EXLIBRIS : “EXL-01 combined with nivolumab for advanced NSCLC refractory to immunotherapy”

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire De Lille

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

Trial duration

16 Jul 2024 → ongoing

Decision date (initial)

2024-04-05

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

• Organization name: ISS (Investigator Sponsored Studies) laboratoire Exeliom

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To assess the efficacy of EXL01 and nivolumab combination, with respect to rate of Progression-Free Survival (PFS) at 3 months, defined as the rate of alive and non-progressive subjects as per iRECIST 1.1 over the study subjects, as assessed by the investigator, at 3 months from the inclusion

Secondary objectives 5

1. To assess the safety and tolerability of the combination of EXL01 and nivolumab, within the 6 first weeks of treatment.
2. To assess efficacy of the combination of EXL01 and nivolumab , with respect to : Objective Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS), Disease Control Rate (DCR) and Duration of Response (DoR) during the follow-up period.
3. To assess the safety and tolerability of the combination of EXL-01 and nivolumab , during the whole sequence of treatment and follow-up.
4. To identify molecular (genomic, metabolic, proteomic) biomarkers that may be indicative of clinical response/resistance, safety, and/or the mechanism of action of the EXL-01 combination with nivolumab.
5. To identify immune and microbial mechanisms that may be indicative of clinical response/resistance, safety, and/or the mechanism of action of the EXL-01 combination with nivolumab.

Conditions and MedDRA coding

Patients (male or female) ≥18 years old with histologically or cytologically documented inoperable advanced/metastatic Non-Small-Cell Lung Cancer (NSCLC)

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Patients (male or female) ≥18 years old.
2. ECOG Performance status (PS) 0-1 (WHO).
3. Histologically or cytologically documented inoperable advanced/metastatic NSCLC. (inoperable stage III not amenable to radiation therapy or surgery, stage IV).
4. No alterations of key driver oncogenes including EGFR (mutations), ALK (fusions), ROS1 (fusions), MET (METex14 mutations), HER2 (exon 20 insertions), RET (fusions) or BRAF (V600E mutations). KRAS mutations are allowed.
5. Must have previously received anti-PD(L)1 agent and platinum-based chemotherapy, either concomitantly or sequentially. Last dose to have been administered more than 15 days prior to first dose of study drug.
6. Must have progressed within 6 months after first dose of anti-PD(L)1 given either alone or in combination with platinum-based chemotherapy
7. Must have received all validated available standard therapies.
8. Measurable disease according to iRECIST 1.1.
9. Adequate haematological, renal and liver functions within 72 hours before the first dose of study treatment (Absolute Neutrophil Count ≥ 1500/µL ; Platelets ≥ 100 000/µL; Hemoglobin ≥ 9.0 g/dL; Creatinine Clearance ≥ 50 mL/min; Total Bilirubin ≤ 1.5 x ULN; AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN for participants with liver metastasis))
10. Obtention of an informed written consent before any specific procedure of the study.
11. Patient affiliated to and covered by social security for standard of care.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following applies:. - Not a WOCBP as defined in 7.3.1. OR -A WOCBP who agrees to use a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), prior to the first dose of study treatment until at least 5 months after the last dose of nivolumab or 1 month after last dose of EXL01, which ever comes last. The Investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study treatment. In addition, WOCBP agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the purpose of reproduction during the study and until at least 5 months after the last dose of nivolumab. Note: The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk of inclusion of WOCBP with an early undetected pregnancy.
13. A male participant is eligible to participate if he agrees to use a highly effective method of contraception,and refrains from donating sperm for the duration of the study and for at least 5 months after the last dose of Nivolumab or 1 months after the last dose of EXL01, which event comes last, unless confirmed to be azoospermic (vasectomized or secondary to medical cause), or abstains from heterosexual intercourse as his preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent.
14. Women of child-bearing potential must have a negative pregnancy test within 24h before administration of investigational product.

