Lymphoma
Conditions
Keywords
Lymphoma
Brief summary
This is an open-label, randomized trial in relapsed refractory subjects with mantle cell lymphoma (MCL).
Interventions
Temsirolimus 175 mg IV once a week for 3 weeks; followed by 75 mg IV once a week
Any of the following single agent treatments: 1. Fludarabine 25 mg/m2 IV over 30 minutes daily for 5 consecutive days, every 28 days or oral administration, as appropriate. 2. Chlorambucil 0.1 (0.1-0.2) mg/kg PO daily for 3 to 6 weeks as required OR 0.4 (0.3 0.8) mg/kg PO every 21 to 28 days 3. Gemcitabine 1 gm/m2 IV over 30 minutes on days 1, 8 and 15 every 28 days or day 1 and day 8 every 21 days 4. Cyclophosphamide 300 (200-450) mg/m2 PO daily for 5 consecutive days every 21 to 28 days, OR 600 (400-1200) mg/m2 IV every 21 to 28 days 5. Cladribine 5 mg/m2 IV daily for 5 consecutive days, every 28 days for 2-6 cycles depending on response, 6. Etoposide 50 (50-150) mg/m2 IV daily for 3-5 days every 21 to 28 days OR 100 (50 300) mg/m2 PO daily for 3-5 days every 21 to 28 days 7. Prednisone 40 (20-60) mg/m2 PO daily or every other day 8. Dexamethasone 20(20-40) mg PO/IV daily for 5 consecutive days, every 14 - 28 day
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Mantle cell lymphoma (MCL) confirmed with histology, immunophenotype, and cyclin D1 analysis * Received 2 to 7 prior therapies which may include hematopoietic stem cell transplant (i.e. induction + consolidation + maintenance) * Prior treatment with an alkylating agent and an anthracycline, rituximab, individually or in combination, and status that is at least one of the following: * Primary disease refractory to at least 2 regimens; * Refractory to at least 1 regimen after first relapse; * Refractory or untreated after second or greater relapse; * Refractory to first line and relapsed after second line. Chemotherapy combinations may include, but are not limited to: CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisone), R-CHOP (Rituximab, Cyclophosphamide, doxorubicin, vincristine, prednisone), FCM (Fludarabine, cyclophosphamide, mitoxantrone), R-FCM (Rituximab,Fludarabine, cyclophosphamide, mitoxantrone), ICE(Ifosfamide, carboplatin, etoposide), DHAP (Dexamethasone, cisplatin, cytarabine) and hyper-CVAD (Cyclophosphamide, doxorubicin, vincristine, dexamethasone).
Exclusion criteria
* Subjects who are less than or equal to six month from allogeneic hematopoietic stem cell transplant and who are on immunosuppressive therapy or have evidence of graft versus host disease * Prior investigational therapy within 3 weeks of first dose. Investigational therapy is defined as treatment that is not approved for any indication. * Active central nervous system (CNS) metastases, as indicated by clinical symptoms, cerebral edema, requirement for corticosteroids and/or progressive growth. (Treated CNS metastases must be stable for \> 2 weeks prior to Day 1.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | The period from randomization until disease progression, death or date of last contact. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | Assessment of complete or partial response (CR, PR) or uncomplete response (CRu) using Response Evaluation Criteria in Solid Tumors. CR: 1) No disease evident. 2) Lymph node, nodal mass regressed to normal size. 3) Previously enlarged organ ↓ size. 4) Bone marrow clear on repeat aspirate, biopsy. CRu: CR 1 and 3, at least 1 of following: Lymph node regressed \>75%. Bone marrow ↑ number or aggregate size, no cytologic/architectural atypia. PR: ≥50% ↓ index lesion, no size ↑ in other nodes, liver, spleen. Splenic and hepatic nodule regressed ≥50%. No new disease. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | Time from the first documentation of objective tumor response to first date that recurrence or progressive disease (PD) was objectively documented; censored at last valid tumor assessment. |
| Overall Survival (OS) | Baseline up to 5 years | Overall survival is the duration from randomization to death. For participants who are alive, overall survival is censored at the last contact. |
| Time to Tumor Progression (TTP) | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | TTP: time from randomization to first documentation of objective tumor progression (including recurrence); censored at last valid tumor assessment. |
| Time to Failure (TTF) | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | TTF is defined as the time from randomization to the date of the first documentation of Progressive Disease (PD), the date of treatment discontinuation except completion of treatment, or date of death (any cause). |
| Time to Response | Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5) | Time between the date of randomization and the first date of objective response for participants with a confirmed objective response. |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
September 5, 2007: Sponsor conducted primary analysis of progression free survival. As a result of these preliminary data, participants receiving investigator choice therapy and those receiving 175/25 mg temsirolimus could cross over to receive treatment with 175/75 mg temsirolimus (Protocol Amendment 5).
