A Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer

Sponsor

Genentech, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04302025

Collaborator

Blueprint Medicines Corporation (Industry)

Enrollment

Locations

Arms

99.7

Anticipated Duration (Months)

3.1

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This trial will evaluate the efficacy and safety of various therapies in patients with Stage IB, IIA, IIB, IIIA, or selected IIIB resectable and untreated non-small cell lung cancer (NSCLC) tumors that meet protocol-specified biomarker criteria

Condition or Disease	Intervention/Treatment	Phase
Non-small Cell Lung Cancer	Drug: Alectinib Drug: Entrectinib Drug: Vemurafenib Drug: Cobimetinib Drug: Pralsetinib Drug: Atezolizumab Drug: SBRT Procedure: Resection Drug: Chemotherapy	Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

80 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

NAUTIKA1: Multicenter, Phase II, Neoadjuvant and Adjuvant Study of Multiple Therapies in Biomarker-Selected Patients With Resectable Stages IB-III Non-Small Cell Lung Cancer

Actual Study Start Date :

Nov 6, 2020

Anticipated Primary Completion Date :

Mar 31, 2023

Anticipated Study Completion Date :

Feb 28, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ALK Cohort Participants will receive up to 8 weeks of alectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with alectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of alectinib.	Drug: Alectinib Participants will receive oral alectinib twice per day (BID) Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes Drug: Chemotherapy Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
Experimental: ROS 1 Cohort Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib.	Drug: Entrectinib Participants will receive oral entrectinib daily Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes Drug: Chemotherapy Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
Experimental: NTRK Cohort Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib.	Drug: Entrectinib Participants will receive oral entrectinib daily Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes Drug: Chemotherapy Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
Experimental: BRAF Cohort Participants will receive up to 8 weeks of vemurafenib plus cobimetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with vemurafenib plus cobimetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of of vemurafenib plus cobimetinib.	Drug: Vemurafenib Participants will receive oral vemurafenib BID Drug: Cobimetinib Participants will receive oral cobimetinib daily Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes Drug: Chemotherapy Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
Experimental: RET Cohort Participants will receive up to 8 weeks of pralsetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with pralsetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of pralsetinib.	Drug: Pralsetinib Participants will receive oral pralsetinib daily Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes Drug: Chemotherapy Participants will receive standard of care (SOC) chemotherapy as determined by the treating physician
Experimental: PD-L1 Cohort Participants with positive PD-L1 in ≥1% tumor cells will receive 4 cycles of atezolizumab neoadjuvant treatment. During neoadjuvant Cycle 1 of atezolizumab, patients will also receive low-dose SBRT (8Gy X 3). Adjuvant treatment consists of SOC treatment as determined by the investigator, per NCCN guidelines	Drug: Atezolizumab Atezolizumab will be administered by intravenous (IV) infusion Drug: SBRT Patients will receive SBRT given concurrently starting with the first dose of atezolizumab Procedure: Resection Participants will receive surgical resection of the primary tumor along with selected lymph nodes

Outcome Measures

Primary Outcome Measures

Tyrosine kinase inhibitor (TKI): Proportion of Participants with Major Pathologic Response (MPR) [After surgical resection (approximately study Week 8)]
MPR is defined as </=10% residual viable tumor cells as scored by local pathologists
Checkpoint inhibitor (CPI) cohort: Pathological complete response (pCR) [After surgical resection (approximately study Week 8)]
Scored by local pathologists; defined as lack of any viable tumor cells on review of hematoxylin and eosin (H&E) slides after complete evaluation of a resected lung cancer specimen including all sampled regional lymph nodes

