uncontrolled diabetes
- Uncontrolled hypertension
- Myocardial infarction within the past 6 months

PRIOR CONCURRENT THERAPY:

See Disease Characteristics
Recovered from prior therapy
Prior cisplatin and/or gemcitabine hydrochloride allowed
At least 2 weeks since prior investigational agents that were administered as part of an exploratory IND study
At least 4 weeks since prior participation in a regulatory IND study
At least 4 weeks since prior radiotherapy or surgery
- Prior irradiated tumors are considered for biopsy if signs of disease progression are present
More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)
No other concurrent chemotherapy
No other concurrent investigational agents
No other concurrent anticancer therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00678132

Locations

United States, Maryland
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Clinical Trials Office - Warren Grant Magnusen Clinical Center 888-NCI-1937

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Principal Investigator:

Giuseppe Giaccone, MD, PhD

NCI - Medical Oncology Branch

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

No publications provided

Study ID Numbers:	CDR0000595394, NCI-08-C-0128, P07286
Study First Received:	May 13, 2008
Last Updated:	August 1, 2009
ClinicalTrials.gov Identifier:	NCT00678132 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

unspecified adult solid tumor, protocol specific

Study placed in the following topic categories:

Antimetabolites
Anti-Infective Agents
Immunologic Factors
Radiation-Sensitizing Agents

Cisplatin
Gemcitabine
Immunosuppressive Agents
Antiviral Agents

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Enzyme Inhibitors

Immunosuppressive Agents
Antiviral Agents
Pharmacologic Actions
Cisplatin
Radiation-Sensitizing Agents
Therapeutic Uses
Gemcitabine

ClinicalTrials.gov processed this record on September 11, 2009