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Protocol CAM307: A Phase 3 Study to Evaluate the Efficacy and Safety of Front-line Therapy with Alemtuzumab (Campath®) vs Chlorambucil in Patients with Progressive B-Cell Chronic Lymphocytic Leukemia
NAME OF SPONSOR/COMPANY Genzyme Corporation INVESTIGATORS AND STUDY CENTER(S) This was a multi-center study conducted at 44 study centers. There were 9 centers in the United States and 35 centers in Europe. PUBLICATION (REFERENCE) STUDIED PERIOD Date of first patient randomized: 05 DEC 2001 PHASE OF DEVELOPMENT Phase 3 OBJECTIVES The primary objective of this study was to demonstrate that Campath is superior to chlorambucil as front-line therapy in patients with progressive B-CLL as measured by progression-free survival (PFS). The secondary objectives of this study were to evaluate:
METHODOLOGY This was a Phase 3, open-label, multicenter, randomized, comparative study of Campath versus chlorambucil as front line therapy in patients with progressive B-CLL. Eligible patients were to have previously untreated, Rai stage I-IV disease, and be experiencing progression of their B-CLL requiring treatment. Patients were randomized on a 1:1 basis to either the Campath or chlorambucil treatment group. Patients enrolled in the Campath treatment group received a maximum of 12 weeks of Campath. Patients enrolled in the chlorambucil treatment group received a maximum of 12 months of chlorambucil. Response to treatment was to be determined by the investigator based on the 1996 NCIWG criteria. The investigator was to determine the date of progression for each patient based on the definitions provided in the protocol. An independent response review panel (IRRP) was to determine response to treatment and the date of progressive disease (PD) for each patient using the same assessment criteria. The IRRP members were to be blinded to the treatment assignment in order to provide an unbiased assessment. During the post-treatment follow-up period, all patients were to be evaluated for the assessment of disease status, safety, and survival. All patients were to be followed on a monthly basis until the time of disease progression, administration of alternative therapy, or through 18 months following the first dose of study medication, whichever was soonest. For those patients who had not progressed as of the 18-month post-first dose time point, follow up was to continue every 3 months until the time of progression or requirement for alternative therapy. Patients who progressed on study were to be followed every 3 months for survival. NUMBER OF PATIENTS (PLANNED AND ANALYZED) The planned sample size of this study was 284 patients (142 per treatment arm). Patients were to be randomized on a 1:1 basis to receive either Campath (Arm A) or chlorambucil (Arm B). The total enrollment in the study was 297 patients (213 male; 84 female); 149 (50%) of patients were randomized to Campath arm and 148 (50%) of patients were randomized to chlorambucil arm. DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: After signing a written informed consent, patients who met the following criteria were eligible to participate in the study:
− Disease-related B symptoms (fever of greater than 38°C [100.5°F] for ≥2 weeks without evidence of infection, night sweats without evidence of infection, weight loss >10% within previous 6 months). − Evidence of progressive marrow failure as manifested by: o a decrease in hemoglobin to <11 g/dL, or o a decrease in platelet count to <100 × 109/L within the previous 6 months, or o a decrease in absolute neutrophil count (ANC) to <1.0 × 109/L within the previous 6 months. − Progressive splenomegaly to >2 cm below the left costal margin or other organomegaly with progressive increase over 2 consecutive clinic visits ≥2 weeks apart. − Progressive lymphadenopathy with at least 5 sites of involvement with either two nodes at least 2 cm in longest diameter or one node ≥5 cm in longest diameter with progressive increase over 2 consecutive clinic visits ≥2 weeks apart. − Progressive lymphocytosis with an increase of >50% over a 2-month period, or an anticipated doubling time of <6 months.
