Stage III NSCLCPhase 1InductionNCT04287894

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

A Phase 1 study testing Durvalumab, Tremelimumab and Pemetrexed in people with Stage III NSCLC, run by The Netherlands Cancer Institute at 1 site in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 years and older
Conditions the study is for: Stage III NSCLC
What is being tested?: Durvalumab, Tremelimumab and Pemetrexed
Type of treatment: Surgery or procedure
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 18 participants
Where: 1 siteNetherlands
Study dates: 28 Dec 2018to 4 Nov 2024
Phase: Phase 1
Are there results?: None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 years and older
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Provision of signed, written and dated informed consent prior to any study specific procedures.
2. 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.
5. Patients should be able to receive concurrent chemo radiotherapy treatment as approved by the MDM.
6. 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.

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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).
9. 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.

Who cannot join

1. Patients with grade 3 dyspnoea or worse at baseline (according to CTCAE version 4.03).
2. Prior radiotherapy to the thorax. 3. Participation in another clinical study with an investigational product during the last 4 weeks.
4. 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.
6. 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.
7. 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.
8. Any condition that, in the opinion of the investigator, would interfere with evaluation of the CRT or interpretation of patient safety or study results.

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9. 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.
10. 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:
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.
Receipt of a live, attenuated vaccine within 30 days prior to enrolment or anticipation that such a live, attenuated vaccine will be required during the study.
Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1 or anti-PD-L1 therapeutic antibodies.
Treatment with systemic immunostimulatory agents (including but not limited to interferons or IL-2) within 14 days or five half-lives of the drug (whichever is shorter) prior to enrolment. 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, topical steroids, or local steroid injections (eg, intra articular injection)
Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication)
Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., one-time dose of dexamethasone for nausea) may be enrolled in the study. The use of inhaled corticosteroids for chronic obstructive pulmonary disease, mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension, and low-dose supplemental corticosteroids for adrenocortical insufficiency are allowed.
13. History of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or evidence of active pneumonitis on screening chest computed tomography scan.
14. History of active primary immunodeficiency 15. History of allogeneic transplantation 16. Severe infections within 28 days prior to enrolment, including, but not limited to, hospitalization for complications of infection, bacteraemia, or severe pneumonia or received oral or IV antibiotics within 2 weeks prior to enrolment. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible.

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

Antoni van Leeuwenhoek - Netherlands Cancer Institute
Amsterdam, North Holland, 1066 CX

Other trials in Netherlands

About this study

Official title: A Phase Ib, Open-label, Single-center Study to Assess the Safety of Cancer-immunotherapy Induction With Tremelimumab and Durvalumab Prior to Chemoradiotherapy and/or Resection in the Treatment of Locally Advanced NSCLC.

Read the detailed description

Patients with pathologically proven stage III NSCLC will be treated with CIT-induction. In the feasibility phase, the first cohort (cohort 1A) will receive only 1 course of the immunotherapy doublet followed by a single dose of Durvalumab (Figure 1). The 2nd cohort (Figure 1, cohort 2A) will open for inclusion if 5 to 6 out of 6 patients complete CIT-CRT according to the safety rules (paragraph 6.1.3). In next cohort two courses of Tremelimumab and Durvalumab will be administered. The expansion cohort will be opened (Figure 1, cohort 2B) if this is well tolerated. Patients will be enrolled for cohort 1B in case < 5 out of 6 patients complete CIT-CRT in cohort 2A.

Conditions: Stage III NSCLC
Being tested: Durvalumab, Tremelimumab, Pemetrexed, Cisplatin, chemo radiotherapy
Keywords: No prior radiotherapy to the thorax., undergoing EBUS and/or mediastinoscopy.
Medical subject headings: Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

DurvalumabDrug
The IP will be given to the patient as long as there is a clinical benefit, in invertigator's judgment. Per day, 1500 mg
TremelimumabDrug
Per day 75mg
PemetrexedDrug
500 mg/m2 on day 1 every 3 weeks for 2 cycles
CisplatinDrug
6 mg / m2 on day 1 every 3 weeks for 2 cycles
chemo radiotherapyRadiation
Once-daily fraction, 2 Gy per fraction. Total dose is 60 Gy.
ResectionProcedure or surgery
After CIT-CRT

Study groups in NCT04287894
Study group	Role	What they receive
Cohort 1A (firste cohort)	Experimental	1 course Durvalumab (1500mg) + Tremelimumab (75mg) + 1 course of Durvalumab (1500mg) followed by CRT Receives: 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 Receives: 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 Receives: Drug: Durvalumab; Drug: Tremelimumab; Drug: Pemetrexed; Drug: Cisplatin; Radiation: chemo radiotherapy; Procedure: Resection

What is being measured

The primary outcome is the main question the study is designed to answer.

