Lenalidomide and Paclitaxel in Advanced Solid Tumors

Phase Ib of CC-5013 and Paclitaxel in Patients With 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

Study Overview

• Status: Unknown
• Conditions: Advanced Solid Tumors
• Intervention / Treatment: Drug: Lenalidomide (CC-5013)

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Anticipated): 28
• Phase: Phase 1

Contacts and Locations

Study Locations

• Italy
  • Milan, Italy, 20133
    • Fondazione IRCSS Istituto Nazionale dei Tumori
• Switzerland
  • Bellinzona, Switzerland, 6500
    • Istituto Oncologico della Svizzera Italiana

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: CC-5013 in combination with Paclitaxel; Cohorts of 3 evaluable patients will initially be entered within each dose level, sequentially. In each dose level the second and third patient will enter 2 weeks after the first one. The second and third patient may be treated simultaneously, except if a DLT is reported in the first patient, in which case the second and third patient should be treated sequentially, at least one week apart. Dose escalation will be done when all the patients included in each DL will finish the first treatment cycle. Three additional patients will be sequentially entered (separated by one week each other) if one DLT is observed in cycle 1 among the first 3 patients entered within a dose level. If a DLT is observed in a second patient at this dose level, no further dose escalation will be allowed and the dose level will be considered the MTD. Once the RD (one level below the MTD) has been defined, additional patients (up to 12) will be treated in order to confirm the safety profile of the combination.

Drug: Lenalidomide (CC-5013); CC-5013 given PO daily on D1-D14 every 21 days and Paclitaxel administered IV over 1 hour on d1 and 8 every 21 days until tumor progression or unacceptable toxicity

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Define the MTD of the combination of CC-5013 and paclitaxel in patients with advanced solid tumors	Number of Dose-Limiting Toxicities (DLTs)	4 weeks after the first drug administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety profile of the drug combination	Physical examination, laboratory and instrumental assessments and AE type and frequency	from the first administration to 30 days after the trial end
Pharmacokinetics of CC-5013 and paclitaxel given in combination	CC-5013 and paclitaxel plasma concentration	untill 4 weeks after the first drug administration
the pharmacodynamic effects of CC-5013 and paclitaxel given in combination	Increase (%) in selected serum cytokines (IL2, IL6, IL10, IL12, TNFα, γIF and TGFβ). T-cell phenotyping: T-cell markers (CD4/CD45RA/CCR7/CD3,CD8/CD45RA/CCR7/CD3); Treg markers: CD4/CD25/FoxP3; NKcells: CD16+/CD56+	from the first drug administration to 30 days after trial end
Evidence of antitumor activity in selected tumor types	Response Rate according to RECIST criteria	From the first drug administration to 30 days after the trial end

Collaborators and Investigators

• Sponsor: Southern Europe New Drug Organization
• Collaborators: Celgene Corporation
• Investigators: Study Chair: Cristiana Sessa, MD, Istituto Oncologico della Svizzera Italiana -6500 Bellinzona, Switzerland

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Anticipated): December 1, 2011
• Study Completion (Anticipated): March 1, 2012

Study Registration Dates

• First Submitted: June 30, 2010
• First Submitted That Met QC Criteria: June 30, 2010
• First Posted (Estimate): July 1, 2010

Study Record Updates

• Last Update Posted (Estimate): September 13, 2011
• Last Update Submitted That Met QC Criteria: September 12, 2011
• Last Verified: September 1, 2011

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Lenalidomide
• Other Study ID Numbers: S095LEPT01