Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Registry Information

Alternate Title

ABT-888 and Topotecan Hydrochloride in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Ovarian Epithelial Cancer or Primary Peritoneal Cancer

Basic Trial Information

Objectives

1. To determine the maximum-tolerated dose of ABT-888 and topotecan hydrochloride in patients with advanced solid tumors. (Phase I)
2. To identify any anti-tumor activity of this treatment combination, as assessed by objective response in patients with advanced solid tumors.
3. To provide preliminary view as to difference in response and toxicity based on BRCA mutation status. (Phase I MTD)
4. To determine whether topotecan hydrochloride stimulates ADP-ribose polymer formation in circulating peripheral blood mononuclear cells. (Phase I)
5. To determine whether ABT-888 inhibits basal or topotecan hydrochloride-stimulated ADP-ribose polymer formation. (Phase I)
6. To assess the confirmed response rate of patients with relapsed or refractory ovarian epithelial cancer or primary peritoneal cancer treated with this regimen. (Phase II)
7. To assess the toxicity of this regimen in patients with ovarian epithelial cancer or primary peritoneal cancer. (Phase II)
8. To identify any pharmacokinetic interactions between ABT-888 and topotecan. (Phase II)
9. To determine whether topotecan hydrochloride stimulates ADP-ribose polymer formation in circulating tumor cells and whether ABT-888 modulates this. (Phase II)
10. To assess differences in the toxicity and/or efficacy of this regimen based on BRCA1/2 mutational status. (Phase II)
11. To determine whether pretreatment tumor cell levels of topoisomerase I, poly (ADP-ribose) polymerase, BRCA1, BRCA2, XRCC1, TDP1, P-glycoprotein, or BCRP predict response to this regimen. (Phase II)
12. To identify, in an exploratory manner, any transcriptional profiles that may predict response to this regimen. (Phase II)

Entry Criteria

Disease Characteristics:

• Diagnosis of 1 of the following:
  • Histologically confirmed malignant solid tumor (phase I)
    • Metastatic or unresectable disease
    • Disease for which standard curative measures or other therapy definitely capable of extending life does not exist
  • Histologically confirmed ovarian epithelial or primary peritoneal cancer (phase II)
    • Radiological evidence of recurrence at a previous site of disease OR biopsy-confirmed disease if the site represents a new site of disease
    • Refractory to platinum-based therapy OR relapsed < 1 year after receiving a prior platinum-based regimen

• Measurable disease, defined as ≥ 1 lesion whose longest diameter can be accurately measured as ≥ 2.0 cm with conventional techniques or as ≥ 1.0 cm with spiral CT scan

• No known CNS metastases
  • Brain metastases that have been successfully treated and stable for ≥ 6 months are allowed provided there is no requirement for corticosteroids and there is no seizure activity

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 4 weeks since prior investigational therapy or ancillary therapy considered investigational (i.e., utilized for a non-FDA-approved indication and in the context of a research investigation)
• More than 4 weeks since prior chemotherapy (6 weeks for mitomycin C and nitrosoureas) and recovered
• More than 4 weeks since prior immunotherapy, biologic therapy, or radiotherapy
• No prior radiotherapy to > 25% of bone marrow
• No history of dose reductions for neutropenia or thrombocytopenia with prior chemotherapy
• No more than 2 prior therapeutic regimens for ovarian epithelial cancer or primary peritoneal cancer
  • Prior full dose chemotherapy in conjunction with radiotherapy will be considered prior therapy
  • Prior hormonal therapy (e.g., leuprolide, aromatase inhibitor, or tamoxifen) will be allowed and not included as a prior chemotherapy
• Concurrent hormonal therapy for prostate cancer allowed
• No concurrent specific treatment for a prior malignancy (other than hormonal therapy)
• No concurrent enrollment in any other study involving a pharmacologic agent (e.g., drugs, biologics, immunotherapy approaches, or gene therapy) whether for symptom control or therapeutic intent

Patient Characteristics:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• ANC ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Hemoglobin ≥ 9.0 g/dL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT or AST ≤ 2.5 times ULN (ALT ≤ 3 times ULN or AST ≤ 5 times ULN in the presence of hepatic metastases)
• Creatinine ≤ 1.5 times ULN
• INR ≤ 1.4 (unless receiving therapeutic doses of coumadin)
• PTT ≤ 36 seconds
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Willing to return to Mayo Clinic for follow up
• Willing to provide biologic specimens as required for translational research
• Able to swallow and absorb medication
• No concurrent uncontrolled illness including, but not limited to, any of the following:
  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situation that would limit compliance with study requirements
• No NYHA class III-IV heart disease
• No myocardial infarction within the past 6 months
• No congestive heart failure requiring the use of ongoing maintenance therapy for life-threatening ventricular arrhythmias
• Not immunocompromised (other than that related to the use of corticosteroids)
• No known HIV positivity
• No other active malignancy except for nonmelanoma skin cancer or carcinoma in situ of the cervix
• No known seizure disorder
• No comorbid systemic illness or other severe concurrent disease that, in the judgement of the investigator, would make the patient inappropriate for study entry or interfere significantly with the proper assessment of the safety and toxicity of study treatment

Expected Enrollment

A total of 104 patients (56 for phase I and 48 for phase II) will be accrued for this study.

Outcomes

Toxicity (Phase I)
Confirmed tumor response (Phase II)

Overall survival
Progression-free survival
Duration of response
Time to treatment failure
Poly (ADP-ribose) level
Pharmcokinetic interactions
BRCA1 and BRCA 2 mutation status
Biomarker expression as measured by IHC staining
Gene expression in responders vs non-responders

Outline

Patients receive oral ABT-888 once daily on days 1-3, 8-10, and 15-17*. Patients also receive topotecan hydrochloride IV over 30 minutes on days 2, 9, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

 [Note: *Patients do not receive ABT-888 on days 1-3 during course 2.]

Patients undergo blood and urine sample collection periodically for pharmacokinetic, pharmacogenetic, and other correlative laboratory studies. Patients enrolled in phase II also undergo tumor tissue collection at baseline for biomarker laboratory studies.

After completion of study treatment, patients are followed up every 3-6 months for up to 5 years.

Trial Contact Information

Trial Lead Organizations

Mayo Clinic Cancer Center

Michael Menefee, MD, Principal investigator		Ph: 904-953-7290

U.S.A.
Arizona
	Scottsdale
	Mayo Clinic Scottsdale
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Florida
	Jacksonville
	Mayo Clinic - Jacksonville
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623
Minnesota
	Rochester
	Mayo Clinic Cancer Center
		Clinical Trials Office - All Mayo Clinic Locations	Ph:  507-538-7623

Registry Information
Official Title		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
Trial Start Date		2009-10-29
Trial Completion Date		2012-10-09 (estimated)
Registered in ClinicalTrials.gov		NCT01012817
Date Submitted to PDQ		2009-11-02
Information Last Verified		2012-01-30
NCI Grant/Contract Number		CA066912

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