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Clinical Trial for Patients With a Stage IV Childhood Renal Tumor, Comparing Upfront Vincristine, Actinomycin-D and Doxorubicin (Standard Arm) With Upfront Vincristine, Carboplatin and Etoposide (Experimental Arm) (RANDOMET)

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ClinicalTrials.gov Identifier: NCT03669783
Recruitment Status : Not yet recruiting
First Posted : September 13, 2018
Last Update Posted : September 13, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique Hopitaux De Marseille

Brief Summary:

Nephroblastoma (Wilms tumor, WT) is the most common renal tumor of childhood representing ± 6% of all childhood malignancies. The diagnosis is established on clinical and radiological grounds. Metastases are visible on conventional imaging in at least 12% of nephroblastoma patients; however, an additional ~15% of patients have nodules on CT-scan only. The treatment consists of neoadjuvant (preoperative) chemotherapy, nephrectomy and risk-based adjuvant chemotherapy ± radiation therapy (RT) to the flank and/or metastases. For truly localized tumors, overall survival is > 85% (high risk histology excluded). Several high risk biological characteristics have been identified: diffuse anaplasia, gain of 1q chromosome, loss of heterozygosity 1p + 16q, blastemal residual volume.

For metastatic nephroblastoma, the standard neo-adjuvant chemotherapy includes 3 drugs: vincristine, actinomycin-D and doxorubicin (VAD). Long-term survival is 82% (1). However, two issues arise. First, the use of doxorubicin ± concomitant RT might be associated with cardiac and pulmonary sequelae (4-17% of congestive heart failure) (2), and actinomycin-D is associated with hepatic toxicity (3). Second, patients with "CT-only" nodules are treated according to "localized disease". However, their outcome is poorer than that of truly "localized disease" (4-6).

The efficacy of carboplatin and etoposide is known for a long time; these drugs are used as second line treatment or for high-risk histology nephroblastoma. Therefore, an alternate chemotherapy has been designed that combines drugs shown as highly efficacious in nephroblastoma, i.e., Vincristine, Carboplatin and Etoposide (VCE). VCE has been used for the treatment of other pediatric malignancies. For metastatic nephroblastoma, the switch from VAD to VCE and the associated reduction of actinomycin-D and doxorubicin is expected to reduce the chemotherapy-related long-term toxicity. In addition, VCE could potentially decrease the rate of patients requiring pulmonary RT. Finally VCE may have a beneficial effect on tumor high risk biological characteristics.

French patients with nephroblastoma have been treated for > 40 years according to SIOP protocols collaborating in the SIOP Renal Tumour Study Group (SIOP-RTSG). This group has designed an international randomized phase III clinical trial for the evaluation of VCE versus VAD in patients with metastatic renal tumors (>>90% having nephroblastoma), in order to decrease the long-term toxicity while at least preserving, if not improving, the treatment efficacy. In addition, the issue of "CT-only" nodules and their adequate treatment needs to be solved. In previous protocols, the treatment strategy was based on the diagnosis of pulmonary metastases (~90% of all metastases) by conventional pulmonary X-ray. Central Radiological Review (CRR) is planned for the initial staging using CT ± MRI, as it is expected to more accurately detect patients with metastatic disease, including patients with "CT-only" nodules. In addition, CRR will be set up for real-time response assessment during treatment, in order to reliably determine who require pulmonary RT and which postoperative chemotherapy.

Therefore, the main trial objectives are:

  • Explore the non-inferiority (efficacy) of neoadjuvant VCE chemotherapy (experimental arm) as compared to the standard arm with VAD.
  • Provide central radiological review (CRR) at diagnosis and after neoadjuvant chemotherapy in order to determine more precisely the appropriate treatment for each patient.

The primary objective of the RCT is to investigate the metastatic complete response rate (MetCR, including very good partial response (VGPR)) of neoadjuvant 6 weeks of VAD as compared to neoadjuvant VCE in stage IV renal tumours using CRR. Several international studies have shown that MetCR is a good surrogate endpoint for survival.

The postoperative treatment, secondary objectives as well as the intended methodology are detailed in the research project.

The total number of patients is 406 patients for the entire phase III trial running in the 12 major SIOP countries (max 110 patients in France).

