SADDRIN-1: Sarcomas and DDR-Inhibition; a Combined Modality Study
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
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. 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 are the new drugs AZD1390 and AZD7648, targeting ATM (Ataxia Telangiectasia Mutated) and DNA-dependent protein kinase PK, respectively.
Study Design
Arms and Interventions
| 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 10 mg is proven safe the next cohort will be 40 and thereafter 80 mg |
Combination Product: AZD1390 + radiotherapy
AZD1390 combined with preoperative radiotherapy
|
| Other: AZD7648 the experimental oral drug AZD7648 (starting dose once daily 10 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 20 and thereafter40 mg |
Combination Product: AZD7648 + radiotherapy
AZD7648 combined with preoperative radiotherapy
|
Outcome Measures
Primary Outcome Measures
- safety [2 years]
all adverse events
- tolerability [30 days]
adverse events and more specific woundhealing
Eligibility Criteria
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 (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);
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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;
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WHO Performance Status ≤ 2;
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Able and willing to undergo preoperative RT;
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Able and willing to undergo definitive surgery;
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Able and willing to comply with regular follow-up visits;
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Able and willing to swallow and retain oral medication;
Exclusion Criteria:
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Patients with any type soft tissue sarcoma located above the clavicles.
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Prior malignancies; except another malignancy and disease-free for ≥ 5 years, or completely resected non-melanomatous skin carcinoma or successfully treated in situ carcinoma;
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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);
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Ewing sarcoma and other PNET family tumors, rhabdomyosarcomas (both pediatric and adult), bone sarcomas;
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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;
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Female patients who are pregnant or breast feeding;
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Antoni van Leeuwenhoek | Amsterdam | Netherlands | 1066CX |
Sponsors and Collaborators
- The Netherlands Cancer Institute
- Leiden University Medical Center
- University Medical Center Nijmegen
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- M21SAD