Avelumab With Bempegaldesleukin With or Without Talazoparib or Enzalutamide in Advanced or Metastatic Solid Tumors

DLTs were graded according to NCI- CTCAE version 4.03 and coded using the latest version of Medical Dictionary for Regulatory Activities (MedDRA) preferred term (PT) as event category and MedDRA primary system organ class (SOC) body term as Body System category.

Time frame: Cycle 1 of the treatment period (28 days)

Population: The DLT-evaluable analysis set included all enrolled participants in Phase 1b who receive at least one dose of the combination treatment and either experience DLT during the first cycle (28 days) of treatment, or complete the DLT observation period for the first cycle of treatment without a DLT.

DR was defined, for participants with a confirmed Objective Response (OR), as the time from the first documentation of OR to the date of first documentation of progressive disease (PD) or death due to any cause. The documentation of PD was defined using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. If a subject had not had an event (PD or death), DR was censored at the date of last adequate tumor assessment. As there were no objective responses in the study, no participant met the definition of analysis population.

Time frame: Approximately 8 months (246 days).

Population: All participants treated in combination A who achieved an OR.

Liver Function Tests of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBILI) were used to assess possible drug induced liver toxicity. The number of participants with at least one of the following laboratory results were summarized below: 1. (ALT ≥3 × ULN or AST ≥3 × ULN) post-baseline. 2. TBILI ≥2 × ULN post-baseline. 3. (ALP ≤2 × ULN or missing) post-baseline.

Time frame: Day 1, Day 15 of each treatment cycle

Population: The safety analysis set included all participants who received at least one dose of study drug.

ADA against avelumab and NKTR-214 in serum samples was determined and reported separately for ADA never-positive, ADA ever-positive participants, baseline ADA positive, treatment-boosted ADA, treatment-induced ADA, transient ADA response, persistent ADA response. For all participants, blood for ADA samples was drawn from the contralateral arm of the avelumab and NKTR-214 infusion.

Time frame: Day 1 of Cycle 1, 2 and end of treatment (EOT).

Population: The immunogenicity analysis set was a subset of the safety analysis set and included participants who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2.

nAb in serum samples was determined and reported separately for nAb never-positive, nAb ever-positive, baseline nAb positive, treatment-induced nAb, transient nAb response, persistent nAb response.

Time frame: Day 1 of Cycle 1, 2 and EOT

Population: The immunogenicity analysis set was a subset of the safety analysis set and included participants who had at least one ADA/nAb sample collected for avelumab, NKTR-214, or IL-2.

Adverse events (AEs) were any untoward medical occurrences in a participant or clinical study participants, temporally associated with the use of study intervention, whether or not considered related to the study intervention. Treatment-emergent adverse events (TEAEs) were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment through minimum (30 days + last dose of study treatment). A Serious Adverse Event (SAE) was defined as any untoward medical occurrence that, at any dose: a. Results in death, b. Was life-threatening, c. Required inpatient hospitalization or prolongation of existing hospitalization, d. Resulted in persistent disability/incapacity, e. Was a congenital anomaly/birth defect. Causality to study treatment was determined by the investigator.

Time frame: Approximately 6 months (190 days)

Population: The safety analysis set included all participants who received at least one dose of study drug.

Overall survival (OS) was defined as the time from the date of first dose of study treatment to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. OS time was summarized using the Kaplan-Meier method.

Time frame: Approximately 8 months (246 days).

Population: All participants treated in Combination A.

PD-L1 expression level in baseline tumor tissue, and in on-treatment tumor tissue was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and/or inflammatory cells in regions of interest. PD-L1 expression level in baseline tumor tissue and in on-treatment tumor tissue were under pathological analyses, assisted by image analysis. Participants were classified as positive or negative according to scoring algorithms and cut-offs established from internal or external sources.

Time frame: On-treatment biopsy is required to be collected on Cycle 1 between Days 9 and 14 for participants in Combination A.

Population: The biomarker analysis set for biomarkers that were only measured at screening was a subset of the safety analysis set and included participants who had at least one baseline biomarker assessment.

Cmax was defined as the maximum observed plasma concentration at the end of infusion. Ctrough was defined as the predose concentration at the end of dosing interval.

Time frame: Blood samples were collected on Day 1 and Day 15 in Cycle 1 and Cycle 2 for avelumab. Blood samples were collected on Day 1, Day 3, Day 4 and Day 8 in Cycle 1, Day1 and Day 8 in Cycle 2 for NKTR-214.

Population: The PK parameter analysis set was a subset of the safety analysis set and included participants who had at least one of the PK parameters of interest for avelumab, NKTR-214, IL-2, talazoparib, enzalutamide, or N-desmethyl-enzalutamide.

Progression-Free Survival (PFS) was defined as the time from the date of first dose of study treatment to the date of the first documentation of PD or death due to any cause, whichever occurred first. PFS data were censored on the date of the last adequate tumor assessment for participants who did not have an event (PD or death), for participants who started new anti-cancer therapy prior to an event, or for participants with an event after two or more missing tumor assessments. Participants who did not have an adequate baseline tumor assessment or who did not have any adequate post-baseline tumor assessments were censored on the date of first dose of study treatment unless death occurred on or before the time of the second planned tumor assessment, in which case the death was considered an event. PFS time was summarized using the Kaplan-Meier method.

Time frame: Approximately 8 months (246 days).

Population: All participants treated in Combination A.

TTR was defined, for participants with objective response, as the time from the date of first dose of study treatment to the first documentation of objective response (Complete Response or Partial Response) which was subsequently confirmed. As there were no objective responses in the study, no participant met the definition of analysis population.

Time frame: Approximately 8 months (246 days).

Population: All participants treated in combination A who achieved an OR.