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Escalating Doses of Torisel in Combination With Three Chemotherapies Regimens: R-CHOP, R-FC or R-DHA for Patients With Relapsed/Refractory Mantle Cell Lymphoma (MCL). (T³)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
French Innovative Leukemia Organisation
Information provided by (Responsible Party):
The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier:
NCT01389427
First received: July 4, 2011
Last updated: April 13, 2016
Last verified: April 2016
  Purpose

This is a multicenter, open label, three arms, Phase IB study.

A dose escalation phase of Temsirolimus (Torisel™) administered in intravenous (IV) at day 2, day 8 and day 15 in combination with three chemotherapies regimens for patients in relapsed/refractory Mantle Cell Lymphoma (MCL):

  • Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (R-CHOP) administered every 3 weeks for 6 cycles,
  • Rituximab-Fludarabine-Cyclophosphamide (R-FC) administered every 4 weeks for 6 cycles,
  • Rituximab-Aracytine high dose-Dexamethasone (R-DHA) administered every 4 weeks for 6 cycles.

Condition Intervention Phase
Mantle Cell Lymphoma Refractory
Drug: Torisel dose 15 mg and R-CHOP
Drug: Torisel dose 15 mg and R-FC
Drug: Torisel dose 15 mg and R-DHA
Drug: Torisel dose 25 mg and R-CHOP
Drug: Torisel dose 50 mg and R-CHOP
Drug: Torisel dose 75 mg and R-CHOP
Drug: Torisel dose 25 mg and R-FC
Drug: Torisel dose 50 mg and R-FC
Drug: Torisel dose 75 mg and R-FC
Drug: Torisel dose 25 mg and R-DHA
Drug: Torisel dose 50 mg and R-DHA
Drug: Torisel 75 mg and R-DHA
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Multicenter Phase IB Dose Escalation Study to Evaluate the Safety, Feasibility and Efficacy of the Torisel-Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (T-R-CHOP), Torisel-Rituximab-Fludarabine-Cyclophosphamide (T-R-FC) and Torisel-Rituximab-Aracytine High Dose-Dexamethasone (T-R-DHA) for the Treatment of Patients in Relapsed/Refractory Mantle Cell Lymphoma

Resource links provided by NLM:


Further study details as provided by The Lymphoma Academic Research Organisation:

Primary Outcome Measures:
  • Incidence of Dose Limiting Toxicities (DLT) [ Time Frame: 56 days ] [ Designated as safety issue: Yes ]
    The evaluable for DLT population is the subset of patients from all treated population with a DLT assessment at the two first cycles.


Secondary Outcome Measures:
  • Complete Response Rate(CR) after 4 cycles and at the end of treatment [ Time Frame: 28 days up to 42 days after the last treatment dose ] [ Designated as safety issue: No ]
    Response at the end of treatment will be assessed after four cycles and at the end of complete treatment if the patient received all planned cycles or at withdrawal. Patients without response assessments (due to whatever reason) will be considered non-responders. A descriptive analysis will also be performed considering as non-responders all patients who relapsed or died during the treatment phase even if they were prematurely withdrawn as responders.

  • Progression-free survival (PFS) [ Time Frame: From the date of inclusion to the date of first documentated disease progression, relapse or death from any cause up to 3 years ] [ Designated as safety issue: No ]
    Progression-Free Survival will be measured from the date of inclusion to the date of first documented disease progression, relapse or death from any cause, according to the Cheson 2007 criteria. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.

  • Duration of Response [ Time Frame: From the date of first documentation of a response to the date of first documented evidence of progression/relapse or death from any cause up to 3 years ] [ Designated as safety issue: No ]
    Duration of response will be measured from the date of first documentation of a response (CR or PR at the end of treatment) to the date of first documented evidence of progression/relapse or death from any cause, according to the Cheson 2007 criteria. Responding patients and patients who are lost to follow up will be censored at their last tumor assessment date.

  • Overall Response at the end of treatment [ Time Frame: 28 days up to 42 days after the last treatment dose ] [ Designated as safety issue: No ]
    The same disease response assessment used for complete response rate will be considered to determine the Overall Response Rate. A Patient will be defined as a responder if he/she has a complete response (CR/CRu) or partial response (PR) after four cycles and at the end of treatment. A descriptive analysis will also be performed considering as non-responders all patients who relapsed or died during treatment phase even if they were prematurely withdrawn as responders.

