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A Phase I/II Trial to Evaluate the Safety, Feasibility and Efficacy of the Addition of Temsirolimus to a Regimen of Bendamustine and Rituximab for the Treatment of Patients With Follicular Lymphoma or Mantle Cell Lymphoma in First to Third Relapse

Phase 1/Phase 2
18 Years
Open (Enrolling)
Follicular Lymphoma, Mantle Cell Lymphoma

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Trial Information

A Phase I/II Trial to Evaluate the Safety, Feasibility and Efficacy of the Addition of Temsirolimus to a Regimen of Bendamustine and Rituximab for the Treatment of Patients With Follicular Lymphoma or Mantle Cell Lymphoma in First to Third Relapse

The first part of the study is a phase I study in which the maximum tolerated dose of the
combination of Temsirolimus, Bendamustine and Rituximab will be established. In the phase I
part of the trial 3 patients will be included in each dose level. After inclusion of 3
patients, each patient has to receive at least 2 complete cycles without DLT until the
enrolment into the next cohort can be initiated. In case of one DLT, 3 additional patients
will be added to the specific dose level. If a second DLT appears, the last dose level
without DLT will be considered the standard dose for the phase II trial. If the third dose
level is achieved without any DLT, there will be no further dose escalation.

In the phase II proportion of the trial, after establishment of a maximum tolerated dose,
the efficacy of the combination regimens in two different patient cohorts will be evaluated.
In the one cohort, 30 patients with relapsed mantle cell lymphoma will be treated; the
second cohort will be composed of 30 patients with relapsed follicular lymphoma.

Inclusion Criteria:

- Histologically proven diagnosis of follicular non-Hodgkin's lymphoma grades l, II or
IIIA or mantle cell lymphoma (including Cyclin D1 expression) according to the World
Health Organization classification

- Documented relapse or progression following at least one but not more than 3
antineoplastic treatments

- At least 1 measurable tumor mass (>1.5 cm x >1.0 cm) or bone marrow infiltration

- Subjects 18 years or older

- Status post. high dose therapy or no transplantation option available or patient
refuses an aggressive treatment strategy

- Subjects (or their legally acceptable representatives) must have signed an informed
consent document indicating that they understand the purpose of and procedures
required for the study and are willing to participate in the study

- Adequate bone marrow reserve: Platelets of at least 75000/µl, absolute neutrophil
count at least 1500/µl. In case of extensive bone marrow infiltration and lower
platelet or absolute neutrophil counts, patients can not be included in the phase I
part of the trial. In the phase II proportion of the trial patients may be included
with a platelet count of more or equal to 50000/µl on the discretion of the
investigator, if thrombocytopenia is associated with massive bone marrow

- Adequate hepatic and renal function

- Alanine aminotransferase <2.5 x upper limit of normal (ULN); Aspartate
aminotransferase <2.5 x ULN, Total bilirubin <1.5 x ULN

- Measured or calculated creatinine clearance >50 mL/min

- Eastern Cooperative Oncology Group [ECOG] performance Status 0-2

- Female subject must be postmenopausal (for at least 6 months), surgically sterile,
abstinent, or, if sexually active, be practicing an effective method of birth control
(e.g., prescription oral contraceptives, contraceptive injections, intrauterine
device, double-barrier method, contraceptive patch, male partner sterilization)
before entry and throughout the study; and have a negative serum ß-hCG pregnancy test
at screening

Exclusion Criteria:

- Lymphoma other than MCL or FL

- Active central nervous System lymphoma. Brain MRI is required only if clinically

- Pregnancy or breast feeding women

- Severe concomitant disease (e.g. uncontrolled arterial hypertension, heart failure
(NYHA III-IV), uncontrolled diabetes mellitus, pulmonary fibrosis, uncontrolled

- Active uncontrolled infections including HIV-positivity, active Hep B or C

- Mental status precluding patient's compliance

- Comedication with strong CYP 3A4/5-inhibitors or -inducers (Appendix 22.7)

- Prior treatment with Temsirolimus

- Known CD20 negativity

- Patients refractory to Bendamustine in a prior treatment line, defined as relapse
within 1 year after initiation of first cycle. Exception: termination of treatment
prior to third scheduled cycle for reasons other than toxicity.

- Status post allogeneic transplantation

- Peripheral neuropathy or neuropathic pain of Grade 2 or worse

- Diagnosed or treated for a malignancy other than NHL except: adequately treated
non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, DCIS of
the breast, or other solid tumors curatively treated with no evidence of disease for
>5 years

- Concurrent treatment with another investigational agent. Concurrent participation in
non-treatment studies is not excluded.

- Known intolerance to sirolimus or derivates, or Bendamustine or Rituximab.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase I: MTD / Phase II: ORR

Outcome Description:

phase II: ORR is evaluated approx. 6 weeks after end of treatment

Outcome Time Frame:

Phase I: 2 months (start cycle 3), Phase II: 6 months

Safety Issue:


Principal Investigator

Georg Hess, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Department of Hematology, Oncology and Pneumology, Universitätsmedizin der Johannes Gutenberg-Universität, Mainz, Germany


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

January 2010

Completion Date:

December 2014

Related Keywords:

  • Follicular Lymphoma
  • Mantle Cell Lymphoma
  • temsirolimus
  • bendamustine
  • rituximab
  • mantle cell lymphoma
  • follicular lymphoma
  • Lymphoma
  • Lymphoma, Follicular
  • Lymphoma, Mantle-Cell