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A Phase I/II Trial of ABT-888, an Inhibitor of Poly (ADP-ribose) Polymerase (PARP), and Topotecan (TPT) in Patients With Solid Tumors (Phase I) and Relapsed or Refractory Ovarian Cancer or Primary Peritoneal Cancer (Phase II) After Prior Platinum Containing First-Line Chemotherapy

Phase 1/Phase 2
18 Years
Open (Enrolling)
Recurrent Ovarian Epithelial Cancer, Recurrent Primary Peritoneal Cavity Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

A Phase I/II Trial of ABT-888, an Inhibitor of Poly (ADP-ribose) Polymerase (PARP), and Topotecan (TPT) in Patients With Solid Tumors (Phase I) and Relapsed or Refractory Ovarian Cancer or Primary Peritoneal Cancer (Phase II) After Prior Platinum Containing First-Line Chemotherapy


I. To determine the maximum tolerated dose of the combination of ABT-888 (veliparib) and
weekly topotecan (topotecan hydrochloride) in adult patients with advanced solid tumors.
(Phase I) II. To identify any anti-tumor activity of this treatment combination, as assessed
by objective response in patients with advanced solid tumors. (Phase I) III. To assess the
confirmed response rate for patients with epithelial ovarian cancer or primary peritoneal
carcinoma treated with the combination of ABT-888 and weekly topotecan.

IV. To assess the toxicity of the combination of ABT-888 and weekly topotecan in patients
with epithelial ovarian cancer or primary peritoneal carcinoma. (Phase II)


I. To identify any pharmacokinetic interactions between ABT-888 and topotecan. (Phase I and
II) II. Phase I MTD: to provide preliminary view as to difference in response and toxicity
based on BRCA mutation status. (Phase I) III. To determine whether topotecan stimulates
adenosine diphosphate (ADP)-ribose polymer formation in circulating peripheral blood
mononuclear cells. (Phase I) IV. To determine whether ABT-888 inhibits basal or
topotecan-stimulated ADP-ribose polymer formation. (Phase I) V. To determine whether
topotecan stimulates ADP-ribose polymer formation in circulating tumor cells and whether
ABT-888 modulates this. (Phase II) VI. To assess differences in the toxicity and/or efficacy
of this regimen based on BRCA 1/2 mutational status. (Phase II) VII. To determine whether
pretreatment tumor cell levels of topoisomerase I, poly ADP-ribose polymerase (PARP), BRCA1,
BRCA2, XRCC1, tyrosyl-deoxyribonucleic acid (DNA) phosphodiesterase 1 (TDP1), P-glycoprotein
or breast cancer resistance protein (BCRP) predict response to this regimen. (Phase II)
VIII. To identify, in an exploratory manner, any transcriptional profiles that may predict
response to this regimen. (Phase II)

OUTLINE: This is a phase I, dose escalation study of veliparib and topotecan hydrochloride
followed by a phase II study.

Patients receive veliparib orally (PO) on days 1-3, 8-10, and 15-17 (veliparib is omitted on
days 1-3 of course 2) and topotecan hydrochloride intravenously (IV) over 30 minutes on days
2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up at 3 months (Phase I) or every
3 or 6 months for 5 years (Phase II).

Inclusion Criteria:

- PHASE I: Adult patients with histologically confirmed solid tumor malignancy that is
metastatic or unresectable and for which standard curative measures or other therapy
definitely capable of extending life expectancy does not exist

- PHASE II: All patients enrolled in the Phase II portion of this trial must have a
history of biopsy-proven ovarian or primary peritoneal cancer at Mayo Clinic, and
radiological evidence of recurrence at a previous site of disease, or biopsy
confirmation if the site represents a new site of disease; patients must have
received =< 2 prior therapeutic regimens and must be either refractory to
platinum-based therapy or have relapsed < 1 year after receiving a prior
platinum-based regimen

- Patients must have measurable disease with at least one lesion whose longest diameter
can be accurately measured as >= 2.0 cm with conventional techniques or as >= 1.0 cm
with spiral computed topography (CT); if spiral CT is used, it must be used for both
pre- and post- treatment tumor assessments

- Absolute neutrophil count >= 1500/mcL

- Hemoglobin >= 9.0 g/dL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5x the upper limit of normal (ULN)

