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Phase 1/2 Study of Lenalidomide and Cetuximab in Patients With Advanced Solid Tumors

Phase 1/Phase 2
18 Years
80 Years
Open (Enrolling)
Solid Tumors

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Trial Information

Phase 1/2 Study of Lenalidomide and Cetuximab in Patients With Advanced Solid Tumors

Background: For metastatic cancer such as head and neck, lung and colorectal cancer,
standard therapy comprises chemotherapy regimen partially in combination with monoclonal
antibodies blocking the vascular endothelial growth factor (VEGF) or the epidermal growth
factor receptor (EGFR). When disease progression occurs during or after these treatment
options have been applied, no established therapy is available and the clinical development
of new strategies is warranted. Lenalidomide (Revlimid®) is a thalidomide derivative and
belongs to the so-called ImiDs, a class of immunostimulatory molecules. IMiDs have profound
effects on the immune system. Obviously, IMiDs are able to function as co-stimulatory
molecule for mature T cells. In addition, IMiDs are able to mitigate the negative effects of
CTLA-4 signalling. On the molecular level, IMiDs induce phosphorylation of CD28, underlining
the concept that they act as costimulatory signals during T cell activation. Furthermore,
the induction of specific CTL responses by dendritic cells (DC) is enhanced and the activity
of suppressive regulatory T cells (Treg) inhibited.

In addition to their effects on cells of the adaptive immune system, IMiDs also target the
innate immune response. Natural killer cells (NK) as well as natural killer T-cells (NKT)
are activated by Immunomodulatory Drugs (IMiDs), and the effects of IMiDs on NK and NKT
cells might further contribute to the immune-activating properties of ImiDs.

Therefore the rationale of the combination of lenalidomide with a therapeutic IgG1 antibody
such as cetuximab (Erbitux®) is based on the fact that several reports suggest a role of
antibody-dependent cellular cytotoxicity (ADCC) as a mode of action of cetuximab.

However, the exact definition of these anti-cancer mechanisms of lenalidomide alone and in
combination with cetuximab in vivo require further investigation in early clinical trials.

The goal of this phase I/II trial is to define the toxicity of the combination of
lenalidomide and cetuximab and to study potential effects on the tumor and the immune

Subjects meeting all inclusion criteria will be enrolled in cohorts of three patients to
receive a single, oral dose of lenalidomide administered on Days 1-28 and intravenous (IV)
infusions of cetuximab (400 mg/m2 first infusion only, then 250 mg/m2 subsequently)
administered on Days 1, 8, 15, and 22 of each 28-day cycle.

Prior to combination therapy, there will be a 21 day lead in treatment period with
lenalidomide monotherapy (Days -21 to -1). Combination treatment will start at Day 1. Tumor
biopsies will be taken before monotherapy lenalidomide treatment (between d-25 and -22) and
between Day -3 and -1 (before starting cetuximab). A third tumor biopsy will be taken
between Cycle 1 Day 21 and 28 after starting combination therapy. Cycles will be repeated
every 28 days. All subjects will continue on study drug until disease progression,
unacceptable toxicity or treatment discontinuation for any other reason. The MTD of
lenalidomide will be defined as the highest dose level at which no more than 1 out of 6
subjects experience a dose-limiting toxicity (DLT) during the first cycle of administration
in combination with cetuximab. Safety measurements and analysis will be performed at each

Inclusion Criteria:

Disease Characteristics:

1. Patients signed informed consent.

2. Histologically or cytologically confirmed SCCHN, NSCLC, or metastatic colorectal

3. At least one unidimensionally measurable lesion.

4. 18 - 80 years of age.

5. Eastern Cooperative Oncology Group (ECOG) performance status of <= 1.

6. Female subjects of childbearing potential must:

- Understand that the study medication could have an expected teratogenic risk

- Agree to use, and be able to comply with, effective contraception without
interruption, 4 weeks before starting study drug, throughout study drug therapy
(including dose interruptions) and for 4 weeks after the end of study drug
therapy, even if she has amenorrhoea. An alternative would be an absolute and
continued sexual abstinence.