Patients who met following criteria would be excluded:
Patients with a diagnosis of mantle cell lymphoma TEST PRODUCT, DOSE, AND MODE OF ADMINISTRATION Campath was to be administered intravenously (IV) daily at a starting dose of 3 mg and escalated to 30 mg as tolerated. The dose was to be increased from 3 mg to 10 mg when the dose was well tolerated; the same procedure was to be followed when the dose was increased from 10 mg to 30 mg. All subsequent doses of Campath were to be 30 mg administered three times per week (maintenance dose) for up to 12 weeks, inclusive of dose escalation period(s). DURATION OF TREATMENT Patients treated with Campath received thrice weekly treatment for a maximum of 12 weeks of therapy (inclusive of dose escalation period(s)). Patients treated with chlorambucil received treatment every 28 days for a maximum of 12 cycles. Patients treated with Campath and chlorambucil were assessed for disease status every 4 weeks during therapy by physical exam, chest x-ray as clinically indicated, and analysis of blood and bone marrow by flow cytometry. Study treatment with either Campath or chlorambucil was to stop if there was evidence of progressive disease, the investigator thought a change of therapy would be in the best interest of the patient, the patient requested discontinuation, there was an unacceptable toxicity, patient developed autoimmune anemia or autoimmune thrombocytopenia, the patient became pregnant or failed to use adequate birth control (for those patients who were able to conceive), or the patient was unable to comply with the protocol. Treatment with Campath was also discontinued if there was no evidence of CLL by flow cytometry analysis of the bone marrow or if there was no improvement since baseline after 4 or 8 weeks of Campath treatment. Patients in the Campath arm who had evidence of progressive disease >6 months after achieving a CR or partial response (PR) could receive a second course of Campath. Treatment with chlorambucil was also discontinued at any time if there was a complete remission, or a response that achieved a plateau, i.e., no further reduction in lymph node size, organomegaly, or lymphocyte count over 2 months of treatment. REFERENCE THERAPY, DOSE AND MODE OF ADMINISTRATION Chlorambucil was to be administered at a dose of 40 mg/m2 orally once every 28 days. Treatment was to be repeated every 28 days for a maximum of 12 cycles. CRITERIA FOR EVALUATION Criteria for Evaluation – Efficacy Criteria for Evaluation – Safety STATISTICAL METHODS Statistical Methods – Efficacy The primary and secondary efficacy analyses were based on the IRRP’s determination of eligibility (Rai stage and B-CLL diagnosis), response, and date of disease progression after response for all patients. Summary statistics included sample size, mean, standard deviation, median, and range for continuous variables, where appropriate; number and percent were to be used for categorical variables. All confidence intervals for parameters to be estimated were constructed with a significance level of alpha = 0.05. Time to event distributions of PFS, duration of response, survival, time to treatment failure, and time to alternative treatment were estimated using Kaplan-Meier method. Statistical Methods – Safety SUMMARY / CONCLUSIONS Summary / Conclusions (Patients)
Summary / Conclusions (Efficacy) There were 191 events of PD or death (82 in the Campath arm and 109 in the chlorambucil arm) used for the primary analysis of PFS. The comparison between treatment arms, tested using the log-rank test stratified by Rai stage (I-II vs III-IV), is highly significant, p=0.0001 (see Figure 1). The hazard ratio of PFS estimated after adjustment by Rai stage (I-II vs III-IV) is 0.58 (95% confidence interval (CI: 0.431, 0.768), indicating that the risk of progression or death in B-CLL patients treated with Campath as first line therapy is 42% less than for those treated with chlorambucil. The overall Kaplan-Meier median PFS was 14.6 months (95% CI: 12.3, 21.7 months) for patients in the Campath arm and 11.7 months (95% CI: 9.9, 13.2 months) for patients in the chlorambucil arm (figure 1 The estimated crude hazard ratios illustrate the separation of the 2 Kaplan-Meier curves over time (see Figure 1), suggesting a stronger benefit of Campath treatment at later time points on study compared to immediately after the start of treatment. At 6 months on study (after randomization), the estimated risk of progression or death is 9% less for Campath patients than that for chlorambucil patient. The estimated decrease in the risk of progression or death is 31% less and 70% less for Campath patients than for chlorambucil patients at 12 months and 18 months on study, respectively. Patients with Rai stage I-II disease had a longer PFS than patients with Rai stage III-IV disease. Patients with Rai stage I-II disease in the Campath arm had the best outcome of the 2 treatment arms and Rai stage groups; Kaplan-Meier median PFS was 21.7 months (95% CI: 14.0, not reached) vs 12.5 months (95% CI: 10.9, 14.8) in the chlorambucil arm. For patients with Rai stage III-IV disease, the Kaplan-Meier median PFS was 10.2 months (95% CI: 8.5, 18.1 months) for patients in the Campath arm and 8.5 months (95% CI: 4.7, 12.9 months) for patients in the chlorambucil arm. In an exploratory analysis, the Kaplan-Meier median PFS was 14.6 months (range: 12.0 to 24.4 months) for patients reporting a CMV event during therapy, which compares to the overall PFS (n=149) of 14.6 months (range: 12.3 to 21.7 months). This result suggests that the treatment efficacy as measured by PFS was not compromised in patients who experienced CMV events while on study. Results for response rate, duration of response, overall survival, time to treatment failure, and time to alternative treatment are summarized below and presented in Table 2, Summary of Efficacy Results. Response Rate Results Among the Rai stage I-II patients, a higher ORR was observed in the Campath arm, 87.1%, compared to the 63.5% ORR in the chlorambucil arm. Similarly, a higher ORR was observed among the Rai stage III-IV patients, 76%, in the Campath arm compared to 38.8% ORR in the chlorambucil