Exclusion criteria 29

1. Small cell lung cancer or tumors with mixed histology including a SCLC component.
2. Current probiotics administration, or planned probiotics administration during treatment course (other than EXL01).
3. Other cancer treated within 3 years before inclusion except baso-cellular skin carcinoma or cervical / bladder in situ carcinoma
4. Known symptomatic CNS metastases and/or carcinomatous meningitis. Participants with asymptomatic brain metastases (ie, no neurological symptoms and no requirements for corticosteroids > 10mg/d prednisone equivalent) may participate.
5. Inability to receive study information and to give informed consent
6. Patient unable to have a clinical follow-up due to psychological, familial, social or geographical reasons.
7. Legal incapacity (people in jail), or under supervision (i.e. guardianship or curatorship).
8. Has a systemic infection or other serious infection requiring systemic treatment within 30 days prior to Screening.
9. Has a known history of or newly diagnosed infection with HIV. Documentation of a prior negative HIV test within 6 months prior to Screening may be used in place of a Screening test
10. Has a known active HBV (defined as HbsAg reactive) or HCV (defined as HCV RNA [qualitative] is detected) infection. Documentation of negative HBV (HbsAg) and HCV (qualitative HCV RNA) tests within 30 days prior to Screening may be used in place of a Screening test.
11. Has known Tuberculosis infection.
12. History of active autoimmune disease including but not limited to rheumatoid polyarthritis, myasthenia, autoimmune hepatitis, systemic Lupus, Wegener's granulomatosis, vascular thrombosis associated with antiphospholipid syndrome, Sjogren’s syndrome with interstitial pulmonary disease, recent Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis.
13. Diagnosis of immunodeficiency of is receiving systemic treatment with corticosteroids with greater dose than 10 mg prednisone equivalent daily, within 14 days before initiation of the immunotherapy induction. Inhaled, nasal or topic corticosteroids are allowed.
14. Living attenuated vaccine received within the 30 previous days
15. Has received Fecal Microbiota Transplantation within 3 months prior to Screening.
16. General serious condition such as uncontrolled congestive cardiac failure, uncontrolled cardiac arrythmia, uncontrolled ischemic cardiac disease (unstable angina or history of myocardial infarction within the previous 6 months), history or stroke within the 6 previous months.
17. History of severe immune-mediated toxicity (≥ grade 3) under immunotherapy treatment.
18. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease.
19. Received prior radiotherapy within 1 week of start of study intervention or have had a history of radiation pneumonitis. Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
20. Had major surgery or significant trauma within 4 weeks before the first dose of study drug
21. Had ongoing or active infection within 2 weeks before the first dose of study drug
22. Active inflammatory intestinal disease (Crohn disease, Hemorrhagic recto-colitis, coeliac disease) or any serious chronic intestinal disease with uncontrolled diarrhea, or other inflammatory disease requiring anti-inflammatory medications.
23. Other contra-indications for anti-PD(L)1 antibodies.
24. Has a known history or newly diagnosed GI parasitic infection within 3 months prior to Screening.
25. have not recovered (ie, > Grade 2 is considered not recovered) from adverse reactions due to previous line of antineoplastic treatment at the time of study entry, with the exception of alopecia.
26. Has a history of hypersensitivity to EXL01 and/or any excipients, as listed in the IB. Has a history of hypersensitivity to EXL01 and/or any excipients, which are listed in the IB, and/or to soybean or soy-containing products.
27. Has a history of hypersensitivity to nivolumab.
28. Has difficulties in swallowing.
29. Has received prohibited medication within 14 days or 5-half-lives (whichever is longer) before the first dose of study drug.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The progression-free survival rate (PFS Rate) at 3 months for the assessment of efficacy, defined as the rate of alive and non-progressive subjects as per iRECIST 1.1 over the study subjects, at 3 months from the inclusion.

Secondary endpoints 10

1. The number of Grade ≥ 3 treatment-related AE, using CTCAE, occurring during the first 6 weeks of treatment.
2. The Progression Free Survival, defined as the time from inclusion to the first documented disease progression or death due to any cause, whichever occurs first.
3. The ORR (Overall Response Rate) as per iRECIST1.1 for the assessment of efficacy, defined as the rate of confirmed Complete Response (CR) or Partial Response (PR) over the study subjects efficacy responses.
4. The Overall Survival, defined as the time from inclusion to the date of death due to any cause.
5. The Disease Control Rate, defined as the rate of confirmed Complete Response (CR), or Partial Response (PR), or Stable Disease (SD) over the study subjects efficacy responses.
6. The Duration of Response, for participants who demonstrate confirmed CR or PR, defined as the time from first documented evidence of CR or PR until disease progression or death due to any cause, whichever occurs first.
7. The frequency, type and grade of adverse events, using CTCAE version 5, from the inclusion to the end of the follow-up period, for every patients included.
8. The number of discontinuations of study intervention due to an adverse event.
9. The molecular (genomic, metabolic, proteomic) determinants of response or resistance to treatment (PFS at 3 months), using blood samples and/or tumor tissue.
10. The immune and microbial determinants of response or resistance (PFS at 3 months) or tolerability to treatment (number of Grade ≥3 AEs), using blood and stool samples.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire De Lille

Sponsor organisation

Centre Hospitalier Universitaire De Lille

Address

2 Avenue Oscar Lambret, Cs 70001 Cs 70001

City

Lille Cedex

Postcode

59037

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Alexis CORTOT

Public contact point

Organisation

Centre Hospitalier Universitaire De Lille

Contact name

Alexis CORTOT

Third parties 1

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications