Nivolumab/Ipilimumab and Chemotherapy Combination in Advanced NSCLC Patients With HIV, HBV, HCV and Long Covid Syndrome

Study type: Phase 2 - Interventional Trial Number of patients to be enrolled: 105 Participating countries: Italy Study drugs: nivolumab and ipilimumab Cohort A: HBV and HCV patients Cohort B: HIV patients Cohort C: Long COVID syndrome The stratification factors are HBV/HCV positive (cohort A), HIV positive (cohort B), patients with Long Covid syndrome (Cohort C), histology (squamous vs non-squamous histology), and gender (male vs female).

Participants (≥ 18 years) must have histologically confirmed metastatic or unresectable non-small cell lung cancer (both non-squamous and squamous), without sensitizing EGFR, ALK, ROS1, BRAF and NTRK alterations, with chronic viral infections, such as HBV and HCV in cohort A and HIV in cohort B and with Long Covid syndrome in Cohort C.

The study is a multicenter, open-label trial designed according to Bryant and Day and including 1) a screening phase to establish study eligibility, 2) an open-label treatment phase, in which patients will receive nivolumab plus ipilimumab in combination with histology-based chemotherapy (2 induction cycles) to ascertain its safety, defined as incidence of grade 3 or 4 (G3/4) treatment-related adverse events (TRAEs) and activity, 3) and a follow-up phase to monitor survival status and subsequent therapies.

In detail, the study includes:

1. A screening phase to establish study eligibility (including, for example, the availability of tumour tissue for molecular analyses) and document baseline assessments.
2. An open-label treatment phase, in which patients will be treated with 2 cycles of chemotherapy and nivolumab plus ipilimumab until disease progression, unacceptable toxicity or for a maximum of 2 years. Upon disease progression or completion of trial treatment, further therapy will be at the discretion of the treating physician.
3. A follow-up phase, to monitor safety, survival status and subsequent therapies.

Eligibility Criteria:
Inclusion Criteria:

* Participants must have histologically confirmed diagnosis of metastatic or unresectable NSCLC;
* No sensitizing EGFR, ALK, ROS1, BRAF and NTRK alterations;
* Eastern Cooperative Oncology Group (ECOG) score 0-1 (physically able to carry out light housework or office work through to being fully active as they were before cancer);
* No prior systemic anticancer therapy;
* Tissue or Programmed death-ligand 1 (PD-L1) results available;
* HIV-1 or HIV-2 chronic infection, defined as i) a positive HIV 1-2 western blot or other FDA/CE approved HIV confirmatory test (regardless the results of the HIV 1-2 screening test used \[2nd, 3rd, 4th generation tests, rapid tests or laboratory tests (i.e., ELISA, EIA, CLIA, etc.)\], ii) the referring physician's written record that HIV infection was documented, with supporting information on the participant's relevant medical history and/or current antiretroviral treatment for HIV infection;
* Only subjects with chronic or resolved HBV infections might be eligible. Chronic HBV infections is defined as: the persistence of HBsAg positivity for more than 6 months (regardless HBeAg result, HBV-DNA level and the presence of liver necroinflammation). Resolved HBV infection is defined by: the absence of liver inflammation (clinically and laboratory), HBsAg negativity and HBsAb (anti-HBs antibodies) and HBcAb (anti-HBc IgG) positive result;
* Only subjects with resolved HCV infections might be eligible. Subjects with a newly diagnosed chronic HCV infection (defined as: positive HCV antibodies + detectable HCV-RNA) should be treated for HCV infection before enrollment. Acute HCV infection \[defined as a positive HCV-RNA and i) a negative serological HCV assay (HCV-Ab) or ii) a positive serological HCV assay (HCV-Ab) with a negative test 6 months earlier\] cannot be enrolled in the study.
* Patients with past HCV infection, with no evidence of chronic infection (i.e., anti-HCV antibody positivity, HCV-RNA negativity) should be excluded;
* Patients with confirmed Long Covid syndrome or PASC defined, as suggest by World Health Organization (WHO), as "condition occurs in individuals with a history of probable or confirmed SARS CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms and that last for at least 2 months and cannot be explained by an alternative diagnosis". This condition must be present at enrollment;
* Participants must have a nasopharyngeal swab positive for Sars-Cov2 within 12 months before enrolment;
* Participants must be either off corticosteroids, or on a stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent) for at least 2 weeks prior to first treatment;
* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; scans must have been performed within 4 weeks prior to registration.
* Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug;
* Ability to understand and to sign a written informed consent document.

Exclusion Criteria:

* Eastern Cooperative Oncology Group (ECOG) score ≥2;
* Untreated symptomatic brain metastases or leptomeningeal metastases;
* Another active concomitant malignancy;
* Active, known or suspected, autoimmune disease;
* Active HBV or HCV infection, presence of any infectious disease requiring specific treatment.
* Active Sars-Cov2 infection.