Phase II Study of Radiotherapy Followed by Durvalumab and Ceralasertib in Stage III NSCLC Patients With Thoracic Relapses +/- Oligometastases After PACIFIC Regimen

NCT06680050 | Recruiting Phase 2 DMC

• 1 other identifier: 2024-515942-18-01
• Study Type: interventional
• Target: 21
• Locations: 2 countries
• Sites: 9

Brief Summary

Aim of this phase 2 study is to explore the safety and efficacy of thoracic re-irradiation +/- SBRT to oligometastases (\<3) followed after an interval of 2 weeks by durvalumab and ceralasertib for patients with thoracic relapses +/- oligometastases after PACIFIC or PACIFIC-like (concurrent or sequential chemo-radiotherapy followed by maintenance durvalumab) regimens.

Conditions

Non Small Cell Lung Cancer NSCLC

Outcome Measures

Primary Outcomes (2)

• Safety and tolerability, in terms of number of grade 3 or higher adverse events judged as at least possibly related to study treatment regimen

  within 6 months from the start of study treatment

• PFS

  PFS is defined as the time from the date of enrolment until the date of first disease progression or death to any cause, whichever comes first.

  12 months

Secondary Outcomes (4)

• ORR

  12 months

• Efficacy in terms of PFS rate

  6 and 12 months

• Efficacy in terms of OS

  6 and 12 months

• Efficacy in terms of OS rate

  6 and 12 months

Study Arms (1)

Radiotherapy followed by Durvalumab+Ceralasertib

EXPERIMENTAL

Drug: Durvalumab (MEDI4736); Drug: Ceralasertib; Radiation: radiotherapy

Interventions

Ceralasertib DRUG

Ceralasertib dose will be administered orally, 240mg BID, approximately 12 ± 2 hours apart, days 1 to 7 q28 (Q4W), up to progression or unacceptable toxicity.

Radiotherapy followed by Durvalumab+Ceralasertib

radiotherapy RADIATION

Loco-regional recurrences of the primary tumor and regional lymph node metastases will be treated with a total dose of 36 to 50 Gy in daily fractions with a dose of 2 to 3 Gy per fraction. Two weeks from the last dose of radiotherapy, a systemic treatment with durvalumab and ceralasertib will be started.

Radiotherapy followed by Durvalumab+Ceralasertib

Durvalumab (MEDI4736) DRUG

Durvalumab will be administered via IV infusion at a dose of 1500 mg on day 8 Q4W until confirmed disease progression unless there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.

Radiotherapy followed by Durvalumab+Ceralasertib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Provision of signed, written and dated informed consent and any locally required authorization
• Male or female aged 18 years or older
• ECOG Performance Status of 0-2
• Life expectancy ≥ 6 months at the start of treatment
• Body weight \>30kg
• Maintenance treatment with durvalumab for a minimum of 3 months
• Histologically or cytologically documented locally advanced NSCLC at relapse
• Measurable disease as defined by RECIST v1.1
• Documented tumor cell PD-L1 status at first diagnosis and/or at relapse
• Thoracic progression as defined by PACIFIC protocol, with or without a maximum of 3 metastatic lesions amenable to local radiotherapy (at discretion of treating center)
• Interval of \> 12 months between the end of the first thoracic radiotherapy (PACIFIC)
• Pre-treatment whole body CT scan with i.v. contrast medium
• Pre-treatment CT-PET scan
• Pre-treatment brain MRI
• Evidence of post-menopausal status, or negative urinary/serum pregnancy test for female pre-menopausal patients

You may not qualify if:

• Patients who discontinued durvalumab due to local or systemic progression during the maintenance phase \< 12 months after the end of CRT
• Patients who experienced, during the maintenance phase with durvalumab after CRT, grade 3 or more documented immune-related toxicity (with the exception of fully recovered endocrine toxicities) or grade 3 or more radiation-induced pneumonitis.
• Any unresolved toxicity NCI CTCAE from previous anticancer therapy not completely resolved or not resolved to baseline prior to screening for this study with the exception of alopecia, vitiligo, and the laboratory values defined below
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
• Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Any toxicity that led to permanent discontinuation of prior immunotherapy
• Patients with more than 3 distant metastases (non-oligometastatic disease)
• Patients with metastatic disease progression not amenable for radical radiotherapy such as malignant ascites, pleural or pericardial effusion, diffuse lymphangiosis of skin or lung, diffuse bone marrow metastasis, metastasis invading the GI tract, abdominal masses/abdominal organomegaly, identified by physical exam that is not measurable by reproducible imaging techniques.
• Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
• Diagnosis of ataxia telangiectasia
• Patients harboring targetable genomic alterations, such as EGFR, HER-2 or MET exon14 skipping mutations, ALK, ROS1, RET or NTRK rearrangements. Molecular profiling can be assessed on archival tumor samples or on new tissue or liquid biopsy.
• Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• Concurrent participation (including the follow-up period) in another clinical study with an investigational product or during the last 4 weeks unless it is an observational (non-interventional) clinical study.
• Any concurrent chemotherapy, immunotherapy, biological or hormonal therapy only for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

Sponsors & Collaborators

• Mario Negri Institute for Pharmacological Research: lead

Study Sites (9)

ASST degli Spedali Civili di Brescia

Brescia, Italy

NOT YET RECRUITING

Azienda Ospedaliero Universitaria Careggi

Florence, Italy

RECRUITING

IRCCS Ospedale Policlinico San Martino, Genova

Genova, Italy

RECRUITING

ASST Grande Ospedale Metropolitano Niguarda

Milan, Italy

RECRUITING

Fondazione IRCCS Istituto Nazionale dei Tumori

Milan, Italy

RECRUITING

Azienda ospedaliera di Padova

Padua, Italy

NOT YET RECRUITING

Azienda Ospedaliero - Universitaria di Parma

Parma, Italy

NOT YET RECRUITING

University Hospital of Geneva

Geneva, Switzerland

NOT YET RECRUITING

University Hospital Zurich

Zurich, Switzerland

NOT YET RECRUITING

Related Publications (1)

• Filippi AR, Rulli E, Signorelli D, Willmann J, Durham A, De Simone I, Santoni A, Galli F, Carlucci L, Torri V, Lo Russo G, Addeo A, Guckenberger M. Rationale and Design of the AUSTRAL trial: An Open-Label, Multicenter, Phase II Study Evaluating Radiotherapy Followed by Durvalumab (MEDI4736) and Ceralasertib (AZD6738) in Stage III NSCLC Patients With Thoracic Relapses and/or Oligometastases After the PACIFIC Regimen. Clin Lung Cancer. 2025 Dec;26(8):e633-e638. doi: 10.1016/j.cllc.2025.07.006. Epub 2025 Jul 12.

  PMID: 40781023 DERIVED

MeSH Terms

Interventions

durvalumab; ceralasertib; Radiotherapy

Intervention Hierarchy (Ancestors)

Therapeutics

Central Study Contacts

Irene De Simone, Project manager

CONTACT

+39 02 39014661; irene.desimone@marionegri.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 30, 2024
• First Posted: November 8, 2024
• Study Start: August 7, 2025
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): January 1, 2029
• Last Updated: December 18, 2025

Record last verified: 2025-12

Locations

CH (2); IT (7)