Dose-finding Study of CAELYXTM and RAD001 in Patients With Advanced Solid Tumors

September 12, 2011 updated by: Southern Europe New Drug Organization

This is a dose finding, open-label, uncontrolled, dose-escalation trial to determine the Maximum Tolerated Dose (MTD) and the Recommended Dose (RD) of the combination RAD001 (escalating daily dose) and CaelyxTM (fixed dose) to patients with advanced solid tumors.

Other purposes of the study are:

  1. define the safety profile of the combination after repeated administrations
  2. define hints of antitumor activity, to be confirmed in subsequent disease-oriented expansion phases at the RD.
  3. define the pharmacokinetic profile of the combination

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

mTOR inhibitors are a new class of targeted antitumor agents which showed interesting antitumor activity in a variety of solid tumors, including prostate, soft tissue sarcomas , ovarian, endometrial, kidney, and breast cancer. They also exert an antiangiogenic effect and are almost devoid of bone marrow toxicity as single agents which makes them suitable for combination with cytotoxic drugs.

Anthracyclines are among the most used and effective cytotoxic agents, and in solid tumors their indications include, among others, breast, ovary, endometrial, prostate cancer. Liposomal Doxorubicin (CaelyxTM) could be an adequate replacement of doxorubicin to avoid potential side effects such as cardiotoxicity, alopecia, GI toxicity.

Testing a combination regimen including mTOR inhibitors and anthracyclines in those tumors which are known to be sensitive to both compounds is of high clinical interest and worthwhile.

Study Type

Interventional

Enrollment (Actual)

54

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Milan, Italy, 20141
        • Istituto Europeo di Oncologia
      • Milan, Italy, 20133
        • Fondazione IRCSS Istituto Nazionale dei Tumori
  • Switzerland
      • Bellinzona, Switzerland, 6500
        • Istituto Oncologico della Svizzera Italiana

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 75 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Histological/cytological diagnosis of solid tumors types for which treatment with an anthracycline containing combination might be indicated.
  2. Documented progressive disease prior to entry in the study
  3. Though not a primary endpoint of this study when possible presence of measurable and/or evaluable disease according to modified RECIST criteria (histological/cytological confirmation of the neoplastic nature of a solitary lesion is not required in this dose finding study). For patients with no measurable disease (prostate and ovarian cancer) serum tumor marker (CA125 and PSA) is acceptable.
  4. Preferentially ≤ 2 prior chemotherapies for advanced disease
  5. An ECOG performance status of 0 or 1
  6. Serum cholesterol <350 mg/dL and triglycerides <400 mg/dL
  7. Adequate hematological, liver and renal function (hemoglobin ≥ 9g/dL, absolute neutrophil count [ANC] ≥ 1.5 x 109/L; platelets ≥ 100 x 109/L, bilirubin ≤ UNL; alkaline phosphatase ≤ 1.5 x UNL; AST, ALT ≤ UNL or 2.5 x UNL in case of liver metastases; albumin ≥ 2.5 g/dL; creatinine ≤ UNL.
  8. Male and female patients who are not surgically sterile or postmenopausal must agree to use reliable methods of birth control for the duration of the study until 30 days after the last dose of study drug
  9. Able to understand and give written informed consent
  10. Abdomen/Pelvis CT scans in the 4 weeks before planned treatment start
  11. HBV/HCV testing in the 2 weeks before treatment start in specific categories of patients with hepatitis B and C risk factors and in additional patients at the discretion of the investigators.

Exclusion Criteria:

  1. Prior Caelyx TM
  2. Prior anthracycline therapy within last 12 months
  3. Patients with endometrial ca. who received both chemotherapy and radiotherapy as palliative treatment. Patients who received both chemotherapy and radiotherapy as adjuvant treatment would be accepted provided that treatment has been completed more than 2 years before inclusion; if treatments has been completed less than 2 years the inclusion will be accepted only after Study Chair's approval.
  4. Documented resistance to anthracycline therapy i.e progression whilst on therapy or within 6 months after the end of therapy having achieved a response or stable disease or after adjuvant therapy.
  5. Prior cumulative dose of > 360 mg/m2 of doxorubicin or equivalent doxorubicin cardiotoxic dose and/or LVEF (echo or MUGA) < 50%.
  6. Known metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, had a negative imaging study within 4 weeks of study entry, is clinically stable with respect to the tumor at the time of study entry, and is not receiving steroid therapy or taper
  7. Prior therapy with rapamycin, mTOR inhibitors or tacrolimus

