Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioma

Astrocytoma

Neuroblastoma

Medulloblastoma

Rhabdomyosarcoma

Hepatoblastoma

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Myosarcoma

Neoplasms, Connective and Soft Tissue

Sarcoma

Neuroepithelioma

Soft Tissue Sarcoma

LDE225/sonidegib capsules were supplied to the Investigators at dose strengths of 50 mg, 100 mg, 200 mg, and 250 mg.

LDE225

Novartis Pharmaceuticals

Phase I dose-escalation study to characterize the safety, tolerability, pharmacokinetics and pharmacodynamics of LDE225 given orally on a daily dosing schedule in children with recurrent or refractory medulloblastoma, or other tumors potentially dependent on Hedgehog signaling pathway.

Phase II study is to assess preliminary efficacy in both adult and pediatric patients with recurrent or refractory MB.

A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB

A Phase I/II Study of LDE225 in Pediatric Patients With Recurrent or Refractory Medulloblastoma or Other Tumors Potentially Dependent on the Hedgehog-signaling Pathway and Adult Patients With Recurrent or Refractory Medulloblastoma

DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications. DLT included any grade 3 or 4 clinically-evident toxicity, Hematology: ≥ CTCAE grade 3 neutropenia (ANC \<1.0x10\^9/L); ≥ CTCAE grade 3 thrombocytopenia (platelets \<50x10\^9/L); ≥ CTCAE grade 3 anemia (Hgb \<80 g/L); Febrile neutropenia (ANC \<1x10\^9/L, fever ‡ 38.5°C), Renal: ≥ CTCAE grade 3 serum creatinine (\>3xULN), Hepatic: ≥ CTCAE grade 3 total bilirubin (\>3xULN); ≥ 10xULN ALT elevation; grade 2 total bilirubin (\>1.5ULN) together with ≥ grade 3 ALT elevation (\>5xULN), Cardiac: ≥ CTCAE grade 3, Other AEs: ≥ CTCAE grade 3 vomiting or nausea despite optimal antiemetic therapy, diarrhea despite optimal antidiarrheal treatment.

MTD was defined as highest dose level for which no more than 1 participant in a dose cohort experienced dose-limiting toxicity (DLT), based on Bayesian logistic regression model (BLRM) employing the escalation with overdose control (EWOC) principle. DLT was defined as an adverse event (AE) or abnormal laboratory value assessed as unrelated to disease, disease progression, intercurrent illness, or concomitant medications.k

The tumor response to the sonidegib treatment was measured by ORR. The ORR was defined as the percentage of participants with partial response or complete response as their best overall response. Participants with stable disease, progressive disease tumor assessment were considered as non-responders. Response evaluation criteria was gadolinium chelate-enhanced brain tumor magnetic resonance imaging (Gd-MRI) for Medulloblastoma and central nervous system (CNS) tumors and response evaluation criteria in solid tumors (RECIST) version 1.0 for non-CNS tumors assessed by MRI. Complete Response (CR), Progressive Disease (PD) and Incomplete Response/Stable Disease (SD) were defined as disappearance of all non-target lesions, unequivocal progression of existing non-target lesions and Neither CR nor PD, respectively.

An AE was defined as any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not related to study drug. A SAE was defined as an event which was fatal or life threatening, required or prolonged hospitalization, was significantly or permanently disabling or incapacitating, constituted a congenital anomaly or a birth defect, or encompassed any other clinically significant event that could jeopardize the participant or require medical or surgical intervention to prevent one of the aforementioned outcomes. Treatment related AEs were defined as AEs that were suspected to be related to study treatment as per investigator. On-treatment deaths were deaths which occurred up to 30 days after last date of study treatment.

AUC(0-24h) was defined as the area under the drug concentration time curve calculated using linear trapezoidal summation from time zero to 24 hours after dosing.

Tmax was defined as the time required to reach maximum observed plasma concentration. Tmax was directly determined from the raw plasma concentration time data.

Maximum observed plasma concentration following drug administration was calculated from the raw plasma concentration time data.

ORR was determined in the participants with mutations on Hh gene (Hh positive) and the participants without mutations on Hh gene (Hh negative).

Duration of overall response (complete response (CR) or partial response (PR)) was calculated for those participants whose best overall response was CR or PR. The start date was the date of the first documented tumor response (CR or PR) and the end date was the date of the event defined as the first documented progression or death due to underlying cancer or after the same treatment line. If a participant did not have a progression or death, the duration of response was censored at the date of last adequate tumor assessment in that treatment line.

