Thoracic Radiotherapy Plus Durvalumab in Elderly and/or Frail NSCLC Stage III Patients Unfit for Chemotherapy (TRADE-hypo)

• ClinicalTrials.gov Identifier: NCT04351256
• Recruitment Status: Recruiting
• First Posted: April 17, 2020
• Last Update Posted: November 30, 2022
• Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Collaborators: Thoraxklinik-Heidelberg gGmbH; AstraZeneca
• Information provided by (Responsible Party): Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest

Tracking Information

• First Submitted Date: February 29, 2020
• First Posted Date: April 17, 2020
• Last Update Posted Date: November 30, 2022
• Actual Study Start Date: May 20, 2020
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 15, 2020)

• Toxicity (pneumonitis) [ Time Frame: up to 35 months ]
  Toxicity, defined by the occurence of treatment-related pneumonitis grade ≥ 3
• Objective response [ Time Frame: up to 35 months ]
  Objective response evaluated at 12 weeks (3 months) after first durvalumab administration according to RECIST 1.1 criteria

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: April 15, 2020)

• treatment-related AEs and SAEs [ Time Frame: up to 35 months ]
  Occurence of treatment-related AEs and SAEs according to CTCAE V5.0
• frequency of abnormal laboratory parameters (hematology panel, chemistry panel, Thyroid-stimulating hormone (TSH)) [ Time Frame: up to 35 months ]
  Frequency of abnormal values of laboratory parameters
• Progression Free Survival (PFS) [ Time Frame: up to 35 months ]
  PFS according to RECIST 1.1
• Duration of Clinical Benefit [ Time Frame: up to 35 months ]
  Duration of Clinical Benefit (Duration of Complete Response (CR), Partial Response (PR), Stable Disease (SD)) according to RECIST 1.1
• Metastasis-Free Survival (MFS) [ Time Frame: up to 35 months ]
  Time from the date of allocation / randomization to the date of first observed metastatic lesion (investigator assessment according to RECIST 1.1) or death from any cause
• Overall survival [ Time Frame: up to 35 months ]
  time from the date of treatment allocation to the date of death
• Quality of Life (FACT-L) [ Time Frame: up to 35 months ]
  measured by FACT-L questionnaire
• objective response rate [ Time Frame: up to 35 months ]
  Descriptive sub-group analyses of efficacy in relation to PD-L1 expression levels (<°1% vs ≥°1%)

• Original Secondary Outcome Measures: Same as current

Current Other Pre-specified Outcome Measures (submitted: April 15, 2020)

Vulnerability assessment based on the G8-screening questionnaire [ Time Frame: up to 35 months ]

Vulnerability assessment based on the G8-screening questionnaire and its association to survival and outcome

• Original Other Pre-specified Outcome Measures: Same as current

Descriptive Information

• Brief Title: Thoracic Radiotherapy Plus Durvalumab in Elderly and/or Frail NSCLC Stage III Patients Unfit for Chemotherapy
• Official Title: Thoracic Radiotherapy Plus Durvalumab in Elderly and/or Frail NSCLC Stage III Patients Unfit for Chemotherapy - Employing Optimized (Hypofractionated) Radiotherapy to Foster Durvalumab Efficacy
• Brief Summary: This is a randomized, open-label, multicenter, phase II trial investigating the combination of thoracic radiotherapy plus Durvalumab in patients with locally advanced, unresectable NSCLC (stage III) that are unfit for chemotherapy (e.g. due to age and/or frailty).

Detailed Description

This trial investigates the feasibility and treatment efficacy when combining durvalumab treatment with either conventionally fractionated (CON-group) or hypofractionated thoracic radiotherapy (HYPO-group) in previously untreated NSCLC stage III patients prone to radiotherapy only.

A safety lead-in phase with stop-and-go design will precede full enrollment into the HYPO-group.

Tumor tissue as well as blood and stool samples will be collected for future biomarker analysis.

It is hypothesized that TRT combined with concurrent durvalumab administration in patients with unresectable stage III NSCLC, who are not amenable to sequential radio-/chemotherapy

1. is safe and feasible,
2. will improve treatment efficacy by a synergistic effect of checkpoint inhibition and the photon-induction of immunostimulatory pathways.
3. will have an effect on the immunological characteristics of the tumor, the microenvironment, and the systemic immune response, such as upregulation of PD-L1 or secretion of stimulatory cytokines and recruitment and priming of immunocompetent cells, which might then mediate the "abscopal effect" beyond the irradiated targets.

• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Durvalumab treatment and Thoracic Radiotherapy

Masking: None (Open Label)
Primary Purpose: Treatment

• Condition: NSCLC, Stage III

Intervention

• Drug: Durvalumab Injection [Imfinzi]
  Durvalumab fixed dose of 1,500 mg
• Radiation: Thoracic Radiotherapy (TRT) conventionally
  Conventionally fractionated TRT consisting of 30 x 2 Gy (60 Gy) within 6 weeks
• Radiation: Thoracic Radiotherapy (TRT) hypofractionated
  Hypofractionated TRT consisting of 20 x 2,75 Gy (55 Gy) within 4 weeks

Study Arms

• Experimental: Arm A (HYPO group)
  • Durvalumab at a fixed dose of 1,500 mg as an IV infusion over 1 hour, on day 1, to be repeated every 4 weeks (Q4W) for a maximum of 12 cycles
  • Thoracic radiation therapy (TRT): hypofractionated thoracic radiotherapy consisting of 20 x 2,75 Gy (55 Gy) within 4 weeks (+9 days)
  Interventions:

