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

NCT01148628 | Unknown Phase 1

• 1 other identifier: S065RDCX01
• Study Type: interventional
• Target: 54
• Locations: 2 countries
• Sites: 3

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

Conditions

Advanced Solid Tumors

Outcome Measures

Primary Outcomes (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.

  4 weeks

Secondary Outcomes (3)

• Safety profile of drug combination

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

• Response Rate

  every 8 weeks

• PK parameters

  until 14 days post infusion

Study Arms (1)

RAD 001 in combination with CaelyxTM

EXPERIMENTAL

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

Interventions

RAD 001 in combination with Caelyx DRUG

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.

RAD 001 in combination with CaelyxTM

Eligibility Criteria

• Age: Up to 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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.

You may not qualify if:

• Prior Caelyx TM
• Prior anthracycline therapy within last 12 months
• 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
• 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)

Sponsors & Collaborators

• Southern Europe New Drug Organization: lead
• Novartis: collaborator
• Schering-Plough: collaborator

Study Sites (3)

Fondazione IRCSS Istituto Nazionale dei Tumori

Milan, 20133, Italy

Location

Istituto Europeo di Oncologia

Milan, 20141, Italy

Location

Istituto Oncologico della Svizzera Italiana

Bellinzona, 6500, Switzerland

Location

Related Publications (9)

• 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.

  PMID: 11821896 BACKGROUND

• 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

  BACKGROUND

• 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.

  PMID: 14749128 BACKGROUND

• 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.

  PMID: 9693094 BACKGROUND

• 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.

  PMID: 12826431 BACKGROUND

• 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.

  BACKGROUND

• 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.

  BACKGROUND

• 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.

  PMID: 10964334 BACKGROUND

• 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.

  PMID: 9336354 BACKGROUND

MeSH Terms

Interventions

Everolimus; liposomal doxorubicin

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Study Officials

• Cristiana Sessa, MD

  Istituto Oncologico della Svizzera Italiana- Ospedale s.Giovanni - 6500 Bellinzona, Switzerland

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 11, 2010
• First Posted: June 22, 2010
• Study Start: October 1, 2007
• Primary Completion: March 1, 2011
• Study Completion: December 1, 2011
• Last Updated: September 13, 2011

Record last verified: 2011-09

Locations

CH (1); IT (2)