Non-small Cell Lung Cancer
Conditions
Brief summary
This clinical research study is being carried out in two parts, Phase 1 and Phase 2. The primary purpose of the Phase 1 portion of the study is to observe the safety of the combination of rociletinib and MPDL3280A in EGFR-mutant NSCLC patients. The primary purpose of the Phase 2 portion of the study is to evaluate the safety and anti-tumor effects of the combination of rociletinib and MPDL3280A, at the best doses for the combination determined in Phase 1, in patients with EGFR-mutant NSCLC.
Detailed description
This is a Phase 1b/2, open-label, non-randomized, multicenter study evaluating the safety and efficacy of rociletinib administered in combination with MPDL3280A. Phase 1: This will be the dose finding phase of the study. Patients will be enrolled to available Dosing Cohort. Patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status, will be enrolled. Phase 2: Patients will be enrolled into 2 groups. Group A will enroll eligible first-line patients who are EGFR TKI treatment-naïve and chemotherapy-naïve. Group B will enroll eligible patients who have progressed after prior first- or second-generation EGFR TKI, regardless of T790M mutation status.
Interventions
DRUGRociletinib
A novel, potent, covalent (irreversible) small molecule, tyrosine kinase inhibitor (TKI) administered orally (PO) to patients with EGFRm NSCLC.
DRUGMPDL3280A
A human IgG1 monoclonal antibody administered intravenously (IV)
Sponsors
Genentech, Inc.
Clovis Oncology, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* ECOG performance status of 0 or 1 * Adequate hematological and biological function, confirmed by defined laboratory values * Histologically or cytologically documented metastatic or unresectable, locally advanced or metastatic NSCLC, with one or more activating EGFR mutation (eg, G719X, exon 19 deletion, L858R, L861Q) and absence of exon 20 insertion * Measurable disease as defined by RECIST v1.1 * Biopsy of tumor tissue for central evaluation, within 60 days prior to the first day of study treatment * For Phase 1 and Phase 2 Group B, progression after prior 1st or 2nd generation EGFR TKI (eg, erlotinib, gefitinib, afatinib). Previous chemotherapy for NSCLC is allowed. * For Phase 2 Group A, EGFR TKI treatment-naïve and chemotherapy-naïve
Exclusion criteria
* Unresolved toxicities from prior therapy * Symptomatic, untreated or unstable central nervous system or leptomeningeal metastases * Previous treatment with rociletinib or MPDL3280A, or other 3rd generation EGFR TKI (eg, AZD-9291, HM61713), or PD 1 axis targeted therapy (eg, anti PD 1 or anti-PD L1) * Prior treatment with CD137 agonists or other immune checkpoint blockade therapies, including anti-CTLA-4 therapeutic antibodies * Uncontrolled pleural effusion, pericardial effusion or ascites requiring recurrent drainage procedures * Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab (bisphosphonate use for prevention of skeletal events allowed) * Known hypersensitivity to any component of the MPDL3280A or rociletinib formulations or history or hypersensitivity to chimeric humanized antibodies or fusion proteins * History of autoimmune disease * History of prior allogeneic hematopoietic stem cell transplantation or prior solid organ transplantation * Treatment with systemic immunosuppressive medications within 2 weeks prior to first day of study treatment (inhaled corticosteroids and mineralocorticoids allowed) * Live attenuated vaccine within 4 weeks prior to first day of study treatment * Active tuberculosis, active hepatitis, or positive HIV status * Class II to IV heart failure as defined by the New York Heart Association functional classification system * Untreated or uncontrolled cardiovascular disease or other symptomatic cardiac dysfunction * QTCF \> 450 ms, inability to measure QT interval on ECG, personal or family history of long QT syndrome, requirement for medications that have the potential to prolong the QT interval * History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computerized tomography (CT) scan (history of radiation pneumonitis in radiation field may be allowed) * Other malignancies within 5 years prior to enrollment, with the exception of carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer, or ductal carcinoma in situ
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate Per RECIST v1.1 in Phase 2 | Approximately every 6-9 weeks | To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: * Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. * Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI. |
| Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites | Treatment Day 1 and Day 15 | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
| Minimum Concentration (Cmin) of Rociletinib and Metabolites | Approximately every 6 weeks up to 24 months | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
| Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites | Treatment Day 1 and Day 8 | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
| Maximum Concentration (Cmax) of MPDL3280A | Cycle 1 Day 1 | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
| Minimum Concentration (Cmin) of MPDL3280A | Approximately every 6 weeks up to 24 months | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
| Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03 | Continuously, up to approximately 18.5 months | The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A. |
| Maximum Concentration (Cmax) of Rociletinib and Its Metabolites | Treatment Day 1 and Day 15 | Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 | Approximately every 6-9 weeks, up to 24 months | Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC). |
| Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 | Approximately every 6-9 weeks, up to 24 months | Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC). |
| Number of Patients Alive at Study Termination | Up to approximately 18.5 months | Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study. |
| Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA | Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months | Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned. |
| Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2 | Approximately every 6-9 weeks, up to 24 months | Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC). |
Countries
United States
Participant flow
Recruitment details
Three patients were enrolled at a single center in the United States.
Pre-assignment details
The Dose Finding Phase included a 7 day Run in Period of rociletinib monotherapy, at the Dosing Cohort-defined dose level, prior to the initiation of combination treatment.
