Trial Information

Lenalidomide in Conjunction With Methotrexate, Leucovorin, Cytarabine and Rituximab for the Treatment of Relapsed or Refractory CD20-positive Aggressive Lymphomas: an Open-label, Multicenter Phase I/II Trial

Phase I

The goal of the phase I part of the study is to determine the maximum tolerated doses of
methotrexate and cytarabine able to be combined with once-per-cycle rituximab and full-dose
3-weeks-on/1-week-off lenalidomide in 28-day treatment cycles. Methotrexate and cytarabine
will be given three times per cycle, preferably on days 1, 8 and 15. If short-term toxicity
precludes once-per-week dosing, treatment may be delayed by a maximum of 3 days, e.g. the
second injection of methotrexate and cytarabine may be delayed until day 11 and the third
injection until day 21. The doses of methotrexate and cytarabine will be adjusted to permit
administration of three doses per cycle without the need to postpone the subsequent
treatment cycle by more than 7 days.

Dose limiting toxicity will be determined by increasing the doses of methotrexate and
cytarabine in sequential patient cohorts in a 3 + 3 design. Because tolerance to
lenalidomide and cytotoxic agents are likely to decrease with increasing numbers of
treatment cycles, evaluation of dose-limiting toxicity will be confined to the first two
cycles. The requirement for dose reductions in subsequent treatment cycles will not be rated
as dose-limiting toxicity.

If no dose-limiting toxicity is observed in 3 patients treated at the same dose level, the
next 3 patients will be treated at the next higher dose level. If a single patient
experiences dose-limiting toxicity, another 3 patients will be treated at the same dose
level. If no more than one dose-limiting toxicity is observed in 6 patients treated at that
level, the next 3 patients will be treated at the subsequent dose level. If two or more of 3
- 6 patients treated at the same level experience dose-limiting toxicity, dose escalation
will be stopped. The dose level below the level where dose-limiting toxicity was observed
defines the maximum tolerated dose.

The toxicity profiles of methotrexate (mucositis, hepatotoxicity) and cytarabine
(hematotoxicity, hepatotoxicity) differ. In order to determine the maximum tolerated dose of
each compound, further dose escalation of one or other drug may be required after the
maximum tolerated dose of the methotrexate/cytarabine combination (as defined in dose levels
1 - 5, see below) has been determined. If dose-limiting hematotoxicity occurs without
concomitant dose-limiting mucositis or hepatotoxicity, the dose of methotrexate may be
escalated without concomitant increase of the cytarabine dose. Conversely, if severe
mucositis occurs without concomitant dose-limiting hematotoxicity or hepatotoxicity, the
dose of cytarabine may be escalated without concomitant increase of the methotrexate dose.
Dose modifications of individual drugs will be made by the coordinating principal
investigator according to the observed toxicities using the levels defined for the
methotrexate/cytarabine combination.

Toxicities observed during the first two treatment cycles will be reported to the trial
office within 7 days after their occurrence (in case of serious adverse events within 24
hours). Based on the predefined criteria listed below the coordinating principal
investigator and the trial coordinator will decide whether or not a toxicity fulfils the
requirements of a dose-limiting toxicity. After inclusion of up to 6 patients on the same
dose level the coordinating principal investigator and the trial coordinator will decide
according to the principles outlined in this protocol whether it is safe to move on to the
next dose level. If rating a toxicity as dose-limiting is equivocal and/or no agreement is
obtained between the coordinating principal investigator and the trial coordinator, the
principal investigators of all participating trial sites will be included in the decision
making process. Stepping-up to the next dose level will require more votes to be in favor of
than against dose escalation.

