Clinical trial NCT01389427: 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).
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Mantle Cell Lymphoma Refractory
Lead sponsor: The Lymphoma Academic Research Organisation
Sponsor class: OTHER
Collaborators: name: French Innovative Leukemia Organisation
First posted: 2011-07-08
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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 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.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLT)
timeFrame: 56 days
Secondary outcomes:
measure: Complete Response Rate(CR) after 4 cycles and at the end of treatment
timeFrame: 28 days up to 42 days after the last treatment dose
measure: Progression-free survival (PFS)
timeFrame: From the date of inclusion to the date of first documentated disease progression, relapse or death from any cause up to 3 years
measure: Duration of Response
timeFrame: 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
measure: Overall Response at the end of treatment
timeFrame: 28 days up to 42 days after the last treatment dose
measure: Overall Survival (OS)
timeFrame: From the date of inclusion to the date of first documentated disease progression, relapse or death from any cause up to 3 years
measure: Safety of association Temsirolimus with the three chemotherapy regimens
timeFrame: From the date of informed consent signature to 28 days after the last drug administration
Other outcomes:
Locations:
city: Grenoble Cedex 9
country: France
facility: CHU de Grenoble MICHALLON
state: Hôpital Nord 217
city: Nantes cedex
country: France
facility: Hôtel Dieu - Université de Nantes
state: Place Alexis Ricordeau
city: Creteil
country: France
facility: Hôpital Henri Mondor
city: Dijon
country: France
facility: CHU de Dijon
city: Montpellier
country: France
facility: Hôpital Saint-Eloi
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Necker
city: Pessac
country: France
facility: Groupe hospitalier Sud Hôpital Haut-Lévêque
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Rennes
country: France
facility: CHU Pontchaillou
city: Tours
country: France
facility: CHU de Tours - Hôpital Bretonneau
Study officials:
name: Steven LE GOUILL, Professor
role: PRINCIPAL_INVESTIGATOR
References: