Combining radiation therapy with a new drug for soft tissue sarcoma treatment

Sarcomas and DDR-Inhibition; a Neoadjuvant Phase I Combined Modality Study.

This study is testing a new drug combined with radiation therapy to see if it helps people with soft tissue sarcoma feel better and have fewer problems after treatment.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: The Netherlands Cancer Institute (Academic / other)
• Drugs / interventions: durvalumab, chemotherapy, immunotherapy, radiation
• Locations: 1 site (Amsterdam)
• Trial ID: NCT05116254 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the safety and tolerability of a combined modality treatment for patients with newly diagnosed, non-metastatic soft tissue sarcoma. The approach involves administering a DNA Damage Response inhibitor, AZD1390, alongside radiotherapy, with or without the immunotherapy durvalumab. The study aims to assess systemic toxicities, wound healing post-surgery, and to define the recommended phase 2 dose (RP2D) for these combinations. By enhancing the effectiveness of radiotherapy, the trial seeks to improve patient outcomes and reduce local relapses.

Who should consider this trial

Good fit: Ideal candidates are adults with newly diagnosed intermediate to high-grade soft tissue sarcoma localized to the extremities.

Not a fit: Patients with metastatic disease or those unable to undergo preoperative radiotherapy and definitive surgery may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could lead to improved tumor response rates and reduced local relapses in soft tissue sarcoma patients.

How similar studies have performed: Other studies have explored similar approaches combining radiotherapy with DDR inhibitors, showing promising results in enhancing treatment efficacy.

Eligibility criteria

Inclusion Criteria:

* Histologically confirmed newly diagnosed intermediate to high grade soft tissue sarcoma localized to the extremities, for which the standard treatment is a combination of RT and surgery (in other words deep seated and/or \> 5cm in largest tumor diameter and/or an anticipated close resection margin and/or grade II/III according to the FNCLCC definition);
* Patients staged by at least a CT scan of the chest (and a CT scan of the abdomen, if deemed indicated according to local practices, e.g. in case of a myxoid liposarcoma). Staging may also be performed by FDG-PET scanning and or total body MRI scans. This staging procedure should not reveal metastatic disease. If, however, a low metastatic burden is detected such that this does not preclude the application of both preoperative RT and definitive surgery, patients are allowed to participate;
* WHO Performance Status ≤ 2;
* Able and willing to undergo preoperative RT;
* Able and willing to undergo definitive surgery;
* Able and willing to comply with regular follow-up visits;
* Able and willing to swallow and retain oral medication;
* Age ≥ 18 years;
* Body weight \>30kg;
* Must have a life expectancy of at least 12 weeks;
* Adequate organ function as defined in Table 5;
* Signed written informed consent prior to any study specific procedures or sampling

Exclusion Criteria:

* Patients with any type soft tissue sarcoma located above the clavicles.
* Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma;
* Patients with recurrent sarcomas who underwent prior RT to the target lesion (if the primary sarcoma was managed by surgery only and no perioperative RT, patients are eligible);
* Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), bone sarcomas;
* Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial;
* Female patients who are pregnant or breast feeding;
* Intention to perform an isolated limb perfusion, instead of a tumor resection;
* Neoadjuvant chemotherapy to be scheduled between end of RT and definitive surgery is not allowed. (neoadjuvant chemotherapy before start of study RT is allowed);
* Concomitant treatment with medicines listed as 'prohibited' or 'excluded';
* Treatment with moderate and strong inhibitors or inducers of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St John's Wort);

Additional criteria for durvalumab plus AZD1390:

* Past medical history of allogenic organ transplantation;
* Past medical history of leptomeningeal carcinomatosis;
* Past medical history or active autoimmune or inflammatory disorders
* History or presence of primary immunodeficiency
* Presence of active hepatitis infections or HIV
* Treatment with or prior use of immunosuppressive medication within 2 weeks before the start of treatment
* Prior treatment with anti-PD-1, anti PD-L1 or anti CTLA-4 immunotherapy

Where this trial is running

Amsterdam

• Antoni van Leeuwenhoek — Amsterdam, Netherlands (Recruiting)

Study contacts

• Principal investigator: Rick Haas, MD Prof — The Netherlands Cancer Institute
• Study coordinator: Rick Haas, MD Prof

Conditions Soft Tissue Sarcoma Adult; soft tissue sarcoma; radiotherapy; DNA Damage Response