Dose-limiting toxicities are:

- any of the following on the day of methotrexate/cytarabine injection (day 8 + ≤ 3 days
/ day 15 + ≤ 6 days of the first or second treatment cycle; day 1 of the second or
third cycle which is equivalent to day 29 + ≤ 7 days of the previous cycle):
neutrophils < 500/µl, platelets < 25.000/µl, creatinine clearance < 60 ml/min,
bilirubin ≥ 3,0 mg/dl, serum AST/GOT or ALT/GPT ≥ 6 x upper limit of normal, mucositis
grade 3 or 4

- requirement for dose reduction of methotrexate/cytarabine in the first or second
treatment cycle

- fewer than 21 days of lenalidomide in the first or second treatment cycle

- toxicity-related delay of second or third treatment cycle by more than 7 days

- any other toxicity preventing continuation of therapy according to protocol in the
first or second treatment cycle (except allergic reactions)

Depending on previous treatment history patients will vary in their tolerance to the LeMLAR
regimen. To provide maximum therapeutic benefit, the doses of methotrexate and cytarabine
will be escalated within individual patients after cycles 2 and 4 as detailed below provided
no dose limiting toxicities occurred in previous treatment cycles. Dose escalation in cycles
3 to 6 in individual patients will not be used to determine dose-limiting toxicity. This
will only be done in cycles 1 and 2.

Patients should receive 6 treatment cycles unless tumor progression, unacceptable toxicity
or treatment intolerance occurs. Treatment intolerance includes physician or patient
preference to discontinue or change treatment in a manner not compatible with the protocol.
If treatment according to the LeMLAR protocol is prematurely stopped, its result must be
documented by the procedures outlined in the protocol.

Definition of dose levels of methotrexate and cytarabine (cohorts of 3 - 6 patients):

Level 1

Cycles 1 - 2: methotrexate 30 mg/m², cytarabine 75 mg/m²; cycles 3 - 4: if no dose-limiting
toxicity occurs in cycles 1 and 2: methotrexate 60 mg/m², cytarabine 150 mg/m²; cycles 5 -
6: if no dose-limiting toxicity occurs in cycles 3 and 4: methotrexate 90 mg/m², cytarabine
225 mg/m²

Level 2

Cycles 1 - 2: methotrexate 60 mg/m², cytarabine 150 mg/m²; cycles 3 - 4: if no dose-limiting
toxicity occurs in cycles 1 and 2: methotrexate 90 mg/m², cytarabine 225 mg/m²; cycles 5 -
6: if no dose-limiting toxicity occurs in cycles 3 and 4: methotrexate 120 mg/m², cytarabine
300 mg/m²

Level 3

Cycles 1 - 2: methotrexate 90 mg/m², cytarabine 225 mg/m²; cycles 3 - 4: if no dose-limiting
toxicity occurs in cycles 1 and 2: methotrexate 120 mg/m², cytarabine 300 mg/m²; cycles 5 -
6: if no dose-limiting toxicity occurs in cycles 3 and 4: methotrexate 150 mg/m², cytarabine
375 mg/m²

Level 4

Cycles 1 - 2: methotrexate 120 mg/m², cytarabine 300 mg/m²; cycles 3 - 6: if no
dose-limiting toxicity occurs in cycles 1 and 2: methotrexate 150 mg/m², cytarabine 375
mg/m²

Level 5

Cycles 1 - 6: methotrexate 150 mg/m², cytarabine 375 mg/m²

If treatment with dose level 1 in cycles 1 and 2 proves unfeasible, the dose of lenalidomide
will be reduced in steps of 5 mg until treatment can be given according to schedule.

Phase II

The results of the phase I part of the trial will be summarized and submitted as an interim
report to Celgene. Initiation of phase II will require reliable data defining the maximum
tolerated dose and demonstration of clinical activity in at least some of the patients
treated in phase I.

A total of 20 evaluable patients will be treated at the maximum tolerated dose level. If in
phase I three patients were treated at the maximum tolerated dose, another 15 will be added
in phase II. If six patients were treated in phase I, another 12 will be included in phase
II.

Patients in the phase II part will receive a maximum of 6 treatment cycles. If no
dose-limiting toxicity occurs in the first two cycles, the doses of methotrexate and
cytarabine may be escalated in cycles 3 and 4, and, in case of no toxicities in cycles 3 and
4, again in cycles 5 and 6. Treatment will be stopped prematurely in case of tumor
progression, unacceptable toxicity, intolerance or physician or patient preference.