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

Alternate Title

ABT-263 in Treating Patients With Relapsed or Refractory Lymphoid Cancer

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Biomarker/Laboratory analysis, Treatment	Active	18 and over	NCI	NCI-07-C-0006 NCI-P7060, ABBOTT-M06-814, NCT00408811

Special Category: NIH Clinical Center trial, NCI Web site featured trial

Objectives

1. Determine the maximum tolerated dose of ABT-263 on a 14/21 day dosing schedule in patients with relapsed or refractory T-cell or B-cell lymphoid malignancy. (Phase Ib)
2. Determine the maximum tolerated dose of ABT-263 on a 21/21 day continuous dosing schedule in these patients. (Phase Ib)
3. Determine the dose-limiting toxicity of this drug on a 14/21 day dosing schedule in these patients. (Phase Ib)
4. Determine the dose-limiting toxicity of this drug on a 21/21 day dosing schedule in these patients. (Phase Ib)
5. Determine the recommended Phase 2 dose (RPTD) and schedule of of ABT-263 in these patients.
6. Determine the pharmacokinetic profile of this drug in these patients. (Phase I)
7. Determine the effect of food on bioavailability of this drug in these patients. (Phase Ia)
8. Determine the safety of this drug at the RPTD and schedule in these patients.
9. Determine, preliminarily, the efficacy of this drug, including biomarkers, in these patients. (Phase II)

Entry Criteria

Disease Characteristics:

• Histologically confirmed B- or T-cell lymphoid malignancies meeting the following criteria*:
  • Refractory OR progressive disease
  • Received at least 1 prior chemotherapy treatment for a lymphoid malignancy



• No prior or concurrent diagnosis of the following*:
  • Post-transplant lymphoproliferative disease
  • Burkitt's-like lymphoma
  • Lymphoblastic lymphoma/leukemia
  • Multiple myeloma
  • HIV-associated lymphoma



• Histologically confirmed follicular lymphoma meeting the following criteria**:
  • No more than 4 prior conventional chemotherapy regimens
  • Measurable disease or lesions with ≥ 1 disease site meeting the following criteria:
    • Measurable disease with cytologically and/or histologically confirmed neoplastic nature of solitary lesions
    • Lesions that can be accurately measured in ≥ 1 dimension with the longest diameter ≥ 10 mm



• At least 1 of the following available for pharmacodynamic analyses**:
  • Core-needle biopsy of malignant lymph node obtained at screening
  • Bone marrow aspirate or core obtained at screening (positive for lymphoma)
  • Archived tumor tissue with no intervening treatment since biopsy (e.g., from debulking, tissue obtained at relapse, or bone marrow sample)



• Patients with chronic lymphocytic leukemia and/or small lymphocytic lymphoma must have measurable disease by the 1996 National Cancer Institute Working Group Guidelines for Chronic Lymphocytic Leukemia (NCI-WG) criteria with CT imaging**



• Must have documented brain imaging by MRI or CT scan negative for subdural or epidural hematoma ≤ 28 days prior to study treatment when clinically indicated (e.g., patients over the age of 70 years)



• No prior or concurrent cancer-related CNS disease (lymphoid or nonlymphoid)

 [Note: *Phase I]

 [Note: **Phase II]

Prior/Concurrent Therapy:

• See Disease Characteristics
• More than 3 days since prior consumption of grapefruit or grapefruit products
• More than 3 months since prior rituximab therapy, except for patients who have objective disease progression after rituximab treatment (Phase II)
• More than 7 days since prior steroid therapy
• More than 28 days since prior and no other concurrent anticancer therapy, including the following:
  • Chemotherapy
  • Immunotherapy
  • Radiotherapy
  • Hormonal therapy
  • Biologic therapy
  • Other investigational therapy
• If taking selective serotonin reuptake inhibitor antidepressants (e.g., fluoxetine), must be on stable dose for at least 21 days prior to study drug
• No prior or concurrent allogeneic or autologous stem cell transplantation
• No concurrent anticoagulation therapy or other drugs that affect platelet function
• No concurrent surgery
• No concurrent use of the following medications:
  • Anticoagulants (e.g., warfarin, clopidogrel bisulfate, acetylsalicylic acid, ibuprofen, tirofiban)
  • CYP2C8 inhibitors (e.g., glitazones and statins)
  • CYP2C9 inhibitors (e.g., quinidine, metronidazole, phenytoin, tolbutamide)
  • CYP3A inhibitors (e.g., ketoconazole, clarithromycin)
  • Disulfiram
• Concurrent low-dose aspirin (i.e. maximum of 100 mg/day) allowed provided circulating platelet count has been ≥ 50,000/mm³ for two courses of ABT-263

