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

Primary Purpose

Soft Tissue Sarcoma Adult

Status

Recruiting

Phase

Phase 1

Locations

Netherlands

Study Type

Interventional

Intervention

AZD1390 + radiotherapy

About this trial

This is an interventional treatment trial for Soft Tissue Sarcoma Adult focused on measuring soft tissue sarcoma, radiotherapy, DNA Damage Response

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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);
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;

Sites / Locations

Antoni van LeeuwenhoekRecruiting

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

AZD1390

Arm Description

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

Outcomes

Primary Outcome Measures

Drug safety

all adverse events

Drug tolerability

adverse events and more specific woundhealing

Secondary Outcome Measures

Tumor regression

pathological remission

Local control rates

Histopathological response and MRI

Rate of R0 resection

Histological examination of surgical specimens

Rate of R1 resection

Histological examination of surgical specimens

Full Information

NCT ID

NCT05116254

First Posted

October 14, 2021

Last Updated

April 24, 2023

Sponsor

The Netherlands Cancer Institute

Collaborators

Leiden University Medical Center, University Medical Center Nijmegen

1. Study Identification

Unique Protocol Identification Number

NCT05116254

Brief Title

Sarcomas and DDR-Inhibition; a Combined Modality Study

Acronym

SADDRIN-1

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 18, 2022 (Actual)

Primary Completion Date

March 1, 2024 (Anticipated)

Study Completion Date

March 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The Netherlands Cancer Institute

Collaborators

Leiden University Medical Center, University Medical Center Nijmegen

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. 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.

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 is the new drugs AZD1390, targeting ATM (Ataxia Telangiectasia Mutated).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Soft Tissue Sarcoma Adult

Keywords

soft tissue sarcoma, radiotherapy, DNA Damage Response

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Sequential Assignment

Model Description

1 cohorts

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

AZD1390

Arm Type

Other

Arm Description

Intervention Type

Combination Product

Intervention Name(s)

AZD1390 + radiotherapy

Intervention Description

AZD1390 combined with preoperative radiotherapy

Primary Outcome Measure Information:

Title

Drug safety

Description

all adverse events

Time Frame

2 years

Title

Drug tolerability

Description

adverse events and more specific woundhealing

Time Frame

30 days

Secondary Outcome Measure Information:

Title

Tumor regression

Description

pathological remission

Time Frame

After 5 weeks of RT and DDRi-based drug treatment

Title

Local control rates

Description

Histopathological response and MRI

Time Frame

2 years

Title

Rate of R0 resection

Description

Histological examination of surgical specimens

Time Frame

Directly after surgery

Title

Rate of R1 resection

Description

Histological examination of surgical specimens

Time Frame

Directly after surgery

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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; 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;

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Rick Haas, MD PhD

Phone

+31205129111

r.haas@nki.nl

First Name & Middle Initial & Last Name or Official Title & Degree

Neeltje Steeghs, MD PhD

Phone

+31205129111

n.steeghs@nki.nl

Facility Information:

Facility Name

Antoni van Leeuwenhoek

City

Amsterdam

ZIP/Postal Code

1066CX

Country

Netherlands

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Rick Haas, MD, PhD

Phone

+31205129111

r.haas@nki.nl

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Sarcomas and DDR-Inhibition; a Combined Modality Study

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