Neoplasms

All Conditions

Rare Diseases

Sarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

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.

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.

Part 1: A dose escalation part with the aim to assess the safety of the proposed combination. Eligible patients will be treated with a fixed dose of pazopanib (800mg/d, continuously) and escalating doses of HDM201. Both study drugs 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 or withdrawal of consent.

Part 2: An extension part with a fixed dose of pazopanib (800mg/d, continuously) and the recommended phase 2 dose of HDM201 determined during the dose escalation part. Both study drugs 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 or withdrawal of consent.

Pazopanib

HDM201

Jean-Yves BLAY, MD

Philippe CASSIER, MD

Mariella SPALATO CERUSO, MD

Antoine ITALIANO, MD

Coriolan LEBRETON, MD

Florent PEYRAUD, MD

Maud TOULMONDE, MD

Medhi BRAHMI, MD

Lucas DE CRIGNIS, MD

Brunhilde HANVIC, MD

Aurélie SWALDUZ, MD

Armelle VINCENEUX, MD

Hélène VANACKER, MD

Loic VERLINGUE, MD

Catherine TERRET, MD

Thibaud VALENTIN, MD

Carlos-Alberto GOMEZ-ROCA, MD

Iphigénie KORAKIS, MD

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.

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).

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 pazopanib in combination with HDM201. This method allows continual accrual (i.e. the study will be opened to accrual continually) throughout the trial while using the 6-week toxicity endpoint as basis of dose escalation.

Dose allocation will be centrally defined, before each inclusion considering the DLT observed in all patients previously evaluated, and the current toxicity status of patients who have not received a full 2-cycle treatment (i.e. DLT period is still ongoing).

* A cumulative experience of 4 cycles at a given DL is required before allowing dose escalation to the next DL. Cumulative experience is defined as the addition of observation periods of all included and treated patients.
* A maximum of 6 patients can be included and treated at a same dose level before reassessment occurred.

HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas

A Multicenter, Phase I/II Study Evaluating the Clinical Impact of HDM201 + Pazopanib in Patients With P53 Wild-type Advanced/ Metastatic Soft Tissue Sarcomas (AMPHISARC)

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.

progression-free rate at 24 weeks (24W-PFR)

Novartis

National Cancer Institute, France

Centre Leon Berard

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas	NCT05180695	Advanced Soft-t... Metastatic Soft...	Pazopanib HDM201	18 Years -	Centre Leon Berard
HDM201 and Pazopanib in Patients With P53 Wild-type Advanced/Metastatic Soft Tissue Sarcomas	NCT05180695	Advanced Soft-t... Metastatic Soft...	Pazopanib HDM201	18 Years -	Centre Leon Berard

Spots Global Cancer Trial Database for p53 wild type