- Serum glutamic pyruvic transaminase (SGPT) (alanine aminotransferase [ALT]) or serum
glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 2.5 x
ULN in the absence of hepatic metastasis; SGPT (ALT) =< 3 x ULN or SGOT (AST) =< 5 x
ULN in the presences of hepatic metastasis

- Creatinine =< 1.5 x ULN

- International normalized ratio (INR) =< 1.4 unless receiving therapeutic doses of

- Partial thromboplastin time (PTT) =< 36 seconds

- Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0, 1, or 2

- Ability to provide informed consent

- Willingness to return to a Mayo Clinic institution for follow up

- Life expectancy >= 12 weeks

- Willingness to provide the biologic specimens is required by the protocol; this is
part of the mandatory translational research component; these specimens include:

- PHASE I: peripheral blood for plasma pharmacokinetic analysis and peripheral
blood mononuclear cell (PBMC) polymer assessment from 0-24 h after drug
administration on days 1 and 2 of cycle 1 as well as day 2 of cycle 2; urine for
assessment of ABT-888 renal clearance for 24 h after administration of drugs on
days 1 and 2 of cycle 1 as well as day 2 of cycle 2; and a pretreatment
peripheral blood sample for possible sequencing of the BRCA1, BRCA2 loci as well
as possible pharmacogenomic analysis

- PHASE II: all of the above samples plus a pretreatment biopsy for biological
studies and sequence analysis of the BRCA1 and BRCA2 loci

- Note: The goals of this study include assessment of the biologic effects on
surrogate markers of the agent(s) being tested and are, therefore, contingent
upon availability of the biologic specimens

- Women of childbearing potential only: Negative urine or serum pregnancy test done =<
7 days prior to registration

- Able to swallow and absorb the medication

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Any of the following prior therapies:

- Chemotherapy =< 4 weeks prior to registration

- Mitomycin C/nitrosoureas =< 6 weeks prior to registration

- Immunotherapy =< 4 weeks prior to registration

- Biologic therapy =< 4 weeks prior to registration

- Radiation therapy =< 4 weeks prior to registration

- Radiation to > 25% of bone marrow

- Investigational therapy or any ancillary therapy considered investigational
(utilized for a non-Food and Drug Administration [FDA]-approved indication and
in the context of a research investigation) =< 4 weeks prior to registration;
subjects with prostate cancer will be permitted to continue hormone therapy

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- New York Heart Association classification III or IV

- Known central nervous system (CNS) metastases or seizure disorder; patients with
known brain metastases that have been successfully treated and stable for >= 6 months
without requirement for corticosteroids and without seizure activity will be eligible

- Any of the following, because this study involves both ABT-888, an investigational
agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and
newborn are unknown, and topotecan, an agent that has known genotoxic, mutagenic and
teratogenic effects:

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
including patients known to be human immunodeficiency virus (HIV) positive

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Other active malignancy, except non-melanotic skin cancer or carcinoma-in-situ of the
cervix; NOTE: If there is a history of prior malignancy, they must not be receiving
other specific treatment (other than hormonal therapy) for their cancer

- History of myocardial infarction =< 6 months, or congestive heart failure requiring
use of ongoing maintenance therapy for life-threatening ventricular arrhythmias

- More than 2 prior chemotherapy regimens for the current malignancy; full dose
chemotherapy used in conjunction with concurrent radiation therapy will be included
as prior therapy; NOTE: Prior hormonal therapy (e.g. leuprolide, aromatase
inhibitors, tamoxifen) will be allowed and not included as a prior chemotherapy

Type of Study:


Study Design:

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

Outcome Measure:

MTD of topotecan hydrochloride and veliparib, determined according to incidence of dose-limiting toxicity (DLT), graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (Phase I)

Outcome Description:

The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized. The grade 3+ adverse events will also be described and summarized in a similar fashion. Toxicity incidence by BRCA mutation will also be evaluated for the patients enrolled in the expanded Phase I MTD cohort. Frequency distribution, graphical techniques, and other descriptive measures will form the basis of these analyses.

Outcome Time Frame:

4 weeks

Safety Issue:


Principal Investigator

Michael Menefee

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

January 2011

Completion Date:

Related Keywords:

  • Recurrent Ovarian Epithelial Cancer
  • Recurrent Primary Peritoneal Cavity Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Ovarian Neoplasms
  • Peritoneal Neoplasms
  • Neoplasms
  • Neoplasms, Glandular and Epithelial



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