Safety Study of ABT-888 Plus Topotecan Hydrochloride to Treat Patients With Solid Tumors and Lymphomas

Background:

- The PARP family of enzymes is characterized by the ability to poly (ADP-ribosyl)ate
protein substrates. PARP-1 and PARP-2 play a critical role in the maintenance of
genomic stability by regulating a variety of DNA repair mechanisms.

- Poly (ADP-ribosylated) PARP-1 has been shown to block the formation of topo 1-DNA
cleavage and accelerate the removal of camptothecin-stabilized topo 1-DNA complexes.
PARP-1 inhibition may therefore prevent efficient repair of DNA damage induced by
topoisomerase 1 inhibitors. ABT-888 is an oral PARP inhibitor and topotecan is a
topoisomerase I inhibitor.

Objectives:

- Establish the safety and tolerability of the combination of ABT-888 with topotecan
hydrochloride in patients with refractory solid tumors and lymphomas.

- Establish the maximum tolerated dose of the combination of ABT-888 with topotecan
hydrochloride.

- Evaluate the pharmacokinetics of each agent alone and in combination.

- Determine the effects of the study treatment on the level of PARP inhibition and DNA
damage in PBMCs and tumor samples.

Eligibility:

- Patients with histologically documented solid tumors and lymphoid malignancies
(lymphoma and CLL) whose disease has progressed following standard therapy or who have
no acceptable standard treatment options.

- No major surgery, radiation or chemotherapy within four weeks prior to study
enrollment, and recovered from toxicities of prior therapies to at least eligibility
levels.

Study Design:

- Cycle 1, dose levels -1 to 7 and 1B: Topotecan (TPT) will be administered intravenously
over 30 minutes as a single dose on days 1-5. Starting on day 2, ABT-888 will be
administered orally twice a day on a q12 hour schedule for 4 days (D2-5). Following the
completion of study drug administration on day 5, no further treatment will be
administered for the rest of this 21-day cycle. Growth factors will be administered
prophylactically starting Cycle 1 to patients on dose level 1B only.

- Cycle 2 and beyond, dose levels -1 to 7 and 1B: ABT-888 will be administered twice a
day on a q12 hour schedule orally on days 1-5. TPT will be given IV daily from days
1-5, in a 21-day cycle. Growth factors will be administered prophylactically to
patients on dose level 1B only.

- All cycles, dose levels -2 and 1A to 5A: ABT-888 will be administered on day 1 only for
dose levels -2 and 1A, 2A, 3A, and 4A. For dose level 5A, ABT-888 will be administered
on days 1 and 2 of each cycle. TPT will be given IV daily from days 1-5, in a 21-day
cycle.

- Dose escalation will proceed as outlined below. Once maximum tolerated dose (MTD) is
established, 6 additional patients will be enrolled at the MTD to further define the
dose and evaluate PD studies at this dose level.

-INCLUSION CRITERIA:

1. Patients with histologically documented solid tumors and lymphoid malignancies
(lymphoma and CLL) who are refractory to standard therapy or who have no acceptable
standard treatment options. Patients with lymphoid malignancies will be eligible if
their disease has progressed following standard therapy and if stem cell
transplantation is not indicated or has been refused.

2. Any prior therapy must have been completed greater than or equal to 4 weeks prior to
enrollment on protocol and the participant must have recovered to eligibility levels
(CTCAE Grade less than or equal to 1) from prior toxicity. Prior radiation or surgery
should have been completed greater than or equal to 4 weeks prior to study enrollment
and all associated toxicities resolved to eligibility levels. Patients must be
greater than or equal to 2 weeks since any investigational agent administered as part
of a Phase 0 study, and should have recovered to eligibility levels from any
toxicities.

3. Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of ABT-888 in patients less than 18 years of age,
children are excluded from this study, but may be eligible for future pediatric Phase
I combination trials.

4. ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to
60 percent).

5. Life expectancy of greater than 3 months.

6. Patients must have normal organ and marrow function as defined below:

- absolute neutrophil count greater than or equal to 1,500/mcL

- platelets greater than or equal to 100,000/mcL

- total bilirubin less than 1.5 times institutional upper limit of normal

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine less than 1.5 times institutional upper limit of normal

OR

-creatinine clearance greater than or equal to 60 mL/min for patients with creatinine
levels above institutional normal.

7. The effects of ABT-888 on the developing human fetus are unknown. For this reason and
because topotecan hydrochloride 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, for the
duration of study participation, and for 30 days after completion of study. Should a
woman become pregnant or suspect she is pregnant while participating in this study,
she should inform her treating physician immediately.

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

EXCLUSION CRITERIA:

1. 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 from adverse events due to agents administered more than 4 weeks earlier.
Patients must be greater than or equal to 2 weeks since any investigational agent
administered as part of a Phase 0 study, and should have recovered to eligibility
levels from any toxicities.

Patients who have been administered ABT-888 as part of a single or limited dosing
study, such as a Phase 0 study, should not be excluded from participating in this
study solely because of receiving prior ABT-888.

Patients who have received prior TPT should not be excluded solely because of
receiving prior TPT.

2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, prolonged QTc interval (greater than msec), or psychiatric illness/social
situations that would limit compliance with study requirements.

3. Patients with known brain mestastases or a history of seizures are excluded from this
clinical trial.