Patient Characteristics:

• ECOG performance status 0-1
• Absolute neutrophil count ≥ 1,500/μL
• Platelet count ≥ 125,000/mm³
• Hemoglobin ≥ 10.0 g/dL
• Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 50 mL/min
• AST and ALT ≤ 1.5 times upper limit of normal (ULN) (2.5 times ULN for patients with hepatic involvement)
• Bilirubin ≤ 1.5 times ULN (unless Gilbert's syndrome is present)
• aPTT, PT, and INR normal
• No nonchemotherapy-induced, thrombocytopenic-associated bleeding within the past year
• No underlying predisposition to bleeding
• Not currently exhibiting signs of bleeding
• No history of platelet autoantibodies or autoimmune phenomena, including the following:
  • Immune thrombocytopenic purpura
  • Autoimmune hemolytic anemia
• No active peptic ulcer disease or other hemorrhagic esophagitis/gastritis
• No significant history of disease in any of the following body systems that, in the opinion of the investigator, would adversely affect study participation:
  • Cardiac
  • Renal
  • Neurologic
  • Psychiatric
  • Endocrinologic
  • Metabolic
  • Immunologic
  • Hepatic
• No other prior or concurrent active malignancy within the past 3 years except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or malignancy confined and surgically resected with curative intent
• No other clinically significant uncontrolled conditions, including, but not limited to, the following:
  • Active systemic fungal infection
  • Fever and neutropenia within the past week
• No HIV positivity
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception

Expected Enrollment

Outcomes

Safety
Maximum tolerated dose (Phase I)
Progression-free survival (Phase II)
Objective response rate (Phase II)
Time to tumor progression (Phase II)
Overall survival (Phase II)
Duration of overall survival (Phase II)
ECOG performance status (Phase II)
Response to treatment (Phase II)

Outline

This is a multicenter, phase I, dose-escalation study followed by an open-label, phase II study.

• Phase I: This is the dose-escalation portion for the study.
  • Phase Ia: Patients receive oral ABT-263 once daily on days -3 and 1-14 of course 1 and on days 1-14 of all subsequent courses.
  
  
  
  • Phase Ib: Patients receive oral ABT-263 once daily on days 1-21.
  
  
  

  Courses repeat every 21 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

  Cohorts of 3-6 patients receive escalating doses of ABT-263 until the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD) is determined. The MTD or RPTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

  Blood samples are acquired periodically during study treatment. Samples are examined for pharmacokinetics and proteomics.




• Phase II: Patients receive oral ABT-263 at the MTD or RPTD determined in phase I.

  Core-needle biopsies are acquired prior to treatment, during, and after completion of study treatment. Samples are examined by immunohistochemistry and fluorescent in situ hybridization (FISH) for pharmacogenetic and chromosomal translocation analyses.

After completion of study treatment, patients are followed at 21 and 30 days and periodically for 2 years.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Wyndham Wilson, MD, PhD, Principal investigator		Ph: 301-435-2415

U.S.A.
Maryland
	Bethesda
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937

Related Information

Web site for additional information
Featured trial article

Registry Information
Official Title		A Phase 1/2a Study Evaluating the Safety, Pharmacokinetics and Efficacy of ABT-263 in Subjects with Relapsed or Refractory Lymphoid Malignancies
Trial Start Date		2006-10-01
Trial Completion Date		2010-10-01 (estimated)
Registered in ClinicalTrials.gov		NCT00408811
Date Submitted to PDQ		2006-10-18
Information Last Verified		2009-06-21

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