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Advanced Solid TumorsPhase 1NCT01148628

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

A Phase 1 study testing RAD 001 in combination with Caelyx in people with Advanced Solid Tumors, run by Southern Europe New Drug Organization at 3 sites in 2 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages Up to 75 years
Conditions the study is for
Advanced Solid Tumors
What is being tested?
RAD 001 in combination with Caelyx
Could I receive a placebo?
No, everyone receives an active treatment
How many people
54 participants
Where
3 sitesin 2 countries
Study dates
Oct 2007to Dec 2011
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 75 years
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Histological/cytological diagnosis of solid tumors types for which treatment with an anthracycline containing combination might be indicated.
  • Documented progressive disease prior to entry in the study
  • 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.
  • Preferentially ≤ 2 prior chemotherapies for advanced disease
  • An ECOG performance status of 0 or 1
  • Serum cholesterol <350 mg/dL and triglycerides <400 mg/dL
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  • 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.
  • 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
  • Able to understand and give written informed consent
  • Abdomen/Pelvis CT scans in the 4 weeks before planned treatment start
  • 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.

Who cannot join

  • Prior Caelyx TM
  • Prior anthracycline therapy within last 12 months
  • 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.
  • 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.
  • Prior cumulative dose of > 360 mg/m2 of doxorubicin or equivalent doxorubicin cardiotoxic dose and/or LVEF (echo or MUGA) < 50%.
  • 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
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  • Prior therapy with rapamycin, mTOR inhibitors or tacrolimus
  • 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)
  • Pre-existing malabsorption syndrome, irritable bowel syndrome or other clinical situation which could affect oral absorption
  • Ongoing toxicity associated with prior anticancer therapy (except peripheral neuropathy of ≤ grade 1 by NCI toxicity criteria and alopecia)
  • Another primary malignancy within the past three years (except for non-melanoma skin cancer and cervical carcinoma in situ)
  • Known Grade 3 or 4 hypersensitivity to macrolide antibiotics (e.g., clarithromycin, erythromycin, azithromycin)
  • Significant uncontrolled cardiovascular disease
  • Active infection requiring systemic therapy
  • Known HIV infection
  • 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
  • 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

Trial locations and contacts

3 sites in 2 countries.

3 sites in 2 countries

Italy2 sites
  • Fondazione IRCSS Istituto Nazionale dei Tumori

    Milan, 20133

  • Istituto Europeo di Oncologia

    Milan, 20141

Other trials in Italy

Switzerland1 site
  • Istituto Oncologico della Svizzera Italiana

    Bellinzona, 6500

Other trials in Switzerland

About this study

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
Read the 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.

Being tested
RAD 001 in combination with Caelyx

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RAD 001 in combination with CaelyxDrug

    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.

Study groups in NCT01148628
Study groupRoleWhat they receive
RAD 001 in combination with CaelyxTMExperimentalRAD001 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.
Receives: Drug: RAD 001 in combination with Caelyx

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Maximum Tolerated Dose (MTD) and Recommended Dose (RD)

    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.

    Measured: 4 weeks

Secondary outcomes (3)
  1. Safety profile of drug combination

    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.

    Measured: from the first dose of investigational medication to 30 days after trial end.

  2. Response Rate

    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).

    Measured: every 8 weeks

  3. PK parameters

    PK parameters: terminal half life (T1/2), Total Body Clearance (ClTB), apparent volume of distribution (Vss), Cmax, Tmax, AUC0-48h, AUC0-inf

    Measured: until 14 days post infusion

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Jun 2010 (estimated)
  2. Study startOct 2007
  3. Primary completionMar 2011
  4. Study completionDec 2011 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
54 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01148628
Sponsor's protocol ID
S065RDCX01
Status last verified
Sep 2011
First submitted
11 Jun 2010
Last updated
13 Sep 2011
Results posted
No
Data monitoring committee
No

Publications

  • Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, Bruns CJ, Zuelke C, Farkas S, Anthuber M, Jauch KW, Geissler EK. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002 Feb;8(2):128-35. doi: 10.1038/nm0202-128.

    PubMed 11821896
  • Pollock Rea: Cell shrinkage, cell cycle arrest and anti-angiogenesis underlie the anti-tumor activity of the m-TOR inhibitor AP23573, AACR-NCI-EORTC International Conference, 2003, pp Abstr. B160

  • Tan C, Cruet-Hennequart S, Troussard A, Fazli L, Costello P, Sutton K, Wheeler J, Gleave M, Sanghera J, Dedhar S. Regulation of tumor angiogenesis by integrin-linked kinase (ILK). Cancer Cell. 2004 Jan;5(1):79-90. doi: 10.1016/s1535-6108(03)00281-2.

    PubMed 14749128
  • Brown NS, Bicknell R. Thymidine phosphorylase, 2-deoxy-D-ribose and angiogenesis. Biochem J. 1998 Aug 15;334 ( Pt 1)(Pt 1):1-8. doi: 10.1042/bj3340001.

    PubMed 9693094
  • Parmar MK, Ledermann JA, Colombo N, du Bois A, Delaloye JF, Kristensen GB, Wheeler S, Swart AM, Qian W, Torri V, Floriani I, Jayson G, Lamont A, Trope C; ICON and AGO Collaborators. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet. 2003 Jun 21;361(9375):2099-106. doi: 10.1016/s0140-6736(03)13718-x.

    PubMed 12826431
  • Stewart, C. F. and Ratain, M. J. Topoisomerase interactive agents. In: V. T. DeVita, Jr., S. Hellman, and S. A. Rosenberg (eds.), Cancer: Principles and practice of oncology, pp. 452-467. Philadelphia: Lippincott-Raven Publishers, 1997.

  • Riggs, C. E. J. Antitumor antibiotics and related compounds. In: M. C. Perry (ed.) The chemotherapy source book, 2nd edition, pp. 345-386. Baltimore: Williams and Wilkins, 1997.

  • Lyass O, Uziely B, Ben-Yosef R, Tzemach D, Heshing NI, Lotem M, Brufman G, Gabizon A. Correlation of toxicity with pharmacokinetics of pegylated liposomal doxorubicin (Doxil) in metastatic breast carcinoma. Cancer. 2000 Sep 1;89(5):1037-47. doi: 10.1002/1097-0142(20000901)89:53.0.co;2-z.

    PubMed 10964334
  • Ranson MR, Carmichael J, O'Byrne K, Stewart S, Smith D, Howell A. Treatment of advanced breast cancer with sterically stabilized liposomal doxorubicin: results of a multicenter phase II trial. J Clin Oncol. 1997 Oct;15(10):3185-91. doi: 10.1200/JCO.1997.15.10.3185.

    PubMed 9336354

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing RAD 001 in combination with Caelyx in people with Advanced Solid Tumors, run by Southern Europe New Drug Organization at 3 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 22 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 13 Sep 2011. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 3 sites in Italy, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Maximum Tolerated Dose (MTD) and Recommended Dose (RD) (time frame: 4 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01148628, which also lists 9 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Sep 2011.

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