Pediatric participants received LDE225 233 mg/m\^2 once daily through oral route.

Pediatric Participants, LDE225 233 mg/m^2

Pediatric participants received LDE225 372 mg/m\^2 once daily through oral route.

Pediatric Participants, LDE225 372 mg/m^2

Pediatric participants received LDE225 425 mg/m\^2 once daily through oral route.

Pediatric Participants, LDE225 425 mg/m^2

Pediatric participants received LDE225 680 mg/m\^2 once daily through oral route.

Pediatric Participants, LDE225 680 mg/m^2

Adult participants were treated with LDE225 800 mg capsule once daily.

Adult Participants, LDE225 800 mg

Pediatric Participants received LDE225 233 mg/m\^2 once daily through oral route.

Pediatric Participants received LDE225 372 mg/m\^2 once daily through oral route.

Pediatric Participants received LDE225 425 mg/m\^2 once daily through oral route.

Pediatric Participants received LDE225 680 mg/m\^2 once daily through oral route.

Adult Participants were treated with LDE225 800 mg capsule once daily.

Total

≤ 10 years

>10 years to 17 years

18-65 years

Age, Customized

Sex: Female, Male

The analysis was performed in full analysis set population, defined as all the participants who received at least one dose of sonidegib.

The Phase I and Phase II patients are pooled and summarized by dose levels. One pediatric patient enrolled in the Phase II portion at the 680 mg/m2 dose was pooled with 21 pediatric patients enrolled in Phase I at the same dose

Study Director

The analysis was performed in full analysis set (FAS), defined as all the participants who received at least one dose of sonidegib.

Number of Participants With Dose-limiting Toxicities (DLT) in Phase I

All participants received LDE225 233, 372, 425, 680, 800 mg/m\^2 once daily through oral route until disease progression, unacceptable toxicity, or consent withdrawal.

All Participants

The MTD for the pediatric population was not established in this study. MTD was not achieved since 1 or no DLT was observed. The recommended phase II dose was established based on the safety, pharmacokinetics, and clinical responses observed.

Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use

AEs suspected to be drug related

AEs leading to discontinuation

On-treatment deaths

SAEs

The analysis was performed in safety set (SS), defined as all the participants who received at least 1 dose of sonidegib.

Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Treatment Related AEs and Death During the Study

Cycle 1/Day 1 (n=11, 15, 11, 19)

Cycle 1/Day 22 (n=9, 14, 9, 15)

The analysis was performed in pharmacokinetic analysis set (PAS), defined as all the participants who received at least one (full or partial) dose of sonidegib and provided at least one evaluable pharmacokinetic (PK) blood sample. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Area Under the Drug Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC0-24h) of Sonidegib in Phase I

Cycle 1/Day 1 (n=11, 15, 10, 17)

Cycle 1/Day 22 (n=9, 12, 9, 15)

The analysis was performed in PAS population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of Sonidegib in Phase I

Maximum Observed Plasma Concentration (Cmax) of Sonidegib in Phase I

All the pediatric Participants were treated with LDE225 dose determined in the Phase I (233, 372, 425 and 680 mg/m\^2).

Pediatric Participants

60 patients with known (Hedgehog) Hh pathway activation status were analyzed, 10 patients, including all 5 patients with an objective response (3 with pediatric) , were Hh-positive (+). No Hh-negative patient had an objective response.

Percentage of Pediatric Participants With Objective Response Rate (ORR) by Hedgehog (Hh) Signaling Pathway Status

The analysis was performed in FAS population. Here "Number of participants analysed" signifies treatment responders for the specified reporting group.

