Study for Evaluating the Safety and Feasibility of Fecal Microbiota Transplant in Stage II-III NSCLC Patients Using ICI Responders as Donors (MIGRANT)

Phase II Randomized Clinical Trial for Evaluating the Safety and Feasibility of Fecal Microbiota Transplant (FMT) in Stage II-III Non-small Cell Lung Cancer (NSCLC) Patients, Using Immune Checkpoint Inhibitors (ICI) Responders as Donors.

This is a randomized, phase II, multi-centre clinical trial.

Sample size: 68 patients (Experimental Arm (Durvalumab + chemotherapy + FMT capsules): 34 patients, Control Arm (Durvalumab + chemotherapy): 34 patients)

Population: Patients with stage IIA, IIB, IIIA and IIIB (only T3N2) non-small cell lung cancer

In the Experimental arm, patients will receive Fecal Microbiota Transplant. Once done, the patient will start neoadjuvant treatment with Durvalumab + Chemotherapy .

In the Control arm, patients will receive neoadjuvant treatment with Durvalumab + Chemotherapy.

After neoadjuvant/induction treatment every patient will be evaluated to decide if the patient is a candidate for surgery or not. Patients that are R0 after surgery will receive Adjuvant treatment with Durvalumab.

The primary objective is to evaluate the pathological Complete Response (pCR) rate.

The total trial duration will be 6.5 years approximately.

This is a randomized, phase II, multi-centre clinical trial stratified according to PDL1 status (≥50 % or <50%), and Akkermansia positive vs negative.

In the pre-treatment phase, donors will be selected for preparing the fecal microbiota transplant with their samples.

After that, patient's candidate with stage IIA, IIB, IIIA and IIIB (only T3N2) non-small cell lung cancer to study will be randomized in two different arms.

In the Experimental arm, after randomization, patients will receive treatment with Rifaximin. Once done, the patient will start neoadjuvant treatment with Durvalumab IV + Chemotherapy for several cycles.

In the Control arm, after randomization patients will receive neoadjuvant treatment with Durvalumab IV + Chemotherapy for several cycles.

After neoadjuvant/induction treatment every patient will be evaluated by a multidisciplinary team in each participant hospital to decide if the patient is a candidate for surgery or not.

Patients that are R0 confirmed by surgical pathology evaluation after surgery will receive Adjuvant treatment with Durvalumab IV.

Sample size: 68 patients (Experimental Arm (Durvalumab + chemotherapy + FMT capsules): 34 patients, Control Arm (Durvalumab + chemotherapy): 34 patients)

The primary objective is to evaluate the pathological Complete Response (pCR) rate in the intention to treat population (ITT population)

The total trial duration will be 6.5 years approximately.

Inclusion Criteria:

• Previously untreated patients with histologically- or cytologically- documented NSCLC who present stage IIA, IIB, IIIA or IIIB (only T3N2) disease (according to 8th version of the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology)
• PET scan and brain CT or MRI at baseline to confirm the absence of distant disease
• ECOG (Performance status) 0-1
• Adequate hematologic and organ function.
• All patients are notified of the investigational nature of this study and signed a written in-formed consent in accordance with institutional and national guidelines, including the Declaration of Helsinki prior to any trial-related intervention
• Adequate lung function: Forced Espiratoy Volumen in 1 second (FEV1) >50% of normal volume and Difusion Capacity of the Lungs for Carbon Monoxide (DLCO) >40% of normal value
• Patients aged ≥ 18 years at the time of study entry
• Body weight > 30Kg (for durvalumab monotherapy)
• PDL1 analyzed (value in %)
• For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective forms of contraception that results in a low failure rate (< 1% per year) when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment.
• For male patients with female partners of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate when used consistently and correctly, and to continue its use for 6 months after the last dose of trial treatment.
• Oral contraception should always be combined with an additional contraceptive method because of a potential interaction with the study drugs. The same rules are valid for male patients involved in this clinical study if they have a partner of childbirth potential. Male patients must always use a condom.
• Women who are not postmenopausal (≥ 12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 8 days prior to initiation of study drug.
• Patients is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up
• Presence of at least one measurable lesion by CT-SCAN, as defined by RECIST v1.1.
• Patients with a life expectancy ≥12 weeks.
• Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations

Exclusion Criteria:

• Patients with known sensitizing mutation or an amplification in the epidermal growth factor receptor (EGFR) gene or any variety of alterations of ALK oncogene.
• Known STK-11 ligand alterations, MDM2 amplifications or ROS1 translocations.
• Weight loss >10% within the previous 3 months.
• Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
• Patients with other active malignancy requiring concurrent intervention and/or concurrent treatment with other investigational drugs or anti-cancer therapy
• History of active primary immunodeficiency
• History of another primary malignancy.
• Active or prior documented autoimmune or inflammatory disorders.
• Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization.
• Pleural or pericardial effusion.
• Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction.
• Positive test for HIV.
• Patients with positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection.
• Patients with history of allergy to study drug components/excipients.
• Active tuberculosis.
• Severe infections within 4 weeks prior to be included in the study.
• Major surgical procedure other than for diagnosis within 28 days prior to inclusion or anticipation of need for a major surgical procedure during the course of the study.
• Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or renders the patient at high risk from treatment complications.
• Patients with medical, mental, neurological or psychological condition which in the opinion of the investigator would not permit the patient to understand the patient information sheet or comply with study procedures.
• Treatment with any other investigational agent with therapeutic intent within 28 days prior to initiation of study treatment.
• Patients with uncontrolled comorbidities that may affect the clinical trial compliance.
• Women who are pregnant or in the breastfeeding period or male or female patients of reproductive potential who are not willing to employ effective birth control from screening to 90 days after the last dose of durvalumab monotherapy.
• Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
• Patients must be informed that they are not allowed to donate blood during the treatment period of this clinical trial.
• Prior randomization or treatment in a previous durvalumab clinical study regardless of treatment arm assignment.
• Receipt of a live attenuated vaccine within 30 days prior to the first dose of investigational product (IP).
• Concurrent enrollment in another clinical study, except in cases where the study is observational (non-interventional) or the patient is in the follow-up phase of a previous interventional study.