A Study of Avelumab, Binimetinib and Talazoparib in Patients With Locally Advanced or Metastatic RAS-mutant Solid Tumors

Any adverse events (AEs) occurring in the first cycle of treatment (28 days) which were attributable to study drugs and met DLT criteria. DLT was defined as hematologic: Grade 4 neutropenia lasting\>5 days; febrile neutropenia; neutropenic infection; Grade \>=3 thrombocytopenia with bleed; Grade 4 thrombocytopenia; Grade 4 anemia; non-hematologic: Grade ≥3 toxicities (with some exceptions) ; Grade≥3 creatinine phosphokinase (CPK) with creatinine \>= 1.5xbaseline; Grade 3 troponin increase with cardiac toxicity; potential Hy's Law cases; eye disorders: retinopathy or retinal detachment Grade≥3; retinal vascular disorder; Grade≥3 uveitis, blurred vision, flashing lights, floaters or others for \>21 consecutive days; other Grade 4; cardiac disorders: absolute LVEF decrease \>10% and the LVEF was below LLN; other Grade≥3; respiratory disorders: interstitial lung disease Grade≥2; bronchospasm Grade 3; skin and subcutaneous tissue disorders; non-adherence to treatment schedule; dose reductions.

Time frame: From date of first study treatment to day 28 of study treatment (Up to 28 days)

Population: The safety analysis set included all enrolled participants who receive at least 1 dose of study treatment. The DLT-evaluable analysis set was a subset of the safety analysis set and included all enrolled participants in Phase 1b who were eligible for the study, received at least one dose of the combination treatment, and either experienced DLT during the first cycle (28 days) of treatment, or completed the DLT observation period for the first cycle of treatment without DLT.

Confirmed OR, defined as a complete response (CR) or partial response (PR) per RECIST v1.1. CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 mm. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. Both CR and PR must be confirmed by repeated assessments performed no less than 4 weeks after the criteria for response were first met.

Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).

Population: Due to the early termination of this study, Phase 2 was not initiated and therefore no Phase 2 efficacy results were collected and summarized.

DR is defined, for patients with OR, as the time from the first documentation of objective response (CR or PR) to the date of first documentation of PD or death due to any cause. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.

Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).

Population: The full analysis set included all enrolled participants who received at least 1 dose of study treatment and achieved objective response: only 1 participant in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 participant).

Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.

Time frame: Post dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12

Population: Number of participants analyzed: participants who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number analyzed: participants who had avelumab concentrations above the LLQ at specific time point.

Cmax was the maximum observed plasma concentration and was directly observed from data. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.

Time frame: Post dose on Day 1 and Day 8 of Cycle 1

Population: Number of participants analyzed: participants who had at least 1 concentration measurement for binimetinib. Number analyzed: participants who had binimetinib concentrations above the LLQ at specific time point. When Cmax for binimetinib was planned to be evaluated, data collecting for Avelumab+Binimetinib cohort had already been done. Therefore, data of Cmax for binimetinib in Avelumab+Binimetinib groups hadn't been collected.

The category of nAb included nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.

Time frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months

Population: Participants in the safety analysis set had at least one ADA/nAb sample collected for avelumab. Due to the low observed immunogenicity rate, nAb analysis was not conducted.

An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Treatment-emergent adverse event (TEAE) means event between first dose of study treatment and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. An SAE was an AE resulting in any of death; inpatient hospitalization; life-threatening experience; disability; congenital anomaly or deemed significant for any other reason. Symptoms of infusion-related reactions (IRRs) may include, but were not limited to, fever, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Grade 3: severe or medically significant but not immediately life-threatening, hospitalization or prolongation of existing hospitalization indicated, disabling, limiting self-care ADL; Grade 4: life-threatening consequence, urgent intervention indicated; Grade 5: death related to AE.

Time frame: From the first dose of study treatment through minimum (30 days + last dose of study treatment, start day of new anti-cancer drug therapy - 1 day) assessed for a maximum duration of up to 31 months

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment.

Samples positive for ADA were analyzed for titer. Blood samples were collected for avelumab immunogenicity testing. Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab. Treatment-induced ADA was defined as participants with ADA-negative at baseline and had at least one positive post-baseline ADA result; or if participant did not have a baseline sample, the participant had at least one positive post-baseline ADA result.

Time frame: from the first dose of study up to Day 1 of Cycle 12 for a maximum of 12 months

Population: Participants in the safety analysis set had at least one ADA/nAb sample collected for avelumab, so only two groups (Avelumab+Binimetinib 30mg \[Phase 1b\] and Avelumab+Binimetinib 45mg \[Phase 1b\]) were analyzed.

Laboratory abnormalities were graded by NCI CTCAE version 4.03. Alanine aminotransferase increased, alkaline phosphatase increased, aspartate aminotransferase increased, blood bilirubin increased, creatine phosphokinase (cpk) increased, creatinine increased, gamma-glutamyl transferase (ggt) increased, hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase increased, serum amylase increased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.

