Study No.: Title: Rationale: Phase: Study Period: Study Design: Centres: Indication: Treatment: Objectives: Primary Outcome/Efficacy Variable:

Transcription

1 The study listed may include approved and non-approved uses, formulations or treatment regimens. The results reported in any single study may not reflect the overall results obtained on studies of a product. Before prescribing any product mentioned in this Register, healthcare professionals should consult prescribing information for the product approved in their country. Study No.: BEX [formerly CP ] Title: Phase II multicenter study of cyclophosphamide, vincristine, and prednisone (CVP) followed by Iodine-131 anti- B1 antibody for patients with untreated low-grade non-hodgkin s lymphoma (NHL). Rationale: The rationale for this clinical trial was based on encouraging results in low-grade and transformed lowgrade NHL subjects treated with Iodine 131 Anti B1 Antibody (hereafter referred to as tositumomab and Iodine I 131 tositumomab, TST/I-131 TST) in Phase I, II, and III studies. In particular, study BEX (formerly RIT II 003) enrolled previously untreated subjects with low-grade NHL. An interim analysis of the first 32 subjects enrolled in BEX demonstrated a response rate of 100%, with a complete response (CR) rate of 56%. However, a higher incidence of seroconversion to human anti-murine antibody (HAMA) positivity (41%) was seen in untreated subjects enrolled in the BEX study. In BEX104514, CVP was administered prior to TST/I-131 TST to decrease the incidence of HAMA positivity. CVP is one of the most commonly administered first-line chemotherapy regimens for low-grade NHL. Phase: II Study Period: February 10, 2000 to February 03, 2012 Study Design: This was a Phase II, single-arm, open-label, multicenter study of the efficacy and safety of sequential administration of 6 cycles of CVP followed by TST/I 131 TST in subjects with previously untreated low-grade NHL. Subjects were routinely evaluated for safety and response to treatment and were followed until disease progression or death. All subjects who received study treatment were included in the analyses. After 2 years or disease progression, whichever occurred first, subjects entered a 10 year follow-up study to evaluate duration of response, safety, and survival (Study BEX104528). Centres: Three centers in the U.S.A Indication: Previously untreated low-grade NHL Treatment: CVP was administered as follows: cyclophosphamide 400 mg/m 2 po on Days 1 5; vincristine 1.4 mg/m 2 IV on Day 1 (2.0 mg maximum dose); prednisone 100 mg/m 2 po on Days 1 5. CVP cycles were repeated every 3 weeks for a total of six cycles and had to be completed within 20 weeks unless delayed for toxicity. CVP was adjusted for absolute neutrophil count (ANC) <1500 cells/mm 3 and/or platelet count <100,000 cells/mm 3. Subjects who completed 3 cycles of CVP, regardless of response, were eligible for TST/I-131 TST treatment. Subjects with rapidly progressive disease prior to completing 3 cycles of CVP could be removed from the study. TST/I-131 TST treatment consisted of two phases: an initial dosimetric dose (5 mci IV) was used to determine the rate of whole body clearance of radioactivity (residence time) in order to calculate a total body radiation dose and determine how many mci of iodine I 131 tositumomab were required to deliver the therapeutic dose. Both the dosimetric dose and the therapeutic dose were immediately preceded by an infusion of 450 mg unlabeled tositumomab. Subjects were treated with saturated solution potassium iodide (SSKI), Lugol s solution, or potassium iodide tablets starting at least 24 hours prior to the