  • Overall Survival (OS) [ Time Frame: From the date of inclusion to the date of first documentated disease progression, relapse or death from any cause up to 3 years ] [ Designated as safety issue: No ]
    Overall survival will be measured from the date of inclusion to the date of death from any cause. Patients who are alive at the time of analysis will be censored at the date of the last contact.

  • Safety of association Temsirolimus with the three chemotherapy regimens [ Time Frame: From the date of informed consent signature to 28 days after the last drug administration ] [ Designated as safety issue: Yes ]

    All subjects who received at least one dose of Temsirolimus (Torisel™) will be considered evaluable and will be included in the safety analysis.

    Analysis of safety will be performed by summarizing adverse events, laboratory data, vital signs and ECOG per-formance status. When applicable, a summary of safety data will also be performed by cycle.



Estimated Enrollment: 63
Study Start Date: November 2011
Estimated Study Completion Date: October 2016
Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Torisel 15 mg
Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 15 mg
Drug: Torisel dose 15 mg and R-CHOP
Torisel in association with Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (R-CHOP) administered every 3 weeks (21 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm A cohort -1
Drug: Torisel dose 15 mg and R-FC
Torisel in association with Rituximab-Fludarabine-Cyclophosphamide (R-FC) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm B cohort -1
Drug: Torisel dose 15 mg and R-DHA
Torisel in association with Rituximab-Aracytine (high dose)-Dexamethasone (R-DHA) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm C cohort -1
Experimental: Torisel 25 mg
Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 25 mg
Drug: Torisel dose 25 mg and R-CHOP
Torisel in association with Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (R-CHOP) administered every 3 weeks (21 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm A cohort 1
Drug: Torisel dose 25 mg and R-FC
Torisel in association with Rituximab-Fludarabine-Cyclophosphamide (R-FC) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm B cohort 1
Drug: Torisel dose 25 mg and R-DHA
Torisel in association with Rituximab-Aracytine (high dose)-Dexamethasone (R-DHA) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm C cohort 1
Experimental: Torisel 50 mg
Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 50 mg
Drug: Torisel dose 50 mg and R-CHOP
Torisel in association with Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (R-CHOP) administered every 3 weeks (21 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm A cohort 2
Drug: Torisel dose 50 mg and R-FC
Torisel in association with Rituximab-Fludarabine-Cyclophosphamide (R-FC) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm B cohort 2
Drug: Torisel dose 50 mg and R-DHA
Torisel in association with Rituximab-Aracytine (high dose)-Dexamethasone (R-DHA) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm C cohort 2
Experimental: Torisel 75 mg
Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 75 mg
Drug: Torisel dose 75 mg and R-CHOP
Torisel in association with Rituximab-Cyclophosphamide-Doxorubicin-Vincristine-Prednisone (R-CHOP) administered every 3 weeks (21 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm A cohort 3
Drug: Torisel dose 75 mg and R-FC
Torisel in association with Rituximab-Fludarabine-Cyclophosphamide (R-FC) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm B cohort 3
Drug: Torisel 75 mg and R-DHA
Torisel in association with Rituximab-Aracytine (high dose)-Dexamethasone (R-DHA) administered every 4 weeks (28 days) for 6 cycles for patients in relapsed/refractory Mantle Cell Lymphoma (MCL).
Other Name: Arm C cohort 3

Detailed Description:

This is a three arms trial that investigates Temsirolimus (Torisel™) in combination with three chemotherapy regimens (R-CHOP, R-FC or R-DHA).

Primary Objective:

- To assess the feasibility of these three chemotherapy regimens in combination with Temsirolimus (Torisel™) and to assess the incidence of dose limiting toxicities (DLT) during the two first cycles of Temsirolimus (Torisel™) in combination with three chemotherapy regimens in order to determine the maximal tolerate dose (MTD) in a dose escalating study design in a population of patients in relapsed/refractory Mantle Cell Lymphoma (MCL).

Secondary objectives:

  • To assess the safety of the association Temsirolimus with the three chemotherapy regimens,
  • To determine the efficacy of the association of Temsirolimus (Torisel™) and these three chemotherapy regimens after 4 cycles and after 6 cycles at the end of treatment: response rate and complete response rate (CR), progression-free survival (PFS), response duration (RD) and overall survival (OS).

