Clinical trial NCT00550615: Dasatinib in Relapsed or Refractory Non-Hodgkin's Lymphoma
Official title: A Phase I/II Study of Dasatinib in Relapsed or Refractory Non-Hodgkin's Lymphoma (NHL) (BMS Protocol 180129)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Non-Hodgkin's Lymphoma
Keywords: Non-Hodgkins Lymphoma
Relapsed Non Hodgkins Lymphoma
Refractory Non Hodgkins Lymphoma
Dasatinib
Lead sponsor: University of Nebraska
Sponsor class: OTHER
Collaborators: name: Bristol-Myers Squibb
First posted: 2007-10-30
Enrollment: 38
Sex: ALL
Minimum age (years): 19
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary Objective:

* To determine the maximum tolerated dose (MTD) of Dasatinib in relapsed or refractory non-hodgkin's lymphoma (NHL) patients and to determine the safety of Dasatinib in NHL.

Secondary Objectives:

* To assess the complete and overall response rates for all Phase I and Phase II patients and to determine overall survival and event free survival for all Phase I and Phase II patients.
* To assay the levels of kinase activity in NHL specimens and correlate this activity to patient outcomes.

Detailed description: Primary:

* To determine the Maximum Tolerated Dose (MTD) of Dasatinib in relapsed or refractory Non-Hodgkin's lymphoma (NHL) patients and to determine the safety of Dasatinib in NHL

Secondary Objective:

* To assess the complete and overall response rates for all Phase I and Phase II patients and to assay the levels of kinase activity in NHL specimens and correlate this activity to patient outcomes.
* To determine overall survival and event free survival for all Phase I and Phase II patients.

Treatment Plan

This study has two phases of treatment, Phase I and Phase II. The Phase I portion of the trial will consist of a dose escalation plan with 3-6 patients being enrolled into each dose cohort. The doses of Dasatinib used in Phase I are 100 mg, 150 mg, and 200 mg. The dose that is found to be tolerated the best and also has the best treatment results will be used for Phase II. An additional 29 patients will be enrolled into Phase II.

All patients will receive Dasatinib in this study. Dasatinib will be administered orally (by mouth) once daily for 28 day cycles. A cycle will be considered 28 days. Dosing will be continuous with no interruptions, unless instructed to interrupt treatment by the treating physician.

The patient will be restaged after every 2 cycles of therapy, every even cycle. Therapy may continue as long as there are no clinical signs of NHL progressing and the patient is tolerating the treatment with no side effects related to the therapy. If the patient is removed from study for any reason, he/she will be followed for survival until death.

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed diagnosis of non-hodgkin's lymphoma that is recurrent or refractory after at least one prior therapy and for which no other potentially curative therapy is available.
* Subject, age \> or = 19 years
* Performance status (ECOG) 0-2
* Patients must have relapsed or refractory disease after at least one prior systemic therapy, with at least a 3 week interval from the completion of the most recent chemotherapy or radiotherapy regimen. Recover to ≤ grade 1 from all toxicities related to the prior treatments is required.
* Patients must be ineligible or relapsed after an autologous or allogeneic stem cell transplant if clinically appropriate.
* Adequate Laboratory Parameters:

  * ANC ≥ 1000/μL
  * Platelet count ≥ 50,000/μL
  * Total bilirubin \< 2.0 times the institutional upper limit of normal (ULN)
  * Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN
  * Serum creatinine \< 2.0 times the institutional ULN
  * PTT within institutional normal limits
* Ability to take oral medication (dasatinib must be swallowed whole)
* Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (sensitivity \< or = 25IU HCG/L) within 72 hours prior to the start of study drug administration
* Persons of reproductive potential must agree to use an adequate method of contraception throughout treatment and for at least 6 months after study drug is stopped
* Signed written informed consent including HIPAA according to institutional guidelines

Exclusion Criteria:

* No malignancy \[other than the one treated in this study\] which required systemic treatment within the past 3 years.
* Concurrent medical condition which may increase the risk of toxicity, including:

  * Clinically significant pleural or pericardial effusion
  * Clinically-significant coagulation or platelet function disorder (e.g. known von Willebrand's disease)
* Cardiac Symptoms, consider the following:

  * Uncontrolled angina, congestive heart failure or MI within (6 months)
  * Diagnosed congenital long QT syndrome
  * Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes)
  * Prolonged QTc interval on pre-entry electrocardiogram (\> 450 msec)
  * Subjects with hypokalemia or hypomagnesemia if it cannot be corrected
* History of significant bleeding disorder unrelated to cancer, including:

  * Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease)
  * Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)
  * Ongoing or recent (\< or = 3 months) significant gastrointestinal bleeding
* Concomitant Medications, consider the following prohibitions:

  * Drugs that are generally accepted to have a risk of causing Torsades de Pointes including: (Patients must discontinue drug 7 days prior to starting dasatinib.) quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide, dofetilide,erythromycin, clarithromycin, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
  * The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy.
  * Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy
  * Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia.
  * Patient may not be receiving any prohibited CYP3A4 inhibitors
* Women:

  * Are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks 6 months after cessation of study drug
  * Have a positive pregnancy test at baseline
  * Are pregnant or breastfeeding
* Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious) illness

Primary outcomes:
measure: Maximum Tolerated Dose
timeFrame: after 1-28 day cycle of therapy
Secondary outcomes:
measure: Number of Participants With Clinical Response Rates
timeFrame: after 2-28 day cycles of therapy
Other outcomes:
Locations:
city: Omaha
country: United States
facility: University of Nebraska Medical Center, Internal Medicine Section of Oncology/Hematology
state: Nebraska
Study officials:
affiliation: University of Nebraska
name: Julie Vose, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Jemal A, Siegel R, Ward E, Murray T, Xu J, Smigal C, Thun MJ. Cancer statistics, 2006. CA Cancer J Clin. 2006 Mar-Apr;56(2):106-30. doi: 10.3322/canjclin.56.2.106.
citation: Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol. 1998 Aug;16(8):2780-95. doi: 10.1200/JCO.1998.16.8.2780.
citation: SPRYCEL (dasatinib) Tablets Prescribing Information. Bristol-Myers Squibb Company, Princeton, NJ. June 2006
citation: SPRYCEL® (dasatinib) BMS-354825 Bristol-Myers Squibb Investigator Brochure, Version #5, 2006.
citation: SPRYCEL® (dasatinib) BMS-354825 Bristol-Myers Squibb Investigator Brochure, Version #6 in print, 2006.
citation: Sprangers M, Feldhahn N, Herzog S, Hansmann ML, Reppel M, Hescheler J, Jumaa H, Siebert R, Muschen M. The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Oncogene. 2006 Aug 17;25(36):5056-62. doi: 10.1038/sj.onc.1209510. Epub 2006 Mar 27.
citation: Zhu DM, Tibbles HE, Vassilev AO, Uckun FM. SYK and LYN mediate B-cell receptor-independent calcium-induced apoptosis in DT-40 lymphoma B-cells. Leuk Lymphoma. 2002 Nov;43(11):2165-70. doi: 10.1080/1042819021000032935.
citation: Mahadevan D, Spier C, Della Croce K, Miller S, George B, Riley C, Warner S, Grogan TM, Miller TP. Transcript profiling in peripheral T-cell lymphoma, not otherwise specified, and diffuse large B-cell lymphoma identifies distinct tumor profile signatures. Mol Cancer Ther. 2005 Dec;4(12):1867-79. doi: 10.1158/1535-7163.MCT-05-0146.
citation: Thompson MA, Stumph J, Henrickson SE, Rosenwald A, Wang Q, Olson S, Brandt SJ, Roberts J, Zhang X, Shyr Y, Kinney MC. Differential gene expression in anaplastic lymphoma kinase-positive and anaplastic lymphoma kinase-negative anaplastic large cell lymphomas. Hum Pathol. 2005 May;36(5):494-504. doi: 10.1016/j.humpath.2005.03.004.
citation: Hochhaus, A. et al. Dasatinib (SPRYCEL) 50mg or 70mg BID Versus 100mg or 140mg QD in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Resistant or Intolerant to Imatinib: Results of the CA180-034 Study. American Society of Hematology, 2006 Meeting Abstracts, Part 1, Volume 108, Issue 11, November 16, 2006.
citation: Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, Coiffier B, Fisher RI, Hagenbeek A, Zucca E, Rosen ST, Stroobants S, Lister TA, Hoppe RT, Dreyling M, Tobinai K, Vose JM, Connors JM, Federico M, Diehl V; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007 Feb 10;25(5):579-86. doi: 10.1200/JCO.2006.09.2403. Epub 2007 Jan 22.