  8. Prior anticancer treatment (chemotherapy, radiotherapy, hormonal, immunotherapy, biological response modifiers, signal transduction inhibitors, etc) within 4 weeks prior to the first dose of RAD001; the interval is ≥ 2 weeks for signal transduction inhibitors with a half-life known to be <24 hours, and is ≥ 6 weeks for nitrosourea or mitomycin. The following exceptions are allowed:

    • hormonal therapy (e.g., Megace) for appetite stimulation
    • nasal, ophthalmic, and topical glucocorticoid preparations
    • a stable dose of corticosteroids for at least two weeks
    • low dose maintenance steroid therapy for other conditions
    • physiologic hormone replacement therapy (e.g., thyroid supplementation for thyroid deficiency or oral replacement glucocorticoid therapy for adrenal insufficiency)
  9. Pre-existing malabsorption syndrome, irritable bowel syndrome or other clinical situation which could affect oral absorption
  10. Ongoing toxicity associated with prior anticancer therapy (except peripheral neuropathy of ≤ grade 1 by NCI toxicity criteria and alopecia)
  11. Another primary malignancy within the past three years (except for non-melanoma skin cancer and cervical carcinoma in situ)
  12. Known Grade 3 or 4 hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin)
  13. Significant uncontrolled cardiovascular disease
  14. Active infection requiring systemic therapy
  15. Known HIV infection
  16. Inadequate recovery from any prior surgical procedure or having undergone any major surgical procedure within 2 weeks prior to the first dose of RAD001. Patients having undergone recent placement of a central venous access port will be considered eligible if they have recovered
  17. Presence of any other life-threatening illness or organ system dysfunction which, in the opinion of the Investigator, would either compromise the patient's safety or interfere with evaluating the safety of the study drug

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: RAD 001 in combination with CaelyxTM

RAD001 will be given p.o. at increasing doses (no intra-patient)and CaelyxTM will be administered i.v. at a fixed dose.

At each dose level 3 to 6 patients will be entered, according to toxicities observed; the first 3 patients can be treated simultaneously; subsequent patients can be treated after the first 3 have been observed for at least one cycle (4 weeks).

The dose escalation process will be discontinued once the MTD has been achieved and the RD will be evaluated in a subsequent expansion part of the study.
Drug: RAD 001 in combination with Caelyx
RAD001 (tablets; 2.5mg) is administered daily at 5, 7.5, 10 mg. CAELYXTM (vials; 50 mg/25mL)is administered i.v.every 4 weeks at 40mg/m2. One treatment cycle is 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Maximum Tolerated Dose (MTD) and Recommended Dose (RD)
Time Frame: 4 weeks
The Maximum Tolerated Dose (MTD) is defined as the dose in which 2 of 3 or 2 of 6 patients experience a Dose Limiting Toxicity (DLT).The Recommended Dose (RD) is defined as one dose level below the MTD.
4 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety profile of drug combination
Time Frame: from the first dose of investigational medication to 30 days after trial end.
Safety will be assessed by physical examination, interim history, and laboratory assessments. Adverse events will be graded according to the NCI-CTCAE, version 3.0.
from the first dose of investigational medication to 30 days after trial end.
Response Rate
Time Frame: every 8 weeks
For patients with measurable disease overall tumor response is performed according to RECIST criteria. For patients with non measurable disease (prostate and ovarian cancer) response can be assessed according to serum tumor markers (Rustin criteria for CA 125 and criteria for PSA response).
every 8 weeks
PK parameters
Time Frame: until 14 days post infusion
PK parameters: terminal half life (T1/2), Total Body Clearance (ClTB), apparent volume of distribution (Vss), Cmax, Tmax, AUC0-48h, AUC0-inf
until 14 days post infusion

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Southern Europe New Drug Organization

Collaborators

Novartis
Schering-Plough

Investigators

  • Study Chair: Cristiana Sessa, MD, Istituto Oncologico della Svizzera Italiana- Ospedale s.Giovanni - 6500 Bellinzona, Switzerland

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2007

Primary Completion (Actual)

March 1, 2011

Study Completion (Anticipated)

December 1, 2011

Study Registration Dates

First Submitted

June 11, 2010

First Submitted That Met QC Criteria

June 21, 2010

First Posted (Estimate)

June 22, 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

Other Study ID Numbers

  • S065RDCX01

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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