Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outline
Published Results
Related Publications
Trial Contact Information

Alternate Title

COL-3 in Treating Patients With Refractory Metastatic Solid Tumors or Lymphoma

Basic Trial Information

Phase Type Status Age Sponsor Protocol IDs Phase I Treatment Completed 18 and over NCI NCI-98-C-0015F MB-396, NCI-T97-0082, T97-0082

Objectives

I. Characterize the pharmacokinetic profile of COL-3 and determine whether any 
pharmacodynamic correlations can be made between plasma concentrations and 
clinical activity, biological activity, and toxicity in patients with 
refractory metastatic solid tumors or lymphoma.

II. Determine the maximum tolerated dose of COL-3 in these patients.

III. Characterize the toxic effect profile of COL-3, both acute complications 
and after prolonged therapy.

IV. Evaluate the correlation between a bioassay using a rat model system with 
plasma concentrations of COL-3, clinical outcome, and changes in biological 
endpoints.

V. Assess the clinical importance of several biological endpoints and the 
impact of COL-3 on biomarkers.

Entry Criteria

Disease Characteristics:

Histologically proven refractory metastatic solid tumors or lymphoma
 Bone scan or CT scan evidence of metastatic disease
  Patients with tumor marker evidence of disease only not eligible

Disease progression must be documented by at least one of the following:
  Two consecutively rising tumor markers
  At least one new metastatic deposit on Tc-99 bone scintigraphy
  Progression of soft tissue metastases
  Development of new area of malignant disease (measurable or evaluable) 

Patients with metastatic melanoma, non-small cell lung cancer, and renal cell
carcinoma are eligible without prior therapy

No brain metastases

No primary CNS malignancies

Prior/Concurrent Therapy:

Biologic therapy:
 At least 4 weeks since biologic therapy and recovered
 No concurrent biologic therapy

Chemotherapy:
 At least 4 weeks since chemotherapy and recovered
 At least 6 weeks since nitrosoureas, mitomycin, or carboplatin
 At least 3 months since suramin 
 No concurrent chemotherapy

Endocrine therapy:
 At least 4 weeks since hormonal therapy and recovered
 Concurrent luteinizing hormone releasing hormone (LHRH) agonist for prostate
  cancer patients (unless orchiectomy has been performed) but must have failed
  antiandrogen withdrawal

Radiotherapy:
 At least 4 weeks since radiotherapy and recovered
 No concurrent radiotherapy

Surgery:
 Recovered from prior surgery 

Other:
 No concurrent anticonvulsant therapies (phenobarbital or phenytoin)
 No concurrent rifampin

Patient Characteristics:

Age:
 18 and over

Performance status:
 ECOG 0-2

Life expectancy:
 Greater than 3 months

Hematopoietic:
 Absolute granulocyte count at least 1,500/mm3
 Hemoglobin at least 9.0 g/dL
 Platelet count at least 120,000/mm3

Hepatic:
 Bilirubin normal
 ALT or AST less than 2.5 times upper limit of normal
  
Renal:
 Creatinine no greater than 1.5 mg/dL (if greater than 1.5 mg/dL, obtain 24
  hour urine collection)
 Creatinine clearance greater than 60 mL/min

Cardiovascular:
 No history of unstable angina pectoris
 No myocardial infarction within 6 months of study
 No New York Heart Association class II-IV congestive heart failure
 
Pulmonary:
 No chronic obstructive lung disease requiring oxygen
 
Other:
 Not HIV positive
 Not pregnant or nursing
 Negative pregnancy test
 Effective contraception must be used during and up to 2 months after study
 Patients with prostate cancer who have not undergone castration must have
  concurrent LHRH 
 No acute illness or serious untreated infection
 No uncontrolled seizures 

Expected Enrollment

A maximum of 35 patients will be accrued for this study.

Outline

This is a dose escalation study.

Patients receive an oral test dose of COL-3 for course 1, followed by 28 days 
of oral COL-3 administered 5-24 days after test dose. Course 2 and all 
subsequent courses are 28 days. At least 1-3 patients must complete 28 days of 
oral COL-3, before dose escalation can proceed.

Maximum tolerated dose (MTD) is defined as the highest dose level at which 
fewer than 2 of 6 patients treated for at least 28 days did not experience 
grade 3 or greater nonhematologic toxicity or grade 4 or greater hematologic 
toxicity.

Patients remain on COL-3 until disease progression or unacceptable toxic 
effects are observed.

Patients are followed at approximately 2 weeks.

Ghate JV, Turner ML, Rudek MA, et al.: Drug-induced lupus associated with COL-3: report of 3 cases. Arch Dermatol 137 (4): 471-4, 2001.[PUBMED Abstract]

Rudek MA, Figg WD, Dyer V, et al.: Phase I clinical trial of oral COL-3, a matrix metalloproteinase inhibitor, in patients with refractory metastatic cancer. J Clin Oncol 19 (2): 584-92, 2001.[PUBMED Abstract]

Rudek MA, Horne M, Figg WD, et al.: Reversible sideroblastic anemia associated with the tetracycline analogue COL-3. Am J Hematol 67 (1): 51-3, 2001.[PUBMED Abstract]

Rudek MA: Phase I clinical trial of Col-3, matrix metalloproteinase inhibitor. [Abstract] Technical Reports 5 (9): 12, 2000. Available online. Last accessed April 22, 2004.

Rudek MA, March CL, Bauer KS Jr, et al.: High-performance liquid chromatography with mass spectrometry detection for quantitating COL-3, a chemically modified tetracycline, in human plasma. J Pharm Biomed Anal 22 (6): 1003-14, 2000.[PUBMED Abstract]

Lush RM, Rudek MA, Figg WD: Review of Three New Agents That Target Angiogenesis, Matrix Metalloproteinases, and Cyclin-Dependent Kinases. Cancer Control 6 (5): 459-465, 1999.[PUBMED Abstract]

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

William Dahut, MD, Protocol chair		Ph: 301-435-8183 Email: dahutw@mail.nih.gov