Liposarcoma
Conditions
Keywords
Liposarcoma, MDM2 inhibition, cdk4 inhibition, HDM201, LEE011
Brief summary
To determine the MTD/RP2D of the HDM201 and LEE011 combination and evaluate whether the combination is safe and has beneficial effects in patients with liposarcoma.
Interventions
DRUGHDM201
DRUGLEE011
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with histologically documented, locally advanced or metastatic WD/DD liposarcoma who have received at least one prior systemic therapy * Patients with radiologic progression, defined by RECIST v.1.1, occurring while on/or within 6 months after last systemic treatment, prior to enrollment * ECOG performance status of 0-1
Exclusion criteria
* Prior treatment with compounds with the same mode of action * Patients with TP53 mutated tumors, if the molecular status is known * Symptomatic central nervous system metastases * Inadequate organ function * Previous and concomitant therapy that precludes enrollment, as defined by protocol Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment. | 5 years | DLTs in the first cycle of treatment. |
| Phase Ib: Exposure to HDM201 and LEE011 as measured by AUC 0-24h | 5 years | as measured by AUC0-24h |
| Phase II: Progression free survival (PFS) | 5 years | To assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase Ib/II: anti-tumor activity endpoint (BOR, PFS) | 5 years | Run-in part to assess PD effect of HDM201 and LEE011 and a potential relationship with clinical outcome |
| Phase Ib/II: Incidence and severity of AEs and SAEs | 5 years | Run-in part to assess safety of HDM201 in combination with LEE011 |
| Phase Ib/II: number of patients with dose interruptions and reduction | 5 years | Run-in part To assess tolerability of HDM201 in combination with LEE011 |
| Phase Ib/II: dose intensity | 5 years | Run-in part To assess tolerability of HDM201 in combination with LEE011 |
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax | 5 years | Run-in part to evaluate PK parameters of HDM201 and LEE011 |
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Tmax | 5 years | Run-in part to evaluate the PK parameters of HDM201 and LEE011 |
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast | 5 years | Run-in part to evaluate the PK parameters of HDM201 and LEE011 |
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUCtau | 5 years | Run-in part to evaluate the PK parameters of HDM201 and LEE011 |
| Phase Ib/II: Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15) | 5 years | Run-in part measure of GDF-15 fold-change in protein levels (PD direct targets of p53) to assess PD changes from baseline in blood and a potential relationship with clinical outcome. |
| Phase Ib/II: Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2) | 5 years | Run-in part measure of p21 and MDM2 protein levels by IHC (H-Score) (p53 and CDK4 pathways) to assess changes from baseline of PD markers in tumor tissue and a potential relationship with clinical outcome. |
| Phase Ib: BOR, ORR and PFS as per RECIST v1.1, assessed by investigator | 5 years | Run-in part to assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma |
| Phase II: BOR, ORR and PFS as per RECIST v1.1, assessed by investigator | 5 years | Run-in part to further assess the anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma |
Countries
Canada, France, Germany, Singapore, Spain, Taiwan
Outcome results
None listed