3-AP and Gemcitabine in Treating Patients With Advanced Solid Tumors or Lymphoma

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

Conditions: Primary Central Nervous System Hodgkin Lymphoma; Stage IV Small Lymphocytic Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Splenic Marginal Zone Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Stage III Grade 3 Follicular Lymphoma; Small Intestine Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Recurrent Mantle Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Waldenström Macroglobulinemia; Stage III Adult Diffuse Large Cell Lymphoma; Recurrent Small Lymphocytic Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Burkitt Lymphoma; Stage III Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Recurrent Adult Hodgkin Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult T-cell Leukemia/Lymphoma; Anaplastic Large Cell Lymphoma; Stage IV Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage III Mycosis Fungoides/Sezary Syndrome; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Stage IV Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Intraocular Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Unspecified Adult Solid Tumor, Protocol Specific; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Mantle Cell Lymphoma; Primary Central Nervous System Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Stage IV Grade 1 Follicular Lymphoma

Treatments: Drug: gemcitabine hydrochloride; Drug: triapine

Study type: Interventional

Funder types: NIH

Identifiers

NCT00293345

OSU 05016 (Other Identifier)

NCI-7043

U01CA076576 (U.S. NIH Grant/Contract)

NCI-2009-00119 (Registry Identifier)

OSU-2005C0031

7043 (Other Identifier)

CDR0000455043

Details and patient eligibility

About

This phase I trial is studying the best dose of 3-AP and the side effects of giving 3-AP together with gemcitabine in treating patients with advanced solid tumors or lymphoma. Drugs used in chemotherapy, such as 3-AP and gemcitabine (GEM), work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. 3-AP may help gemcitabine kill more cancer cells by making the cells more sensitive to the drug. 3-AP may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Full description

PRIMARY OBJECTIVES:

I. To determine the maximal tolerable dose (MTD) of 3-AP administered as a 24 hour infusion in combination with and fixed-dose gemcitabine hydrochloride (GEM) in patients with advanced solid tumors or lymphomas.

SECONDARY OBJECTIVES:

I. To define the qualitative and quantitative toxicities of the 3-AP/GEM combination in regard to organ specificity, time course, predictability, and reversibility.

II. To document the therapeutic response of this combination in those patients when possible.

III. To measure deoxycytidine triphosphate (dCTP) levels in peripheral blood mononuclear cells (PBMCs) before and after treatment at specified times and try to correlate findings to activity and toxicity of 3-AP.

IV. To perform limited pharmacokinetic analysis.

OUTLINE: This is a dose-escalation study of 3-AP (Triapine®).Patients receive 3-AP (Triapine®) IV over 24 hours followed by gemcitabine hydrochloride IV over 100-125 minutes on days 1 and 8. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

Patients achieving complete response (CR) receive 1 additional course of therapy beyond documented CR.Cohorts of 3-6 patients receive escalating doses of 3-AP (Triapine®) until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.After completion of study treatment, patients are followed periodically for 2 years.

Enrollment: 30 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically or cytologically confirmed advanced solid tumors or lymphoma

  • Disease considered incurable using standard treatment

• ECOG performance status ≤ 2

• Life expectancy > 12 weeks

• WBC ≥ 3,000/mm^3

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• Total bilirubin normal

• AST/ALT ≤ 2.5 times upper limit of normal

• Creatinine normal OR creatinine clearance ≥ 60 mL/min

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception prior to and during study treatment

• No history of allergic reactions attributed to compounds of similar chemical or biologic composition to 3-AP (Triapine®) and/or gemcitabine hydrochloride

• No known glucose-6-phosphate dehydrogenase (G6PD) deficiency

• No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements

• No pulmonary disease (e.g., dyspnea at rest, supplemental oxygen requirement, or baseline oxygen saturation < 92%)

• Prior gemcitabine hydrochloride allowed if given as a standard 30-minute infusion

  • At least 4 weeks since prior gemcitabine hydrochloride

• Patient may have received < 2 lines of chemotherapy in the metastatic setting

• No prior 3-AP (Triapine®) or fixed-dose gemcitabine hydrochloride

• At least 6 weeks since prior nitrosoureas or mitomycin C

• More than 3 weeks since prior radiotherapy

• No other concurrent investigational agents

• No concurrent combination antiretroviral therapy in HIV-positive patients

• No other concurrent anticancer agents or therapies

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

---

30 participants in 1 patient group

Treatment (gemcitabine hydrochloride, triapine)

Experimental group

Description:

Patients receive 3-AP (Triapineî) IV over 24 hours followed by gemcitabine hydrochloride IV over 100-125 minutes on days 1 and 8. Treatment repeats every 3 weeks for 12 courses in the absence of disease progression or unacceptable toxicity.

Treatment:

Drug: triapine

Drug: gemcitabine hydrochloride