Comparison Of 2 Doses Of Temsirolimus (Torisel) In Patients With Mantle Cell Lymphoma

Aktiv komparator: temsirolimus (Torisel) 175mg weekly x 3, then 75mg weekly

Medicin: temsirolimus

175mg IV once a week for first 3 weeks, followed by 75mg IV once a week until disease progression, provided that patient is tolerating treatment and getting clinical benefit

Andre navne:

• Torisel

Medicin: temsirolimus

75mg IV once a week until until disease progression, provided that patient is tolerating treatment and getting clinical benefit

Andre navne:

• Torisel

Aktiv komparator: temsirolimus (Torisel) 75mg weekly

Medicin: temsirolimus

175mg IV once a week for first 3 weeks, followed by 75mg IV once a week until disease progression, provided that patient is tolerating treatment and getting clinical benefit

Andre navne:

• Torisel

Medicin: temsirolimus

75mg IV once a week until until disease progression, provided that patient is tolerating treatment and getting clinical benefit

Andre navne:

• Torisel

Independently Assessed Progression-free Survival (PFS)

PFS is defined as the time from randomization to first documentation of disease progression by the independent assessor or to death due to any cause, whichever occurred first.

PFS = (earliest date of progression or death due to any cause- randomization date+1)/30.4.

PFS assessment was done using EMA guidelines for sensitivity analysis censoring.

Participants who were alive and progression-free at the time of analysis were censored on the date of last assessment; participants without adequate baseline assessment or without post-baseline assessments were censored on the randomization date; participants who died or progressed after 2 or more missed visits were censored on the date of last tumor assessment prior to the missing visit; and participants who started new anti-cancer therapy prior to death or progression were censored on the date of last tumor assessment prior to the start of anti-tumor treatment.

Overall Survival (OS)

OS is defined as the time from the date of randomization to the date of death due to any cause.

Independent Assessment - Objective Response Rate (ORR = CR + PR)

ORR is defined as the percentage of participants with confirmed CR or PR according to the Cheson Criteria relative to all randomized Participants. Tumor responses were determined using information from objective measurements from computed tomography information including B-symptom evaluation, physical examination, ECOG performance status, assessment of liver and spleen, laboratory assessments such as bone marrow biopsies and/or aspirates, biochemical markers of disease activity and hematology results.

Participants who did not have on-study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the (CT) scans, as well as clinical assessment of ORR.

Investigator's Assessment ORR (ORR = CR + PR)

ORR is defined as the percentage of participants with confirmed CR or PR according to the Cheson Criteria relative to all randomized Participants. Tumor responses were determined using information from objective measurements from computed tomography information including B-symptom evaluation, physical examination, ECOG performance status, assessment of liver and spleen, laboratory assessments such as bone marrow biopsies and/or aspirates, biochemical markers of disease activity and hematology results.

Participants who did not have on-study radiographic tumor re-evaluation or who died, progressed or dropped out for any reason prior to reaching a CR or PR were counted as non-responders in the (CT) scans, as well as clinical assessment of ORR.

Investigator Assessed PFS

PFS is defined as the time from randomization to first documentation of disease progression by the independent assessor or to death due to any cause, whichever occurred first.

PFS = (earliest date of progression or death due to any cause- randomization date+1)/30.4.

PFS assessment was done using EMA guidelines for sensitivity analysis censoring.

Participants who were alive and progression-free at the time of analysis were censored on the date of last assessment; participants without adequate baseline assessment or without post-baseline assessments were censored on the randomization date; participants who died or progressed after 2 or more missed visits were censored on the date of last tumor assessment prior to the missing visit; and participants who started new anti-cancer therapy prior to death or progression were censored on the date of last tumor assessment prior to the start of anti-tumor treatment.

Percentage of Participants With Treatment-Emergent Infection- Related Adverse Events (AEs) With Grade 2 or Higher as Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

An AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Treatment emergent adverse event=as an event that emerged during treatment period that was absent before treatment, or worsened during treatment period relative to pretreatment state. Treatment-emergent infection-related AEs included events: pneumonia, bronchitis, infection, herpes simplex, oral candidiasis and sepsis. Grading by NCI CTCAE Version 3.0.: Grade 1= mild; Grade 2= moderate; Grade 3= severe; Grade 4= life-threatening; urgent intervention indicated; Grade 5= death.

Percentage of Participants With Treatment-Emergent Bleeding-Related AEs With Grade 2 or Higher as Per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)

An AE was any untoward medical occurrence in participant who received study drug without regard to possibility of causal relationship. Treatment emergent adverse event=as an event that emerged during treatment period that was absent before treatment, or worsened during treatment period relative to pretreatment state. Treatment-emergent bleeding related AEs included events: epistaxis and ecchymosis. AE were assessed according to maximum severity grading based on NCI CTCAE Version 4.03.Grade 1=mild; Grade 2=moderate; within normal limits. Grade 3=severe or medically significant but not immediately life-threatening; Grade 4=life-threatening or disabling; urgent intervention indicated; Grade 5=death.

Quantify the Potential Effect of TEMSR on AUC and Cmax

Potential TEMSR effects were investigated by calculating the ratio of AUCs with and without concomitant TEMSR from the model-estimated effect of TEMSR on apparent clearance (CL/F) values and using individual ratios of observed Cmax values with and without concomitant temsirolimus, for both parent and metabolite. The AUC mean ratio was calculated as 1 / mean shift on apparent clearance from TEMSR, and the 90% CI of the AUC ratios was calculated as 1 / 90% CI of the shift on apparent clearance from TEMSR.

AUC: Area under plasma concentration-time curve from time zero to infinity Cmax: Characterization of maximum observed plasma concentration