Secondary Outcome Measures

Proportion of Participants with MPR [After surgical resection (approximately study Week 8)]
Defined as ≤10% residual viable tumor cells) based on surgical resection as defined by Hellmann et al. (2014) and Travis et al. (2020) TKI cohorts: MPR will be scored by a central pathology committee consensus read CPI cohort: MPR will be scored by local pathologists and central pathology committee consensus read
Proportion of Participants with pCR [After surgical resection (approximately study Week 8)]
defined as lack of any viable tumor cells on review of H&E slides after complete evaluation of a resected lung cancer specimen, including all sampled regional lymph nodes TKI cohorts: pCR will be scored by local pathologists and a central pathology committee consensus read CPI cohort: pCR will be scored by a central pathology committee consensus read
Pathological Regression Based on Weighted % Viable Tumor Cell Assessment [After surgical resection (approximately study Week 8)]
Investigator-Assessed Response Objective Response Rate (ORR) per RECIST v1.1 [After neoadjuvant treatment (after approximately study Week 8)]
Pathological Complete Response (pCR) as Assessed by Local and Central Pathology Laboratories [At the time of surgical resection (approximately study Week 8)]
Defined as the absence of any viable tumor in main tumor bed at the time of surgical resection, as assessed by local and central pathology laboratories
Disease-Free Survival (DFS) [From the first date of no disease to local or distant recurrence or death from any cause, whichever occurs first, through the end of the study (up to 8 years)]
Event-Free Survival (EFS) [From first dose of study treatment to first documented disease progression per RECIST v1.1, or local or distant disease recurrence as determined by investigator, or death from any cause, whichever occurs first, through the end of study (up to 8 years)]
Overall Survival (OS) [From the first dose of study medication to death from any cause, through the end of the study (up to 8 years)]
Percentage of Participants with Adverse Events (AEs) [Up to 8 years]
Nodal downstaging, defined as percentage of patients with reduced stages in mediastinal nodes at surgery [After surgical resection (approximately study Week 8)]
Circulating tumor DNA ctDNA Clearance Rate [Prior to surgery (before study Week 8)]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria for Neoadjuvant Therapy:

Pathologically documented NSCLC: Stage IB, IIA, IIB, IIIA, or selected IIIB, including T3N2, or T4 (by size criteria, not by mediastinal invasion) NSCLC (based on the 8th edition of the American Joint Committee on Cancer [AJCC] Non-Small Cell Lung Cancer Staging system
T4 primary NSCLC will be allowed only on the basis of size
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.
Molecular testing results from CLIA-certified laboratories and 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 ≥ 1% tumor cells as determined by FDA-approved test
Measurable disease, as defined by RECIST v1.1
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 participant is medically operable
Adequate pulmonary function to be eligible for surgical resection with curative intent
Adequate cardiac function to be eligible for surgical resection with curative intent
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
Male participants must be willing to use acceptable methods of contraception
Female participants of childbearing potential must agree to use acceptable methods of contraception

Inclusion Criteria for Adjuvant Therapy

Participants whose tumors lack radiographic progression
ECOG Performance Status of 0 or 1
Adequate hematologic and end-organ function

Exclusion Criteria

NSCLC that is clinically T4 by virtue of mediastinal organ invasion or Stage IIIB by virtue of N3 disease
Any prior therapy for lung cancer, including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, within 2 years
Participants with prior lung cancer that have been in remission for <2 years with the exception of minimally invasive adenocarcinoma or incidental typical carcinoid tumors
Major surgical procedure within 28 days prior to Cycle 1, Day 1
Participants known to be positive for HIV are excluded if they meet any of the following criteria: CD4+ T-cell count of <350 cells/microliters; detectable HIV viral load; history of an opportunistic infection within the past 12 months; on stable antiretroviral therapy for <4 weeks
Severe infection within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infections, or any active infection that, in the opinion of the investigator, could impact participant safety
Pregnant or lactating, or intending to become pregnant during the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
2	USC Norris Cancer Center	Los Angeles	California	United States	90033
3	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
4	UCLA Hematology Oncology	Los Angeles	California	United States	90095
5	The Center for Cancer Prevention and Treatment at St.Joseph Hospital of Orange	Orange	California	United States	92868
6	UC Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
7	Yale Cancer Center	New Haven	Connecticut	United States	06520
8	MedStar Georgetown University Hospital (Lombardi Comprehensive Cancer Center)	Washington	District of Columbia	United States	20007
9	Sylvester Comprehensive Cancer Center - Deerfield Beach	Miami	Florida	United States	33136
10	Moffitt Cancer Center	Tampa	Florida	United States	33612
11	Dana-Farber Cancer Institute; Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
12	University of Michigan	Ann Arbor	Michigan	United States	48109
13	Karmanos Cancer Institute - Farmington Hills/Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
14	University of Missouri Health Care; Ellis Fischel Cancer Center	Columbia	Missouri	United States	65212
15	HCA Midwest Health	Kansas City	Missouri	United States	64132
16	Washington University School of Medicine; Sitemann Cancer Center	Saint Louis	Missouri	United States	63110
17	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
18	Laura and ISAAC Perlmutter Cancer Center at NYU Langone.	New York	New York	United States	10016
19	Columbia University Medical Center	New York	New York	United States	10032
20	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
21	University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
22	Ohio State University; Hemat/Onc	Columbus	Ohio	United States	43210
23	Tennessee Oncology	Nashville	Tennessee	United States	37203
24	MD Anderson Cancer Center	Houston	Texas	United States	77030
25	Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
26	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109