Clinical trial NCT01536561: Study of Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas and Extended Study to Determine the Safety and Efficacy of Coulter Clone® 131Iodine-B1 Radioimmunotherapy of Advanced Non-Hodgkin's Lymphoma
Official title: Phase I Study of Radiolabeled Monoclonal Antibody Anti-B1 for the Treatment of B-Cell Lymphomas
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma, Non-Hodgkin
Keywords: Tositumomab and/or Iodine I 131 Tositumomab
B-cell non-Hodgkin's lymphoma
Dose-limiting toxicity
Bexxar
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2012-02-22
Enrollment: 59
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: Phase I/II, single-center, dose-escalation study of the safety, pharmacokinetics, dosimetry, and efficacy of TST/I-131 TST for the treatment of patients with chemotherapy-refractory or resistant low-grade, intermediate-grade, or high-grade B-cell lymphoma. Subjects received 1 to 3 dosimetric doses followed by a therapeutic dose of TST/I-131 TST. Study BEX104526 was a follow-up study of the long-term safety and efficacy data from the surviving patients who completed at least 2 years of follow-up following administration of TST/I 131 TST on Study BEX104728.

Dosimetric dose: Subjects received 1 to 3 dosimetric doses of TST/I-131 TST, followed by a therapeutic dose of TST/I-131 TST. Subjects received various doses of unlabeled TST (0, 95 or 475 mg) to determine the dose of unlabeled TST that optimized the radiation dose delivered to the tumor by TST/I-131 TST. The unlabeled TST was followed by 5 milliCurie (mCi) of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance for the subject and the activity (in mCi) of I-131 required to deliver the desired TBD of radiation during the therapeutic dose. Because 475 mg was determined to be the optimal pre-dose of TST in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of TST.

Therapeutic dose: Groups of 3-6 subjects were enrolled at successively higher whole-body radiation dose levels beginning at a total body dose (TBD) of 25 centiGray (cGy). The TBD of each subsequent dose level was escalated by 10 cGy. Subjects who had undergone bone marrow transplantation (BMT) underwent a separate dose escalation (10 cGy TBD increase per dose level) beginning at a TBD level of 65 cGy. The MTD was defined as the highest dose level at which 0/3 or 1/6 subjects experienced dose-limiting toxicity (DLT). DLT was defined as follows:

Any Grade 4 hematologic toxicity (National Cancer Institute \[NCI\] criteria) lasting greater than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade 3 or 4 nonhematologic toxicity Redosing. Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response.

Retreatment. Subjects who achieved partial (PR) or complete response (CR) were considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was administered for the repeat therapeutic dose.

Detailed description: Phase I/II, single-center, dose-escalation study of the safety, pharmacokinetics, dosimetry, and efficacy of TST/I-131 TST for the treatment of patients with chemotherapy-refractory or resistant low-grade, intermediate-grade, or high-grade B-cell lymphoma. Subjects received 1 to 3 dosimetric doses followed by a therapeutic dose of TST/I-131 TST. Study BEX104526 was a follow-up study of the long-term safety and efficacy data from the surviving patients who completed at least 2 years of follow-up following administration of TST/I 131 TST on Study BEX104728.

Dosimetric dose: Subjects received 1 to 3 dosimetric doses of TST/I-131 TST, followed by a therapeutic dose of TST/I-131 TST. Subjects received various doses of unlabeled TST (0, 95 or 475 mg) to determine the dose of unlabeled TST that optimized the radiation dose delivered to the tumor by TST/I-131 TST. The unlabeled TST was followed by 5 milliCurie (mCi) of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance for the subject and the activity (in mCi) of I-131 required to deliver the desired TBD of radiation during the therapeutic dose. Because 475 mg was determined to be the optimal pre-dose of TST in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of TST.

Therapeutic dose: Groups of 3-6 subjects were enrolled at successively higher whole-body radiation dose levels beginning at a total body dose (TBD) of 25 centiGray (cGy). The TBD of each subsequent dose level was escalated by 10 cGy. Subjects who had undergone bone marrow transplantation (BMT) underwent a separate dose escalation (10 cGy TBD increase per dose level) beginning at a TBD level of 65 cGy. The MTD was defined as the highest dose level at which 0/3 or 1/6 subjects experienced dose-limiting toxicity (DLT).

