Non-small Cell Lung CancerPhase 1NCT03509584
Phase I Multicenter Trial Combining Nivolumab, Ipilimumab and Hypo-fractionated Radiotherapy for Pretreated Advanced Stage Non-small Cell Lung Cancer Patients
A Phase 1 study testing hypofractionated radiotherapy, nivolumab and Ipilimumab in people with Non-small Cell Lung Cancer, run by Assistance Publique Hopitaux De Marseille at 1 site in France.
Trial summary
Nivolumab is superior to docetaxel monotherapy as second line treatment in advanced stage non-small cell lung cancer (NSCLC) patients. However, the long term survival advantage seems to be limited to a 20% proportion of treated patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Non-small Cell Lung Cancer
- What is being tested?
- hypofractionated radiotherapy, nivolumab and Ipilimumab
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteFrance
- Study dates
- 7 Jun 2018to 2 Jul 2019
- 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
- Advanced NSCLC
- One site of measureable disease by RECIST 1.1
- Eligible for localized palliative radiotherapy of a bone lesion as per current national and international recommendations (part #1) or
- Ability to tolerate hypo-fractionated radiotherapy of a tumoral lesion chosen according to the lower risk of radiation adverse event (lymph node > subcutaneous > liver > bone > lung) (part #2)
- Received at least one prior line of therapy for incurable or metastatic NSCLC
- Disease progression at study entry
Who cannot join
- Received systemic anticancer therapy within the previous 21 days
- Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or concurrent illness, unrelated to the tumor, requiring active therapy
- Any condition requiring concurrent systemic immunosuppressive therapy
- Known immunodeficiency disorders, either primary or acquired
- Bone lesion with indication of surgery (part #1) ; especially in case of spinal compression.
- Known leptomeningeal disease
Show all 10Show fewer
- Active malignancies within 12 months with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
- Prior treatment with immune checkpoints inhibitors
- Administration of a live, attenuated vaccine within 30 days prior to first dose of study drug
- Long-term use of systemic corticosteroids (unless to a dose of 20mg of methylprednisolone)
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase I Multicenter Trial Combining Nivolumab, Alone or With Ipilimumab, Plus Hypo-fractionated Radiotherapy for Pretreated Advanced Stage Non-small Cell Lung Cancer Patients
Nivolumab is superior to docetaxel monotherapy as second line treatment in advanced stage non-small cell lung cancer (NSCLC) patients. However, the long term survival advantage seems to be limited to a 20% proportion of treated patients. To date, no definitive biomarker, including tumor cells or infiltrative cells PD-L1 expression, has been demonstrated to predict nivolumab (or other PD1 or PD-L1 inhibitors) efficacy. Ipilimumab has also suggested efficacy in the same patient population. Finally, the addition of ipilimumab to nivolumab has a suggested better efficacy over nivolumab alone in advanced stage NSCLC patients with an acceptable safety profile.
In parallel, hypo-fractionated radiotherapy alone has been suggested to elicit the immune system activity as demonstrated by the occurrence of an abscopal effect. Some case reports in melanoma but also lung cancer patients reinforced this hypothesis.
Read more
Furthermore, preclinical and clinical data suggest that radiation may have a synergistic effect with antibodies targeting the immune checkpoints (PD1, PD-L1, CTLA4) and improve antitumor efficacy. Moreover, it has been shown that fractionated radiotherapy delivered in combination with aPD-1 or aPD-L1 mAbs is able to generate efficacious CD8þ T-cell responses that will in turn improve local tumor control, long-term survival, and protection against tumor rechallenge.
Therefore, the combination of single fraction or hypo-fractionated radiotherapy with the anti PD1 nivolumab and/or the anti CTLA4 ipilimumab warrants further investigation. However, a large number of doses, sequences and schedules remain possible. In order to select the best combination, a mathematical modeling of immunotherapy in cancer and its synergy with radiotherapy has been set up. This work provides with mathematical formulas to link the drug serum concentrations of nivolumab and ipilimumab, and the dose of radiation therapy, to the immune response. In silico, the single and three fractions schedule have been found to have the same efficacy while activation of the immune response seems to be better using a hypo-fractionated (less than 6 fractions) radiotherapy in vivo.
- Conditions
- Non-small Cell Lung Cancer
- Being tested
- hypofractionated radiotherapy, nivolumab, Ipilimumab
- 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.
hypofractionated radiotherapyRadiation
Stereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction
nivolumabDrug
administration of nivolumab
IpilimumabDrug
administration of ipilimumab
| Study group | Role | What they receive |
|---|---|---|
| part #1a | Experimental | non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy Receives: Radiation: hypofractionated radiotherapy; Drug: nivolumab |
| part #1b | Experimental | non-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy Receives: Radiation: hypofractionated radiotherapy; Drug: nivolumab; Drug: Ipilimumab |
| part #2a | Experimental | NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) Receives: Radiation: hypofractionated radiotherapy; Drug: nivolumab |
| part #2b | Experimental | NSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) Receives: Radiation: hypofractionated radiotherapy; Drug: nivolumab; Drug: Ipilimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Incidence of immune related adverse events
evaluate the safety of the combination of the radiotherapy plus nivolumab alone or in combination with ipilimumab, by physical examinations
Measured: 48 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted26 Apr 2018
- Study start7 Jun 2018
- Primary completion2 Jul 2019
- Study completion2 Jul 2019
Why it stopped: SAFETY
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Non-small Cell Lung CancerStudies of the same condition, open and under way.
