Clinical Trial of Rapamycin and Irinotecan in Pediatric Patients With Refractory Solid Tumors (RAPIRI)

Phase I Clinical Trial of Rapamycin and Irinotecan in Pediatric Patients With Refractory Solid Tumors

Therapeutic solutions to treat solid tumors that are resistant to conventional treatments are now limited. Laboratory data in animals (on pediatric tumors such as brain tumors, sarcomas and neuroblastomas) have shown that the combination of irinotecan (HIF1alpha inhibitor) and rapamycin (mTOR inhibitor) allowed to block development of blood vessels in the tumor and could, in some cases, stop its progression. This drug combination has already been tested in adult patients with refractory tumors and seems to give encouraging results with stabilization of the tumor. The dose and toxicity of irinotecan and rapamycin are known when these drugs are administered separately and in a context different from that of refractory tumors. RAPIRI is a phase I clinical trial whose principal objectives are to determine the maximum dose at which these two molecules may be administered and to assess the safety of this new combination of drugs.

Study Overview

• Status: Completed
• Conditions: Refractory Solid Tumors in Children
• Intervention / Treatment: Drug: Combined administration of irinotecan and rapamycin

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Hôpital des Enfants - Groupe Hospitalier Pellegrin
  • Lille, France, 59020
    • Centre Oscar Lambret
  • Lyon, France, 67008
    • Institut Hémato-Oncologie Pédiatrique (IHOP)
  • Marseille, France, 13005
    • CHU La Timone
  • Nantes, France, 44093
    • CHU Mère-Enfants
  • Paris, France, 75005
    • Institut Curie
  • Strasbourg, France, 67098
    • Hôpitaux Universitaires de Strasbourg
  • Toulouse, France, 31059
    • Hôpital Des Enfants
  • Villejuif, France, 94805
    • Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age >= 1 year old and =< 21 years old;
• Refractory solid tumors, histologically proven at diagnosis (no additional biopsy needs to be performed for the purpose of the study);
• Relapsed or refractory solid tumors after standard treatment or phase II, III-IV clinical trials treatment have failed;
• Karnofsky or Lansky status >= 70%;
• Life expectancy >= 8 weeks;
• No chemotherapy / radiotherapy within 4 weeks before entry into the study;

• Adequate biological parameters :

  • Absolute neutrophil count >= 1.0 x 109/L;
  • Platelet count >= 100 x 109/L;
  • Hemoglobin >= 8 mg/dL;
  • Total bilirubine =< 1.5 ULN;
  • Transaminases =< 2.5 ULN (=< 5 ULN in case of liver metastases);
  • Creatinine clearance (Cockroft) >= 70 mL/min/1.73 m2;
  • Normal coagulation profile with prothrombin >= 70%, TCA =< 35 and fibrinogen >= 2 g/L;
• Patients with 1 to 3 previous therapeutic lines are eligible;
• No current grade >= 2 organ toxicity based on NCI-CTCAE version 3.0;
• All patients with reproductive potential must have an effective method of birth control while on study;
• Negative pregnancy test in females when indicated;
• Informed written consent signed by patients or their parents or legal guardians;
• Patient who was informed of the results of prior medical consultation;
• Patient having a social insurance.

Exclusion Criteria:

• Patient with a constitutional anomaly of coagulation and/or of hemostasis (type hemophilia, von Willebrand disease, congenital clotting factor deficit, platelet disorder), exposing them to increased risk of bleeding;
• Pre-treatment with a mTOR inhibitor;
• Other simultaneous malignancy;
• Concurrent administration of any other anti-tumour therapy;
• Known hypersensitivity or contraindication to study drugs or ingredients;
• Severe concomitant disease (e.g. infection disease);
• Patient unable for medical follow-up;
• Pregnancy and/or lactation;
• Patient included in another clinical drug trial;
• Patient taking drugs interfering with pharmacology of rapamycin and/or irinotecan (e.g. drugs interfering with CYP3A4);
• Patient under judicial protection.

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: rapamycin+irinotecan at a given dose	Drug: Combined administration of irinotecan and rapamycin; This phase I trial is a dose escalation study of irinotecan + rapamycin with a 3+3 statistical design.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the maximum tolerated dose (MTD) of irinotecan and rapamycin combination in children with refractory solid tumors.	The Dose-Limiting Toxicity (DLT) of the drug combination is determined during the first cycle (J1 to J28) of treatment. MTD will be defined as the dose level immediately below the dose level at which 2 patients in a cohort of 3 to 6 patients will have experienced a DLT.	28 days
Characterize the pharmacokinetics of rapamycin and irinotecan during the first cycle of treatment.	Pharmacokinetic parameters for rapamycin will be evaluated at days 1 and 8 of the first cycle of treatment. Pharmacokinetic parameters for irinotecan will be evaluated at day 1 of the first cycle of treatment. Pharmacokinetic profile will be modelized for each patient.	Day1 + day8

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Collaborators: Gustave Roussy, Cancer Campus, Grand Paris
• Investigators: Principal Investigator: Natacha ENTZ-WERLE, MD, PhD, Hôpitaux Universitaires de Strasbourg

Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2011
• Primary Completion (Actual): February 20, 2013
• Study Completion (Actual): February 20, 2013

Study Registration Dates

• First Submitted: November 12, 2010
• First Submitted That Met QC Criteria: January 24, 2011
• First Posted (Estimate): January 25, 2011

Study Record Updates

• Last Update Posted (Actual): December 9, 2019
• Last Update Submitted That Met QC Criteria: December 6, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Topoisomerase I Inhibitors; Irinotecan; Sirolimus
• Other Study ID Numbers: 4791