Duration of Response by Treatment

Complete response

Partial response

Stable disease

Progressive disease

Objective response rate

All adult Participants were treated with sonidegib 800 mg once daily in phase II portion of the study. Pediatric patients were also enrolled in phase II portion of the study at the recommended phase II pediatric dose - 680 mg/m\^2

Adult Participants

Percentage of Participants With Objective Response Rate (ORR) by Treatment

Pediatric Participants received LDE225 680 mg/m\^2 once daily through oral route. The Phase I , Phase II patients are pooled and summarized by dose levels. One pediatric patient enrolled in the Phase II portion at the 680 mg/m2 dose was pooled with 21 pediatric patients enrolled in Phase I at the same dose

Phase I

Phase II

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Diseases and Abnormalities at or Before Birth

Wilms Tumor

Sarcoma, Ewing

Wilms' Tumor

Ewing Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Vincristine

Topoisomerase I Inhibitors

Enzyme Inhibitors

Tubulin Modulators

Antimitotic Agents

Expansion phase: Schedule B - Sequential dosing schedule: Of a 21-day cycle, regorafenib will be dosed sequentially, following administration of VI: Vincristine：intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 8 to Day 21.

Expansion phase: Schedule A - Concomitant dosing schedule: Of a 21-day cycle, regorafenib will be concomitantly administered with vincristine and irinotecan (VI): Vincristine: intravenous bolus, 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg), Day 1 and Day 8. Irinotecan: intravenously over 1 hour, 50 mg/m2/day, Day 1 to Day 5. Regorafenib: orally, at a starting dose level of 72 mg/m2 (subjects 2 to less than 18 years old) or 60 mg/m2 (subjects 6 to less than 24 months old) once daily, Day 1 to Day 14.

Dose escalation phase: This phase of the study has been completed

Regorafenib will be given orally once a day, across cycles of 21 days each. During each cycle regorafenib is taken for 2 weeks followed by one week off the drug. Doses of the study drug used in this study are age-dependent and the children's dose will been adjusted based on the age and the body surface area and given either as tablets or granulate.

Regorafenib (BAY73-4506)

Vincristine will be given at a dose of 1.5 mg/m2 (0.05 mg/kg for subjects ≤ 10 kg, maximum 2.0 mg) on Day 1 and Day 8 in 21-day cycles.

Vincristine (Cellcristin®)

Irinotecan will be administered at a starting dose of 50 mg/m2/day from Day 1 to Day 5, in 21 day cycles.

Irinotecan (Irinotecan Cell pharm®)

Bayer Study Director

Dose escalation phase of the study :

To define the safety profile, maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of regorafenib administered orally as a single agent in a 3-weeks-on/1- week-off schedule in repeating cycles of 28 days in pediatric subjects with solid malignant tumors recurrent or refractory to standard therapy. To characterize the pharmacokinetics (PK) of regorafenib The dose escalation phase of the study has been completed.

Expansion phase:

To define the safety profile, MTD and the RP2D of regorafenib administered orally in combination with backbone chemotherapy (vincristine and irinotecan) at relapse in pediatric subjects with rhabdomyosarcoma (RMS) and other solid malignant tumors recurrent or refractory to standard therapy.

Expansion Phase of the study:

Subjects must have relapsed/refractory RMS or a solid malignant tumor (Ewing sarcoma, hepatoblastoma, neuroblastoma and Wilms tumor).

A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy

A Multi-center, Open-label, Non-randomized, Phase I Dose Escalation Study of Regorafenib (BAY 73-4506) in Pediatric Subjects With Solid Malignant Tumors That Are Recurrent or Refractory to Standard Therapy

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

MTD is defined as the dose level at which none or 1 of 6 participants experiences dose-limiting toxicity (DLT), when at least 2 of 3-6 participants experience a DLT at the next highest dose

In order to establish a RP2D, the MTD cohort will be expanded to have at least 12 evaluable subjects to confirm the RP2D. It is expected that at least 15 subjects evaluable for DLTs will be necessary to establish the RP2D of the combination"

Individual listings of adverse events will be provided. The incidence of treatment-emergent adverse events and drug-related adverse events, respectively, will be summarized by worst NCI-CTCAE v 4.0 grade and by dose level

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase I Dose Finding and Safety Study of Oral LDE225 in Children and a Phase II Portion to Assess Preliminary Efficacy in Recurrent or Refractory MB	NCT01125800	Medulloblastoma Rhabdomyosarcom... Neuroblastoma Hepatoblastoma Glioma Astrocytoma	LDE225	12 Months - 18 Years	Novartis
A Phase I Dose Finding Study in Children With Solid Tumors Recurrent or Refractory to Standard Therapy	NCT02085148	Pediatric Oncol...	Regorafenib (BA... Vincristine (Ce... Irinotecan (Iri...	6 Months - 18 Years	Bayer

Spots Global Cancer Trial Database for rhabdomyosarcoma,