Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma

NCT ID: NCT01467986

Last Updated: 2020-10-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 130 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-08-31
• Study Completion Date: 2020-09-30

Brief Summary

Children, adolescents and young adults with high risk relapsed or treatment refractory neuroblastoma (rNB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

The multimodal metronomic approach combining molecular targeted drugs (rapamycin and dasatinib) with conventional chemotherapy (irinotecan and temozolomide) will be investigated in a randomized fashion as new treatment strategy for patients with rNB. The intention is to assess the therapeutic benefit of molecular targeted drugs for the treatment of rNB.

The combination of irinotecan and temozolomide showed activity in the treatment of several solid organ tumors, brain tumors and neuroblastoma. In one study rNB patients received a median of 5 courses of 5 days irinotecan and temozolomide every 3 to 4 weeks with a cumulative dose of 35% lower than in the RIST design. 33% had disease regression with 8% CR or PR. A phase II study in rNB also using irinotecan and temozolomide with a substantially lower intensity showed a response rate of 15%.

The combination of a mTOR inhibitor with a multi-kinase inhibitor demonstrated in preclinical studies a synergistic effect on cell cycle arrest, apoptosis and sensitization for radio- and chemotherapy. It is assumed that this combination of molecular targeted drugs with a tolerable conventional chemotherapy consisting of irinotecan and temozolomide can substantially improve the outcome of this patient population. A group of 20 rNB patients treated with the RIST therapy approach in a compassionate use setting showed an overall survival of 55% at a median of 80 weeks with a tolerable adverse event profile.

Conditions

Neuroblastoma Recurrent

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: FACTORIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Irinotecan, Temozolomide

Patients randomized to the control arm receive irinotecan (I) and temozolomide (T) alone.

Group Type: ACTIVE_COMPARATOR

Temozolomide

Intervention Type: DRUG

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Irinotecan

Intervention Type: DRUG

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Rapamycin, Dasatinib, Temozolomide, Irinotecan

Patients with rNB receive on the study arm the experimental combination of rapamycin (R)- mTOR Inhibitor, dasatinib (D)- protein kinase inhibitor irinotecan (I)- cytostatic topoisomerase-I-inhibitor and temozolomide (T)- Antineoplastic agent

Group Type: EXPERIMENTAL

Dasatinib

Intervention Type: DRUG

Pharmacotherapeutic Group: protein kinase inhibitor ATC-Code: L01XE06 Excipients: Tablet core: Lactose monohydrate, Cellulose, microcrystalline, Croscarmellose sodium, Hydroxypropyl cellulose, Magnesium stearate. Film-coating: Hypromellose, Titanium dioxide, Macrogol 400 Formulation: film coated tablet Route of Administration: orally. Patients should be instructed to swallow the tablets as a whole and not to split, chew, or crush them.

Rapamycin

Intervention Type: DRUG

Pharmacotherapeutic Group: Immunosuppressive agents - mTOR Inhibitors ATC-Code: L04A A10 Excipients: Polysorbat 80, Phosal 50 PG ((3-sn-Phosphatidyl)cholin from Soy beans, Propylenglycol, lipid acid mono- and -diglyzeride from Soy oil, Ethanol (1,5% bis 2,5%), Soy liid acid and Palmitoyl ascorbic acid) Formulation: Oral solution Route of Administration:orally

Irinotecan

Intervention Type: DRUG

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Temozolomide

Intervention Type: DRUG

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Interventions

Dasatinib

Pharmacotherapeutic Group: protein kinase inhibitor ATC-Code: L01XE06 Excipients: Tablet core: Lactose monohydrate, Cellulose, microcrystalline, Croscarmellose sodium, Hydroxypropyl cellulose, Magnesium stearate. Film-coating: Hypromellose, Titanium dioxide, Macrogol 400 Formulation: film coated tablet Route of Administration: orally. Patients should be instructed to swallow the tablets as a whole and not to split, chew, or crush them.

Intervention Type: DRUG

Rapamycin

Pharmacotherapeutic Group: Immunosuppressive agents - mTOR Inhibitors ATC-Code: L04A A10 Excipients: Polysorbat 80, Phosal 50 PG ((3-sn-Phosphatidyl)cholin from Soy beans, Propylenglycol, lipid acid mono- and -diglyzeride from Soy oil, Ethanol (1,5% bis 2,5%), Soy liid acid and Palmitoyl ascorbic acid) Formulation: Oral solution Route of Administration:orally