dosimetric dose and continuing daily for 14 days following the therapeutic dose. Objectives: The objectives of this study were to assess the efficacy, pharmacokinetics, and safety of the sequential administration of CVP x 6 cycles followed TST/I-131 TST for subjects with previously untreated low-grade non-nhl). Primary Outcome/Efficacy Variable: The primary endpoint was the response rate (complete response [CR], complete clinical response [CCR], complete response unconfirmed [CRu], partial response [PR]) of the sequential administration of CVP chemotherapy x 6 cycles followed by TST/I-131 TST for subjects with previously untreated lowgrade NHL. Secondary Outcome/Efficacy Variable(s): The secondary efficacy endpoints for this study were CR rate, duration of response, duration of CR, progression-free survival (PFS), and time to treatment failure. The pharmacokinetic endpoint was total body residence time of TST/I-131 TST following the dosimetric dose. The secondary safety endpoints included the percent of subjects converting to HAMA positivity, the incidence of adverse events (AEs), hematologic toxicity (nadir, time-to-nadir, and time to recovery), use of supportive care, and survival. 1

2 Statistical Methods: All analyses were performed using data from all subjects who were enrolled in the study and who received at least 1 dose of study drug (intent-to-treat [ITT]-Exposed population). Kaplan-Meier methodology was used to analyze time-to-event endpoints. Two-sided 95% confidence intervals (CI) were calculated for response rates and for the medians for the time-to-event endpoints. CIs were presented without adjustment for multiple outcomes. All analyses performed included data from Study BEX as well as data from subjects who enrolled in the extended follow-up study, Study BEX A CR was defined as the disappearance of all clinical and radiographic evidence of disease and a negative bone marrow biopsy; all lymph nodes and nodal masses assessed radiographically had a product of perpendicular diameters (PPD) less than or equal to 1.0 cm 2. A CCR was defined as complete resolution of all disease-related symptoms, but residual foci thought to be residual scar tissue were present. A CRu was defined as the disappearance of all clinical and radiographic evidence of disease and with involved organs decreased in size and no longer palpable, with one or more of the following: (1) residual lymph node mass >1.5 cm in greatest diameter that regressed by >75% in the sum of the products of perpendicular diameters (SPD), and (2) indeterminate bone marrow biopsy results. A PR was defined as 50% decrease in the SPD of all measurable baseline lesions with no new sites of disease. A confirmed response (CR, CCR, CRu, PR) required a response to be confirmed by 2 separate response evaluations at least 4 weeks apart. Progressive disease (PD) was defined as 50% increase from nadir in the PPD of a single lesion or the SPD for all measurable disease. Patients who did not meet criteria for CR, CCR, CRu, PR or PD were defined to have stable disease (SD). Duration of response, PFS, and overall survival (OS) were estimated using the Kaplan-Meier method. The median durations of response, CR, PFS, time to treatment failure, and OS were calculated. PFS analyses treated subject withdrawals for reasons other than progression or death as independent censoring. Ninety-five percent confidence intervals (CI) were calculated for response rates and time to progression. Analyses were performed using the ITT population (all subjects who received any CVP or TST/I-131 TST treatment). Study Population: Subjects 18 years of age with CD20-positive, untreated, stage