Protocol Number: 07-C-0203

Title:

A Phase I Study of ABT-888 in Combination with Topotecan Hydrochloride in Adults with Refractory Solid Tumors and Lymphomas

Number:

07-C-0203

Summary:

Background:

-PARP is an enzyme that is involved in the repair of damage to DNA. Levels of the enzyme are higher in tumor cells than in normal cells, and may play a part in resistance to cancer chemotherapy and radiation therapy. ABT-888 is an experimental drug that inhibits PARP and may help to increase the effectiveness of cancer treatments designed to damage DNA in cancer cells.

-Topotecan is a drug approved by the Food and Drug Administration for treating certain cancers.

-This dose escalation study will test the two drugs at successively higher doses in small groups of patients until the highest safe dose is determined.

Objectives:

-To test the safety of the combination of ABT-888 and Topotecan (TPT) and determine the highest dose of each drug that can be safely given to humans. This is the maximum tolerated dose (MTD).

-To learn how the combination of ABT-888 and TPT works in humans and how the body handles the drugs.

-To determine the side effects of the combination of ABT-888 and TPT at the tested doses.

Eligibility:

-Patients with solid tumors, lymphomas and chronic lymphocytic leukemia whose disease has progressed following standard therapy or for whom standard treatments are not available.

Design:

-ABT-888 and TPT are given in 21-day treatment cycles. At the start of the study, TPT is infused through a vein over 30 minutes about a week before cycle 1 starts. Starting on day 1 of cycle 1, ABT-888 is given by mouth twice a day for 7 days. TPT is given through a vein daily for 4 days starting on day 2. After the last dose of ABT-888 day 7, no more treatment is given for the rest of the 21-day cycle.

-For the remaining cycles, ABT-888 is given twice a day by mouth on days 1 to 7 of each cycle, and TPT is given through a vein daily on days 1 to 5 of each cycle.

-The first three to six patients enrolled in the study take the smallest study dose of the drugs. If they do not develop significant adverse side effects, successive small groups of patients take the drug at increasingly higher doses until the MTD is reached. Additional patients enrolled receive the MTD.

-Patients have periodic clinic visits for their TPT infusions and for tests and examinations. Evaluations include measurement of vital signs, physical examinations, blood and urine tests, electrocardiograms and CT or other imaging tests, such as ultrasound or MRI. Tumor biopsies may be requested to study the effects of the drugs on the tumor. Biopsies are optional.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

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 situtations that would limit compliance with study requirements.

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

Special Instructions:

Currently Not Provided

Keywords:

PARP Inhibitor

Advanced Cancer

Combination Therapy

Early Trial

Recruitment Keyword(s):

Cancer

Solid Tumor

Lymphoma

Condition(s):

Solid Tumors

Lymphomas

Investigational Drug(s):

ABT-888

Investigational Device(s):

None

Intervention(s):

Drug: ABT-888

Drug: Topotecan

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s):

Ame JC, Rolli V, Schreiber V, Niedergang C, Apiou F, Decker P, Muller S, Hoger T, Menissier-de Murcia J, de Murcia G. PARP-2, A novel mammalian DNA damage-dependent poly(ADP-ribose) polymerase. J Biol Chem. 1999 Jun 18;274(25):17860-8.

Ame JC, Spenlehauer C, de Murcia G. The PARP superfamily. Bioessays. 2004 Aug;26(8):882-93. Review.

Berger NA, Adams JW, Sikorski GW, Petzold SJ, Shearer WT. Synthesis of DNA and poly(adenosine diphosphate ribose) in normal and chronic lymphocytic leukemia lymphocytes. J Clin Invest. 1978 Jul;62(1):111-8.

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