All subjects who received at least one dose of Temsirolimus (Torisel™) will be considered evaluable and will be included in the safety analysis.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with histologically or cytologically confirmed refractory or relapsed Mantle Cell Lymphoma (at initial diagnosis or relapse),
  2. Ann Arbor Stage I-IV with at least one tumor site measurable,
  3. Patients who received prior therapy (at least one but no more than three lines therapies) for Mantle Cell Lymphoma (MCL),
  4. Aged ≥ 18 years,
  5. ECOG performance status 0, 1 or 2,
  6. Adequate hepatic and renal function :

    • Serum Glutamic Oxaloacetic Transaminase (SGOT)/AST or Serum Glutamic Pyruvic TransaminaseSGPT/ALT ≤ 3.0 x upper limit of normal (ULN),
    • Serum Total Bilirubin ≤ 1.5 mg/dL (26 μmol/L) except in case of hemolytic anemia,
    • Serum Creatinine ≤ 2 mg/dL (177 μmol/L) or calculated Creatinine Clearance (Cock-croft-Gault formula) of ≥ 50 mL /min
  7. Adequate bone marrow reserve :

    • Absolute neutrophil count (ANC) ≥ 1 G/L (1,000 cells/mm³)
    • Platelets count ≥ 50 G/L
    • Hemoglobin ≥ 9.0 g/dL,
  8. Signed and date informed consent,
  9. Life expectancy of ≥ 90 days (3 months)

Exclusion Criteria:

  1. Other types of lymphomas, e.g. B-cell lymphoma,
  2. Contraindication to any drug contained in the three chemotherapy regimens (R-CHOP, R-FC, R-DHA),
  3. Tested positive for HIV,
  4. Active Hepatitis B and/or C,
  5. Exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited, to active systemic fungal infection, diagnosis of fever and neutropenia,
  6. Any serious active disease or co-morbid medical condition (according to investigator's decision),
  7. Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form,
  8. Received a biological agent for anti-neoplastic intent within 30 days prior to the first dose of study drug,
  9. Use of any standard or experimental anti-cancer drug therapy within 30 days prior to the first dose of study drug,
  10. Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 3 years,
  11. Left Ventricular Ejection Fraction < 45% (calculated by echocardiographic or scintigraphic method),
  12. Pregnancy or breast feeding women,
  13. Women of childbearing potential who not willing to use an adequate method of birth controls for the duration of the study and for twelve months after the end of treatment,
  14. Male patient whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for twelve months after the end of treatment.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01389427

Locations
France
CHU de Grenoble MICHALLON
Grenoble Cedex 9, Hôpital Nord 217, France, 38043
Hôtel Dieu - Université de Nantes
Nantes cedex, Place Alexis Ricordeau, France, 44093
Hôpital Henri Mondor
Creteil, France, 94010
CHU de Dijon
Dijon, France, 21000
Hôpital Saint-Eloi
Montpellier, France, 34295
Hôpital Saint Louis
Paris, France, 75475
Hôpital Necker
Paris, France, 75743
Groupe hospitalier Sud Hôpital Haut-Lévêque
Pessac, France, 33604
Centre Hospitalier Lyon Sud
Pierre Benite, France, 69310
CHU Pontchaillou
Rennes, France, 35003
CHU de Tours - Hôpital Bretonneau
Tours, France, 37000
Sponsors and Collaborators
The Lymphoma Academic Research Organisation
French Innovative Leukemia Organisation
Investigators
Principal Investigator: Steven LE GOUILL, Professor
  More Information

Responsible Party: The Lymphoma Academic Research Organisation
ClinicalTrials.gov Identifier: NCT01389427     History of Changes
Other Study ID Numbers: T³ 
Study First Received: July 4, 2011
Last Updated: April 13, 2016
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Mantle-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Dexamethasone acetate
Dexamethasone
Prednisone
Dexamethasone 21-phosphate
Liposomal doxorubicin
Fludarabine
Fludarabine phosphate
Cyclophosphamide
Rituximab
Doxorubicin
Vincristine
Everolimus
Sirolimus
Cytarabine
BB 1101
Vidarabine Phosphate
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on December 09, 2016