III/IV or bulky (tumor diameter 5 cm) stage II, low-grade non-hodgkin s B-cell lymphoma were eligible for this study. Subjects had Karnofsky performance status 60%, total bilirubin and creatinine <1.5 times the upper limit of normal [ULN], AST <5 times ULN, absolute neutrophil count >1,500 cells/ L, and a platelet count >100,000 cells/ L. Subjects with central nervous system involvement, human immunodeficiency virus infection, serum HAMA, and other malignancies active within five years were ineligible for this study. Other exclusion criteria included obstructive hydronephrosis, New York Heart Association class III or IV heart disease, active infections, and intermediate- or high-grade NHL. ITT-Exposed Number of Subjects: Enrollment in BEX Planned, N 30 Entered, N 30 Received CVP, n (%) 30 (100) Received the dosimetric dose and therapeutic dose, n (%) 30 (100) Withdrawal from BEX104514, N (%) 30 (100) Enrolled in long term follow-up Study BEX a, n (%) 22 (73.3) Withdrawn due to progressive disease, n (%) 5 (16.7) Lost to follow-up 3 (10.0) a. Six subjects who enrolled in BEX had progressive disease while on Study BEX Withdrawals from BEX104528, n (% subjects enrolled in BEX104528) Completed follow-up 16 (72.7) Death 4 (18.2) Lost to follow-up 1 (4.6) Withdrawn due to non-compliance 1 (4.6) Demographics N (ITT) 30 Females: Males 17:13 Age, median (range) years 51.5 (34 to 72) White, n (%) 28 (93.3) Time from initial diagnosis to enrollment, median (range) months 3.7 (0 to 95) 2

3 Efficacy Results: () Unconfirmed response rate, n [%] (95% CI) 30 (100) [100, 100] (42.1, Not Reached) Unconfirmed complete response, n [%] (95% CI) 21 (70) [54, 86] (74.8, Not Reached) Unconfirmed clinical complete response, n [%] (95% CI) 0 Not applicable Unconfirmed complete response unconfirmed, n [%] (95% CI) 7 (23) [8, 38] 18.4 (7.0, Not Reached) Unconfirmed partial response, n [%] (95% CI) 2 (7) [0, 16] 38.1 (3.7, 72.4) Confirmed response rate, n [%] (95% CI) b 30 (100) [100, 100] (42.1, Not Reached) Confirmed complete response, n [%] (95% CI) 21 (70) [54, 86] (74.8, Not Reached) Confirmed clinical complete response, n [%] (95% CI) 0 Not applicable Confirmed complete response unconfirmed, n [%] (95% CI) b 6 (20) [(6, 34] 15.4 (7.0, Not Reached) Confirmed partial response, n [%] (95% CI) 2 (7) [0, 16] 38.1 (3.7, 72.4) b. One subject with an unconfirmed CRu had divergent initial and confirmed response assessments and was not included in an individual, confirmed response category (CR, CCR, Cru, or PR) but was included among overall confirmed responders. Median progression-free survival, months (95% CI) (38.3, Not Reached) Median time to treatment failure, months (95% CI) 78.9 (36.5, Not Reached) Median overall survival, months (95 % CI) Not Reached Alive at last study visit, n (%) 21 (7) Dead, n (%) 9 (30) Total body residence time, median (range) hours (93 to 126) All AEs (serious and non-serious), regardless of relationship to study drug, were recorded on the AE CRF from the time of enrolment to 12 weeks following the therapeutic dose of TST/I-131 TST, or until administration of alternative therapy for the subject s NHL, whichever occurred first. Subsequent to this time frame, only AEs that were considered by the investigator to be possibly or probably associated with the administration of study drug were to be reported. AEs that occurred in more than one subject in any group, n (%) Period after CVP, prior to Dosimetric Dose Period After TST/I 131 TST Combined Regimen Period ANY EVENT 30 (100) 30 (100) 30 (100) Absolute neutrophil count < 1,000/mm 3 25 (83) 15 (50) 29 (97) White blood cell < 2,000/mm 3 16 (53) 17 (57) 23 (77) Fatigue 14 (47) 15 (50) 23 (77) Neutropenia 21 (70) 4 (13) 21 (70) Alopecia 21 (70) 1 (3) 21 (70) Nausea 15 (50) 3 (10) 16 (53) Somnolence 0 13 (43) 13 (43) Platelets <50,000 cells/ mm 3 1 (3) 12 (40) 12 (40) Leukopenia 9 (30) 3 (10) 9 (30) Cough 6 (20) 5 (17) 9 (30) Headache 7 (23) 3 (10) 10 (33) Arthralgia 7 (23) 3 (10) 9 (30) 3