Safety of CIT-induction with Tremelimumab and Durvalumab prior to CRT in stage III NSCLC
Number of patients who complete the multimodality treatment.
Measured: 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.
Measured: At 7 weeks
Disease free survival (DFS)
Measured: 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)
Measured: From date of randomization until the date of death assessed up to 100 months
1-Year disease control rate (DCR)
Measured: week -1 (baseline) until 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

28 Dec 20184 Nov 2024

First posted27 Feb 2020
Study start28 Dec 2018
Primary completion4 Nov 2024
Study completion4 Nov 2024

Why it stopped: Based on initially defined safety rules not continued with expansion phase of study (too much toxicity with neo-adjuvant immunotherapy)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Other trials for Stage III NSCLCStudies of the same condition, open and under way.
More trials run by The Netherlands Cancer InstituteThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1
Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Enrolment: 18 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT04287894
Sponsor's protocol ID: N17DTL
Acronym: Induction
Status last verified: Nov 2024
First submitted: 24 Oct 2019
Last updated: 6 Nov 2024
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Study at a glance

From the registry record, last updated by the sponsor on 6 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: A Phase Ib, Open-label, Single-center Study to Assess the Safety of Cancer-immunotherapy Induction With Tremelimumab and Durvalumab Prior to Chemoradiotherapy and/or Resection in the Treatment of Locally Advanced NSCLC.
ClinicalTrials.gov ID: NCT04287894
Acronym / sponsor ID: Induction / N17DTL
Conditions: Stage III NSCLC
Keywords: No prior radiotherapy to the thorax., undergoing EBUS and/or mediastinoscopy.
Phase: Phase 1
Study type: Interventional
Recruitment status: TerminatedReason stopped: Based on initially defined safety rules not continued with expansion phase of study (too much toxicity with neo-adjuvant immunotherapy)
Enrolment: 18 participants (actual)
Lead sponsor: The Netherlands Cancer InstituteUniversity, hospital or other
Collaborators: AstraZeneca
Study start: 28 Dec 2018 (actual)
Primary completion: 4 Nov 2024 (actual)
Study completion: 4 Nov 2024 (actual)
First posted: 27 Feb 2020 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Non-randomised
Intervention model: Single group
Masking: None (open label)
Number of arms: 3

Arm	Type	Receives
Cohort 1A (firste cohort)	Experimental	Drug: Durvalumab, Drug: Tremelimumab, Drug: Pemetrexed, Drug: Cisplatin, Radiation: chemo radiotherapy, Procedure: Resection1 course Durvalumab (1500mg) + Tremelimumab (75mg) + 1 course of Durvalumab (1500mg) followed by CRT
Cohort 2A	Experimental	Drug: Durvalumab, Drug: Tremelimumab, Drug: Pemetrexed, Drug: Cisplatin, Radiation: chemo radiotherapy, Procedure: Resection2 course Durvalumab (1500mg) + Tremelimumab (75mg) followed by CRT
Cohort 2B	Active comparator	Drug: Durvalumab, Drug: Tremelimumab, Drug: Pemetrexed, Drug: Cisplatin, Radiation: chemo radiotherapy, Procedure: Resection2 course Durvalumab (1500mg) + Tremelimumab (75mg) followed by CRT

Who may qualify

Ages: 18 years and older
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (10 listed)

Provision of signed, written and dated informed consent prior to any study specific procedures.
2. 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.
5. Patients should be able to receive concurrent chemo radiotherapy treatment as approved by the MDM.
6. 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).

Key exclusion criteria (24 listed)

1. Patients with grade 3 dyspnoea or worse at baseline (according to CTCAE version 4.03).
2. Prior radiotherapy to the thorax. 3. Participation in another clinical study with an investigational product during the last 4 weeks.
4. 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.
6. 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.
7. 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.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
DurvalumabThe IP will be given to the patient as long as there is a clinical benefit, in invertigator's judgment. Per day, 1500 mg	Drug	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B
TremelimumabPer day 75mg	Drug	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B
Pemetrexed500 mg/m2 on day 1 every 3 weeks for 2 cycles	Drug	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B
Cisplatin6 mg / m2 on day 1 every 3 weeks for 2 cycles	Drug	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B
chemo radiotherapyOnce-daily fraction, 2 Gy per fraction. Total dose is 60 Gy.	Radiation	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B
ResectionAfter CIT-CRT	Procedure or surgery	Cohort 1A (firste cohort), Cohort 2A, Cohort 2B

Primary outcome

Safety of CIT-induction with Tremelimumab and Durvalumab prior to CRT in stage III NSCLC
Time frame: 3 months after the last radiation dose.
Number of patients who complete the multimodality treatment.

4 secondary outcomes

the percentage of patients with mediastinal and / or radiological down-staging following CIT-induction allowing a complete resection.
Time frame: At 7 weeks
Disease free survival (DFS)
Time frame: 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)
Time frame: From date of randomization until the date of death assessed up to 100 months
1-Year disease control rate (DCR)
Time frame: week -1 (baseline) until 12 months

Results and safety

The study was stopped early (reason given: Based on initially defined safety rules not continued with expansion phase of study (too much toxicity with neo-adjuvant immunotherapy)). Results are not available in the source record.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 6 Nov 2024.
Individual participant dataSharing planned: Undecided

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

W Theelen, MD principal investigator

The Netherlands Cancer Institute

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Durvalumab, Tremelimumab and Pemetrexed in people with Stage III NSCLC, run by The Netherlands Cancer Institute at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 10 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 6 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Safety of CIT-induction with Tremelimumab and Durvalumab prior to CRT in stage III NSCLC (time frame: 3 months after the last radiation dose.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04287894.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2024.