Phase II a Randomized Study of Iodine-131 Anti-b1 Antibody Versus Anti-b1 Antibody in Chemotherapy-relapsed/Refractory Low-grade or Transformed Low-grade Non-Hodgkin's Lymphoma (NHL)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 78
- 主要终点
- Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator
研究概览
简要总结
Subjects were randomized to receive either tositumomab (Anti-B1 Antibody) and iodine I 131 tositumomab (Arm A) or unlabeled tositumomab (Arm B). Subjects randomized to Arm B were allowed to cross over and receive I 131 tositumomab once their disease had progressed as long as they still fulfilled the protocol entry criteria (except for exclusion criterion 12, prior monoclonal antibody therapy) and were human anti-murine antibody (HAMA) negative. Study endpoint assessments of response were conducted by a Masked Independent Randomized Radiographic and Oncologic Review (MIRROR) panel and the Study Investigators' assessments of safety and survival. Subjects who completed at least two years of follow-up in Protocol BEX104515 (formerly Corixa Protocol RIT-II-002) were enrolled in long term follow-up Protocol BEX104526 (formerly Corixa Protocol CCBX001-051), an administrative protocol, 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, disease status, subsequent therapy for NHL, and long-term safety, including the use of thyroid medication, development of hypothyroidism, human anti murine antibody (HAMA), myelodysplastic syndrome, acute myelogenous leukemia, and all other secondary malignancies. Additionally, subjects were followed for the development of any adverse event(s) deemed by the Principal Investigator as being possibly or probably related to a subject's previous treatment with Iodine I-131 tositumomab. Laboratory evaluations consisting of a thyroid stimulating hormone level and a complete blood cell count, with a differential and platelet count, were obtained annually through year 10 post-treatment.
Dosimetric Dose: Subjects received 450 mg of tositumomab IV followed by 5.0 mCi of Iodine I-131 and 35 mg of tositumomab. Following the dosimetric dose, whole body dosimetry was performed on each subject using a total body gamma camera. Whole body anterior and posterior whole body images were obtained at the following timepoints.
- Within one hour of infusion of the dosimetric dose and prior to urination
- 2-4 days after infusion of the dosimetric dose, following urination
- 6-7 days after infusion of the dosimetric dose, following urination Therapeutic Dose: The total body residence time, derived from total body gamma camera counts obtained at the 3 time points, was used to calculate the iodine-131 activity (mCi) to be administered to deliver the therapeutic total body irradiation dose of 65 or 75 cGy. The therapeutic step was administered 7-14 days after the dosimetric step and consisted of tositumomab 450 mg followed by an activity (mCi) of iodine-131 calculated to deliver 75 cGy or 65 cGy of total body irradiation, depending on platelet count, and 35 mg of tositumomab.
For subjects with ≥150,000 platelets/mm3, the recommended dose was the activity of iodine-131 calculated to deliver 75 cGy of total body irradiation; for subjects with NCI Grade 1 thrombocytopenia (platelet counts ≥100,000 but <150,000 platelets/mm3), the recommended dose was the activity of iodine-131 calculated to deliver 65 cGy of total body irradiation.
详细描述
This is a Phase II randomized, controlled, two-arm, open-label, multicenter study comparing the safety and efficacy of tositumomab and iodine I 131 tositumomab to tositumomab for the treatment of chemotherapy-relapsed or refractory low-grade or transformed low-grade B-cell NHL.
Treatment Arm A: Subject will undergo 2 phases of study. In the first phase, termed "dosimetric dose", subjects will receive tositumomab (450 mg) followed by tositumomab (35 mg) that has been trace labeled with 5mCi) Iodine-131 tositumomab. Whole body gamma camera scans will be obtained on day 0, day 2, 3, or 4, and day 6 or 7 following the dosimetric dose. Using the dosimetric data from three imaging time points, a subject-specific dose of iodine I 131 tositumomab to deliver the desired total body dose of radiotherapy will be calculated. In the second phase of the study, termed "therapeutic dose", subjects will receive unlabeled tositumomab (450mg) followed by iodine tositumomab (35mg) labeled with the subject-specific dose of iodine I-131 to deliver a whole body dose of 75 cGy to subjects. Subjects with platelet counts of 100,001 - 149,999 cells/mm3, will receive 65 cGy and subjects who are obese will be doses based on 137% of their lean body mass. Subjects will be treated with either saturated solution potassium iodide (SSKI), Lugol's solution, or potassium iodide tablets starting at least 24 hours prior to the first infusion of the Iodine-131 tositumomab (i.e., the dosimetric dose) and continuing for 14 days following the last infusion of radiolabeled tositumomab (i.e., the therapeutic dose).
Treatment Arm B: Subjects will receive the same amount of unlabeled tositumomab (450 + 35 mg) administered over the same time-frame as Arm A on the study Days 0 and 7 (the day 7 dose may be delayed but no longer than 14 days after the first dose).
Crossover treatment Arm B: Subjects in Arm B may crossover and receive Iodine-131 tositumomab following progression of their lymphoma if they still fulfill the protocol inclusion exclusion criteria (except exclusion criteria#12) and are HAMA-negative.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histologically confirmed low-grade or transformed NHL with evaluable, measurable disease
- •Tumor had to express CD20 antigen
- •One to three prior chemotherapy regimens
- •Karnofsky performance score ≥60% and anticipated survival ≥3 months
- •Absolute neutrophil count (ANC) >1500/mm3 and platelet count >100,000/mm3
- •Adequate renal and hepatic function
- •18 years of age or older.
- •Written informed consent and sign an IRB-approved Informed consent from prior to study entry.
排除标准
- •More than an average of 25% of the intratrabecular marrow space involved by lymphoma in bone marrow biopsy specimens as assessed microscopically within 42 days of study entry. Bilateral posterior iliac crest core biopsies are required if the percentage of intratrabecular space involved exceeds 10% on a unilateral biopsy. The mean of bilateral biopsies must be no more than 25%.
- •Received cytotoxic chemotherapy, radiation therapy, immunosuppressants, or cytokine treatment within FOUR weeks prior to study entry (6 weeks of nitrosourea compounds) or who exhibit persistent clinical evidence of toxicity. The use of steroids must be discontinued at least 1 week prior to study entry.
- •Have undergone prior stem cell transplant.
- •Active obstructive hydronephrosis.
- •Evidence of active infection requiring intravenous antibiotics at the time of study entry.
- •New York Heart Association class III or IV heart disease or other serious illness that would preclude evaluation.
- •Prior malignancy other than lymphoma, except for adequately-treated skin cancer, in situ cervical cancer, or other cancer for which subject has been disease-free for 5 years.
- •Known HIV infection.
- •Known brain or leptomeningeal metastases.
- •Pregnant or nursing. Subjects of childbearing potential must undergo pregnancy test within 7 days of study entry and antibody is not to be administered until a negative result is obtained. For those subjects in Arm B, the pregnancy test must be repeated within 7 days of crossover. Male and female must agree to use effective contraception for 6 months following the therapeutic dose, as applicable.
- •Previous allergic reactions to iodine. This does not include reactions to intravenous iodine-containing contrast materials.
- •Previously given any monoclonal or polyclonal antibodies of any non-human species for either diagnostic or therapeutic purpose. This includes engineered chimeric and humanized antibodies.
- •Previously received radioimmunotherapy .
- •Progressive disease within one year of irradiation arising in a field that has been previously irradiated with >3500 cGy.
- •de novo intermediate or high-grade lymphoma.
- •Received >3 chemotherapy regimens (different or identical agents).
结局指标
主要结局
Number of Participants With Confirmed Complete Response (CR) as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.
Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue. The extent of disease must be unchanged or decreased upon follow-up evaluations. If the extent of disease was unchanged or if further decreases occurred for 6 months or longer, the participant was reclassified as having a CR.
Number of Participants (Par.) With Confirmed Response as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Responses had to be confirmed by 2 separate evaluations occurring \>=4 weeks apart. Par. with confirmed response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Clinical Complete Response (CCR: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present), or Partial Response (PR: \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions).
Number of Participants (Par.) With a Confirmed Complete Response as Assessed by the Masked Independent Randomized Radiology and Oncology Review (MIRROR) Panel
时间窗: The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001
Responses had to be confirmed by 2 separate evaluations occurring \>=4 weeks apart. Par. with confirmed response include those with Complete Response (CR: complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease), Clinical Complete Response (CCR: complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present), or Partial Response (PR: \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions; no new lesions).
