Sarcomas and DDR-Inhibition; a Combined Modality Study (SADDRIN-1)

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

To assess the safety and tolerability profile, in the pre- and perioperative period (up to 30 days post-surgery), of combined modality treatment (CMT) by administering AZD1390 with or without durvalumab and RT concurrently treating newly diagnosed, non-metastatic soft tissue sarcoma patients with DDRi-based CMT, in the specific context of systemic toxicities, wound healing post-surgery and in defining the RP2D for the combinations to support further clinical evaluation.

Study Overview

• Status: Terminated
• Conditions: Soft Tissue Sarcoma Adult
• Intervention / Treatment: Combination product: AZD1390 + radiotherapy; Combination product: AZD1390 + durvlaumab + radiotherapy

Detailed Description

Despite improvements in surgery and radiation for soft tissue sarcoma (STS) patients, local relapses remain an important event for these patients. Most STS subtypes are considered radioresistant and immune cold tumor due to a lack of T-cell infiltration. Investigations into radiosensitization mediated by combining systemic compounds with neoadjuvant radiotherapy (RT) may translate into an increased rate of pathological responses, an increased rate of R0 resections and thus fewer local relapses.

RT is highly potent in inducing DNA damage. Normal cells are usually sufficiently able to repair this damage timely before the next fraction because of an intact DNA Damage Response (DDR) pathway. Frequently, tumor cells have (partial or complete) defects in the DDR pathways rendering them more sensitive to radiation than normal tissues. Inhibition of constituents of the DDR pathways may further widen the therapeutic window of fractionated radiotherapy, and combined with radiotherapy may result in increased tumor T-cell infiltration, creating an opportunity for immunotherapy. Clinical studies into radiosensitization of STS by combinations of radiotherapy and DDR inhibitors with or without immunotherapy are warranted. In this study the DDR candidate inhibitor is new drug candidate AZD1390 targeting ATM (Ataxia Telangiectasia Mutated). The immunotherapy candidate of this study is durvalumab (MEDI4736) targeting PD-L1 (programmed death-ligand 1).

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1066CX
    • Antoni van Leeuwenhoek

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: AZD1390; The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy. Drug will be taken at same day as radiotherapy for 5 weeks at weekdays. When starting dose of 20 mg is proven safe the next cohort will be 100 and thereafter 200, 400 mg	Combination product: AZD1390 + radiotherapy; AZD1390 combined with preoperative radiotherapy
Other: AZD1390 + durvalumab; The experimental oral drug AZD1390 (starting dose once daily 20 mg) will be combined with radiotherapy and durvalumab (fixed dose 1500 mg Q4W, until surgery). Drug will be taken at same day as radiotherapy for 5 weeks at weekdays. The dose of AZD1390 in the AZD1390 plus durvalumab cohort will follow the dosing of the AZD1390 only cohort. When starting dose of 20 mg and the next dose of AZD1390 only has been proven safe, the next cohort will be 100 and thereafter 200, 400 mg.	Combination product: AZD1390 + durvlaumab + radiotherapy; AZD1390 combined with durvalumab and preoperative radiotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Drug safety	all adverse events	2 years
Drug tolerability	adverse events and more specific woundhealing	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor regression	pathological remission	After 5 weeks of RT and DDRi-based drug treatment
Local control rates	Histopathological response and MRI	2 years
Rate of R0 resection	Histological examination of surgical specimens	Directly after surgery
Rate of R1 resection	Histological examination of surgical specimens	Directly after surgery

Collaborators and Investigators

• Sponsor: The Netherlands Cancer Institute
• Collaborators: Leiden University Medical Center; University Medical Center Nijmegen
• Investigators: Principal Investigator: Rick Haas, MD Prof, The Netherlands Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): July 18, 2022
• Primary Completion (Actual): December 9, 2025
• Study Completion (Actual): December 9, 2025

Study Registration Dates

• First Submitted: October 14, 2021
• First Submitted That Met QC Criteria: November 2, 2021
• First Posted (Actual): November 10, 2021

Study Record Updates

• Last Update Posted (Actual): January 23, 2026
• Last Update Submitted That Met QC Criteria: January 21, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: radiotherapy; soft tissue sarcoma; DNA Damage Response
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue; Sarcoma; Therapeutics; Radiotherapy; AZD1390
• Other Study ID Numbers: M21SAD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No