The expected trial duration is 5 years for accrual + 2 years follow-up (the overall 10-year follow-up for long-term toxicity will be an independently funded ancillary study. This duration is required for a reliable evaluation of the cardiac toxicity).

The results of the current trial should be useful for the future protocols for the treatment of all patients with nephroblastoma (metastatic but also localized and bilateral).

The results of this RCT will be worthy for the entire international pediatric oncology community and future patients throughout the world and will be communicated in scientific congresses and high-level peer-reviewed journals.


Condition or disease Intervention/treatment Phase
Childhood Renal Tumor Drug: treatment Vincristin Drug: treatment Actinomycin-D Drug: treatment Doxorubicin Drug: treatment Carboplatin Drug: Etoposide Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Open-label Non-inferiority Phase 3 Clinical Trial for Patients With a Stage IV Childhood Renal Tumor, Comparing Upfront Vincristine, Actinomycin-D and Doxorubicin (Standard Arm) With Upfront Vincristine, Carboplatin and Etoposide (Experimental Arm)
Estimated Study Start Date : January 1, 2019
Estimated Primary Completion Date : July 1, 2026
Estimated Study Completion Date : January 1, 2027


Arm Intervention/treatment
Active Comparator: treatment VAD
Vincristin, Actinomycin-D and Doxorubicin
Drug: treatment Vincristin
1 x Vincristin 1,5mg/m² iv bolus day 1 in week 1,2,3,4,5,6

Drug: treatment Actinomycin-D
1 x Actinomycin D 45µg/kg iv bolus day 1 in week 1, 3, 5

Drug: treatment Doxorubicin
1 x Doxorubicin 50mg/m² 6h Infusion day 1 in week 1,5

Experimental: treatment VCE
Vincristin, Carboplatin and Etoposide
Drug: treatment Vincristin
1 x Vincristin 1,5mg/m² iv bolus day 1 in week 1,2,3,4,5,6

Drug: treatment Carboplatin
1 x Carboplatin 200 mg/m² 1h infusion day 1,2,3 in week 1,4

Drug: Etoposide
1 x Etoposide 100mg/m² 1h infusion day 1,2,3 in week 1,4




Primary Outcome Measures :
  1. Metastatic response assessment by neoadjuvant chemotherapy only [ Time Frame: 6 weeks ]
    percentage of patients with complete response (CR) or Very Good Partial Response (VGPR) of metastasis of nephroblastoma after 6 weeks of preoperative chemotherapy


Secondary Outcome Measures :
  1. Secondary metastatic response assessment [ Time Frame: 6 weeks ]
    percentage of patients after 6 weeks of preoperative chemotherapy achieving a CR after surgery of metastasis at time of nephrectomy

  2. Clinical outcome after treatment [ Time Frame: 2 and 5 years ]
    stage of local tumor (for each arm)

  3. Histological response to preoperative treatment [ Time Frame: 6 weeks ]
    stage distribution of local tumor histological subtype distribution of local tumor (low, intermediate or high risk (LR, IR, HR))



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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • suffering from metastatic renal tumour at initial diagnosis
  • having at least one circumscript, non-calcified (pulmonary) nodule (or other lesion highly suspicious of metastasis according to criteria for metastatic disease) ≥ 3 mm as determined by chest CT-scan and abdominal CT-scan/MRI.
  • Metastatic disease must be confirmed by central review.

Exclusion Criteria:

-


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03669783


Contacts
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Contact: Arnauld VERSCHUUR +33.491.38.84.78 arnauld.verschuur@ap-hm.fr

Sponsors and Collaborators
Assistance Publique Hopitaux De Marseille
Investigators
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Study Director: Jean Olivier ARNAUD Assistance Publique Hopitaux De Marseille

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Responsible Party: Assistance Publique Hopitaux De Marseille
ClinicalTrials.gov Identifier: NCT03669783     History of Changes
Other Study ID Numbers: 2018-07
First Posted: September 13, 2018    Key Record Dates
Last Update Posted: September 13, 2018
Last Verified: August 2018

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Kidney Diseases
Urologic Diseases
Dactinomycin
Carboplatin
Doxorubicin
Liposomal doxorubicin
Etoposide
Etoposide phosphate
Vincristine
Antineoplastic Agents
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Anti-Bacterial Agents
Anti-Infective Agents
Protein Synthesis Inhibitors
Nucleic Acid Synthesis Inhibitors