This is a phase 2/3, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in combination in participants with unresectable, advanced or metastatic NSCLC determined to harbor oncogenic somatic mutations or positive by tumor mutational burden (TMB) assay as identified by two blood-based next-generation sequencing (NGS) circulating tumor DNA (ctDNA) assays.
Recruiting
Phase 2/Phase 3
| Drug | Synonyms | Arms |
|---|---|---|
| Alectinib | RO5424802 | Cohort A: Alectinib 600 Milligrams (mg) |
| Atezolizumab | RO5541267 | Cohort C: Atezolizumab 1200 mg |
| Pemetrexed | Cohort C: Pemetrexed, Cisplatin or Carboplatin | |
| Cisplatin | Cohort C: Pemetrexed, Cisplatin or Carboplatin | |
| Carboplatin | Cohort C: Pemetrexed, Cisplatin or Carboplatin | |
| Gemcitabine | Cohort C: Gemcitabine, Cisplatin or Carboplatin | |
| Entrectinib | RO7102122 | Cohort D: Entrectinib 600 Milligrams (mg) |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Cohort A: Alectinib 600 Milligrams (mg) | Experimental | This cohort includes participants with anaplastic lymphoma kinase (ALK) positive NSCLC. Participants will receive alectinib 600 mg orally twice in a day (BID) until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort A is complete. |
|
| Cohort B: Dose Finding Phase (DFP) Alectinib | Experimental | This cohort includes participants with rearranged during transfection (RET) positive NSCLC. Participants may receive alectinib 900 or 1200 mg orally BID until disease progression, unacceptable toxicity, withdrawal of consent or death if the recommended phase 2 dose (RP2D) is not established in any other clinical study. Participants may receive 750 mg or 600 mg, if it is unsafe to pursue the higher starting dose. Enrollment to Cohort B is complete. |
|
| Cohort B: Dose Expansion Phase (DEP) Alectinib | Experimental | This cohort includes participants with RET positive NSCLC. Participants will receive alectinib at the RP2D established in the DFP of Cohort B or a separate clinical study. Participants will continue receiving study treatment until disease progression, unacceptable toxicity, withdrawal of consent or death. Enrollment to Cohort B is complete. |
|
| Cohort C: Atezolizumab 1200 mg | Experimental | This cohort includes participants with bTMB positive NSCLC. Participants will receive atezolizumab at a dose of 1200 mg administered by IV infusion every 21 days (Q21D) until disease progression, loss of clinical benefit, unacceptable toxicity, withdrawal of consent or death. |
|
| Cohort C: Pemetrexed, Cisplatin or Carboplatin | Active Comparator | This cohort includes participants with bTMB positive, non-squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Carboplatin at a dose of area under the concentration-time curve (AUC) of 5 or 6 IV or cisplatin at a dose of 75 milligrams per meter square (mg/m^2) IV on Day 1 of each cycle combined with pemetrexed at a dose of 500 mg/m^2 IV on Day 1 of each cycle. Pemetrexed may be continued as maintenance therapy every 21 days (Q21D) as per local standard of care. |
|
| Cohort C: Gemcitabine, Cisplatin or Carboplatin | Active Comparator | This cohort includes participants with bTMB positive, squamous NSCLC. Participants will receive 4 or 6 cycles of treatment, with each cycle being 21 days in duration. Gemcitabine 1250 mg/m^2 IV on Days 1 and 8 of every cycle and cisplatin 75 mg/m^2 IV on Day 1 Q21D or gemcitabine 1000 mg/m^2 IV on Days 1 and 8 of every cycle and carboplatin AUC 5 IV on Day 1 Q21D. |
|
| Cohort D: Entrectinib 600 Milligrams (mg) | Experimental | This cohort includes participants with c-ros oncogene 1 positive (ROS1+) NSCLC. Participants will receive entrectinib 600 mg orally once a day (QD) until disease progression, unacceptable toxicity, withdrawal of consent or death. |
|
Inclusion Criteria:
- No prior systemic treatment for unresectable stage IIIB or IV NSCLC
- Histologically or cytologically confirmed diagnosis of unresectable Stage IIIb not
amenable to treatment with combined modality chemoradiation (advanced) or Stage IV
(metastatic) NSCLC
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
- Measurable disease
- Adequate recovery from most recent systemic or local treatment for cancer
- Adequate organ function
- Life expectancy greater than or equal to (>/=) 12 weeks
- For female participants of childbearing potential and male participants, willingness
to use acceptable methods of contraception
Exclusion Criteria:
- Inability to swallow oral medication
- Women who are pregnant or lactating
- Symptomatic, untreated CNS metastases
- History of malignancy other than NSLCL within 5 years prior to screening with the
exception of malignancies with negligible risk of metastasis or death
- Significant cardiovascular disease, such as New York Heart Association cardiac disease
(Class II or greater), myocardial infarction, or cerebrovascular accident within 3
months prior to randomization, unstable arrhythmias, or unstable angina
- Known human immunodeficiency virus (HIV) positivity or autoimmune deficiency syndrome
(AIDS)-related illness
- Either a concurrent condition or history of a prior condition that places the patient
at unacceptable risk if he/she were treated with the study drug or confounds the
ability to interpret data from the study
- Inability to comply with other requirements of the protocol
