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

NCT05180695 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: ET20-297
• Study Type: interventional
• Target: 47
• Locations: 1 country
• Sites: 5

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.

Conditions

Advanced Soft-tissue Sarcoma; Metastatic Soft-tissue Sarcoma

Keywords

P53 wild type; pazopanib; HDM201; RECIST

Outcome Measures

Primary Outcomes (2)

• for dose escalation part: the Maximum tolerated dose (MTD) of HDM201 given in combination with a fixed dose of pazopanib.

  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.

  At the end of cycle 2 (each cycle is 21 days)

• 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.

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

  24W

Study Arms (2)

extension part : Soft-tissue sarcomas with MDM2 amplification

EXPERIMENTAL

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.

Drug: Pazopanib; Drug: HDM201

extension part : Soft-tissue sarcomas with no MDM2 amplification

EXPERIMENTAL

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.

Drug: Pazopanib; Drug: HDM201

Interventions

Pazopanib DRUG

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.

Also known as: Votrient

extension part : Soft-tissue sarcomas with MDM2 amplification; extension part : Soft-tissue sarcomas with no MDM2 amplification

HDM201 DRUG

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.

Also known as: siremadlin

extension part : Soft-tissue sarcomas with MDM2 amplification; extension part : Soft-tissue sarcomas with no MDM2 amplification

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• I1. Male or female patient ≥ 18 years of age
• I2. Histologically or cytologically confirmed diagnosis of soft tissue sarcoma with documented p53 wild-type (wt) status and known MDM2 status (amplification or no amplification).
• I3. Previously treated by at least one prior chemotherapy line of treatment in the advanced/metastatic setting.
• I4. STS subtypes eligible to pazopanib treatment according to respective SmPC Note: The following tumour types are eligible: Fibroblastic (adult fibrosarcoma, myxofibrosarcoma, sclerosing epithelioid fibrosarcoma, malignant solitary fibrous tumours), so-called fibrohistiocytic (pleomorphic malignant fibrous histiocytoma \[MFH\], giant cell MFH, inflammatory MFH), leiomyosarcoma, malignant glomus tumours, skeletal muscles (pleomorphic and alveolar rhabdomyosarcoma), vascular (epithelioid hemangioendothelioma, angiosarcoma), uncertain differentiation (synovial, epithelioid, alveolar soft part, clear cell, desmoplastic small round cell, extra-renal rhabdoid, malignant mesenchymoma, PEComa, intimal sarcoma), malignant peripheral nerve sheath tumours, undifferentiated soft tissue sarcomas not otherwise specified (NOS) and other types of sarcoma (not listed as ineligible)and liposarcoma.
• The following tumour types ARE NOT eligible: All rhabdomyosarcoma that are not alveolar or pleomorphic, chondrosarcoma, osteosarcoma, Ewing tumours/primitive neuroectodermal tumours (PNET), GIST, dermofibromatosis sarcoma protuberans, inflammatory myofibroblastic sarcoma, malignant mesothelioma and mixed mesodermal tumours of the uterus
• I5. Documented progressive disease and presence of at least one measurable lesion according to RECIST 1.1 (Appendix 01) based on screening tumor assessment.
• I6. Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• I7. Adequate organ system function as assessed by the following minimal requirements (within 7 days prior to first administration of study drugs (C1D1)):
• Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L Platelets ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL (5.6 mmol/L). Transfusion is not allowed within 2 weeks of screening assessment.
• aspartate transaminase and alanine aminotransferase ≤ 2.5x Upper limit of normal or up to 5 Upper limit of normal in case of liver metastasis Bilirubin ≤ 1.5 Upper limit of normal (except in the setting of isolated Gilbert syndrome) Serum creatinine clearance ≥ 30 mL/min (calculated by CKD-EPI -Appendix 03) Calcium, magnesium and potassium within normal limits. Urine Protein to Creatinine ratio (UPC) \<1; if UPC ≥1, 24-hour urine protein must be \<1g (use of urine dipstick for renal function assessment is not acceptable).
• I8. Adequate cardiovascular function:
• QTcF (corrected QT using Fridericia) ≤450ms, from 3 electrocardiograms on screening ECG, within 14 days prior to C1D1 Resting blood pressure systolic \<140 mmHg and diastolic\< 90 mmHg, Left Ventricular Ejection Fraction ≥50% as determined by transthoracic echocardiogram or Multiple Gated acquisition.
• I10. Patients able to swallow orally administered medication and do not have any clinically significant gastrointestinal abnormalities that may alter absorption of study drugs such as malabsorption syndrome or major resection of the stomach or bowels.
• I11. Availability of archival Formalin Fixed Paraffin Embedded tumor sample. This sample must be sent to sponsor once eligibility is confirmed.
• I12. Expansion part only - Presence of at least one biopsiable lesion i.e. at least one lesion with a diameter ≥10 mm, visible by medical imaging and accessible to repeatable percutaneous or endoscopic sampling that permit core needle biopsy without unacceptable risk and suitable for retrieval of a minimum of three, but ideally four, cores using a biopsy needle of at least 16-gauge. Note: RECIST target lesion are not to be biopsied.

You may not qualify if:

• Active peptic ulcer disease
• Known intraluminal metastatic lesion(s) with risk of bleeding
• Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other gastrointestinal conditions with increased risk of perforation
• History of abdominal fistula, gastrointestinal perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
• Forbidden concomitant medications during the study period and Minimal wash-out period before C1D1:
• weeks - Any approved anti-cancer treatment (including hormonotherapy, chemotherapy, biological therapy, targeted therapy or immunotherapy) Note: Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable. Or Any investigational therapy other than the specified therapies in present protocol
• weeks - Radiotherapy - Note: Except palliative radiotherapy on non-target lesions after discussion with the Sponsor
• weeks - Surgery: Major surgical procedure, or significant traumatic injury. Note: If a patient underwent a major surgical procedure, he/she must have adequately recovered from the toxicity (i.e. wound healing) and/or complications from the intervention prior to starting therapy.
• weeks - Live vaccines. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
• week - Medicinal products known to prolong the QT interval and/ or to induce "Torsades de Pointes"
• week - Strong and moderate inducers or inhibitors of CYP3A4/5
• week - Strong inhibitors of P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP)
• Forbidden concomitant medications during the DLT period:
• unless clinically indicated by institutional and/or American Society of Clinical Oncology (ASCO) guidelines - Growth factors targeting the myeloid lineage
• weeks prior treatment start and during the DLT defined period - Prophylactic use of red blood cells and platelet transfusions.

Sponsors & Collaborators

• Novartis: collaborator
• Centre Leon Berard: lead
• National Cancer Institute, France: collaborator

Study Sites (5)

Institut Bergonié

Bordeaux, 33800, France

Location

Centre Léon Bérard

Lyon, 69373, France

Location

Institut Paoli-Calmettes

Marseille, 13273, France

Location

Institut Claudius Regaud

Toulouse, 31059, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

MeSH Terms

Conditions

Sarcoma

Interventions

pazopanib; siremadlin

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Study Design

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

Model Details: 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.

Study Record Dates

• First Submitted: December 7, 2021
• First Posted: January 6, 2022
• Study Start: April 15, 2022
• Primary Completion (Estimated): February 1, 2027
• Study Completion (Estimated): February 1, 2027
• Last Updated: February 10, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (5)