Nautika1: A Multicenter, Phase II, Neoadjuvant And Adjuvant Study Of Multiple Therapies In Biomarker-Selected Patients With Resectable Stages Ib-III Non-Small Cell Lung Cancer (H-52399)

Objective: 

Study ML41591 is an umbrella trial that will evaluate the efficacy and safety of various therapies in patients with Stage IB, IIA, IIB, IIIA, or selected IIIB tumor, nodes, and metastases [TNM] staging resectable and untreated non-small cell lung cancer (NSCLC) tumors that meet protocol-specified biomarker criteria determined in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory.

Inclusion: 

Patients must meet the following criteria for study entry:

NEOADJUVANT THERAPY

• Signed Informed Consent Form
• Age 18 years or older
• Able to comply with the study protocol, in the investigator’s judgment
• Pathologically documented NSCLC

– Stage IB, IIA, IIB, IIIA, or selected IIIB (T3N2 only) NSCLC of squamous or non-squamous histology. Staging should be based on the 8th edition of the American Joint Committee on Cancer (AJCC) / Union Internationale Contre le Cancer (UICC) NSCLC staging system.

– T4 primary NSCLC will be allowed only on the basis of size (tumors greater than 7 cm). Invasion of the diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, and separate tumor nodules in a different ipsilateral lobe is not permitted.

All patients will undergo clinical staging using CT and PET scanning, as well as brain imaging using MRI. Invasive mediastinal staging by either mediastinoscopy or endo- bronchial ultrasonography is highly encouraged for patients with radiographically suspected mediastinal nodal disease (ie, N2) but not mandated if the CT or PET scans showed no evidence of N2 disease.

Biomarker testing results from CLIA-certified laboratories showing at least one of the following abnormalities:

• ALK fusion
• ROS1 fusion
• NTRK1/2/3 fusion
• BRAF V600 mutation
• RET fusion
• PD-L1 expression in greater or equal 1% tumor cells as determined by FDA-approved test

Biomarker results used for patient eligibility should be obtained from the most recent tumor biopsy. Alternatively, and for patients with ALK, ROS1, NTRK1/2/3, and RET fusions, molecular testing results used to determine patient eligibility could have been obtained from a recent blood sample (up to 2 months prior to enrollment) described in the study design.

Measurable disease, as defined by RECIST v1.1

NSCLC must have a solid or subsolid appearance on CT scan and cannot have a purely ground glass opacity appearance. For subsolid lesions, the tumor size (i.e., clinical T stage) should be measured based on the solid component only, exclusive of the ground glass opacity component

Evaluated by the attending surgeon prior to study enrollment to verify that the primary tumor and any involved lymph nodes are technically completely resectable and verify that the patient is medically operable

Adequate pulmonary function to be eligible for surgical resection with curative intent

– Pulmonary function tests (PFTs) must be performed at screening and before surgery per the SOA, and should include lung volumes, spirometry, and a diffusion capacity. Abnormal PFTs may be further evaluated with quantitative ventilation/perfusion scanning or cardiopulmonary exercise testing. Postoperative percent predicted forced expiratory volume in 1 second (FEV1) and diffusion capacity must be greater or equal40% and/or maximal oxygen consumption (VO2 max) should be greater than 10 mL/kg/min.

It is acceptable to have the screening PFT done within 4 months of Cycle 1, Day 1 but it needs to be repeated prior to Cycle 1, Day 1 if clinically indicated.

Adequate cardiac function to be eligible for surgical resection with curative intent

– If clinically indicated, patients with underlying ischemic or valvular heart disease should be evaluated preoperatively by a cardiologist.

ECOG Performance Status of 0 or 1

Adequate hematologic and end-organ function, defined by the following laboratory results obtained within 14 days prior to the first dose of study treatment:

• ANC greater or equal to 1000/uL
• Platelet count greater or equal to 75,000/uL
• Hemoglobin greater or equal to 9.0 g/dL
• AST and ALT less than or equal to 2.5 x upper limit of normal (ULN)
• Serum bilirubin less than or equal to 1.5 x ULN
• Creatinine clearance (CrCl) greater or equal to 60 mL/min

Negative hepatitis B surface antigen (HBsAg) test at screening for cohort

Negative total hepatitis B core antibody (HBcAb) test at screening for cohort, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening

– The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening

– The HCV RNA test will be performed only for patients who have a positive HCV antibody test.

Male patients must be willing to use acceptable methods of contraception (however males in PD-L1 cohort are exempt). Treatment-specific contraceptive requirements can be found in Appendix 3.

Female patients of childbearing potential must agree to use acceptable methods of contraception. Treatment-specific contraceptive requirements can be found in Appendix 3.

Additional inclusion criteria specific to the study drug are contained in the appropriate cohort-specific appendices. Note: The requirements for enrollment into a specific cohort may be more stringent.

ADJUVANT THERAPY (TKI COHORTS)

Patients in the TKI cohorts must meet the following criteria to be eligible to continue to receive adjuvant therapy:

Patients whose tumors lack radiographic progression

ECOG Performance Status of 0 or 1

Adequate hematologic and end-organ function, defined by the following laboratory results obtained per SOC prior to the starting adjuvant therapy in the Adjuvant Treatment Phase:

TKI Cohorts:

• ANC greater or equal to 1000/uL
• Platelet count greater or equal to 75,000/uL
• Hemoglobin greater or equal to 9.0 g/dL; patients may be transfused to meet this criterion
• AST and ALT less than or equal to 2.5 x ULN
• Serum bilirubin less than or equal to 1.5 x ULN
• CrCl greater or equal to 60 mL/min