arm. Among the Rai stage I-II patients, a higher CR rate was observed in the Campath arm, 29.0%, compared to the 3.1% CR rate in the chlorambucil arm. A CR rate of 14.0% was observed for the Rai stage III-IV patients in the Campath arm compared to no CR for the Rai stage III-IV patients in the chlorambucil arm. Elimination of minimal residual disease, (CRm-: a CR by NCIWG criteria and no evidence of disease in the bone marrow by flow cytometry analysis) occurred in 11 of 36 complete responders to alemtuzumab versus none to chlorambucil. Two CRm- patients were determined by the IRRP to be Rai Stage 0 at study entry. Among the remaining 9 patients with Rai I-IV as assessed by the IRRP, there was only 1 report of PD at the time of data cut-off, which had occurred at 24.4 months. In patients with CMV infection, ORR was 83% with 26% CR, and in patients with CMV viremia ORR was 92% with 29% CR. Duration Of Response Results Overall Survival Results Time To Treatment Failure Results Time To Alternative Treatment Results
* Stratified log-rank test Summary / Conclusions (Safety) Adverse Events Most Frequently Reported (≥10%) AEs Regardless of Causality Most Frequently Reported (≥10%) Study Drug Related AEs Serious Adverse Events (SAEs) Most Frequently Reported SAE Infection Events Hematologic Toxicities No patients in the Campath arm developed autoimmune thrombocytopenia, and 2 patients developed autoimmune thrombocytopenia in the chlorambucil arm. One patient in the Campath arm and 2 patients in the chlorambucil arm developed hemolytic anemia, and one patient in the Campath arm developed pure red cell aplasia during the post-treatment follow-up period. The observed hematologic events in both treatment arms were consistent with recognized complications of B-CLL. Discontinuations Due to Adverse Events Deaths on Study CONCLUSION B-cell chronic lymphocytic leukemia (B-CLL) is the most common type of leukemia in adults in Europe and North America. It is a disease for which there is no cure, and mainly affects persons older than 50 years of age. Single agent alkylator therapy, in particular chlorambucil, with or without steroids, has been the standard of care for decades in patients with B-CLL requiring initial treatment. More recently, the development of purine nucleoside analogues, in particular fludarabine, cladribine, and pentostatin, and immunotherapeutic agents, Campath and rituximab, have provided therapeutic advances as single agents, and more recently in combination. Overall survival benefit has not been demonstrated in a single study to date. The CAM307 study was conducted to demonstrate that Campath is superior to chlorambucil as first-line treatment in patients with progressive B-CLL and to provide additional data on the safety profile of Campath. The results from CAM307 demonstrate that Campath is significantly superior to chlorambucil as measured by PFS, response rate and time to alternative therapy in the overall study population of previously untreated patients with B-CLL. The comparison of PFS between treatment arms, tested using the log-rank test stratified by Rai stage (I-II vs III-IV), is highly significant, p=0.0001, with a hazard ratio of 0.58 (95% confidence interval (CI: 0.431, 0.768) after adjustment by Rai stage group. Based on this hazard ratio, the risk of progression or death in B-CLL patients treated with Campath as first line therapy is 42% less than for those treated with chlorambucil. Additionally, 83.2% of patients in the Campath arm had a response of either CR or PR compared to 55.4% of patients in the chlorambucil arm, p <0.0001. There was a significantly higher percentage of CR patients in the Campath arm compared to the chlorambucil arm; 24.2% vs 2.0%, respectively; p <0.0001. The overall Kaplan-Meier median time to alternative treatment was 23.3 months for patients in the Campath arm and 14.7 months for patients in the chlorambucil arm which was highly significant (p=0.0001). Note that the time to alternative treatment does not adjust for the difference in duration of therapy, which is important because patients were generally treated for a maximum of only 12 weeks with Campath vs 12 months with chlorambucil. Thus, the difference in time off active treatment is even greater for the Campath treated patients. The incidence of reported AEs was higher for patients in the Campath arm than for patients in the chlorambucil arm. The most frequently reported AEs during the on-treatment period in the Campath arm were pyrexia, CMV viremia, chills, nausea, hypotension, CMV infection, urticaria, headache, dyspnea, hypertension, rash, fatigue, vomiting, diarrhea, insomnia, and neutropenia. Of these AEs, fatigue, nausea, and vomiting were more frequently reported in patients treated with chlorambucil. Many of the AEs reported in the Campath arm were consistent with infusion-related events, were mild or moderate in severity, and decreased in frequency with subsequent doses. The observed increased incidence of CMV viremia/infection events in the Campath arm compared to the chlorambucil arm may be due to the higher frequency of protocol-mandated CMV testing in the Campath arm. The overwhelming majority of CMV viremia/infection events occurred during the on-treatment period, were mild to moderate in severity, were readily managed and did not appear to effect efficacy. The incidence of non-CMV infections was similar between treatment arms. Hematologic toxicity was common in both treatment arms, however recovery was seen during study or shortly thereafter for most patients. Except for neutropenia and lymphopenia, the incidence of treatment-emergent grade 3 and 4 hematological toxicities including anemia and thrombocytopenia were similar between the two treatment arms. Although the incidence of grade 3 and 4 treatment-emergent neutropenia was higher in the Campath arm, the incidence of infection adverse events (excluding CMV events) was similar. In conclusion, this study demonstrates clinical benefit and a manageable safety profile for the use of Campath as first-line treatment in patients with B-CLL. Based on Report Prepared on: 25 January 2007 |
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