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Phase I Study of 5-Azacytidine and Oxaliplatin in Patients With Advanced Cancers Relapsed or Refractory to Any Platinum Therapy


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Hematopoietic/Lymphoid Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Phase I Study of 5-Azacytidine and Oxaliplatin in Patients With Advanced Cancers Relapsed or Refractory to Any Platinum Therapy


PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose of 5-azacytidine and oxaliplatin combination
regimen in patients with advanced solid tumors or lymphomas relapsed or refractory to any
platinum compound.

II. To define 5-azacytidine and oxaliplatin pharmacokinetics.

SECONDARY OBJECTIVES:

I. For patients treated in the expansion phase of this study: (a) to assess CTR1 score; (b)
to assess changes in global DNA methylation; and (c) to measure changes in oxaliplatin
levels in tumor biopsies between pretreatment and day 12 of the first cycle of 5-azacytidine
plus oxaliplatin therapy.

II. To correlate results of the pharmacokinetic studies of 5-azacytidine and oxaliplatin
with changes in CTR1, changes in global DNA methylation and changes in oxaliplatin levels in
tissue biopsies of patients treated in the expansion phase of this study.

OUTLINE: This is a dose-escalation study.

Patients receive azacitidine IV over 15-30 minutes on days 1-5 and oxaliplatin IV over 2
hours on days 2-5. Treatment repeats every 28 days for up to 6 courses in the absence of
disease progression or unacceptable toxicity.


Inclusion Criteria:



- Patients must have histologically confirmed malignancy (solid tumor or lymphoma) that
is metastatic or unresectable and for which standard curative or palliative measures
are not expected to increase survival by at least 3 months

- Patients must have an advanced cancer relapsed or refractory to any platinum
compound; platinum-refractory disease is defined as disease that does not respond to
a platinum compound-containing regimen or that recurs after treatment with a platinum
compound-containing regimen

- Patients must have had >= 1 prior chemotherapy regimen; there is no maximum allowable
number of prior regimens, provided all other eligibility criteria are met

- Patients must be >= 6 weeks beyond treatment with a nitrosourea or mitomycin-C, >= 4
weeks beyond other chemotherapy or radiotherapy, and must have recovered to =< grade
1 toxicity for any treatment-limiting toxicity of prior therapy; (Exception: patients
may have received palliative low-dose radiotherapy to the limbs 1-4 weeks before this
therapy, provided pelvis, ribs, sternum, scapulae, vertebrae, or skull were not
included in the radiotherapy field)

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Leukocytes >= 4,000/uL

- Absolute neutrophil count >= 1,500/uL

- Platelets >= 100,000/uL

- Total bilirubin =< 1.0 mg/dL

- AST(SGOT)/ALT(SGPT) =< 3 X institutional upper limit of normal

- Creatinine (serum) =< 2.0 mg/dL

- INR of less than or equal to 1.75 per institutional guideline

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) for the duration of study
participation; should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately

- Patients must have the ability to understand and the willingness to sign a written
informed consent document, including consent for the required tumor biopsy (in the
expansion phase), blood, and pharmacokinetics studies

- Tumor should be accessible for repeat biopsy if in the expansion phase; biopsies will
be performed in the expansion phase; the expansion cohort will be between 10 and 20
patients

- Patients must have expected survival of at least 3 months

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered to =< grade 1 treatment-limiting toxicity levels for adverse events due to
agents administered more than 4 weeks earlier; (Exception: patients may have received
palliative low dose radiotherapy to the limbs 1-4 weeks before this therapy, provided
pelvis, ribs, sternum, scapulae, vertebrae, or skull were not included in the
radiotherapy field)

- Patients may not be receiving any other concurrent investigational agents

- Patients must not have a history of allergic reactions attributed to 5-azacytidine,
oxaliplatin, or compounds with a similar composition

- Patients must not have oxaliplatin intolerance

- Patients must not have uncontrolled intercurrent illness, including but not limited
to ongoing or active infection, symptomatic congestive heart failure, unstable angina
pectoris, potentially life-threatening cardiac arrhythmia, and psychiatric
illness/social situations that would limit compliance with study requirements

- Pregnant women are excluded from this study because 5-azacytidine is an
antimetabolite with the potential for teratogenic or abortifacient effects; because
there is an unknown but potential risk for adverse events in nursing infants
secondary to treatment of the mother with 5-azacytidine, breastfeeding should be
discontinued if the mother is treated with 5-azacytidine

- Because patients with immune deficiency are at increased risk of lethal infections
when treated with marrow-suppressive therapy, patients known to be HIV-positive and
receiving anti-retroviral therapy must have both a minimum of 350 CD4+ cells/mm^3 and
no history of AIDS defining conditions except for lymphoma

- Patients who have had surgery within 2 weeks prior to entering the study are not
eligible

- Patients who have been removed from prior platinum-containing therapy due to
platinum-compound cumulative toxicity

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

MTD

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Apostolia-Maria Tsimberidou

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-02909

NCT ID:

NCT01039155

Start Date:

December 2009

Completion Date:

Related Keywords:

  • Hematopoietic/Lymphoid Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030