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A Multi-Center, Randomized, Double-Blind Phase II Study Comparing ABT-888, a PARP Inhibitor, Versus Placebo With Temozolomide in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer


Phase 2
18 Years
N/A
Open (Enrolling)
Both
Recurrent Small Cell Lung Cancer

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Trial Information

A Multi-Center, Randomized, Double-Blind Phase II Study Comparing ABT-888, a PARP Inhibitor, Versus Placebo With Temozolomide in Patients With Relapsed Sensitive or Refractory Small Cell Lung Cancer


PRIMARY OBJECTIVES:

I. To demonstrate an improvement in progression free survival (PFS) at four months in
patients with relapsed sensitive or refractory SCLC receiving ABT-888 and temozolomide
compared to placebo and temozolomide.

SECONDARY OBJECTIVES:

I. Determine the objective response rate (ORR) (based on Response Evaluation Criteria In
Solid Tumors [RECIST] 1.1 criteria) in both arms of the study: ABT-888 and temozolomide and
placebo and temozolomide.

II. Determine the overall survival (OS) of patients in both arms of the study. III.
Determine the ORR, PFS and OS of ABT-888 and temozolomide and placebo and temozolomide, in
the following patient groups: sensitive disease vs. refractory disease; second-line
treatment vs. third-line treatment; brain metastases vs. no brain metastases.

IV. Determine the safety and tolerability of ABT-888 and temozolomide in patients with SCLC.

TERTIARY OBJECTIVES:

I. Evaluate available tumor samples for methylated O6-methylguanine-DNA methyltransferase
(MGMT) promoter by the EpiTyper assay, as well as MGMT expression by immunohistochemistry
and determine if these correlate with PFS, ORR, and OS.

II. Evaluate available tumor samples for poly(ADP ribose) polymerase (PARP)-1, breast cancer
1 (BRCA-1) and RAD51 expression by immunohistochemistry and determine if they correlate with
PFS, ORR, and OS.

III. Evaluate available tumor samples for messenger ribonucleic acid (mRNA) BRCA-1
expression and determine if it correlates PFS, ORR, and OS.

IV. Evaluate available tumor samples for phosphatase and tensin homolog (PTEN) expression by
immunohistochemistry and determine if it correlates PFS, ORR, and OS.

V. Identify and enumerate circulating tumor cells (CTCs) using the Cell Search System in
these patients with SCLC at baseline and at the time of repeat imaging.

VI. Correlate the number of CTCs with PFS and OS at each time point. VII. Correlate the
change in CTCs with radiographic response. VIII. Correlate the number of CTCs at baseline
with patient characteristics (disease burden, location of metastases, progression at
existing sites or new sites of disease).

IX. Evaluate gamma H2AX-positive CTCs using the CellSearch. X. Assess the percentage
increase in DNA fragments during treatment and correlate with outcome in each of the
treatment groups.

XI. In a subset of patients, identify and enumerate CTCs using the CTC-Chip. XII. Compare
the predictive ability of CTC number measured by Veridex CellSearch System and CTC-Chip,
with respect to PFS, ORR and OS.

XIII. Evaluate plasma markers for apoptosis and angiogenesis. XIV. Assess changes in plasma
markers for apoptosis and angiogenesis, including M30, M65, pro-gastrin-releasing peptide
(pro-GRP), soluble vascular endothelial growth factor (sVEGF), sVEGF receptor 2 (sVEGFR2),
and sKIT, and correlate these markers with outcome in the two treatment arms.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive veliparib orally (PO) twice daily (BID) on days 1-7 and temozolomide
PO on days 1-5.

ARM II: Patients receive placebo PO BID on days 1-7 and temozolomide as in Arm I.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 8-12 weeks.


Inclusion Criteria:



- Patients must have histologically or cytologically confirmed small cell lung cancer;
confirmation will be done at Memorial Sloan-Kettering Cancer Center (MSKCC) or
locally for participating sites

- Patients' disease has relapsed or progressed after one or two prior chemotherapy
regimens, one of which must have been an etoposide-platinum doublet; eligible
patients will be defined as follows:

- "Sensitive" disease: Patients who had one previous line of chemotherapy and
maintained an appropriate response for > 60 days

- "Refractory" disease: Those patients with either no response to first-line
chemotherapy or progression =< 60 days after completing treatment, or
"sensitive" or "refractory" disease in need of third-line therapy (i.e.
completed or failed two previous lines of chemotherapy)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Patients with asymptomatic brain metastases that do not require immediate whole brain
radiation therapy and are on stable doses of steroids are allowed

- Patients must have measurable disease, which is defined as at least one lesion that
can be accurately measured in at least one dimension on a computed tomography (CT)
scan as per RECIST version 1.1; brain metastases can be considered measurable disease
if they meet this criterion

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8.5g/dL

- Total bilirubin =< 1.5 mg/dL X institutional upper limit of normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 3.0 X institutional upper limit of normal

- Creatinine =< 1.5 X institutional upper limit of normal OR creatinine clearance >= 50
mL/min/1.73 m^2 for patients with creatinine levels >= 1.5 X upper limit of
institutional normal

- The effects of ABT-888 on the developing human fetus are unknown; for this reason and
because other therapeutic agents or modalities used in this trial are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and 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

- For women of child-bearing potential, negative pregnancy test within 14 days prior to
starting temozolomide and ABT-888

- Ability to understand and the willingness to sign a written informed consent document

- Able to swallow pills

- Patients will not be excluded based on the diagnosis of acquired immune deficiency
syndrome (AIDS); given the increased risk of infection, these patients should have
cluster of differentiation (CD)4 counts above 200 cells/mm^3; patients with AIDS or
human immunodeficiency virus (HIV) not receiving agents with the potential for
pharmacokinetic interactions with ABT-888 may be eligible

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks prior to entering
the study

- Patients who have not recovered from adverse events due to agents administered more
than 3 weeks earlier; toxicities should have resolved to baseline or to within one
grade level of their baseline (not to exceed grade 2)

- Patients who have been administered ABT-888, any other PARP-inhibitor, or
temozolomide

- Patients may not be receiving any other investigational agents

- Patients with leptomeningeal involvement

- Patients with history of seizure

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to ABT-888 or temozolomide

- 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

- Pregnant women are excluded from this study because ABT-888 is PARP inhibitor 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 ABT-888, breastfeeding should be discontinued if the mother is
treated with ABT-888; these potential risks also apply to temozolomide

- Patients with either AIDS or HIV on combination antiretroviral therapy are ineligible
because of the potential for pharmacokinetic interactions with ABT-888; in addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy

- Patients with a synchronous active malignancy requiring treatment

Type of Study:

Interventional

Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Outcome Measure:

Progression-free survival, calculated as the proportion of patients alive and without evidence of disease

Outcome Description:

Compared across the two arms using a Fisher exact test.

Outcome Time Frame:

From randomization to time of progression or death, whichever occurs first, assessed at 4 months

Safety Issue:

No

Principal Investigator

Maria Pietanza

Investigator Role:

Principal Investigator

Investigator Affiliation:

Memorial Sloan-Kettering Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-01130

NCT ID:

NCT01638546

Start Date:

June 2012

Completion Date:

Related Keywords:

  • Recurrent Small Cell Lung Cancer
  • Lung Neoplasms
  • Small Cell Lung Carcinoma

Name

Location

Memorial Sloan-Kettering Cancer CenterNew York, New York  10021
Case Western Reserve UniversityCleveland, Ohio  44106
M D Anderson Cancer CenterHouston, Texas  77030
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins HospitalBaltimore, Maryland  21231