Participants by arm
| Arm | Count |
|---|---|
| Single Arm Rociletinib and MPDL3280A in Combination Rociletinib (CO-1686), a novel, potent, covalent (irreversible) small molecule, tyrosine kinase inhibitor (TKI) administered orally (PO) to patients with EGFRm NSCLC in combination with MPDL3280A, a human IgG1 monoclonal antibody administered intravenously (IV). | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Single Arm Rociletinib and MPDL3280A in Combination |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 66 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 1 / 3 |
Outcome results
Primary
Area Under the Curve (AUC) of Rociletinib and Rociletinib Metabolites
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. AUC0 24 will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Treatment Day 1 and Day 8
Population: Due to the small number of patients enrolled and small number of PK sample collected as a result of early termination of the study, these analyses were not conducted.
Primary
Maximum Concentration (Cmax) of MPDL3280A
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax, for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Cycle 1 Day 1
Population: Due to the small number of patients enrolled and small number of PK samples collected as a result of early termination of the study, these analyses were not conducted.
Primary
Maximum Concentration (Cmax) of Rociletinib and Its Metabolites
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Treatment Day 1 and Day 15
Population: Due to the small number of patients enrolled and small number of PK samples collected as a result of early termination of the study, these analyses were not conducted.
Primary
Minimum Concentration (Cmin) of MPDL3280A
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin for MPDL3280A will be assessed using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Approximately every 6 weeks up to 24 months
Population: Due to the small number of patients enrolled and small number of PK samples collected as a result of early termination of the study, these analyses were not conducted.
Primary
Minimum Concentration (Cmin) of Rociletinib and Metabolites
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Cmin will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Approximately every 6 weeks up to 24 months
Population: Due to the small number of patients enrolled and small number of PK samples collected as a result of early termination of the study, these analyses were not conducted.
Primary
Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03
The safety analyses will be performed using the safety population. Safety data analysis will be conducted on all patients receiving at least one dose of rociletinib or MPDL3280A.
Time frame: Continuously, up to approximately 18.5 months
Population: All patients enrolled in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm Rociletinib and MPDL3280A in Combination | Number of Treatment-emergent Adverse Events, as Assessed by NCI CTCAE v4.03 | 31 Treatment emergent adverse events |
Primary
Objective Response Rate Per RECIST v1.1 in Phase 2
To determine the efficacy of the combination of rociletinib and MPDL3280A based on overall response rate per RECIST v1.1 in the following groups of patients: * Group A: Patients with EGFRm advanced or metastatic NSCLC who have not previously received an EGFR TKI or chemotherapy. * Group B: Patients with EGFRm advanced or metastatic NSCLC who have progressed on a prior EGFR TKI.
Time frame: Approximately every 6-9 weeks
Population: Given the early termination of the study and that no patients were enrolled in Phase 2 of the study, no conclusions can be drawn.
Primary
Time to Maximum Concentration (Tmax) for Rociletinib and Rociletinib Metabolites
Blood sampling for PK analyses of both rociletinib and MPDL3280A will be conducted in all patients treated with rociletinib and MPDL3280A. Tmax will be estimated for rociletinib, using non-compartmental models. Comparisons across dose levels will be made to assess proportionality.
Time frame: Treatment Day 1 and Day 15
Population: Due to the small number of patients enrolled and small number of PK samples collected as a result of early termination of the study, these analyses were not conducted.
Secondary
Duration of Response Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2
Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Time frame: Approximately every 6-9 weeks, up to 24 months
Population: Given the early termination of the study and that no patients were enrolled in Phase 2 of the study, no conclusions can be drawn.
Secondary
Longitudinal Changes in Blood Based Biomarkers (eg, Mutations in EGFR) in ctDNA
Tumor tissue, plasma, and blood specimens will be used for pharmacodynamic assessment of rociletinib and/or MPDL3280A activity, to evaluate the concordance of mutant EGFR detection between tissue and plasma, and to explore biomarkers that may be predictive of response or resistance to rociletinib and/or MPDL3280A. Biomarkers and changes in biomarker status will be investigated for associations with rociletinib and/or MPDL3280A exposure, safety, and clinical activity. Given the limited sample size, no formal statistical analysis is planned.
Time frame: Blood samples will be collected from each patient approximately every 3 weeks, up to 24 months
Population: Due to the small number of patients enrolled and small number of samples collected as a result of early termination of the study, these analyses were not conducted.
Secondary
Number of Patients Alive at Study Termination
Patients who received the combination of rociletinib and MPDL3280A alive at the termination of this study.
Time frame: Up to approximately 18.5 months
Population: Count of the number of enrolled patients alive at study termination.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm Rociletinib and MPDL3280A in Combination | Number of Patients Alive at Study Termination | 2 participants |
Secondary
Objective Response Rate Per Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2
Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Time frame: Approximately every 6-9 weeks, up to 24 months
Population: Given the early termination of the study and that no patients were enrolled in Phase 2 of the study, no conclusions can be drawn.
Secondary
Progression-free Survival Per RECIST v1.1 and Modified RECIST v1.1, Incorporating Immune-related Criteria, in Phase 2
Conventional response criteria may not be adequate to characterize the antitumor activity of immunotherapeutic agents like MPDL3280A, which can produce delayed responses that may be preceded by initial apparent radiological progression, including the appearance of new lesions. Therefore, modified response criteria have been developed that account for the possible appearance of new lesions and allow radiological progression to be confirmed at a subsequent assessment. In this protocol, patients will be permitted to continue study treatment even after modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria for progressive disease are met if the benefit-risk ratio is judged to be favorable. These modified criteria are derived from RECIST version 1.1 (v1.1) conventions and immune related response criteria (irRC).
Time frame: Approximately every 6-9 weeks, up to 24 months
Population: Given the early termination of the study and that no patients were enrolled in Phase 2 of the study, no conclusions can be drawn.