Study of Safety and Efficacy of HDM201 in Combination With LEE011 in Patients With Liposarcoma

Study Overview
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Brief Summary
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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.

Official Title
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A Phase Ib/II, Open-label, Multicenter Study of Oral HDM201 in Combination With Oral LEE011 in Adult Patients With Liposarcoma

Conditions
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Liposarcoma

Intervention / Treatment
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* Drug: HDM201
* Drug: LEE011


Participation Criteria
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Eligibility Criteria
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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/exclusion criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HDM201+LEE011<br> | Drug: HDM201<br> <br> Drug: LEE011<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib: Incidence of Dose Limiting Toxicities (DLTs) during the first cycle of treatment. | DLTs in the first cycle of treatment. | 5 years | 
| Phase Ib: Exposure to HDM201 and LEE011 as measured by AUC 0-24h | as measured by AUC0-24h | 5 years | 
| Phase II: Progression free survival (PFS) | To assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib/II: Incidence and severity of AEs and SAEs | Run-in part to assess safety of HDM201 in combination with LEE011 | 5 years | 
| Phase Ib/II: number of patients with dose interruptions and reduction | Run-in part To assess tolerability of HDM201 in combination with LEE011 | 5 years | 
| Phase Ib/II: dose intensity | Run-in part To assess tolerability of HDM201 in combination with LEE011 | 5 years | 
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Cmax | Run-in part to evaluate PK parameters of HDM201 and LEE011 | 5 years | 
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: Tmax | Run-in part to evaluate the PK parameters of HDM201 and LEE011 | 5 years | 
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUClast | Run-in part to evaluate the PK parameters of HDM201 and LEE011 | 5 years | 
| Phase Ib/II: Pharmacokinetics (PK) parameters of HDM201 and LEE011: AUCtau | Run-in part to evaluate the PK parameters of HDM201 and LEE011 | 5 years | 
| Phase Ib/II: Changes from baseline of Pharmacodynamics (PD) markers in blood (GDF-15) | 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. | 5 years | 
| Phase Ib/II: Changes from baseline of Pharmacodynamics (PD) markers in tumor tissue (p21, MDM2) | 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. | 5 years | 
| Phase Ib/II: anti-tumor activity endpoint (BOR, PFS) | Run-in part to assess PD effect of HDM201 and LEE011 and a potential relationship with clinical outcome | 5 years | 
| Phase Ib: BOR, ORR and PFS as per RECIST v1.1, assessed by investigator | Run-in part to assess the preliminary anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma | 5 years | 
| Phase II: BOR, ORR and PFS as per RECIST v1.1, assessed by investigator | Run-in part to further assess the anti-tumor activity of HDM201 in combination with LEE011 in liposarcoma | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liposarcoma, MDM2 inhibition, cdk4 inhibition, HDM201, LEE011