The following are effective methods of contraception*

- Implant

- Levonorgestrel-releasing intrauterine system (IUS)**

- Medroxyprogesterone acetate depot

- Tubal sterilisation

- Sexual intercourse with a vasectomised male partner only; vasectomy must be
confirmed by two negative semen analyses Ovulation inhibitory progesterone-only
pills (i.e., desogestrel)

* Combined oral contraceptive pills are not recommended. If a subject was using
combined oral contraception, she must switch to one of the methods above. The
increased risk of VTE continues for 4 to 6 weeks after stopping combined oral

- Agree to have a medically supervised pregnancy test with a minimum
sensitivity of 25 mIU/ml not more than 3 days before the start of study
medication once the subject has been on effective contraception for at
least 4 weeks. This requirement also applies to women of childbearing
potential who practice complete and continued abstinence.

- Agree to have a medically supervised pregnancy test every 4 weeks including
4 weeks after the end of study treatment, except in the case of confirmed
tubal sterilization. These tests should be performed not more than 3 days
before the start

- of next treatment. This requirement also applies to women of childbearing
potential who practice complete and continued abstinence

7. Male subjects must

- Agree to use condoms throughout study drug therapy, during any dose interruption
and for one week after cessation of study therapy if their partner is of
childbearing potential and has no contraception.

- Agree not to donate semen during study drug therapy and for one week after end
of study drug therapy.

8. All subjects must

- Agree to abstain from donating blood while taking study drug therapy and for one
week following discontinuation of study drug therapy.

- Agree not to share study medication with another person and to return all unused
study drug to the investigator

Exclusion Criteria:

Prior Treatment:

1. Use of chemotherapy, hormonal therapy, immunotherapy, or any other anticancer or
experimental therapy within 28 days prior to study medication.

2. Active participation in another clinical trial.

3. Radiotherapy within 28 days prior to study medication.

4. Surgery within 28 days prior to study medication (minimally invasive procedures for
the purpose of diagnosis or staging of the disease are permitted).

5. Prior therapy with pomalidomide (CC-4047), lenalidomide, or thalidomide.


6. Absolute neutrophil count (ANC) < 1.5 x 109/L.

7. Platelet count < 100 x 109/L.

8. Creatinine Clearance < 50 mL/min.

9. Bilirubin > 1.5 x Upper Limit Normal (ULN) (> 2.0 x ULN in the presence of Gilbert's

10. Serum aspartate transaminase (AST)/SGOT > 3.0 x ULN (> 5 x ULN in the presence of
liver metastases).

Other Disease State:

11. Untreated, symptomatic brain metastases (brain imaging not required).

12. Venous thromboembolism within 6 months.

13. Current congestive heart failure (New York Heart Association class II-IV).

14. Uncontrolled hypertension

15. Prior malignancies within 5 years, with the exception of treated basal cell/squamous
cell carcinoma of the skin or "in-situ" carcinoma of the cervix or breast.


16. Any condition, including the presence of laboratory abnormalities, which would place
the subject at unacceptable risk if he/she were to participate in the study or
confound the ability to interpret data from the study.

17. Any serious medical condition, laboratory abnormality, or psychiatric illness that
would prevent the subject from signing the informed consent form.

18. Pregnant or lactating females.

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose

Outcome Description:

Determination of the maximum tolerated dose (MTD) of lenalidomide administered in combination with cetuximab. For each cohort of subjects (3 patients), the decision of whether or not to dose-escalate will be made after subjects have received the first treatment cycle of study drug. Once 2 subjects have experienced DLT, enrollment at that dose will end and that dose will be declared to have exceeded the MTD.

Outcome Time Frame:

on the end of every treatment cycle (28 day-cycles).

Safety Issue:


Principal Investigator

Heinz Zwierzina, Prof. Dr.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Medical University of Innsbruck, Deparmtment of Internal Medicince I


Austria: Ethikkommission

Study ID:




Start Date:

March 2010

Completion Date:

December 2011

Related Keywords:

  • Solid Tumors
  • Solid tumors
  • Lenalidomide
  • Cetuximab
  • Colorectal Cancer
  • Non-Small Cell Lung Cancer
  • Head and Neck Cancer
  • Neoplasms