DLT was defined as follows:

Any Grade 4 hematologic toxicity (National Cancer Institute \[NCI\] criteria) lasting greater than 7 days, or Any Grade 3 hematologic toxicity lasting greater than 2 weeks, or Any Grade 3 or 4 nonhematologic toxicity Redosing: Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response.

Retreatment: Subjects who achieved a partial response (PR) or complete response (CR) were considered for retreatment following relapse of their NHL, if progression occurred ≥6 weeks following the therapeutic dose. The original therapeutic dose of TST/I-131 TST was given unless a grade 2 or greater toxicity had been encountered, in which case a reduced dose was administered for the repeat therapeutic dose.

Subjects who completed at least 2 years of follow-up in BEX104728 were enrolled in LTFU Study BEX104526 for continued radiographic response evaluations and safety evaluations every 6 months for years 3 through 5 post-treatment and annually for years 6 through 10 post-treatment. Subjects in BEX104526 were assessed for survival and disease status, including subsequent therapy for NHL, and for long-term safety, including the development of hypothyroidism, myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and any other secondary malignancies. Additionally, subjects were followed for the development of any adverse event(s) (AEs) deemed by the Principal Investigator as being possibly or probably related to a subject's treatment with TST/I-131 TST. Laboratory evaluations, consisting of thyroid stimulating hormone (TSH) level and complete blood cell count with a differential and platelet count, were obtained annually through year 10 post-treatment.

Study assessments included demographic and baseline characteristics; tumor response, duration of response, survival (progression-free survival \[PFS\] and overall survival \[OS\]), adverse events (AEs), incidence of human anti-murine antibody (HAMA), incidence of hypothyroidism, and serious (fatal and non-fatal) adverse events (SAEs).

Dosing;"Dosimetric Doses", Intravenous (IV) administration of unlabeled TST (0, 95 or 475 mg) was administered to determine the dose of unlabeled TST that optimized the radiation dose to the tumor. This was followed by 5 mCi of I-131 TST. Serial whole body sodium iodide scintillation probe counts were obtained daily, for at least 5 days, in order to determine the rate of whole body clearance of radioactivity (residence time). The residence time was used to determine the radioactive clearance from the subject and subsequently the activity (in mCi) of Iodine-131 required to deliver the desired TBD of radiation during the therapeutic dose of TST/I-131 TST. Because 475 mg was determined to be the optimal pre-dose of tositumomab in the first subjects entered, the last 34 subjects received a single dosimetric dose that was preceded by an infusion of 475 mg of tositumomab (Source Data: Listing 13).

"Therapeutic Dose", Groups of 3-6 subjects were treated at successively higher therapeutic whole body radiation doses, beginning at a TBD of 25 cGy. The TBD was escalated in 10 cGy increments in subsequent dose level cohorts until the MTD was achieved. A separate determination of MTD was conducted for subjects who had undergone prior BMT. This was initiated at a TBD of 65 cGy TBD and increased in 10 cGy increments until determination of the MTD. The MTD was defined as the dose at which fewer than 1/3 or 2/6 subjects experienced DLT, i.e. any Grade 4 hematologic toxicity (absolute neutrophil count \[ANC\], platelets, hemoglobin, white blood count \[WBC\] lasting \> 7 days or any Grade 3 hematologic toxicity lasting \> 14 days, as defined in Section 4.1.

Re-Dosing; Subjects who achieved tumor regression were considered for re-dosing, using the original therapeutic dose of TST/I-131 TST, at the time the tumor was no longer shrinking in an attempt to upgrade their response. Patients were not redosed sooner than 6 weeks following a therapeutic dose.

Retreatment (≥6 weeks following therapeutic dose); Subjects who achieved a PR or CR were considered for retreatment following relapse of their NHL. The original therapeutic dose of TST/I-131 TST was given unless a Grade 2 or greater toxicity had been encountered, in which case the dose level immediately below the original dose was administered.

Eligibility criteria: Inclusion Criteria

* Subjects had histologically-confirmed NHL.
* Subjects with low-, intermediate-, or high-grade histologies, according to the International Working Formulation.
* Subjects had relapsed after or had failed to respond to at least 1 prior chemotherapy regimen.
* Subjects had evidence that their tumor tissue expressed the CD20 antigen.

