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)

The Lymphoma Academic Research Organisation

Status and phase: Completed; Phase 2; Phase 1

Conditions: Mantle Cell Lymphoma Refractory

Treatments: Drug: Torisel dose 25 mg and R-FC; Drug: Torisel dose 15 mg and R-CHOP; Drug: Torisel dose 15 mg and R-FC; Drug: Torisel dose 50 mg and R-CHOP; Drug: Torisel dose 50 mg and R-DHA; Drug: Torisel 75 mg and R-DHA; Drug: Torisel dose 25 mg and R-DHA; Drug: Torisel dose 75 mg and R-CHOP; Drug: Torisel dose 50 mg and R-FC; Drug: Torisel dose 25 mg and R-CHOP; Drug: Torisel dose 75 mg and R-FC; Drug: Torisel dose 15 mg and R-DHA

Study type: Interventional

Funder types: Other

Identifiers

NCT01389427

T³

Details and patient eligibility

About

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.

Full 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.

Enrollment: 41 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Single Group Assignment

Masking: None (Open label)

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41 participants in 4 patient groups

Torisel 15 mg

Experimental group

Description:

Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 15 mg

Treatment:

Drug: Torisel dose 15 mg and R-DHA

Drug: Torisel dose 15 mg and R-FC

Drug: Torisel dose 15 mg and R-CHOP

Torisel 25 mg

Experimental group

Description:

Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 25 mg

Treatment:

Drug: Torisel dose 25 mg and R-CHOP

Drug: Torisel dose 25 mg and R-DHA

Drug: Torisel dose 25 mg and R-FC

Torisel 50 mg

Experimental group

Description:

Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 50 mg

Treatment:

Drug: Torisel dose 50 mg and R-FC

Drug: Torisel dose 50 mg and R-DHA

Drug: Torisel dose 50 mg and R-CHOP

Torisel 75 mg

Experimental group

Description:

Chemotherapy (R-CHOP, R-DHA or R-FC) associated to Torisel 75 mg

Treatment:

Drug: Torisel dose 75 mg and R-FC

Drug: Torisel dose 75 mg and R-CHOP

Drug: Torisel 75 mg and R-DHA