4 Anaemia 6 (20) 3 (10) 8 (27) Dyspnoea 8 (27) 1 (3) 8 (27) Myalgia 6 (20) 3 (10) 8 (27) Diarrhoea 6 (20) 2 (7) 8 (27) Pain in extremity 8 (27) 0 8 (27) Nasal congestion 2 (7) 6 (20) 7 (23) Pyrexia 6 (20) 2 (7) 7 (23) Chills 3 (10) 4 (13) 7 (23) Constipation 7 (23) 0 7 (23) Insomnia 6 (20) 1 (3) 7 (23) Paraesthesia 5 (17) 2 (7) 7 (23) Decreased appetite 4 (13) 3 (10) 6 (20) Oropharyngeal pain 5 (17) 2 (7) 6 (20) Asthenia 6 (20) 0 6 (20) Dysuria 4 (13) 2 (7) 6 (20) Stomatitis 6 (20) 0 6 (20) Abdominal distension 4 (13) 1 (3) 5 (17) Febrile neutropenia 5 (17) 0 5 (17) Hyperhidrosis 4 (13) 1 (3) 5 (17) Muscle spasms 5 (17) 0 5 (17) Urinary tract infection 3 (10) 2 (7) 5 (17) Abdominal discomfort 3 (10) 2 (7) 4 (13) Thrombocytopenia 2 (7) 3 (10) 4 (13) Anxiety 3 (10) 1 (3) 4 (13) Back pain 4 (13) 0 4 (13) Dyspnoea exertional 2 (7) 2 (7) 4 (13) Nasopharyngitis 2 (7) 2 (7) 4 (13) Pain 3 (10) 1 (3) 4 (13) Rhinorrhoea 1 (3) 3 (10) 4 (13) Amenorrhoea 3 (10) 0 3 (10) Depression 3 (10) 0 3 (10) Dizziness 2 (7) 1 (3) 3 (10) Dysgeusia 3 (10) 0 3 (10) Groin pain 1 (3) 2 (7) 3 (10) Hypoaesthesia 3 (10) 0 3 (10) Neuropathy peripheral 3 (10) 0 3 (10) Oedema peripheral 2 (7) 1 (3) 3 (10) Petechiae 0 3 (10) 3 (10) Pruritus 0 3 (10) 3 (10) Upper respiratory tract infection 2 (7) 1 (3) 3 (10) Vomiting 3 (10) 0 3 (10) Pain in jaw 2 (7) 1 (3) 2 (7) Skin lesion 2 (7) 1 (3) 2 (7) Abdominal pain 2 (7) 0 2 (7) Abdominal pain upper 1 (3) 1 (3) 2 (7) Acute myeloid leukaemia 0 2 (7) 2 (7) Basal cell carcinoma 0 2 (7) 2 (7) Blood bicarbonate decreased 2 (7) 0 2 (7) Dyspepsia 2 (7) 0 2 (7) Ecchymosis 0 2 (7) 2 (7) Epistaxis 0 2 (7) 2 (7) Erythema 1 (3) 1 (3) 2 (7) Gingival bleeding 0 2 (7) 2 (7) Granulocytopenia 2 (7) 0 2 (7) Hemoglobin <8.0 g/dl 0 2 (7) 2 (7) 4

5 Hyperglycaemia 2 (7) 0 2 (7) Lymphopenia 2 (7) 0 2 (7) Musculoskeletal discomfort 2 (7) 0 2 (7) Neck pain 1 (3) 1 (3) 2 (7) Night sweats 2 (7) 0 2 (7) Oral pain 2 (7) 0 2 (7) Perirectal abscess 2 (7) 0 2 (7) Rash 2 (7) 0 2 (7) Rash macular 2 (7) 0 2 (7) Restlessness 1 (3) 1 (3) 2 (7) Sinus congestion 1 (3) 1 (3) 2 (7) Swelling face 2 (7) 0 2 (7) Tooth disorder 1 (3) 1 (3) 2 (7) Varicose vein 1 (3) 1 (3) 2 (7) Vision blurred 2 (7) 0 2 (7) Weight decreased 1 (3) 1 (3) 2 (7) Serious Adverse Events - On-Therapy n (%) [n considered by the investigator to be related to study medication] Period after CVP, prior to Dosimetric Dose Period After TST/I 131 TST Combined Regimen Period ANY EVENT 7 (23) [ 6] 8 (27) [ 6] 13 (43) [11] Febrile neutropenia 5 (17) [ 5] 0 5 (17) [ 5] Acute myeloid leukaemia 0 2 ( 7) [ 2] 2 ( 7) [ 2] Anaemia 0 2 ( 7) [ 2] 2 ( 7) [ 2] Basal cell carcinoma 0 2 ( 7) [ 1] 2 ( 7) [ 1] Neutropenia 1 ( 3) [ 1] 1 ( 3) [ 1] 2 ( 7) [ 2] Perirectal abscess 2 ( 7) [ 2] 0 2 ( 7) [ 2] Thrombocytopenia 0 2 ( 7) [ 2] 2 ( 7) [ 2] Cerebrovascular accident 1 ( 3) 0 1 ( 3) Cystitis haemorrhagic 1 ( 3) [ 1] 0 1 ( 3) [ 1] Granulocytopenia 1 ( 3) [ 1] 0 1 ( 3) [ 1] Leukopenia 1 ( 3) [ 1] 0 1 ( 3) [ 1] Myelodysplastic syndrome b 0 1 ( 3) [ 1] 1 ( 3) [ 1] Neutropenic infection 1 ( 3) [ 1] 0 1 ( 3) [ 1] Prostate cancer 0 1 ( 3) 1 ( 3) Pyrexia 1 ( 3) [ 1] 0 1 ( 3) [ 1] Squamous cell carcinoma 0 1 ( 3) [ 1] 1 ( 3) [ 1] c. The case of myelodysplastic syndrome (MDS) was later reported to have evolved to acute myeloid leukaemia (AML) after the study had completed. Subjects with fatal SAEs, n (%) [related] Period after CVP, prior to Dosimetric Dose Period After TST/I 131 TST Combined Regimen Period ANY EVENT 0 3 (10) [ 2] 3 (10) [ 2] Acute myeloid leukaemia 0 1 (3) [ 1] 1 (3) [ 1] Myelodysplastic syndrome 0 1 (3) [ 1] 1 (3) [ 1] Prostate cancer 0 1 (3) 1 (3) Hematologic Toxicity ANC Hemoglobin Platelets WBC Subjects with any toxicity, n (%) 27 (90) 23 (77) 30 (100) 29 (97) Median day of onset of nadir