Time frame: Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment.

Laboratory abnormalities were graded by NCI CTCAE version 4.03. Anemia, hemoglobin increased, lymphocyte count decreased, lymphocyte count increased, neutrophil count decreased, platelet count decreased, white blood cell decreased were evaluated. This outcome measure calculated the number of participants with laboratory abnormalities whose maximum on-treatment CTCAE Grade were 1-4.

Time frame: Prior to study drug administration on Days 1 and 15 of each treatment cycle, until 30 days after last dose (assessed for a maximum duration of up to 31 months)

Population: The safety analysis set included all enrolled participants who received at least 1 dose of study treatment.

OS is defined as the time from the 'start date' (date of first study treatment) to the date of death due to any cause. CIs were calculated using Brookmeyer and Crowley method.

Time frame: From date of first study treatment until the date of death due to any cause (assessed for a maximum duration of up to 31 months).

Population: The full analysis set included all enrolled participants who received at least 1 dose of study treatment.

OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' (date of first study treatment) until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met. Clopper-Pearson method was used.

Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).

Population: The full analysis set included all enrolled participants who received at least 1 dose of study treatment.

PD-L1 expression was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and inflammatory cells in regions of interest. DDR gene alterations was defined as the number of somatic and germline mutations present in a panel of genes associated with DDR in baseline tumor derived nucleic acid, in germline nucleic acid and in circulating tumor DNA. TMB was defined as determination/estimation of the frequency of mutations (total and non-synonymous) present in baseline tumor derived nucleic acid samples and in baseline circulating tumor DNA.

Time frame: Baseline

Population: The biomarkers were for the phase 2 part. since phase 2 was not initiated, the results was not provided.

Ctrough was the pre-dose concentration during multiple dosing and was directly observed from data. The lower limit of quantification (LLQ) was 0.20 microgram per milliliter. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.

Time frame: Pre-dose on Day 1, and Day 15 of Cycle 1 (each cycle is 28 days); Day 1 and Day 15 of Cycle 2; and Day 1 of Cycles 3, 5, 9 and 12.

Population: Number of participants analyzed: participants who had at least 1 concentration measurement for avelumab. Therefore, only 2 treatment groups including avelumab were analyzed. Number analyzed: participants who had avelumab concentrations above the LLQ at specific time point.

Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 1.00 ng/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.

Time frame: Predose on Day 15 of Cycle 1 (each cycle is 28 days), Day 1 and Day 15 of Cycle 2, Day 1 of Cycle 3 for avelumab+binimetinib groups, and on Day 8 and Day 15 of Cycle 1, Day 1 of Cycle 2, Day 1 of Cycle 3 for binimetinib+talazoparib groups

Population: Number of participants analyzed: participants who had at least 1 concentration measurement for binimetinib. Number analyzed: participants who had binimetinib concentration values above the LLQ at specific time point.

Ctrough was directly observed from data. Ctrough = concentration prior to study drug administration. The LLQ was 25 pg/mL. Concentration values below the LLQ were set to zero. Geometric Mean analysis was on the log scale. Zero values were not included in geometric mean and geometric coefficient of variation calculation. The geometric coefficient of variation is expressed in percentage.

Time frame: Pre-dose on Days 1, 8 and Day 15 of Cycle 1 (each cycle is 28 days), and on Day 1 of Cycle 2 and Cycle 3

Population: Number of participants analyzed: participants who had at least 1 concentration measurement for talazoparib. Therefore, only 2 treatment groups including talazoparib were analyzed. Number analyzed: participants who had talazoparib concentrations above the LLQ at specific time point.

PFS is defined as the time from the 'start date' (date of first study treatment) to the date of the first documentation of PD or death due to any cause, whichever occurs first. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy. CIs were calculated using Brookmeyer and Crowley method.

Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).

Population: The full analysis set included all enrolled participants who received at least 1 dose of study treatment.

TTR is defined, for patients with an OR, as the time from the 'start date' (date of first study treatment) to the first documentation of objective response (CR or PR) which was subsequently confirmed. OR is defined as complete response (CR) or partial response (PR) according to RECIST v1.1 from the 'start date' until the date of the first documentation of progressive disease (PD). CR was defined as complete disappearance of all target and non-target lesions, with the exception of nodal disease and sustained for at least 4 weeks. PR was defined as at least 30% decrease in the sum of the longest dimensions of target lesions taking as reference the baseline sum longest dimensions. PD was defined as unequivocal progression of pre-existing lesions and if overall tumor burden increased sufficiently to merit discontinuation of therapy.

Time frame: From date of first study treatment until the date of first documentation of progressive disease or death due to any cause (assessed for a maximum duration of up to 31 months).

Population: The full analysis set included all enrolled participants who received at least 1 dose of study treatment and achieved objective response: only 1 participant in the Avelumab+Binimetinib 45mg (Phase 1b) group achieved OR. The summary of this endpoint cannot be estimated due to small sample size (1 participant).