This is a study to evaluate the efficacy, safety, and pharmacokinetics of cobimetinib plus atezolizumab in participants with advanced solid tumors including the following cohorts: squamous cell carcinoma of the head and neck (SCCHN), urothelial carcinoma (UC), and renal cell carcinoma (RCC).
Completed
Phase 2
| Drug | Synonyms | Arms |
|---|---|---|
| Cobimetinib | Cotellic | Cohort 1 - SCCHN - Treatment Naive |
| Atezolizumab | Tecentriq | Cohort 1 - SCCHN - Treatment Naive |
| Atezolizumab Cohort 7 | Tecentriq | Cohort 7 - Biopsy Cohort |
| Name | Type | Description | Interventions |
|---|---|---|---|
| Cohort 1 - SCCHN - Treatment Naive | Experimental | In participants with recurrent or advanced / metastatic SSCHN who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 2 - UC - Treatment Naive | Experimental | In participants with advanced / metastatic UC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 3 - RCC - Treatment Naive | Experimental | In participants with metastatic RCC who are anti-PD-1 and anti-PD-L1 treatment naive, cobimetinib will be administered at the approved dose and schedule of 60 milligrams (mg) once daily (QD) for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 4 - SCCHN - Previous Treatment Exposure | Experimental | In participants with SCCHN whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 5 - UC - Previous Treatment Exposure | Experimental | In participants with UC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 6 - RCC - Previous Treatment Exposure | Experimental | In participants with RCC whose disease has progressed while receiving anti-PD-1 or anti-PD-L1 therapy, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle; and atezolizumab 840 mg by intravenous (IV) infusion on Days 1 and 15 of each 28-day cycle. |
|
| Cohort 7 - Biopsy Cohort | Experimental | In participants with solid non-melanoma, non- hematologic tumors who previously developed primary or secondary resistance to an anti-PD-1 or anti-PD-L1 agent, cobimetinib will be administered at the approved dose and schedule of 60 mg QD for 21 days and 7 days off of each 28-day cycle. The first dose of atezolizumab of 840 mg by IV infusions on Day 15 of Cycle 1. Thereafter, they will receive atezolizumab 840 mg IV infusion Q2W on Days 1 and 15 of Cycle 2 and all subsequent cycles. |
|
Inclusion Criteria:
General Inclusion Criteria:
- Age ≥18 years
- Ability to comply with the study protocol, in the investigator's judgment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
- Life expectancy ≥3 months, as determined by the investigator
- Adequate hematologic and end-organ function
Cancer-Related Inclusion Criteria:
- Patients must have measurable disease by computed tomography (CT) or magnetic
resonance imaging (MRI) scan per RECIST v1.1.
- Availability to provide a representative tumor specimen biopsy
- Evidence of tumor progression on or after the last treatment regimen received and
within 6 months prior to study enrollment
- For women of childbearing potential: agreement to remain abstinent (refrain from
heterosexual intercourse) or use a non-hormonal contraceptive method with a failure
rate of <1% per year during the treatment period and for at least 5 months after the
last dose of atezolizumab and within 3 months after the last dose of cobimetinib
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
contraceptive measures, and agreement to refrain from donating sperm during the
treatment period and for at least 3 months after the last dose of cobimetinib
Exclusion Criteria:
General Exclusion Criteria:
- Inability to swallow medications
- Malabsorption condition that would alter the absorption of orally administered
medications
- Poor peripheral venous access
- Prior treatment with cobimetinib or a MEK inhibitor
- Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies,
including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- Treatment with investigational therapy within 14 days prior to initiation of study
treatment
- Any anti-cancer therapy, including chemotherapy or hormonal therapy, within 2 weeks
prior to initiation of study treatment
- History of severe allergic, anaphylactic, or other hypersensitivity reactions to
chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity to biopharmaceutical agents produced in Chinese hamster ovary
cells or any component of the atezolizumab formulation, or any component of the
cobimetinib formulation
- History of serous retinopathy, retinal vein occlusion (RVO), or evidence of ongoing
serous retinopathy or RVO at baseline
- Major surgical procedure other than for diagnosis within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study
- Uncontrolled tumor-related pain
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring repeated
drainage more than once every 28 days
- Uncontrolled hypercalcemia (ionized calcium >1.5 millimoles per liter [mmol/L],
calcium >12 milligrams per deciliter [mg/dL], or corrected calcium greater than the
upper limit of normal [ULN]) or symptomatic hypercalcemia requiring continued use of
bisphosphonate therapy
- Active or untreated central nervous system (CNS) metastases
- Pregnancy or breastfeeding, or intending to become pregnant during the study
Exclusion Criteria based on Organ Function or Medical History
Cardiovascular
Patients who meet the following cardiovascular exclusion criterion will be excluded from
study entry:
- Left ventricular ejection fraction (LVEF) below the institutional lower limit of
normal or <50%, whichever is lower
Infections Patients who meet any of the following infection exclusion criteria will be