6 Median (95% CI) time to recovery to baseline 77 (70, 91) 76.5 (62, 168) 60.5 (50, 75) (75, 170) (days) after dosimetric dose. Subjects with Grade III/IV toxicity, n (%) 29 (97) 2 (7) 12 (40) 23 (77) Median onset of Grade III/IV toxicity (days) c Median duration of Grade III/IV toxicity (days) Subjects with duration Grade III/IV > 7 (days), n (%) 28 (93) 1 (3) 12 (40) 22 73) d. The date of onset was calculated relative to Day 0, the date the dosimetric was administered. Grade 3/4 toxicities: hemoglobin <8.0 g/dl, platelets <50,000 cells/mm 3, absolute neutrophil count (ANC) <1000 cells/mm 3, and white blood cells (WBC) <2000 cells/mm 3. Thyroid Function Elevated thyroid stimulating hormone 0 (0) (TSH) at baseline, n (%) Low/normal TSH at baseline, n (%) 30 (100) Low/normal TSH post baseline, n 1 (3) (%) Elevated TSH post baseline, n (%) 7 (23) All subjects with hypothyroidism AEs, n (% overall) Subjects with low/normal baseline TSH that developed hypothyroidism, n (%) 1 (3) 1 (3) Supportive Care Received supportive care, n (%) 17 (57) G-CSF/ GM-CSF 16 (53) Erythropoietin 5 (17) Platelet transfusion 4 (13) RBC transfusion 3 (10) Thrombopoietin 0 Conclusions: Thirty subjects were enrolled, and all 30 received CVP and TST/I-131 TST. The median follow-up for the ITT-Exposed population was months (range: months) from the time of the initial CVP dose. Thirty (100%) subjects had both an unconfirmed and confirmed response. Twenty-one (70%) subjects had a confirmed CR and 2 (7%) subjects had a confirmed PR. Seven (23%) subjects had an unconfirmed CRu, whereas 6 (20%) subjects had a confirmed CRu. One subject with an unconfirmed CRu had divergent initial and confirmed response assessments and was not included in an individual, confirmed response category (CR, CCR, Cru, or PR) but was included among overall confirmed responders. The median duration of response was months for confirmed CR, 15.4 months for confirmed CRu, and 38.1 months for confirmed PR. The median progression-free survival was months, and median time to treatment failure was 78.9 months. The median overall survival was not reached during the 10 year follow-up period, and 21 (70%) subjects were alive at study completion. The median total body residence time was hours (range hours). The 5 most frequent reported non-hematologic AEs were fatigue (77%), alopecia (70%), nausea (53%), somnolence (43%), and headache (33%). Hematologic III/IV toxicities included ANC< 1000 cells/mm 3 (97%), hemoglobin < 8.0 g/dl (7%), platelets < 50,000 cells/mm 3 (40%), and WBC <2000 cells/mm 3 (77%); all subjects with grade III/IV hematologic toxicities returned to baseline. There was no conversion to HAMA positivity in any subject throughout the study. All subjects had normal TSH levels at baseline, and 7 subjects developed elevated TSH levels after treatment, one of whom was reported to have developed hypothyroidism. One subject developed MDS 6.3 years after treatment, with evolution to AML reported after the study was completed. Two subjects were reported to have developed spontaneous AML 1.7 and 8.7 years after treatment, one resulting in death. Of 30 subjects, 17 (57%) received supportive care during the course of the combined treatment. 6