Lenalidomide and Paclitaxel in Advanced Solid Tumors

This is a dose finding, open-label, uncontrolled, dose-escalation trial to determine the maximum Tolerated Dose (MTD) of the combination of CC-5013 (Lenalidomide)and paclitaxel in patients with advanced solid tumors.

Other purposes of the study are:

1. Define the safety profile of the CC-5013 and paclitaxel given in combination
2. Define the pharmacokinetics of CC-5013 and paclitaxel given in combination
3. Define the pharmacodynamic effects of the combination by monitoring potential biomarkers of the different biological activities of each component of the regimen
4. Define the optimal biological dose (OBD) and the dose recommended (RD) for phase II studies in selected tumor types (breast, ovary, prostate, NSCLC)
5. Collect evidence of antitumor activity in selected tumor types

The new immunomodulatory drugs (IMiD) derivatives of thalidomide (CC-5013 lenalidomide and CC4047 pomalidomide) are endowed of direct antitumor activity besides the indirect effects attributed to antiangiogenic, antiinflammatory and T-cell co-stimulatory properties.

Combination therapy with cytotoxic agents or other anticancer drugs could lead to additive or synergistic interactions and support their clinical development in tumor types in which the specific activities of IMiDs could be of potential value.

Combinations with weekly paclitaxel could be of interest because of its antiangiogenic activity, antitumor activity in prostate, NSCLC, ovary, breast cancer, tumor types in which IMiD could be of clinical value because of either enhancement of tumor specific immunity (ovary, prostate) or inhibition of Treg function (breast, NSCLC, ovary).

Eligibility Criteria:
Inclusion Criteria:

* Histological/cytological diagnosis of solid tumors for which a treatment with paclitaxel could be indicated (preferentially ovary, breast, prostate, NSCLC)
* Documented progression of the tumor in the 3 months preceding the study
* Expected survival ≥ 3 months
* Age 18-75 years
* ECOG PS 0-1
* measurable/evaluable disease during escalation phase, according to modified RECIST criteria. For patients with ovarian and prostatic cancer, tumor markers (CA125 for ovarian and PSA for prostatic) are accepted as only evidence. Measurable/evaluable disease is mandatory during the RD expansion phase

  •≤ 2 prior lines of chemotherapy for metastatic disease. For ovarian patients reintroduction of a platinum at relapse, after an initial response lasting \> 6 months is considered one chemotherapy regimen only
* Adequate contraception for all fertile patients
* Adequate hematological function as defined by: ANC ≥ 1.5 x 109/L, platelet count ≥100 x 109/L, hemoglobin ≥ 10 g/dL.
* Normal PTand INR; fibrinogen \> lower Normal Limit (LNL)
* Adequate renal function, as defined by: creatinine ≤ 1.5 x UNL
* Adequate hepatobiliary function, as defined by the following baseline liver function tests:

  * total serum bilirubin within upper normal limit (UNL)
  * alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤2.5xUNL or ≤ 5xUNL in case of liver metastases; alkaline phosphatase (AP) ≤ 2.5xUNL. If total alkaline phosphatase (AP) \> 2.5xUNL, alkaline phosphatase liver fraction must be ≤ 2.5xUNL.
  * albumin ≥ 2.5 g/dL

Exclusion Criteria:

* History of DVT or coagulation disturbances
* Need of treatment with oral anticoagulants or LMW heparin
* Clinical resistance to taxanes defined as progression during therapy or within 6 months from the end of adjuvant treatment
* Known or prior hypersensitivity to taxanes or drugs containing chemophor, or to thalidomide (or analogues)
* Preexisting peripheral neuropathy \> grade 1
* Concomitant treatment with non steroid anti-inflammatory agents (NSAIA), high dose steroids or immunosuppressants
* Concomitant hormonal treatment (including those with antiandrogenic)
* Radiotherapy involving \> 30% of the active bone marrow
* Radiotherapy ≤ 4 weeks prior to enrolment
* Other chemotherapy treatment ≤ 4 weeks prior to enrolment, at least 6 weeks for nitrosoureas or mitomycin C, or investigational drugs
* Symptomatic brain metastases
* Active infection
* Gastro-intestinal abnormalities, inability to take oral medication, any condition affecting absorption
* Impaired cardiac function including any of the following:

History of cardiac disease, such as myocardial infarction, in the year prior to enrollment in the clinical trial, symptomatic/uncontrolled angina pectoris, congestive heart failure or uncontrolled cardiac ischemia, or arrhythmia, abnormal left ventricular ejection fraction, or uncontrolled arterial hypertension.

* Major surgery in the two weeks prior to entering the clinical trial
* Concurrent treatment with any other anti-cancer therapy
* History of another neoplastic disease (except basal cell carcinoma of the skin or uterine cervix carcinoma in situ adequately treated), unless in remission for ≥ 5 years
* Patient unable to comply with the study protocol owing to psychological, social or geographical reasons
* Pregnant and lactating women
* Men and women of childbearing potential who are not using an effective method of contraception
* Participation in another clinical trial or treatment with any investigational product within 30 days prior to inclusion in this study