Clinical trial NCT00933335: Study of Safety and Efficacy of a Sequential Regimen Consisting of Three Cycles of Fludarabine Followed by Tositumomab and Iodine I 131 Tositumomab
Official title: Fludarabine Monophosphate Followed by Iodine I 131 Tositumomab for Untreated Low-grade and Follicular Non-Hodgkin's Lymphoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Lymphoma, Non-Hodgkin
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2009-07-07
Enrollment: 38
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 is a single-arm, single institution, phase II study of fludarabine monophosphate followed by Iodine I 131 Tositumomab for patients with previously untreated, advanced-stage (stage III or IV) low-grade, transformed low-grade and follicular non-Hodgkin's lymphoma. The primary objective of the study will be to evaluate the safety of this treatment combination and the secondary endpoint will be to evaluate efficacy.


Eligibility criteria: Inclusion Criteria:

* Patients must be age 18 years or older.
* Patients must have a histologically-confirmed diagnosis of low-grade or follicular non-Hodgkin's B-cell lymphoma.
* Patients must have Ann Arbor stage III or IV extent of disease after completing staging.
* Patients must have bi-dimensionally measurable disease. At least one lesion must have both perpendicular diameters \> 2 cm.
* Patients must have evidence that their tumor expresses the CD20 antigen by immunohistochemistry or flow cytometry.
* Patients must have no previous treatment for NHL.
* Patients must have a Karnofsky performance status of at least 60% and an anticipated survival of at least 3 months.
* Patients must have absolute granulocyte count greater than or equal to 1500 cells/mm3 and a platelet count \> 100,000 cells/mm3 within 14 days of study entry and not require sustained support with hematopoietic cytokines or transfusion of blood products.
* Patients must have adequate renal and hepatic function.
* Patients must sign IRB approved informed consent form(s) prior to study entry.

Exclusion Criteria:

* Patients who received systemic steroids within 1 week of study entry, except patients on maintenance steroid therapy for a non-cancerous disease.
* Patients with evidence of active infection requiring intravenous antibiotics at the time of study entry.
* Patients with New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation.
* Patients with known HIV Infection.
* Patients with known brain or leptomeningeal metastases.
* Patients who are pregnant or nursing. Patients of childbearing potential must undergo a pregnancy test at screening and on the day fludarabine treatment is started. Treatment is not to be administered until a negative result is obtained. Males and females must agree to use effective contraception for 6 months following the iodine I 131 tositumomab therapy.
* Patients with prior malignancy other than lymphoma, except for adequately-treated skin cancer in situ cervical cancer, or other cancer for which the patient has been disease-free for 5 years.
* Patients with hypersensitivity to fludarabine.
* Patients who are receiving either approved or non-approved (through another protocol) anti-cancer drugs or biologics.
* Patients who are HAMA positive.
* Patients with previous allergic reaction to iodine. This does not include reacting to intravenous iodine containing contrast materials.

Inclusion Criteria for Iodine I 131 Tositumomab Therapy

* Patients who completed 3 cycles of fludarabine.
* Patients must have absolute granulocyte count ≥ to 1500/mm3, platelet count of ≥ 100,000/mm3 (≥ 150,000/mm3 if \> 25% bone marrow involvement at restaging), and not require sustained support with hematopoietic cytokines or transfusions with blood products.
* Patients must have adequate renal and hepatic function.

Exclusion criteria for Antibody Therapy

* Patients with active obstructive hydronephrosis.
* Patients with evidence of active infection requiring intravenous antibiotics.
* Patients who are pregnant.