Participants by arm
| Arm | Count |
|---|---|
| Temsirolimus 175/75 mg Temsirolimus 175 milligrams (mg) administered intravenously (IV) once weekly for 3 weeks then 75 mg temsirolimus IV once weekly until disease progression or treatment withdrawal. | 57 |
| Temsirolimus 175/25 mg Temsirolimus 175 mg IV once weekly for 3 weeks then 25 mg temsirolimus IV once weekly until disease progression or treatment withdrawal. | 56 |
| Investigator's Choice Participants received 1 single-agent treatment, chosen by investigator:
1. Fludarabine 25 milligram per meter squared (mg/m\^2) IV daily for 5 consecutive days, every 28 days or oral administration, as needed;
2. Chlorambucil 0.1 (0.1-0.2) mg per kilogram, orally (mg/kg, PO) daily for 3 to 6 weeks as required or 0.4 (0.3-0.8) mg/kg PO every 21 to 28 days;
3. Gemcitabine 1 g/m\^2 IV on Days 1, 8, and 15, every 28 days or Days 1 and 8 every 21 days;
4. Cyclophosphamide 300 (200-450) mg/m\^2 PO daily for 5 consecutive days every 21 to 28 days, or 600 (400-1200) mg/m\^2 IV every 21 to 28 days;
5. Cladribine 5 mg/m\^2 IV daily for 5 consecutive days every 28 days for 2-6 cycles;
6. Etoposide 50 (50-150) mg/m\^2 IV daily for 3-5 days every 21 to 28 days or 100 (50-300) mg/m\^2 PO daily for 3-5 days every 21 to 28 days;
7. Prednisone 40 (20-60) mg/m\^2 PO daily or every other day;
8. Dexamethasone 20 (20-40) mg PO/IV daily for 5 consecutive days every 14 to 28 days. | 56 |
| Total | 169 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| After Treament Cross Over | Death | 0 | 0 | 0 | 1 | 2 |
| After Treament Cross Over | Other | 0 | 0 | 0 | 1 | 2 |
| After Treament Cross Over | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 |
| Prior to Treatment Cross Over | Death | 40 | 41 | 37 | 0 | 0 |
| Prior to Treatment Cross Over | Lost to Follow-up | 0 | 2 | 2 | 0 | 0 |
| Prior to Treatment Cross Over | Other | 15 | 9 | 9 | 0 | 0 |
| Prior to Treatment Cross Over | Withdrawal by Subject | 2 | 1 | 4 | 0 | 0 |
Baseline characteristics
| Characteristic | Temsirolimus 175/75 mg | Temsirolimus 175/25 mg | Investigator's Choice | Total |
|---|---|---|---|---|
| Age, Customized <65 years | 24 years | 17 years | 28 years | 69 years |
| Age, Customized >=65 years | 33 years | 39 years | 28 years | 100 years |
| Sex: Female, Male Female | 9 Participants | 15 Participants | 8 Participants | 32 Participants |
| Sex: Female, Male Male | 48 Participants | 41 Participants | 48 Participants | 137 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 57 / 57 | 56 / 56 | 52 / 54 | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 34 / 57 | 34 / 56 | 14 / 54 | 1 / 3 | 1 / 4 |
Outcome results
Primary
Progression-Free Survival (PFS)
The period from randomization until disease progression, death or date of last contact.