excluded from study entry:
- Positive human immunodeficiency virus (HIV) test at screening
- Active hepatitis B virus (HBV) infection (chronic or acute)
- Active hepatitis C virus (HCV) infection
- Active tuberculosis
- Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
| Measure: | Objective Response Rate (ORR) |
| Time Frame: | Up to approximately 31 months |
| Safety Issue: | |
| Description: | Objective response rate was defined as the percentage of participants with a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart, as determined by the investigators using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. |
| Measure: | Overall Survival (OS) |
| Time Frame: | Up to approximately 31 months |
| Safety Issue: | |
| Description: | Overall survival was defined as the time from enrollment to death from any cause. The median for OS is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| Measure: | Progression-Free Survival (PFS) |
| Time Frame: | Up to approximately 31 months |
| Safety Issue: | |
| Description: | PFS was defined as the time from enrollment to the first occurrence of disease progression as determined by the investigator(s), using RECIST v1.1, or to death from any cause, whichever occurs first. Disease progression was defined as ≥20% increase in in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. |
| Measure: | Duration of Response (DOR) |
| Time Frame: | Up to approximately 22 months |
| Safety Issue: | |
| Description: | DOR was defined as the time from the first occurrence of a documented, confirmed objective response to disease progression as determined by the investigator, using RECIST v1.1, or to death from any cause, whichever occurs first. Objective response was defined as a complete response (CR) or a partial response (PR) on two consecutive tumor assessments ≥4 weeks apart. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. Presented here is median DOR at the time of primary analysis. The median for the duration of response is Kaplan-Meier estimate. 95% CI for median was computed using the method of Brookmeyer and Crowley. |
| Measure: | Disease Control Rate (DCR) |
| Time Frame: | At 16 weeks |
| Safety Issue: | |
| Description: | DCR was defined as the percentage of participants with a complete response (CR), a partial response (PR), or stable disease at 16 weeks as determined by the investigator using RECIST v1.1. CR was defined as disappearance of all lesions. PR was defined as ≥30% decrease in the sum of diameters of target lesions, in the absence of CR, new lesions, and unequivocal progression in non-target lesions. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for disease progression. Disease progression was defined as ≥20% increase in the sum of diameters of target lesions, unequivocal progression in non-target lesions, and/or appearance of new lesions. |
| Measure: | Number of Participants With Adverse Events |
| Time Frame: | Up to approximately 31 months |
| Safety Issue: | |
| Description: | An adverse event is any untoward medical occurrence in a subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An adverse event can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. |
| Measure: | Maximum Plasma Concentration (Cmax) of Cobimetinib |
| Time Frame: | Day 15 of Cycle 3 (cycle is 28 days): 2-4 hours after cobimetinib dose |
| Safety Issue: | |
| Description: | Cmax is the maximum (or peak) concentration that a study drug achieves in the body. |
| Measure: | Minimum Plasma Concentration (Cmin) of Cobimetinib |
| Time Frame: | Day 15 of Cycle 3 (cycle is 28 days): prior to cobimetinib dose |
| Safety Issue: | |
| Description: | Cmin is the minimum (or trough) concentration that a study drug achieves in the body. |
| Measure: | Maximum Serum Concentration (Cmax) of Atezolizumab |
| Time Frame: | 30 minutes following end of atezolizumab infusion on Day 15 of Cycle 3 (each cycle is 28 days) |
| Safety Issue: | |
| Description: | Cmax is the maximum (or peak) concentration that a study drug achieves in the body. |
| Measure: | Minimum Serum Concentration (Cmin) of Atezolizumab |
| Time Frame: | Prior to atezolizumab infusion on Day 1 of Cycles (each cycle is 28 days) 2, 4, 8, 12, and 16, Day 15 of Cycle 3 |
| Safety Issue: | |
| Description: | Cmin is the minimum (or trough) concentration that a study drug achieves in the body. |
| Measure: | Number of Participants With Anti-drug Antibodies (ADAs) |
| Time Frame: | Day 1 of Cycles (each cycle is 28 days) 1, 2, 4, 8, 12, and 16; Day 15 of Cycle 3; at atezolizumab treatment discontinuation visit, and <90 days after last atezolizumab infusion (up to approximately 31 months) |
| Safety Issue: | |
| Description: | Participants were considered to be ADA positive if they were missing data at baseline but developed an ADA response following study drug administration (treatment-induced ADA response), or if they were ADA positive at baseline and the titer of one or more post-baseline samples was at least 4-fold greater (i.e., ≥0.60-titer units) than the titer of the baseline sample (treatment-enhanced ADA response). Participants were considered to be ADA negative if they were missing data at baseline, had a post-baseline ADA result, and all post-baseline samples were negative, or if they were ADA positive at baseline but did not have any post-baseline samples with a titer that was at least 4-fold greater than the titer of the baseline sample (treatment unaffected). |
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Completed |
| Lead Sponsor: | Hoffmann-La Roche |
May 11, 2021