Number of Participants With Confirmed Complete Response (CR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CR. CR is defined as the complete resolution of all disease-related radiological abnormalities and the disappearance of all signs and symptoms related to the disease.
Number of Participants With Confirmed Clinical Complete Response (CCR) as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue.
Number of Participants With Confirmed Clinical Complete Response (CCR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CCR. CCR is defined as the complete resolution of all disease-related symptoms; residual foci, thought to be residual scar tissue, are present. Generally, an unchanging lesion =\<2 cm in diameter by radiographic evaluation or =\<1 cm in diameter by physical examination can be considered scar tissue.
Number of Participants With Confirmed Response Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Participants receiving Unlabeled TST with progressive disease (defined as a \>=25% increase from the nadir value of the sum of the products of the longest perpendicular diameters of all measureable lesions or the appearance of any new lesion. Individual lesions must be \>2 centimeters \[cm\] in diameter by radiographic evaluation or \>1 cm in diameter by physical examination.) were assessed separately before and after receiving the crossover treatment of I 131 TST for confirmed response, which included participants with CR, CCR, and PR.
Number of Participants With Confirmed Complete Response Plus Clinical Complete Response (CR + CCR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST for CR + CCR.
Number of Participants With Confirmed Partial Response (PR) as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Confirmed PR is defined as a \>=50% reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions.
Number of Participants With Confirmed Partial Response (PR) Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator
时间窗: Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.
Participants receiving Unlabeled TST with progressive disease were assessed separately before and after receiving the crossover treatment of I 131 TST confirmed PR. Confirmed PR is defined as a \>=50 percent reduction in the sum of the products of the longest perpendicular diameters of all measurable lesions, with no new lesions.
次要结局
- Number of Participants (Par.) With a Confirmed Response (CR, CCR, or PR) as Assessed by the MIRROR Panel(The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001)
- Overall Survival(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Drug-Related (DR) Adverse Events (AEs) Experienced by 3 or More Participants(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Duration of Response for All Confirmed Responders, Confirmed Complete Responders, and Confirmed Partial Responders(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Time to Progression of Disease or Death as Assessed by the Investigator(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- MIRROR Panel Assessed Progression-free Survival(The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001)
- Number of Participants With an Infection for Which Anti-infectives Were Administered(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- MIRROR Panel Assessments of Duration of Complete Response (Time From the First Documented Response to the First Documented Progression)(The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001)
- Number of Participants With the Indicated Serious Adverse Events (SAE) Related to Study Drug(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Type of Infection(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Nadir Values for ANC, a Hematologic Parameter(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Time to Human Anti-Murine Antibodies (HAMA) Positivity From the First Dosimetric Dose(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- MIRROR Panel Assessments of Duration of Confirmed Response (Time From the First Documented Response to the First Documented Progression)(The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001)
- Time to Progression of Disease or Death in Participants Before and After Crossover From Unlabeled TST to TST and Iodine I 131 TST as Assessed by the Investigator(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- MIRROR Panel Assessed Time to Response (Time From the Date of Enrollment to the First Documented Response (PR, CR, CCR)(The MIRROR panel reviewed responses of participants from 17 July 1998 to 17 January 2001)
- Number of Participants With the Indicated Grade 3 or Grade 4 Drug-related AEs Experienced by 3 or More Participants(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Primary Cause of Death(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Nadir Values for Hemoglobin, a Hematologic Parameter(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Nadir Values for the Hematologic Parameters Platelets and WBC Count(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Grade 3 or Grade 4 Hematologic Toxicities(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Duration of the Indicated Grade 3 or Grade 4 Hematologic Toxicities(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Grade 3 or Grade 4 AEs Experienced by 3 or More Participants(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Time to Nadir and Time to Recovery to Baseline in Hematologic Laboratory Evaluations(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With a Time to Death From the Last Dose of Study Drug Less Than or Equal to 30 Days or More Than 30 Days(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)
- Number of Participants With the Indicated Fatal SAEs Related to Study Drug(Participants were evaluated for up to two years in Study BEX104515 and for up to 11.9 years in Study BEX104526.)