Assess the Safety of Immunotherapy Induction With Tremelimumab and Durvalumab Prior to Chemoradiotherapy and/or Resection in the Treatment

NCT04287894 | Terminated Phase 1

• 1 other identifier: N17DTL
• Study Type: interventional
• Target: 18
• Locations: 1 country
• Sites: 1

Brief Summary

A Phase Ib, Open-label, Single-center study to assess the safety of cancer-immunotherapy induction with Tremelimumab and Durvalumab prior to Chemoradiotherapy in the treatment of locally advanced NSCLC.

Conditions

Stage III NSCLC

Keywords

No prior radiotherapy to the thorax.; undergoing EBUS and/or mediastinoscopy.

Outcome Measures

Primary Outcomes (1)

• Safety of CIT-induction with Tremelimumab and Durvalumab prior to CRT in stage III NSCLC

  Number of patients who complete the multimodality treatment.

  3 months after the last radiation dose.

Secondary Outcomes (4)

• the percentage of patients with mediastinal and / or radiological down-staging following CIT-induction allowing a complete resection.

  At 7 weeks

• Disease free survival (DFS)

  From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months

• Overall survival (OS)

  From date of randomization until the date of death assessed up to 100 months

• 1-Year disease control rate (DCR)

  week -1 (baseline) until 12 months

Study Arms (3)

Cohort 1A (firste cohort)

EXPERIMENTAL

1 course Durvalumab (1500mg) + Tremelimumab (75mg) + 1 course of Durvalumab (1500mg) followed by CRT

Drug: Durvalumab; Drug: Tremelimumab; Drug: Pemetrexed; Drug: Cisplatin; Radiation: chemo radiotherapy; Procedure: Resection

Cohort 2A

EXPERIMENTAL

2 course Durvalumab (1500mg) + Tremelimumab (75mg) followed by CRT

Drug: Durvalumab; Drug: Tremelimumab; Drug: Pemetrexed; Drug: Cisplatin; Radiation: chemo radiotherapy; Procedure: Resection

Cohort 2B

ACTIVE COMPARATOR

2 course Durvalumab (1500mg) + Tremelimumab (75mg) followed by CRT

Drug: Durvalumab; Drug: Tremelimumab; Drug: Pemetrexed; Drug: Cisplatin; Radiation: chemo radiotherapy; Procedure: Resection

Interventions

Durvalumab DRUG

The IP will be given to the patient as long as there is a clinical benefit, in invertigator's judgment. Per day, 1500 mg

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

Tremelimumab DRUG

Per day 75mg

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

Pemetrexed DRUG

500 mg/m2 on day 1 every 3 weeks for 2 cycles

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

Cisplatin DRUG

6 mg / m2 on day 1 every 3 weeks for 2 cycles

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

chemo radiotherapy RADIATION

Once-daily fraction, 2 Gy per fraction. Total dose is 60 Gy.

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

Resection PROCEDURE

After CIT-CRT

Cohort 1A (firste cohort); Cohort 2A; Cohort 2B

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 prior to any study specific procedures.
• \. Male or female aged 18 years or older. 3. WHO performance status of 0 or 1. 4. Pathologically proven NSCLC stage III or inoperable stage II (cT1-3N0-1), according to the 8th edition of the AJCC staging, with a clinical indication for concurrent chemo-irradiation. Patients with locoregional recurrent lung tumour following surgery or a second primary cancer are eligible, unless a pneumonectomy was performed.
• \. Patients should be able to receive concurrent chemo radiotherapy treatment as approved by the MDM.
• \. Body weight \>30kg 7. Negative pregnancy test (urine or serum) for female patients with childbearing potential; 8. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of ≤ 1% per year, during the treatment period and for at least 180 days after the last dose of Durvalumab and Tremelimumab combination therapy or 1 month after the last dose of chemotherapy, whichever is later.
• A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
• Examples of contraceptive methods with a failure rate of ≤ 1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices (IUDs), and copper IUDs.
• The following age-specific requirements apply:
• Women \<50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
• Women ≥50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• \. Adequate organ function. Minimum required laboratory data. 10. No major contra-indications for undergoing EBUS and/or mediastinoscopy. 11. For patients included in the two feasibility cohorts a calculation for the mean lung dose (MLD) for radiotherapy will be performed: in both cohorts at least 2 out of 6 patients with a MLD ≥ 16 need to be included.

You may not qualify if:

• \. Patients with grade 3 dyspnoea or worse at baseline (according to CTCAE version 4.03).
• \. Prior radiotherapy to the thorax. 3. Participation in another clinical study with an investigational product during the last 4 weeks.
• \. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or the follow-up period of an interventional study 5. Recent major surgery within 4 weeks prior to entry into the study (excluding the placement of vascular access) that would prevent administration of chemotherapy.
• \. 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 requirements, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent.
• \. Presence of 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.
• \. Any condition that, in the opinion of the investigator, would interfere with evaluation of the CRT or interpretation of patient safety or study results.
• \. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Durvalumab or Tremelimumab may be included only after consultation with the Study Physician.
• \. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[eg, colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion:
• Patients with vitiligo or alopecia
• Patients with hypothyroidism (eg, following Hashimoto syndrome) 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
• Patients with celiac disease controlled by diet alone 11. Subject noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal; eg, refusal to adhere to scheduled visits 12. General contra-indications for immunotherapy:
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• Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and TB testing in line with local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 polymerase chain reaction is negative for HCV RNA.

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• AstraZeneca: collaborator

Study Sites (1)

Antoni van Leeuwenhoek - Netherlands Cancer Institute

Amsterdam, North Holland, 1066 CX, Netherlands

Location

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

durvalumab; tremelimumab; Pemetrexed; Cisplatin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Glutamates; Amino Acids, Acidic; Amino Acids; Amino Acids, Peptides, and Proteins; Amino Acids, Dicarboxylic; Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Study Officials

• W Theelen, MD

  NKI-AvL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 24, 2019
• First Posted: February 27, 2020
• Study Start: December 28, 2018
• Primary Completion: November 4, 2024
• Study Completion: November 4, 2024
• Last Updated: November 6, 2024

Record last verified: 2024-11

Locations

NL (1)