Sarcomas and DDR-Inhibition; a Combined Modality Study

Study Overview
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Brief Summary
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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 DDRi 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.

Detailed Description
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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. 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 RT. Clinical studies into radiosensitization of STS by combinations of RT and DDR inhibitors are warranted. In this study the candidate inhibitors is the new drugs AZD1390, targeting ATM (Ataxia Telangiectasia Mutated).

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

Conditions
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Soft Tissue Sarcoma Adult

Intervention / Treatment
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* Combination Product: AZD1390 + radiotherapy


Participation Criteria
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Eligibility Criteria
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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; 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;

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: 1 cohorts
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: AZD1390<br>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 10 mg is proven safe the next cohort will be 40 and thereafter 80 mg | Combination Product: AZD1390 + radiotherapy<br>* AZD1390 combined with preoperative radiotherapy<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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soft tissue sarcoma, radiotherapy, DNA Damage Response