Study evaluating the clinical impact of HDM201 + Pazopanib in patients with P53 wild-type advanced/ metastatic soft tissue sarcomas.

Phase 1/2

Recruiting

Conditions: Advanced/ metastatic soft tissue sarcomas

Interventions: Drug: Pazopanib
Drug: HDM201

Registration Number: 2024-510706-86-00

Lead Sponsor: Centre Leon Berard

Brief Summary: This trial is a two-step Phase I/II study comprising:

Part 1: A dose escalation part with the aim to assess the safety of the proposed combination (N= up to 30 patients). In the dose escalation part, eligible patients will be treated with a fixed dose of pazopanib and escalating doses of HDM201.

Part 2: An extension part to collect preliminary data about the clinical activity of the proposed combination according to the 6M-PFR.

Detailed Description: This trial is a two-step Phase I/II study comprising:

Part 1: A dose escalation part with the aim to assess the safety of the proposed combination (N= up to 30 patients). The dose escalation will be conducted according to a sequential and adaptive Bayesian scheme using the method of Time-to-event Continual Reassessment Method (CRM) to guide dose escalation and estimate the Maximum Tolerated Dose.

In the dose escalation part, eligible patients will be treated with a fixed dose of pazopanib (800 mg/d) and escalating doses of HDM201: 60 mg (starting dose); 80 mg; 100 mg; 120 mg. For a safety reason, a dose level of 40 mg is included in case that the first dose level is found to be toxic. In addition, decrease of pazopanib dosing to 600 mg/d could be appropriate following protocol amendment.

To ensure adequate patient safety during the dose escalation part, there will be a 3-day delay between the first and subsequent patients enrolled in each DL cohort to maximize the safety of enrolled patients.

No intra-patient dose escalation is allowed.

Part 2: An extension part to collect preliminary data about the clinical activity of the proposed combination according to the 6 months Progression Free Rate (6M-PFR).

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 58

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
extension part : Soft-tissue sarcomas with MDM2 amplification	HDM201	The aim of each extension cohort is to provide preliminary evidence of anti-tumor activity while refining toxicity data, and to gain insight progressive disease activity and exploratory biological analyses. A maximum of 14 patients patients will be enrolled in this cohort " Soft-tissue sarcomas with MDM2 amplification ". Both study drugs (pazopanib and HDM201) will be administered as long as the patient experiences clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.
extension part : Soft-tissue sarcomas with no MDM2 amplification	HDM201	A maximum of 14 patients patients will be enrolled in this cohort " Soft-tissue sarcomas with no MDM2 amplification". Both study drugs (pazopanib and HDM201) will be administered as long as the patient experiences clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.
extension part : Soft-tissue sarcomas with no MDM2 amplification	Pazopanib	A maximum of 14 patients patients will be enrolled in this cohort " Soft-tissue sarcomas with no MDM2 amplification". Both study drugs (pazopanib and HDM201) will be administered as long as the patient experiences clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.
extension part : Soft-tissue sarcomas with MDM2 amplification	Pazopanib	The aim of each extension cohort is to provide preliminary evidence of anti-tumor activity while refining toxicity data, and to gain insight progressive disease activity and exploratory biological analyses. A maximum of 14 patients patients will be enrolled in this cohort " Soft-tissue sarcomas with MDM2 amplification ". Both study drugs (pazopanib and HDM201) will be administered as long as the patient experiences clinical benefit in the opinion of the investigator or until unacceptable toxicity or symptomatic deterioration attributed to disease progression as determined by the investigator after an integrated assessment of radiographic data and clinical status or withdrawal of consent.

Primary Outcome Measures

Name	Time	Method
for dose escalation part: the Maximum tolerated dose (MTD) of HDM201 given in combination with a fixed dose of pazopanib.	At the end of cycle 2 (each cycle is 21 days)	The starting dose of HDM201 is 60 mg once every 3 weeks. The dose escalation will be conducted according to a sequential and adaptive Bayesian scheme, using the method of TITE-CRM to determine the MTD of HDM201 in combination with pazopanib. The MTD is defined as the dose associated with a probability of Dose Limiting toxicities (DLTs) the closest to 25%. Estimation of MTD will be based upon the estimation of the probability of a DLT. DLTs are defined as any of the following adverse events (AE) graded using NCI-CTCAE occurring during the DLT period (2 first cycles) and assessed as related to at least one of the study drugs: Grade (G) ≥ 4 neutropenia, G ≥ 3 febrile neutropenia, G ≥ 4 thrombocytopenia or G3 if associated with bleeding and requires platelet transfusion. Non-laboratory AEs of G ≥3 for more than 7 days. Any G3 or G4 laboratory value if: Medical intervention is required to treat the subjects, or the abnormality leads to hospitalization.
Expansion part: preliminary data on efficacy of the combination in 2 parallel, independent cohorts of Soft-tissue sarcomas according to Murine double minute 2 (MDM2) status: amplified and non-amplified.	24W	progression-free rate at 24 weeks (24W-PFR)

Secondary Outcome Measures

Name	Time	Method

Trial Locations

Locations (6): Hôpital de la Timone
🇫🇷
Marseille, France
Institut Paoli Calmettes
🇫🇷
Marseille, France
Centre Leon Berard
🇫🇷
Lyon, France
Oncopole Claudius Regaud
🇫🇷
Toulouse Cedex 9, France
Institut Bergonie
🇫🇷
Bordeaux, France
Institut Gustave Roussy
🇫🇷
Villejuif Cedex, France
Hôpital de la Timone
🇫🇷Marseille, France
Florence DUFFAUD
Site contact
0491385708
florence.duffaud@ap-hm.fr