Concomitant Radiotherapy, Tremelimumab & Durvalumab for Advanced NSCLC Patients Progressing on First-line Immunotherapy

NCT05000710 | Active Not Recruiting Phase 2

• 1 other identifier: ESR-17-13252
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

This is an open-label, single-arm, phase 2a trial with a safety run-in cohort followed by a Simon two-step design expansion cohort, of two checkpoint blockage treatments and radiotherapy in the treatment of locally advanced or metastatic NSCLC who have failed first-line immunotherapy (alone or as a combination regimen with chemotherapy). Study objectives: Objective of the safety run-in phase:

• To evaluate safety of the triple combination of irradiation -Durvalumab - Tremelimumab Co-Primary objectives of the entire study:
• To evaluate safety of the triple combination (as for the run-in phase).
• To evaluate response rate on study drug compared to historical data of response to first-line platinum-doublet chemotherapy and 2nd-line docetaxel. Secondary objective:
• To evaluate PFS and OS compared to historical data . Exploratory objectives:
• Examine the mechanism of resistance to first-line immunotherapy .
• Examine the immune response in irradiation -Durvalumab - Tremelimumab treated patients and identify potential predictors of clinical benefit.

Conditions

Metastatic or Locally Advanced NSCLC

Keywords

checkpoint inhibitors; treatment-related toxicity leading to treatment discontinuation; RECIST 1.1

Outcome Measures

Primary Outcomes (3)

• treatment-related toxicity leading to treatment discontinuation (TRTLTD), as assessed by CTC-AE version 5.0.

  number of patients with TRTLTD will be evaluated during the safety run-in phase

  Approximately 2 years

• Incidence of Treatment-Emergent Adverse Events, as assessed by CTCAE version 5.0

  Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA, most updated version) terminology and presented in tables by System Organ Class (SOC) and Preferred Term (PT).

  From day of subject's written consent until study termination, approximately 4.5 years

• Response rate on study treatment (according to investigator assessment, per RECIST 1.1)

  Proportion of subjects showing best overall response of complete response (CR) or partial response (PR)

  Up to 5 months from treatment initiation, approximately 4.5 years overall

Secondary Outcomes (3)

• PFS on study treatment (according to investigator assessement, per RECIST 1.1

  From first dose of immunotherapy until first progression, approximately 4.5 years

• Overall survival (OS)

  From documented metastatic disease until death (or date of last documentation of being alive), approximately 4.5 years

• Change in biomarkers

  5 years

Study Arms (1)

study arm

EXPERIMENTAL

Study treatments include: Durvalumab at D1 and q4w + Tremelimumab at C1D1 and C4D1. Radiotherapy 11 fractions (start at D21).

Drug: Durvalumab; Drug: Tremelimumab; Radiation: Low dose irradiation

Interventions

Durvalumab DRUG

Durvalumab administered IV over 60 minutes at a dose of 1500 mg every 4 weeks

Also known as: Imfinzi, MEDI4736

study arm

Tremelimumab DRUG

Tremelimumab administered IV over 60 minutes at a dose of 300 mg , twice: at C1D1 and C4D1

study arm

Low dose irradiation RADIATION

21 days after the first immunotherapy treatment 11 fractions of 3 Gy will be administrated to metastatic or primary lesion/s over 2 weeks and one day

study arm

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Advanced or metastatic (stage 3 or stage 4) histologically proven NSCLC patients not candidate for curative - intent treatment.
• Have been previously treated with one prior immunotherapy (i.e. anti-PD1 or anti-PD-L1 antibodies, with or without chemotherapy) for advanced or metastatic NSCLC. Additional systemic treatment lines for metastatic disease are not allowed.
• Previous chemotherapy treatment lines administered earlier for non-metastatic disease (adjuvant, neo-adjuvant) are allowed if completed more than six months prior to diagnosis of advanced disease.
• Patients recurring within six months of end of adjuvant/maintenance immunotherapy (e.g. durvalumab post-chemorads) are eligible for the study if no additional systemic treatment was administered prior to enrollment on the study (this situation is considered equivalent to progression on first-line immunotherapy).
• Documented radiologic progression on immunotherapy. Minimal treatment time on first-line immunotherapy is 12 weeks. Progressive disease needs to be confirmed by a repeat scan performed at least 4 weeks after the first objective progression.
• Availability of at least 1 disease site not previously irradiated to serve as a target for radiotherapy. However, a disease site that progressed after having received previously radiotherapy can serve as a radiotherapy target on this trial.
• Availability of at least 1 measurable lesion not previously irradiated that is not planned to be irradiated during the study and measurable as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Availability of at least 1 disease site suitable for biopsy procedure (unless the patient has had a biopsy postprogression on immunotherapy), preferably, at site of disease progression on immunotherapy. Fine needle aspirate , ascites or effusion specimens are not acceptable . Selected sites for biopsy can serve afterwards as radiotherapy targets.
• Patient must have had a treatment free interval of at least 4 weeks from any prior therapy (includes major surgery) before starting of study drugs.
• Minor surgical procedures (as defined by the investigator): 7 post-operative days.
• Patients who receive palliative radiation for nontarget tumour lesions need a washout period of 7 days.
• Have an ECOG performance status of 0 or 1 and a minimum life expectancy of 12 weeks.
• Have adequate normal organ and marrow function, including the following:
• Absolute neutrophil count ≥1.0 × 109/L.
• Platelet count ≥ 75× 109/L.

You may not qualify if:

• Prior exposure to anti CTLA-4, including tremelimumab
• All potential radiotherapy targets involve high risk of significant toxicity.
• Mixed response to immunotherapy, where growth occurred only in a single lesion that is amendable to curative-intent radiotherapy (this criteria aims to exclude patients more likely to benefit from targeted radiotherapy to the growing mass and continuation of immunotherapy).
• Any prior immune-related adverse events grade 3 or higher (as per CTCAE version 5.0).
• Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
• Progressing brain metastasis. Stable brain metastasis (based on at least two brain imaging tests with a 4 week interval or more) are allowed (including non-treated lesions) as long as there no requirement for steroids due to the brain spread for ≥4 weeks prior to start of study treatment.
• History of leptomeningeal carcinomatosis
• Patients whose tumour samples are known to have activating mutations in the EGFR gene, translocations of the ALK gene, or rearrangement of the ROS1 gene that are indicated for treatment by approved TKI therapy are excluded.
• Autoimmune or inflammatory disorders requiring systemic treatment during the year prior to study treatment including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis with the exception of diverticulosis, celiac disease (or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, Sarcoidosis syndrome, Wegener syndrome (granulomatosis with polyangiitis), Graves' disease, rheumatoid arthritis, hypophysitis, uveitis. The following are exceptions to this criterion: Patients with vitiglio or alopecia, Patients with hypothyroidism (eg, following Hashimoto syndrome) and stable on hormone replacement not requiring systemic treatment, Psoriasis not requiring treatment. Additional exceptions are any chronic skin condition that does not require systemic therapy and patients with celiac disease controlled by diet alone. Patients without active disease in the last 5 years may be included but only after consultation with the study physician.
• Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. The following are exceptions to this criterion: Intranasal, inhaled, or topical steroids, or local steroid injections (e.g., intraarticular injection). Systemic corticosteroids at physiologic doses are allowed up to 10 mg/day of prednisone or its equivalent. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) are allowed.
• Active infection with hepatitis B (known positive HBV surface antigen\[HBsAg\] result), hepatitis C or tuberculosis. Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg are eligible.Patients positive for hepatitis C (HCV) antibody are eligible only if the polymerase chain reaction is negative for HCV RNA. Tuberculosis clinical evaluation includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice.
• Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
• Organ transplanted patients.
• Any condition that, in the opinion of the Investigator, would interfere with the evaluation of IP or interpretation of patient safety or study results, including, but not limited to, 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.
• Receipt of live attenuated vaccine within 30 days prior to the first dose of study drugs.

Sponsors & Collaborators

• Sheba Medical Center: lead
• AstraZeneca: collaborator
• Rambam Health Care Campus: collaborator
• Tel-Aviv Sourasky Medical Center: collaborator

Study Sites (1)

Sheba Medical Centre

Ramat Gan, 5265601, Israel

Location

Related Publications (6)

• Frey B, Ruckert M, Weber J, Mayr X, Derer A, Lotter M, Bert C, Rodel F, Fietkau R, Gaipl US. Hypofractionated Irradiation Has Immune Stimulatory Potential and Induces a Timely Restricted Infiltration of Immune Cells in Colon Cancer Tumors. Front Immunol. 2017 Mar 8;8:231. doi: 10.3389/fimmu.2017.00231. eCollection 2017.

  PMID: 28337197 BACKGROUND

• Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.

  PMID: 28885881 BACKGROUND

• Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, Pfirschke C, Voss RH, Timke C, Umansky L, Klapproth K, Schakel K, Garbi N, Jager D, Weitz J, Schmitz-Winnenthal H, Hammerling GJ, Beckhove P. Low-dose irradiation programs macrophage differentiation to an iNOS(+)/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013 Nov 11;24(5):589-602. doi: 10.1016/j.ccr.2013.09.014. Epub 2013 Oct 24.

  PMID: 24209604 BACKGROUND

• Chajon E, Castelli J, Marsiglia H, De Crevoisier R. The synergistic effect of radiotherapy and immunotherapy: A promising but not simple partnership. Crit Rev Oncol Hematol. 2017 Mar;111:124-132. doi: 10.1016/j.critrevonc.2017.01.017. Epub 2017 Feb 4.

  PMID: 28259287 BACKGROUND

• McNamara MJ, Hilgart-Martiszus I, Barragan Echenique DM, Linch SN, Kasiewicz MJ, Redmond WL. Interferon-gamma Production by Peripheral Lymphocytes Predicts Survival of Tumor-Bearing Mice Receiving Dual PD-1/CTLA-4 Blockade. Cancer Immunol Res. 2016 Aug;4(8):650-7. doi: 10.1158/2326-6066.CIR-16-0022. Epub 2016 Jun 4.

  PMID: 27262113 BACKGROUND

• Vetizou M, Pitt JM, Daillere R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CP, Poirier-Colame V, Roux A, Becharef S, Formenti S, Golden E, Cording S, Eberl G, Schlitzer A, Ginhoux F, Mani S, Yamazaki T, Jacquelot N, Enot DP, Berard M, Nigou J, Opolon P, Eggermont A, Woerther PL, Chachaty E, Chaput N, Robert C, Mateus C, Kroemer G, Raoult D, Boneca IG, Carbonnel F, Chamaillard M, Zitvogel L. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015 Nov 27;350(6264):1079-84. doi: 10.1126/science.aad1329. Epub 2015 Nov 5.

  PMID: 26541610 BACKGROUND

MeSH Terms

Conditions

Neoplasm Metastasis

Interventions

durvalumab; tremelimumab; Radiation

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Physical Phenomena

Study Officials

• Jair Bar, Dr

  Shaba Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Deputy Director, Institute of Oncology

Model Details: Single Group Assignment

Study Record Dates

• First Submitted: August 10, 2021
• First Posted: August 11, 2021
• Study Start: December 9, 2021
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): December 1, 2026
• Last Updated: December 5, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will not share

Locations

IL (1)