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Cohort A: Percentage of Participants with Confirmed Objective Response as Assessed by the Investigator Based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Duration of Response as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: PFS as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Duration of Response as Assessed by the Independent Review Facility (IRF) Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: Percentage of Participants with Clinical Benefit Response as Assessed by IRF Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: PFS as Assessed by IRF Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Percentage of Participants with Confirmed Objective Response as Assessed by IRF Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Overall Survival |
| Time Frame: | Baseline up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Percentage of Participants with Adverse Events |
| Time Frame: | Baseline up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: Percentage of Participants who Have Shown Improvement Compared with Baseline in Total Severity Symptom Score as Measured by Symptoms in Lung Cancer (SILC) Scale in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain) |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Time to Deterioration in Patient-Reported Lung Cancer Symptoms (Cough, Dyspnea and Chest Pain) as Measured by SILC Scale |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohort C: Change from Baseline in Patient-Reported Lung Cancer Symptom (Cough, Dyspnea, Chest pain) Score as Measured by the SILC Scale |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Change from Baseline in Health Related Quality of Life (HRQoL) Scores as Measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - C30 (EORTC QLQ-C30) |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: Change from Baseline in HRQoL Scores as Measured by the SILC Scale |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the EORTC QLQ-C30 |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts A, B and D: Change from Baseline in Patient Functioning and Symptoms Score as Measured by the SILC Scale |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | All Cohorts: Health Status Assessed as an Index Score Using the European Quality of Life 5-Dimension 5-Level (EQ-5D-5L) Questionnaire |
| Time Frame: | Baseline, every 4 weeks through Cycle 6 (1 Cycle = 21 or 28 days), every 8 weeks thereafter up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Percentage of Participants with Dose-Limiting Toxicities (DLTs) |
| Time Frame: | Day 1 to Day 28 of Cycle 1 (cycle length = 28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Maximum Plasma Concentration (Cmax) of Alectinib |
| Time Frame: | DFP: pre-dose (0 hours [hr]) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: | DFP: Dose-Finding Phase; DEP: Dose-Expanding Phase. |
| Measure: | Cohort B: Area Under the Concentration-Time Curve from Time Zero to the Last Measurable Concentration (AUC0-last) of Alectinib |
| Time Frame: | DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Time to Reach Cmax (Tmax) of Alectinib |
| Time Frame: | DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Half-Life (t1/2) of Alectinib |
| Time Frame: | DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Metabolite to Parent Exposure Ratio for AUC0-last |
| Time Frame: | DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort B: Metabolite to Parent Exposure Ratio for Cmax |
| Time Frame: | DFP: pre-dose (0 hr) on Day 1 of Cycle 2; 0.5, 1, 2, 4, 6, 8 and 10 hr post-dose on Day 1 of Cycle 2 (1 Cycle=28 days) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort C: Percentage of Participants with Objective Response as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort C: Percentage of Participants Free from Disease Progression as Assessed by the Investigator Based on the RECIST v1.1 at Months 6 and 12 |
| Time Frame: | Months 6, 12 |
| Safety Issue: | |
| Description: |
| Measure: | Cohort D: Time to CNS progression as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to CNS progression (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort D: Time to CNS progression as Assessed by the IRF Based on the RECIST v1.1 |
| Time Frame: | Baseline up to CNS progression (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohort D: Intracranial Tumor Response Rate as Assessed by the Investigator Based on the RECIST v1.1 |
| Time Frame: | Baseline up to disease progression or death (up to approximately 6 years) |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-C30 |
| Time Frame: | Baseline, every 4 weeks until disease progression, up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohorts D: Percentage of Participants who have shown improvement compared with Baseline in patient-reported cognitive function, fatigue, HRQoL, headache and vision disorder per the EORTC QLQ-BN20 |
| Time Frame: | Baseline, every 4 weeks until disease progression, up to approximately 6 years |
| Safety Issue: | |
| Description: |
| Measure: | Cohort D: Mean Plasma Concentration of Entrectinib |
| Time Frame: | Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days). |
| Safety Issue: | |
| Description: |
| Measure: | Cohort D: Mean Plasma Concentration of Entrectinib Metabolite M5 |
| Time Frame: | Pre-dose (0 hr), 1.5 and 4 hr post-dose on Day 1 of Cycles 1, 2, 3, 4 and 5; and pre-dose on Day 1 of each subsequent treatment cycle (1 cycle = 28 days). |
| Safety Issue: | |
| Description: |
| Phase: | Phase 2/Phase 3 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Hoffmann-La Roche |
