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 | Completed Phase 1 Results

• 2 other identifiers: CLDE225X21042010-019348-37
• Study Type: interventional
• Target: 76
• Locations: 6 countries
• Sites: 14

Brief Summary

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.

Conditions

Medulloblastoma; Rhabdomyosarcoma; Neuroblastoma; Hepatoblastoma; Glioma; Astrocytoma

Keywords

Recurrent,; refractory,; medulloblastoma,; rhabdomyosarcoma,; neuroblastoma,; hepatoblastoma,; astrocytoma,; children,; pediatric,; hedgehog pathway inhibitor, adult

Outcome Measures

Primary Outcomes (3)

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

  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.

  Baseline, End of dose escalation part (Day 42)

• Maximum Tolerated Dose (MTD) of Sonidegib for Prolonged Use

  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

  Baseline, End of dose escalation part (Day 42)

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

  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.

  Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)

Secondary Outcomes (6)

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

  Baseline (start of study treatment) up to End of treatment (Within 14 days of last dose)

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

  Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

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

  Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

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

  Pre-dose, 0.5, 1, 2, 4, 7 hours (± 15 min) post-dose at Day 1 and Day 22 of Cycle 1

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

  Baseline, Day 28 of Cycle 2, End of treatment (Within 14 days of last dose)

Study Arms (5)

LDE225 233mg/m2 daily dose

EXPERIMENTAL

Pediatric dose.

Drug: LDE225

LDE225 372mg/m2 daily dose

EXPERIMENTAL

Pediatric dose.

Drug: LDE225

LDE225 425 mg/m2 daily dose

EXPERIMENTAL

Pediatric dose.

Drug: LDE225

LDE225 680 mg/m2 daily dose

EXPERIMENTAL

Pediatric dose.

Drug: LDE225

LDE225 800 mg/m2 daily dose

EXPERIMENTAL

Adult dose

Drug: LDE225

Interventions

LDE225 DRUG

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

Also known as: sonidegib

LDE225 233mg/m2 daily dose; LDE225 372mg/m2 daily dose; LDE225 425 mg/m2 daily dose; LDE225 680 mg/m2 daily dose; LDE225 800 mg/m2 daily dose

Eligibility Criteria

• Age: 12 Months - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Phase I - Patients aged ≥12 months and \<18 years, Phase II - Patients ≥12 months
• Phase I - Histologically confirmed diagnosis of medulloblastoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, high grade glioma, or osteosarcoma, that has progressed despite treatment with standard therapies, or for which no standard treatments are available (patients with brainstem gliomas are excluded). Phase II - Histologically confirmed diagnosis of recurrent or relapsed medulloblastoma with at least one measurable lesion.
• Performance Status: Karnofsky ≥60% for patients \>10 yrs, Lansky ≥50 for patients less than or equal to 10 yrs
• Protocol-defined renal , liver and bone marrow function
• Negative pregnancy test before starting study treatment. If of child bearing potential must use 'highly effective' methods of contraception.
• All patients must consent to provide a tumor sample

You may not qualify if:

• Systemic anti-cancer treatment within 2 weeks prior to first dose (6 weeks for nitrosourea, mitomycin and monoclonal antibodies).
• Focal radiotherapy within 4 weeks prior to first dose, or full spinal radiotherapy within 3 months of first dose.
• Unresolved toxicity greater than CTCAE grade 1 from previous anti-cancer therapy or radiotherapy (excluding neurotoxicity, alopecia, ototoxicity, lymphopenia or other specifications in the eligibility criteria for this study), or incomplete recovery from previous surgery, unless agreed by Novartis and the Principal Investigator (PI) and documented.
• Major surgery, serious illness or traumatic injury within 2 weeks of starting study therapy. Patients anticipated to require major surgery within the first 2 cycles of treatment.
• Patients requiring a nasogastric tube for drug administration (G-tubes are permitted)
• Impaired cardiac function
• Pregnant or breast-feeding females
• Impairment of gastrointestinal (GI) function or GI disease

Sponsors & Collaborators

• Novartis Pharmaceuticals: lead

Study Sites (14)

Children's Healthcare of Atlanta Childern Hosp - ATL

Atlanta, Georgia, 30342, United States

Location

Sidney Kimmel Comprehensive Cancer Center/Johns Hopkins Med. John Hopkins

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute DFCI (3)

Boston, Massachusetts, 02115, United States

Location

Seattle Children's Hospital CPKC412A2114

Seattle, Washington, 98105, United States

Location

Novartis Investigative Site

Parkville, Victoria, 3052, Australia

Location

Novartis Investigative Site

Toronto, Ontario, M5G 1X8, Canada

Location

Novartis Investigative Site

Toronto, Ontario, M5G 2M9, Canada

Location

Novartis Investigative Site

Paris, 75231, France

Location

Novartis Investigative Site

Villejuif, 94805, France

Location

Novartis Investigative Site

Bologna, BO, 40139, Italy

Location

Novartis Investigative Site

Milan, MI, 20133, Italy

Location

Novartis Investigative Site

Roma, RM, 00168, Italy

Location

Novartis Investigative Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

Novartis Investigative Site

Newcastle upon Tyne, NE1 4LP, United Kingdom

Location

MeSH Terms

Conditions

Medulloblastoma; Rhabdomyosarcoma; Neuroblastoma; Hepatoblastoma; Glioma; Astrocytoma; Recurrence

Interventions

sonidegib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neuroectodermal Tumors, Primitive; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Myosarcoma; Neoplasms, Muscle Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms, Complex and Mixed; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Limitations and Caveats

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

Results Point of Contact

• Title: Study Director
• Organization: Novartis Pharmaceuticals

862 -778 -8300

Study Officials

• Novartis Pharmaceuticals

  Novartis Pharmaceuticals

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: May 12, 2010
• First Posted: May 18, 2010
• Study Start: February 1, 2011
• Primary Completion: October 1, 2014
• Study Completion: October 1, 2014
• Last Updated: March 20, 2017
• Results First Posted: March 2, 2016

Record last verified: 2016-02

Locations

AU (1); IT (3); US (4); CA (2); FR (2); GB (2)