Exclusion Criteria

* ≥25% bone marrow involvement.
* Absolute granulocyte count ≥1500 cells/mm3 or platelet count ≤100,000 platelets/mm3.
* Creatinine ≥2.0 mg/dL, bilirubin ≥2.0 mg/dL.
* Cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within 4 weeks of study entry.
* Active infection, collagen vascular disease, vasculitis, glomerulonephritis, New York Heart Association class II or IV heart disease and/or serious illness.
* Prior external beam radiation therapy such that the maximum tolerated dose level for any normal organ would be exceeded by additional irradiation.
* Pregnancy.
* Allergy to iodine or previous sensitization to mouse protein as documented by positive anti-mouse antibody ELISA test.
* Known brain metastases.

Primary outcomes:
measure: Number of Participants (Par.) During Initial Treatment Exposed to the Indicated Dose Levels of the Therapeutic Dose (TD), Re-dose, and Total Dose (TD + Re-dose)
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Number of Participants During Retreatment Exposed to the Indicated Dose Levels of the TD, Re-dose, and Total Dose (TD + Re-dose)
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Maximum Tolerated Dose (MTD) of TST/I 131 TST Evaluated in the Study
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Tumor/Organ Dosimetry of TST/I 131 TST for All Predoses (Initial Treatment)
timeFrame: Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7
Secondary outcomes:
measure: Tumor/Organ Dosimetry at the Indicated Predoses of 475 mg, 95 mg, and 0 mg (Initial Treatment)
timeFrame: Serial anterior and posterior gamma whole body scans were obtained 1 hour after the administration of the dosimetric dose (on Day 0), and then daily for at least 5 days until Day 7
measure: Number of Participants (Par.) With the Indicated Response as Assessed by the Investigator
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Number of Participants (Par.) With Confirmed Response as Assessed by the Investigator
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Duration of Response for All Unconfirmed Responders (CR, CCR, or PR) as Assessed by the Investigator
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Time to Progression of Disease or Death
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Overall Survival
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Half-life: Initial Half-life (t1/2 Alpha) and Terminal Half-life (t1/2 Beta) of I 131 TST for the Antibody Predose Levels of 0 mg, 95 mg, and 475 mg
timeFrame: Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.
measure: Clearance (CL) of I 131 TST for the Indicated Antibody Predose Levels
timeFrame: Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.
measure: Area Under the Concentration Time Curve (AUC) of I 131 TST for the Indicated Antibody Predose Levels
timeFrame: Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion.
measure: Maximum Blood Concentration (Cmax) of I 131 TST for the Indicated Antibody Predose Levels
timeFrame: Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion
measure: Volume of Distribution at Steady State (Vss) of I 131 TST for the Indicated Antibody Predose Levels
timeFrame: Blood samples were collected at the end of the infusion (Study Day 0) and at 0.5, 1, 2, 4, 12, 24, 36, 48, 72, 96, and 120 hours following the end of the infusion
measure: Number of Participants Who Developed Human Anti-mouse Antibodies (HAMA Postivitiy) After Receiving Tositumomab
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Time to HAMA Positivity From the First Dosimetric Dose (Time From Baseline [Dosimetric Dose] to the First Reported Presence of HAMA)
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Number of Participants With the Indicated Type of Infection
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Time to Nadir for the Indicated Hematologic Laboratory Parameters
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Time to Recovery to Baseline for the Indicated Hematologic Laboratory Parameters
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Nadir Values for the Hematologic Parameters ANC, Platelets, and WBC Count
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
measure: Nadir Values for Hemoglobin, a Hematologic Parameter
timeFrame: Participants who completed at least 2 years of follow-up in Study BEX104728 were invited to enroll in BEX104526 for long-term follow-up. Participants were evaluated in Study BEX104728 and Study BEX104526 for up to 15.6 years.
Other outcomes:
Locations:
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Kaminski MS, Estes J, Zasadny KR, Francis IR, Ross CW, Tuck M, Regan D, Fisher S, Gutierrez J, Kroll S, Stagg R, Tidmarsh G, Wahl RL. Radioimmunotherapy with iodine (131)I tositumomab for relapsed or refractory B-cell non-Hodgkin lymphoma: updated results and long-term follow-up of the University of Michigan experience. Blood. 2000 Aug 15;96(4):1259-66.