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: Intent-to-Treat (ITT) Population: All randomized participants at time of primary analysis
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Progression-Free Survival (PFS) | 4.8 months |
| Temsirolimus 175/25 mg | Progression-Free Survival (PFS) | 3.7 months |
| Investigator's Choice | Progression-Free Survival (PFS) | 1.8 months |
Comparison: Two null hypotheses (Ho) tested: 1. PFS distributions for temsirolimus 175/75 mg and investigator's choice treatment groups are identical. 2. PFS distributions for temsirolimus 175/25 mg and investigator's choice treatment groups are identical. Alternative hypothesis (Ha) for each test was that PFS distributions differed.p-value: <0.000195% CI: [0.25, 0.63]Log Rank
p-value: <0.000195% CI: [0.26, 0.65]Log Rank
Secondary
Percentage of Participants With Objective Response
Assessment of complete or partial response (CR, PR) or uncomplete response (CRu) using Response Evaluation Criteria in Solid Tumors. CR: 1) No disease evident. 2) Lymph node, nodal mass regressed to normal size. 3) Previously enlarged organ ↓ size. 4) Bone marrow clear on repeat aspirate, biopsy. CRu: CR 1 and 3, at least 1 of following: Lymph node regressed \>75%. Bone marrow ↑ number or aggregate size, no cytologic/architectural atypia. PR: ≥50% ↓ index lesion, no size ↑ in other nodes, liver, spleen. Splenic and hepatic nodule regressed ≥50%. No new disease.
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: ITT
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Temsirolimus 175/75 mg | Percentage of Participants With Objective Response | 22.2 percentage of participants |
| Temsirolimus 175/25 mg | Percentage of Participants With Objective Response | 5.6 percentage of participants |
| Investigator's Choice | Percentage of Participants With Objective Response | 1.9 percentage of participants |
p-value: 0.0019Fisher Exact
p-value: 0.6179Fisher Exact
Other Pre-specified
Duration of Response
Time from the first documentation of objective tumor response to first date that recurrence or progressive disease (PD) was objectively documented; censored at last valid tumor assessment.
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: ITT subset of participants who had a response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Duration of Response | 7.1 months |
| Temsirolimus 175/25 mg | Duration of Response | 3.6 months |
| Investigator's Choice | Duration of Response | NA months |
Other Pre-specified
Overall Survival (OS)
Overall survival is the duration from randomization to death. For participants who are alive, overall survival is censored at the last contact.
Time frame: Baseline up to 5 years
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Overall Survival (OS) | 11.1 months |
| Temsirolimus 175/25 mg | Overall Survival (OS) | 8.8 months |
| Investigator's Choice | Overall Survival (OS) | 9.5 months |
p-value: 0.305395% CI: [0.46, 1.28]Log Rank
p-value: 0.951595% CI: [0.6, 1.62]Log Rank
Other Pre-specified
Time to Failure (TTF)
TTF is defined as the time from randomization to the date of the first documentation of Progressive Disease (PD), the date of treatment discontinuation except completion of treatment, or date of death (any cause).
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Time to Failure (TTF) | 3.1 months |
| Temsirolimus 175/25 mg | Time to Failure (TTF) | 3.4 months |
| Investigator's Choice | Time to Failure (TTF) | 1.7 months |
p-value: <0.000195% CI: [0.23, 0.56]Log Rank
p-value: <0.000195% CI: [0.26, 0.6]Log Rank
Other Pre-specified
Time to Response
Time between the date of randomization and the first date of objective response for participants with a confirmed objective response.
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: ITT subset of participants with a confirmed objective response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Time to Response | 3.6 months |
| Temsirolimus 175/25 mg | Time to Response | 3.5 months |
| Investigator's Choice | Time to Response | 4.0 months |
95% CI: [0.14, 9.01]
95% CI: [0.1, 13.3]
Other Pre-specified
Time to Tumor Progression (TTP)
TTP: time from randomization to first documentation of objective tumor progression (including recurrence); censored at last valid tumor assessment.
Time frame: Baseline, every 8 weeks up to Year 1, then every 12 weeks up to Year 2, and then every 6 months until tumor progression or death (up to Year 5)
Population: ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Temsirolimus 175/75 mg | Time to Tumor Progression (TTP) | 5.2 months |
| Temsirolimus 175/25 mg | Time to Tumor Progression (TTP) | 3.5 months |
| Investigator's Choice | Time to Tumor Progression (TTP) | 1.9 months |
p-value: 0.000495% CI: [0.23, 0.67]Log Rank
p-value: 0.071295% CI: [0.4, 1.04]Log Rank