Intervention Type: DRUG

Irinotecan

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Intervention Type: DRUG

Temozolomide

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Intervention Type: DRUG

Irinotecan

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Intervention Type: DRUG

Temozolomide

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Intervention Type: DRUG

Other Intervention Names

Sprycel®; Rapamune®; Irinomedac®; Temomedac®; Irinomedac®; Temomedac®

Eligibility Criteria

Inclusion Criteria

• Children, adolescents and young adults less than 25 years
• Signed written informed consent
• Females of childbearing age must have a negative urine pregnancy test prior to starting the study drug. The first pregnancy test must be performed within 10-14 days prior to the start of the study drug and the second pregnancy test must be performed within 24 hours prior to the start of study drug. The subject may not receive the study drug until the investigator has verified that the results of these pregnancy tests are negative.
• Females of childbearing age must comply with the institutional standards of birth control with a pearl index <1%. Contraception must be started at least four weeks before the start of the investigational therapy.
• Females of childbearing age must be willing to abstain from breastfeeding for the duration of the clinical trial and for at least 30 days after discontinuation of the clinical trial.
• Males must agree not to father a child and must use latex condom during any sexual contact with women of childbearing age during and for 6 months after therapy ends or is stopped, even if they have undergone successful vasectomy.
• Willing and able to complete the clinical trial procedures, as described in the protocol
• Non-smoker for at least the previous 3 months. Smoking is not allowed during the entire study period
• Abstain from alcohol within the last 24 hours before screening and before admission to the clinical trial center as well as during the entire clinical trial. The regular daily ethanol intake has to be less than 20g/day for at least the previous three month.
• Patients are required to have an absolute neutrophil count (ANC) ≥ 500/µL, hemoglobin ≥8g/dL (transfusion permitted), and an unsupported platelet count ≥30,000/µL unless:

1. extensive bone marrow involvement was documented

2. patient is refractory or relapsed early after primary therapy

Exclusion Criteria

• Pregnancy, nursing
• Patients who suffered from a thrombotic event and need anticoagulation (i.e. coumadin derivatives or low molecular weight heparin derivatives, LMWH)
• Patients with cardiac arrhythmias especially prolonged QT
• Patients with chronic inflammatory bowel diseases and/or bowel obstruction
• Patients with bilirubin serum levels 1,5 fold above the upper normal limit
• Vaccination with a live virus vaccine during the clinical trial
• Impaired liver function and/or impaired renal function (hepatic and renal index parameter two times above normal range; see below)
• Potentially unreliable subjects, probably non compliant subjects and those judged by the investigator to be unsuitable for the study
• Doubts about the patient's cooperation
• Any contraindications or known hypersensitivity to the IMPs or to any of the other components: (see SPC ("Fachinformation", appendix)
• Known allergic reactions to the treatment medication
• Patients who were treated with radiation and/or chemotherapy for any other oncological condition
• Participation in any other phase I to III trial
• Sexually active patients who refuse to use contraception according to the institutional requirements
• Patients with extremely poor general condition (Karnofsky or Lansky score <50%)
• Neutrophil count (ANC) <500/µL, hemoglobin <8g/dL (transfusion permitted), and an unsupported platelet count <30 000/µL
• 12-lead ECG with QTc>500 msec / QTc>60 msec baseline
• Patients with hepatitis B reactivation

• Maximum Eligible Age: 25 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Regensburg

OTHER

Sponsor Role: lead

Responsible Party

Prof. Dr. med. Selim Corbacioglu

Prof. Dr. med.

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Selim Corbacioglu, MD

Role: PRINCIPAL_INVESTIGATOR

University of Regensburg, Department of Pediatric Hematology and Oncology

Locations

University Hospital Regensburg, Department of Pediatric Hematology and Oncology

Regensburg, , Germany

Countries

Germany

References

Corbacioglu S, Lode H, Ellinger S, Zeman F, Suttorp M, Escherich G, Bochennek K, Gruhn B, Lang P, Rohde M, Debatin KM, Steinbach D, Beilken A, Ladenstein R, Spachtholz R, Heiss P, Hellwig D, Troger A, Koller M, Menhart K, Riemenschneider MJ, Zoubaa S, Kietz S, Jakob M, Sommer G, Heise T, Hundsdorfer P, Kuhnle I, Dilloo D, Schonberger S, Schwabe G, von Luettichau I, Graf N, Schlegel PG, Fruhwald M, Jorch N, Paulussen M, Schneider DT, Metzler M, Leipold A, Nathrath M, Imschweiler T, Christiansen H, Schmid I, Crazzolara R, Niktoreh N, Cario G, Faber J, Demmert M, Babor F, Frohlich B, Bielack S, Bernig T, Greil J, Eggert A, Simon T, Foell J. Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet Oncol. 2024 Jul;25(7):922-932. doi: 10.1016/S1470-2045(24)00202-X.

Reference Type: DERIVED

PMID: 38936379 (View on PubMed)

Other Identifiers

RIST-rNB-2011

Identifier Type: -

Identifier Source: org_study_id