Primary outcomes:
measure: Number of Participants With Any Adverse Event (AE)
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Treatment-related Adverse Event (TRAE)
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Grade 3 or Grade 4 Adverse Event
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Treatment-related Grade 3 or Grade 4 Adverse Event
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Serious Adverse Event (SAE)
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Treatment-related SAE
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With the Indicated Grade 3 and Grade 4 AEs
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With the Indicated Treatment-related AEs Experienced by at Least 10% of Participants in the Combined Regimen
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants Who Were Negative for Human Anti-murine Antibodies (HAMA) at Baseline (Study Entry) But Positive or Negative at Weeks 12 and 25 and at Months 12, 18, and 24
timeFrame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose
measure: Time to HAMA Positivity From the First TST/I 131 TST Dosimetric Dose for the Participants Achieving HAMA Positivity
timeFrame: Day 1 to Day 730 (24 Months) after receiving the dosimetric dose
measure: Number of Participants With Elevated Thyroid-Stimulating Hormone (TSH) Levels at Baseline (Study Entry) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512
timeFrame: Baseline (Week -16) and Weeks 25, 52, 78, 104, 130, 156, 182, 208, 234, 260, 286, 312, 364, 416, 468, and 512
measure: Number of Participants With Thyroid Medication Use Prior to the Therapeutic Dose
timeFrame: Baseline (study entry; Week -16) and Week 2 to Week 3 (prior to the therapeutic dose)
measure: Time to Nadir for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets
timeFrame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
measure: Nadir Values for Absolute Neutrophil Count (ANC)
timeFrame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
measure: Nadir Values for Hemoglobin
timeFrame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
measure: Nadir Values for Platelet Count
timeFrame: up to 120 days following the therapeutic dose (or dosimetric dose for participants who did not receive the therapeutic dose)
measure: Number of Participants With Any Grade 3 or Grade 4 Toxicity (AE) for Hematological Parameters (Absolute Neutrophil Count [ANC], Hemoglobin, and Platelets)
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Duration of Any Grade 3 or Grade 4 Toxicity for Hematological Parameters: Absolute Neutrophil Count (ANC), Hemoglobin, and Platelets
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST dosimetric dose (DD) (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants With Any Infection at Week 16 Post-Fludarabine Treatment and Week 13 Post-TST Treatment Detected by Laboratory Culture of Participant Sample or Investigator Report
timeFrame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
measure: Number of the Indicated Type of Infection Reported by Investigator Based on Laboratory Testing at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
timeFrame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
measure: Number of Participants With a Culture Obtained for Infection at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
timeFrame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
measure: Number of Participants With Positive Culture Results for Infections at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
timeFrame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
measure: Number of Participants With an Anti-infective Administered at Week 16 Post-Fludarabine (Fl) Treatment and Week 13 Post-TST Treatment
timeFrame: Week 16 Post-Fludarabine Treatment (Week -16 to Week 0); Week 13 Post-TST Treatment (Week 1 to Week 13)
measure: Number of Participants Who Received Any Supportive Care After Fludarabine Treatment and After TST Treatment
timeFrame: First day of fludarabine cycle 1 to day prior to TST and iodine I 131 TST DD (Week -16 to Week 1); Day of TST and iodine I 131 TST DD to database release (Week 1 to Week 520)
measure: Number of Participants Receiving the Indicated Type of Supportive Care After Fludarabine Treatment and After TST Treatment
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
Secondary outcomes:
measure: Number of Participants With the Investigator-assessed Confirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Number of Participants With the Investigator-assessed Unconfirmed Responses of Complete Response (CR), Clinical Complete Response (CCR), and Partial Response (PR)
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Number of Participants With Progression of Disease
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Duration of Response for All Confirmed Responders
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Number of Participants With Progressive Disease (PD)
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Time to Disease Progression or Death
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Number of Participants With a Treatment Failure
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Time to Treatment Failure
timeFrame: First day of fludarabine cycle 1 to day prior to TST/I 131 TST dosimetric dose (Week -16 to Week 1); Day of TST/I 131 TST dosimetric dose to database release (Week 1 to Week 520)
measure: Number of Participants Who Died During Their Participation in the Study
timeFrame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520)
measure: Time to Death of Participants During Their Participation in the Study
timeFrame: Day of TST/I 131 TST dosimetric dose to date of database release (Week 1 to Week 520); First day of fludarabine cycle 1 to date of database release (Week -16 to Week 520)
Other outcomes:
Locations:
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Leonard JP, Coleman M, Kostakoglu L, Chadburn A, Cesarman E, Furman RR, Schuster MW, Niesvizky R, Muss D, Fiore J, Kroll S, Tidmarsh G, Vallabhajosula S, Goldsmith SJ. Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma. J Clin Oncol. 2005 Aug 20;23(24):5696-704. doi: 10.1200/JCO.2005.14.803.