Phase I Study of PARP Inhibitor AZD2281 in Combination With Cisplatin and Gemcitabine Hydrochloride in Patients With Unresectable or Metastatic Solid Tumors

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Alternate Title

AZD2281, Cisplatin, and Gemcitabine in Treating Patients With Unresectable or Metastatic Solid Tumors

Basic Trial Information

PhaseTypeStatusAgeSponsorProtocol IDs
Phase IBiomarker/Laboratory analysis, TreatmentClosed18 and overNCINCI-08-C-0128
08-C-0128, P07286, NCT00678132

Special Category: NIH Clinical Center trial



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


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

Entry 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 ≥ 1 month 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

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

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

Expected Enrollment



Primary Outcome(s)

Safety and tolerability
Maximum tolerated dose of PARP inhibitor AZD2281 in combination with cisplatin and gemcitabine hydrochloride
Effect of treatment on PAR and γ-H2AX levels in tumor biopsies and peripheral blood mononuclear cells pre- and post-treatment

Secondary Outcome(s)



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. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic and other laboratory studies. Tumor tissue samples are also collected at baseline and after completion of course 1. 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.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Giuseppe Giaccone, MD, PhD, Principal investigator (Contact information may not be current)
Ph: 301-496-4916

Registry Information

Official TitleA Phase I Combination Study of AZD2281 and Cisplatin Plus Gemcitabine in Adults with Solid Tumors
Trial Start Date2008-02-29
Trial Completion Date2009-12-07 (estimated)
Registered in ClinicalTrials.govNCT00678132
Date Submitted to PDQ2008-04-30
Information Last Verified2009-10-01

Note: The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.