- More trials run by Assistance Publique Hopitaux De MarseilleThe 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
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique Hopitaux De Marseille
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Urielle Desalbres, Study director, Assistance Publique Hôpitaux de Marseille
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03509584
- Sponsor's protocol ID
- 2017-21
- Other IDs
- 2017-001198-18, 2017
- Status last verified
- Jun 2023
- First submitted
- 10 Apr 2018
- Last updated
- 15 Jun 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Jun 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase I Multicenter Trial Combining Nivolumab, Alone or With Ipilimumab, Plus Hypo-fractionated Radiotherapy for Pretreated Advanced Stage Non-small Cell Lung Cancer Patients
- ClinicalTrials.gov ID
- NCT03509584
- Acronym / sponsor ID
- 2017-21
- Conditions
- Non-small Cell Lung Cancer
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: SAFETY
- Enrolment
- 6 participants (actual)
- Lead sponsor
- Assistance Publique Hopitaux De MarseilleUniversity, hospital or other
- Study start
- 7 Jun 2018 (actual)
- Primary completion
- 2 Jul 2019 (actual)
- Study completion
- 2 Jul 2019 (actual)
- First posted
- 26 Apr 2018 (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.
Nivolumab is superior to docetaxel monotherapy as second line treatment in advanced stage non-small cell lung cancer (NSCLC) patients. However, the long term survival advantage seems to be limited to a 20% proportion of treated patients. To date, no definitive biomarker, including tumor cells or infiltrative cells PD-L1 expression, has been demonstrated to predict nivolumab (or other PD1 or PD-L1 inhibitors) efficacy. Ipilimumab has also suggested efficacy in the same patient population. Finally, the addition of ipilimumab to nivolumab has a suggested better efficacy over nivolumab alone in advanced stage NSCLC patients with an acceptable safety profile.
In parallel, hypo-fractionated radiotherapy alone has been suggested to elicit the immune system activity as demonstrated by the occurrence of an abscopal effect. Some case reports in melanoma but also lung cancer patients reinforced this hypothesis.
Furthermore, preclinical and clinical data suggest that radiation may have a synergistic effect with antibodies targeting the immune checkpoints (PD1, PD-L1, CTLA4) and improve antitumor efficacy. Moreover, it has been shown that fractionated radiotherapy delivered in combination with aPD-1 or aPD-L1 mAbs is able to generate efficacious CD8þ T-cell responses that will in turn improve local tumor control, long-term survival, and protection against tumor rechallenge.
Therefore, the combination of single fraction or hypo-fractionated radiotherapy with the anti PD1 nivolumab and/or the anti CTLA4 ipilimumab warrants further investigation. However, a large number of doses, sequences and schedules remain possible. In order to select the best combination, a mathematical modeling of immunotherapy in cancer and its synergy with radiotherapy has been set up. This work provides with mathematical formulas to link the drug serum concentrations of nivolumab and ipilimumab, and the dose of radiation therapy, to the immune response. In silico, the single and three fractions schedule have been found to have the same efficacy while activation of the immune response seems to be better using a hypo-fractionated (less than 6 fractions) radiotherapy in vivo.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| part #1a | Experimental | Radiation: hypofractionated radiotherapy, Drug: nivolumabnon-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy |
| part #1b | Experimental | Radiation: hypofractionated radiotherapy, Drug: nivolumab, Drug: Ipilimumabnon-small cell lung cancer (NSCLC) patients with bone metatase(s) eligible for localized hypo-fractionated radiotherapy |
| part #2a | Experimental | Radiation: hypofractionated radiotherapy, Drug: nivolumabNSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) |
| part #2b | Experimental | Radiation: hypofractionated radiotherapy, Drug: nivolumab, Drug: IpilimumabNSCLC patients eligible for a localized radiotherapy of one target lesion (outside the brain) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- Advanced NSCLC
- One site of measureable disease by RECIST 1.1
- Eligible for localized palliative radiotherapy of a bone lesion as per current national and international recommendations (part #1) or
- Ability to tolerate hypo-fractionated radiotherapy of a tumoral lesion chosen according to the lower risk of radiation adverse event (lymph node > subcutaneous > liver > bone > lung) (part #2)
- Received at least one prior line of therapy for incurable or metastatic NSCLC
Key exclusion criteria (10 listed)
- Received systemic anticancer therapy within the previous 21 days
- Human immunodeficiency virus (HIV), hepatitis B or C, or severe/uncontrolled infections or concurrent illness, unrelated to the tumor, requiring active therapy
- Any condition requiring concurrent systemic immunosuppressive therapy
- Known immunodeficiency disorders, either primary or acquired
- Bone lesion with indication of surgery (part #1) ; especially in case of spinal compression.
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 |
|---|---|---|
| hypofractionated radiotherapyStereotactic hypo-fractionated irradiation (3 x 8 Gys) radiotherapy fraction | Radiation | part #1a, part #1b, part #2a, part #2b |
| nivolumabadministration of nivolumab | Drug | part #1a, part #1b, part #2a, part #2b |
| Ipilimumabadministration of ipilimumab | Drug | part #1b, part #2b |
Primary outcome
Incidence of immune related adverse events
Time frame: 48 weeks
evaluate the safety of the combination of the radiotherapy plus nivolumab alone or in combination with ipilimumab, by physical examinations
Results and safety
The study was stopped early (reason given: SAFETY). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jun 2023.
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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.
Urielle Desalbres study director
Assistance Publique Hôpitaux de Marseille
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 hypofractionated radiotherapy, nivolumab and Ipilimumab in people with Non-small Cell Lung Cancer, run by Assistance Publique Hopitaux De Marseille at 1 site in France.
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 6 inclusion and 10 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 15 Jun 2023. 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 France. 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?
The study was stopped early (reason given: SAFETY). Results are not available in the source record.
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?
Incidence of immune related adverse events (time frame: 48 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 15 Jun 2023.