  • Drug: Durvalumab Injection [Imfinzi]
  • Radiation: Thoracic Radiotherapy (TRT) hypofractionated
• Active Comparator: Arm B (CON group)
  • Durvalumab at a fixed dose of 1,500 mg as an IV infusion over 1 hour, on day 1, to be repeated every 4 weeks (Q4W) for a maximum of 12 cycles
  • Thoracic radiation therapy (TRT): conventional fractions of 30 x 2 Gy (60 Gy) within 6 weeks (+9 days)
  Interventions:

  • Drug: Durvalumab Injection [Imfinzi]
  • Radiation: Thoracic Radiotherapy (TRT) conventionally

• Publications *: Bozorgmehr F, Chung I, Christopoulos P, Krisam J, Schneider MA, Bruckner L, Mueller DW, Thomas M, Rieken S. Thoracic radiotherapy plus Durvalumab in elderly and/or frail NSCLC stage III patients unfit for chemotherapy - employing optimized (hypofractionated) radiotherapy to foster durvalumab efficacy: study protocol of the TRADE-hypo trial. BMC Cancer. 2020 Aug 26;20(1):806. doi: 10.1186/s12885-020-07264-8.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: April 15, 2020): 88
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: March 2023
• Estimated Primary Completion Date: March 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Fully-informed written consent and locally required authorization (European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
2. Age ≥ 18 years.
3. Histologically documented diagnosis of unresectable stage III NSCLC.
4. Non-feasibility of sequential chemo-/radiotherapy as determined by the site's multi-disciplinary tumor board; if there is no tumor board, then this decision will be made by the investigator in consultation with a radiation oncologist, if the investigator is not a radiation oncologist; or by the investigator in consultation with an oncologist, if the investigator is not an oncologist.

5. Fulfills at least one of the following criteria:

   • Performance status (PS) 2 (ECOG scale)
   • ECOG 1 and CCI ≥ 1
   • Age ≥ 70 years
6. Must have a life expectancy of at least 12 weeks.
7. FEV1 ≥ 40%
8. DLCO or DLCO/VA (Hb-corrected, if available) ≥ 40%
9. FVC or VC ≥ 70%
10. At least one measurable site of disease as defined by RECIST 1.1

11. Adequate bone marrow and renal function including the following:

    • Hemoglobin ≥ 9.0 g/dL;
    • absolute neutrophil count ≥ 1.0 x 103/L;
    • platelets ≥75x 109/L;
    • Calculated creatinine clearance ≥30 mL/min as determined by the Cockcroft-Gault equation

12. Adequate hepatic function (with stenting for any obstruction, if required) including the following:

    • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (ULN);
    • AST (SGOT) / ALT (SGPT) ≤ 2.5x institutional ULN
13. Female patients with reproductive potential must have a negative urine or serum pregnancy test within 7 days prior to start of trial.
14. Evidence of post-menopausal status or negative urinary or serum pregnancy test for female pre-menopausal patients.
15. The patient is willing and able to comply with the protocol for the duration of the study, including hospital visits for treatment and scheduled follow-up visits and examinations.

Exclusion Criteria:

1. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study, or during the follow-up period of an interventional study.
2. Participation in another clinical study with an investigational product within 21 days prior to the first dose of the study treatment.
3. Prior immunotherapy or use of other investigational agents, including prior treatment with an anti-Programmed Death receptor-1 (PD-1),anti-Programmed Death-1 ligand-1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte associated antigen-4 (anti-CTLA-4) antibody, therapeutic cancer vaccines.
4. History or current radiology suggestive of interstitial lung disease.
5. Oxygen-dependent medical condition.
6. Any concurrent chemotherapy, investigational product (IMP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer related conditions (eg, hormone replacement therapy) is acceptable.
7. Prior thoracic radiotherapy within the past 5 years before the first dose of study drug.
8. Major surgery (as defined by the Investigator) within 4 weeks prior to enrollment into the study; patients must have recovered from effects of any major surgery. Note: Local non-major surgery for palliative intent is acceptable.

9. Active or prior documented autoimmune or inflammatory disorders (except inflammatory bowel disease [e.g. ulcerative colitis or Crohn's disease]; ( including diverticulitis [with the exception of diverticulosis], celiac disease, systemic lupus erythematosus, Sarcoidosis, or Wegener's syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis). The following are exceptions to this criterion:

   • Patients with vitiligo or alopecia
   • Patients with hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement
   • Any chronic skin condition that does not require systemic therapy
   • Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
10. Active, uncontrolled inflammatory bowel disease [e.g. ulcerative colitis or Crohn's disease]. Patients in stable remission for more than 1 year may be included.
11. Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, interstitial lung disease, 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.

12. History of another primary malignancy except for:

    • Malignancy treated with curative intent and with no known active disease ≥ 3 years before the first dose of IMP and of low potential risk for recurrence
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Farastuk Bozorgmehr, Dr. med.; +49 6221-396 8077; farastuk.bozorgmehr@med.uni-heidelberg.de

Contact: Johanna Riedel, Dr. rer. med.; riedel.johanna@ikf-khnw.de

• Listed Location Countries: Germany

Administrative Information

• NCT Number: NCT04351256
• Other Study ID Numbers: TRADE-hypo; 2019-002192-33 ( EudraCT Number ); AIO-YMO/TRK-0319 ( Other Identifier: AIO ); ESR-18-13893 ( Other Grant/Funding Number: AstraZeneca )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Original Responsible Party: Same as current
• Current Study Sponsor: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Original Study Sponsor: Same as current

Collaborators

• Thoraxklinik-Heidelberg gGmbH
• AstraZeneca

Investigators

• Principal Investigator: Farastuk Bozorgmehr, Dr. med.; Dept. of Thoracic Oncology Thoraxklinik at Heidelberg University

• PRS Account: Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest
• Verification Date: November 2022