Clinical trial NCT00062244: Oblimersen in Treating Patients With Relapsed or Refractory Waldenstrom's Macroglobulinemia
Official title: Phase I/II Study of G3139 (Genasense) in Patients With Waldenstrom's Macroglobulinemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Waldenström Macroglobulinemia
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2003-06-06
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This phase I/II trial is studying the side effects and best dose of oblimersen and to see how well it works in treating patients with relapsed or refractory Waldenstrom's macroglobulinemia. Biological therapies such as oblimersen may interfere with the growth of the cancer cells and slow or stop the growth of Waldenstrom's macroglobulinemia.

Detailed description: PRIMARY OBJECTIVES:

I. To determine the maximally tolerated dose (MTD) and recommended dosing for Genasense in patients with relapsed or refractory WM following prior chemotherapy. (Phase I) II. To determine the response rate to Genasense in patients with relapsed or refractory WM following prior chemotherapy.

III. To determine the safety of Genasense in patients with relapsed or refractory WM following prior chemotherapy.

IV. To describe possible clinical benefit from Genasense treatment of relapsed or refractory WM including duration of response, survival, erythropoietin use, improvement in hemoglobin \> 11 g/dl, and Improvement in platelet count \> 100,000/mm\^3.

OUTLINE: This is a multicenter, dose-escalation study.

Phase I: Patients receive oblimersen IV continuously on days 1-7. Treatment repeats every 3 weeks for up to 8 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 1-6 patients receive escalating doses of oblimersen until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity.

Phase II: Patients receive treatment as in phase I at the MTD of oblimersen. Patients are followed every 3 months for 2 years.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of Waldenstrom's macroglobulinemia (WM) confirmed by both of the following:

  * Bone marrow lymphoplasmacytosis with greater than 10% lymphoplasmacytic cells or aggregates, sheets, lymphocytes, plasma cells, or lymphoplasmacytic cells on bone marrow biopsy
  * Measurable disease, defined by quantitative IgM monoclonal protein greater than 1,000 mg/dL
* Symptomatic relapsed or refractory disease requiring therapy, defined by at least 1 of the following:

  * Impaired bone marrow function due to disease infiltration as demonstrated by any of the following:

    * Hemoglobin less than 11 g/dL
    * Requires epoetin alfa therapy to maintain hemoglobin of at least 11 g/dL
    * Platelet count less than 100,000/mm\^3
  * Symptomatic bulky lymphadenopathy
  * Symptoms attributable to hyperviscosity (e.g., nose bleeding, gingival bleeding, or retinal hemorrhage) or serum viscosity level relative to water greater than 4
* Received at least 1 prior chemotherapy regimen which included chlorambucil, cyclophosphamide, fludarabine, cladribine, or pentostatin
* No secondary leukemia or history of antecedent hematologic disorder (e.g., myelodysplasia) prior to initial onset of WM
* Performance status - ECOG 0-2
* Not specified
* See Disease Characteristics
* Absolute neutrophil count at least 1,000/mm\^3\*
* Platelet count at least 50,000/mm\^3\*
* No bleeding disorder
* Bilirubin no greater than 2 times upper limit of normal (ULN)
* AST less than 1.5 times ULN
* Albumin at least 2.5 g/dL
* PT no greater than 1.5 times ULN
* INR no greater than 1.3
* PTT no greater than 1.5 times ULN
* No history of chronic hepatitis or cirrhosis
* Creatinine no greater than 2 times ULN
* No uncontrolled congestive heart failure
* No active symptoms of coronary artery disease, including the following:

  * Uncontrolled arrhythmias
  * Recurrent chest pain despite prophylactic medication
* No New York Heart Association class III or IV heart disease
* No grade 2 or greater cardiovascular signs and symptoms within the past 4 weeks
* HIV negative
* Direct Coombs' test negative
* No autoimmune thrombocytopenia
* No uncontrolled serious infection
* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* Adequate venous access for 7-day continuous infusion of study drug
* Intellectual, emotional, and physical ability to maintain an ambulatory infusion pump
* No other cancer except adequately treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, or other cancer from which the patient has been disease-free for at least 5 years
* No known hypersensitivity to phosphorothioate-containing oligonucleotides
* No uncontrolled seizure disorder
* More than 21 days since prior immunotherapy for WM
* More than 21 days since prior cytokine, biologic, or vaccine therapy for WM
* More than 8 weeks since prior plasmapheresis or plasma exchange
* No prior allogeneic stem cell transplantation
* No concurrent plasmapheresis or plasma exchange
* See Disease Characteristics
* No concurrent corticosteroid therapy
* More than 21 days since prior radiotherapy for WM
* More than 21 days since prior major surgery for WM
* No prior organ allograft
* Recovered from all prior therapy
* More than 21 days since other prior therapy for WM
* No other concurrent investigational therapy
* No concurrent immunosuppressive drugs
* No concurrent therapeutic anticoagulation therapy

Primary outcomes:
measure: Maximum tolerated dose determined by the number of dose-limiting toxicity incidents graded according to CTC standard toxicity (Phase I)
timeFrame: 21 days
Secondary outcomes:
measure: Adverse events that are classified as either possibly, probably, or definitely related to study treatment (Phase II)
timeFrame: Up to 2 years
measure: Proportion of overall confirmed responses (CR + PR) associated with G3139 (Phase II)
timeFrame: 6 months
measure: Time to progression
timeFrame: Time from registration to the time of progression, assessed up to 2 years
measure: Overall survival
timeFrame: Time from registration to death due to any cause, assessed up to 2 years
measure: Duration of response
timeFrame: From the documentation of response until the date of progression, assessed up to 2 years
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic in Arizona
state: Arizona
city: Washington
country: United States
facility: Howard University Hospital
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic in Florida
state: Florida
city: Baltimore
country: United States
facility: University of Maryland Greenebaum Cancer Center
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
Study officials:
affiliation: Mayo Clinic
name: Morie Gertz
role: PRINCIPAL_INVESTIGATOR
References: