A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors

• ClinicalTrials.gov Identifier: NCT02880371
• Recruitment Status: Terminated
• First Posted: August 26, 2016
• Results First Posted: June 16, 2022
• Last Update Posted: June 16, 2022
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: August 2, 2016
• First Posted Date: August 26, 2016
• Results First Submitted Date: April 4, 2022
• Results First Posted Date: June 16, 2022
• Last Update Posted Date: June 16, 2022
• Actual Study Start Date: September 1, 2016
• Actual Primary Completion Date: September 17, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 21, 2022)

• Phase 1b, Part A: Number of Participants With Dose-Limiting Toxicities (DLT) [ Time Frame: Cycle 1 (up to 21 days) ]
  DLT: adverse event (AE) or abnormal laboratory value not clearly attributable to an extraneous cause, such as disease progression, intercurrent illness, or concomitant medications occurring during 21 days of Cycle 1, met 1 of the criteria A) nonhematologic AEs: recurring grade 2 pneumonitis, grade 3 events (irAE, QTcF prolongation, rash; other grade 3/4 except alopecia, nausea, diarrhea, vomiting, tumor flare, pseudoprogression, endocrinopathy); B) hematology AEs/laboratory abnormalities: grade 4 events except lymphopenia, neutropenia, electrolyte imbalances or abnormalities, grade 3 thrombocytopenia, febrile neutropenia, grade 4 AST/ALT elevation, grade 3 AST/ALT elevation lasting >7 days, associated with bilirubin levels>=2*ULN or international normalized ratio >1.5, grade 3 bilirubin elevation >=3, CK elevation >=grade 3 lasting, increase in creatinine >=1.5*baseline value, dose delay (dose interruption for >14 days) or other (inability to receive at least 67% of ARRY-382 doses).
• Phase 2 Cohorts: Objective Response Rate (ORR) [ Time Frame: From day of first dose to 30 days after last dose (maximum up to 13.5 months) ]
  ORR was defined as the percentage of participants who achieved a best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator review of radiographic disease assessments per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. As per RECIST v1.1: CR = disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures less than (<) 10 millimeter (mm). PR = at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions must be non-progressive disease (PD). The analysis was based on confirmed responses for which CR or PR must be confirmed by repeat disease assessment studies performed no less than 4 weeks after the criteria for response were first met to qualify as CR or PR, respectively.

Original Primary Outcome Measures (submitted: August 23, 2016)

• (Phase 1b/Part A) Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Cycle 1 (up to 21 days) ]
• (Part B) Effect of the combination on circulating biomarkers of immune response [ Time Frame: Duration of Part B is approximately 2.5 years ]
• (Part C) Efficacy of the combination in terms of the objective response rate [ Time Frame: Duration of Part C is approximately 1 year ]

Current Secondary Outcome Measures (submitted: May 21, 2022)

• Phase 1b, Part A: Objective Response Rate (ORR) [ Time Frame: From day of first dose to 30 days after last dose (maximum up to 34.7 months) ]
  ORR was defined as the percentage of participants who achieved a BOR of CR or PR as determined by investigator review of radiographic disease assessments per RECIST v1.1. As per RECIST v1.1: CR = disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures <10 mm. PR = at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. Non-target lesions must be non-PD. The analysis was based on confirmed responses for which CR or PR must be confirmed by repeat disease assessment studies performed no less than 4 weeks after the criteria for response were first met to qualify as CR or PR, respectively.
• Phase 1b, Part A and Phase 2 Cohorts: Duration of Response (DOR) [ Time Frame: From date of first documented CR or PR up to disease progression or death (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  DOR was defined as the time from the date of the first documented response (CR or PR) to the earliest date of disease progression, or death due to any cause after achieving a response. As per RECIST v1.1: CR = disappearance of target and non-target lesions and normalization of tumor markers. Pathological lymph nodes must have short axis measures < 10 mm. PR = at least a 30% decrease in the sum of measures (longest diameter for tumor lesions and short axis measure for nodes) of target lesions, taking as reference the baseline sum of diameters. PD = at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) and an absolute increase of >= 5 mm or appearance of at least 1 new lesion. Unequivocal progression of existing non-target lesions. DOR was estimated using the Kaplan-Meier method.
• Phase 1b, Part A and Phase 2 Cohorts: Progression-Free Survival (PFS) [ Time Frame: From day of first dose until disease progression or death due to any cause or till last tumor assessment date (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  PFS was defined as the time from the date of first dose of study drug to the earliest date of disease progression per RECIST v1.1, or death due to any cause, whichever occurs first. If a participant did not have a PFS event at the time of the analysis cut-off or at the start of any new anticancer therapy, PFS was censored at the date of last adequate tumor assessment. PD = at least a 20% increase in the sum of diameters of measured lesions taking as references the smallest sum of diameters recorded on study (including baseline) and an absolute increase of >= 5 mm or appearance of at least 1 new lesion. Unequivocal progression of existing non-target lesions.
• Phase 1b, Part A and Phase 2 Cohorts: Overall Survival (OS) [ Time Frame: From day of first dose till death due to any cause or date of last contact (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  OS was defined as the time from the start of treatment to the date of death due to any cause. If a death was not observed by the date of the analysis cut-off, OS was censored at the date of last contact. OS was estimated using the Kaplan-Meier method.
• Phase 1b, Part A and Phase 2 Cohorts: Percentage of Participants With Immune-Related Response Rate (irRR) [ Time Frame: From day of first dose till up to end of study treatment (for Phase 1b: maximum up to 33.7 months, for Phase 2: maximum up to 12.5 months) ]
  irRR was defined as the percentage of participants who achieved immune-related best overall response (irBOR) of immune-related CR (irCR) or immune-related PR (irPR), as determined by the investigator per immune related response criteria (irRC). irBOR was the best response using irRC recorded from the start of study treatment until the end of treatment. irCR was the disappearance of all target lesions, irPR was a decrease in tumor burden by 50% or greater by a consecutive assessment at least 4 weeks after first documentation.
• Phase 1b, Part A and Phase 2 Cohorts: Immune-Related Progression-Free Survival (irPFS) [ Time Frame: From the start of treatment to the time of first documented progression, or death (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  irPFS was defined as the time from the start of treatment to the time of first documented progression per irRC, or death due to any cause. irRC criteria for progression for 1) Measurable new lesions: incorporated into the tumor burden (eg, added to the index lesions); do not define progression unless the total measurable tumor burden increases by the required amount (25%); 2) New non-measurable lesions: not considered progression if the total measurable tumor burden is stable or shrinking. For the analysis of irPFS, Kaplan-Meier method was used.
• Phase 2 prOVCA: Change From Baseline in Tumor Markers at Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, Day 8, 15 of Cycle 1 and Treatment Discontinuation [ Time Frame: Baseline, Day 1 of Cycle 1, 2, 3, 4, 5, 6, 7, Day 8, 15 of Cycle 1 and Treatment discontinuation (before 13.5 months) ]
  Tumor markers were measured for tumor type from serum samples obtained from participants in Phase 2. Mean change from baseline was reported in this outcome measure.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring or Worsening Serum Chemistry Laboratory Abnormalities Graded by Common Terminology Criteria for Adverse Events (CTCAE) Grade 4.03 [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Abnormalities: Albumin (hypoalbuminemia),Alkaline phosphatase (ALP increased), Alanine aminotransferase (ALT increased), Aspartate aminotransferase (AST increased),Total bilirubin (TBL increased), Creatinine (increased), Corrected calcium (hypocalcemia/hypercalcemia), Creatine kinase (CK increased), Glucose (hypoglycemia/hyperglycemia), Amylase (increased), Lipase (increased) ,Phosphate (hypophosphatemia), Magnesium (hypomagnesemia/hypermagnesemia), Potassium (hypokalemia/hyperkalemia), Sodium (hyponatremia/hypernatremia). Participants with all grades and grade 3/4 abnormalities were reported. Test abnormalities were graded by CTCAE v4.03 as Grade 1=mild; Grade 2=moderate; Grade 3/Grade 4=severe/life-threatening.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring or Worsening Hematology and Coagulation Laboratory Abnormalities Graded by CTCAE Grade 4.03 [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Hematology abnormalities: Hemoglobin (anemia/hemoglobin increased), Platelets (count decreased), Leukocytes (count decreased/increased), Neutrophils (count decreased), Lymphocytes (count increased/decreased). Coagulation abnormalities: International Normalized Ratio (INR increased), Partial thromboplastin time(PTT)/Activated partial thromboplastin Time (aPTT, time prolonged). Abnormalities were graded by CTCAE grade 4.03 as Grade 1= mild; Grade 2 = moderate; Grade 3/Grade 4 = severe/life-threatening. Participants with all grades and grade 3/4 abnormalities were reported.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring Abnormal Liver Function Tests [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Liver function parameters/abnormalities: Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT): >3* upper limit of normal (ULN), >5*ULN, >8*ULN, >10*ULN, >20*ULN; Bilirubin >1.5*ULN, >2*ULN; Alkaline phosphatase (ALP) >2*ULN, >3*ULN.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Shift in Thyroid Panel Severity From Baseline Grade to Post Baseline Grades [ Time Frame: Baseline, 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Thyroid panel laboratory parameters/abnormalities: thyrotropin, free triiodothyronine (T3), free thyroxine (T4). Shift in thyroid panel severity from baseline grade low, normal, high and missing to the post baseline grades as low, normal, high and missing is reported in this outcome measure.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Clinically Significant Urinalysis Finding [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Urinalysis laboratory parameters/abnormalities: Decimal logarithm of reciprocal of hydrogen ion activity (pH), specific gravity, protein, glucose, ketones, nitrite, blood, leukocyte esterase, microscopy (if urine tested positive for blood or protein). Clinical significance was judged by investigator.
• Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Newly Occurring Clinically Notable Vital Sign Abnormalities [ Time Frame: First dose of study drug up to 30 days after last dose (for Phase 1b: maximum up to 34.7 months, for Phase 2: maximum up to 13.5 months) ]
  Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, body temperature and weight. Low SBP: less than or equal to (<=)90 millimeter of mercury (mmHg) with decrease from baseline of >=20 mmHg. High SBP: >=160 mmHg with increase from baseline of >=20 mmHg. Low DBP: <=50 mmHg with decrease from baseline of >=15 mmHg. High DBP: >=100 mmHg with increase from baseline of >=15 mmHg. Low heart rate: <=50 beats/min with decrease from baseline of >=15 beats/min. High heart rate: >=120 beats/min with increase from baseline of >=15 beats/min. Low temperature: <=36 degree Celsius (C). High temperature: >=37.5 degree C. Low Weight: decrease from baseline >=20%. High weight: increase from baseline >=10%.
• Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of ARRY-382 [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hour(hr) (±5 min), 2 hours(hrs) (±10 min), 4 hrs (±20 min) and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2 ]
  The lower limit of quantitation (LLOQ) for analyte ARRY-382 was 5.00 nanogram per milliliter (ng/mL).
• Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00469099 [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2 ]
  Drug ARRY-382 had its three metabolites AR00469099, AR00469100 and AR00470870. Plasma concentration of metabolite AR00469099 was reported in this outcome measure. The LLOQ for analyte AR00469099 was 1.00 ng/mL.
• Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00469100 [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2 ]
  Drug ARRY-382 had its three metabolites AR00469099, AR00469100 and AR00470870. Plasma concentration of metabolite AR00469100 was reported in this outcome measure. The LLOQ for analyte AR00469100 was 1.00 ng/mL.
• Phase 1b, Part A and Phase 2 Cohorts: Plasma Concentration Versus Time Profile of Metabolite AR00470870 [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration): on Day 15 of Cycle 1, on Day 1 of Cycle 2, 3, 4, 5, 6, 7, 8, 9 , 10; 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) post dose of ARRY-382 on Day 1 of Cycle 1, 2 ]
  Drug ARRY-382 had its three metabolites AR00469099, AR00469100 and AR00470870. Plasma concentration of metabolite AR00470870 was reported in this outcome measure. The LLOQ for analyte AR00470870 was 1.00 ng/mL.
• Phase 1b, Part A and Phase 2 Cohorts: Area Under the Plasma Concentration-Time Curve Over a Dosing Interval at Steady-State (AUCtau, ss) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: 0 to 24 hrs after administration of ARRY-382 on Day 1 of Cycle 2 ]
  AUCtau was defined as area under the plasma concentration-time curve over the dosing interval, where dosing interval was 24 hours.
• Phase 1b, Part A and Phase 2 Cohorts: Maximum Observed Plasma Concentration (Cmax) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration), 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2 ]
  Cmax was obtained from plasma concentration time curve. Cmax at single dose was reported at Cycle1 Day 1 and Cmax at steady state was reported at Cycle 2 Day 1.
• Phase 1b, Part A and Phase 2 Cohorts: Ctrough at Steady State for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration) on Day 1 of Cycle 2 ]
  Measured concentration at the pre-dose at steady-state.
• Phase 1b, Part A and Phase 2 Cohorts: Time to Reach Maximum Observed Plasma Concentration (Tmax) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration), 1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2 ]
  Tmax was obtained from plasma concentration time curve. Tmax at single dose was reported at Cycle 1 Day 1 and Tmax at steady state was reported at Cycle 2 Day 1.
• Phase 1b, Part A and Phase 2 Cohorts: Metabolite-to-Parent Ratio (MR) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration),1 hrs (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2 ]
  Different MR reported for single dose calculated at Cycle 1 Day 1 were as follows: 1) MRAUClast = ratio of AUClast values of the metabolite compared to parent, corrected for molecular weight, where AUClast was area under the plasma concentration-time curve from zero to the last measurable time point; 2) MRCmax = ratio of Cmax values of the metabolite compared to parent, corrected for molecular weight. Different MR reported for steady state calculated at Cycle 2 Day 1 were as follows: 1) MRAUCtau,ss = ratio of AUCtau,ss values of the metabolite compared to parent, corrected for molecular weight, where AUCtau was area under the plasma concentration-time curve over a dosing interval at steady-state; 2) MRCmax,ss = Ratio of Cmax,ss values of the metabolite compared to parent, corrected for molecular weight.
• Phase 1b, Part A and Phase 2 Cohorts: Accumulation Ratio (R) for ARRY-382 and Metabolites (AR00469099, AR00469100, and AR00470870) [ Time Frame: Pre dose of ARRY-382 (120 minutes prior to administration),1 hr (±5 min), 2 hrs (±10 min), 4 hrs (±20 min), and 8 hrs (±30 min) after administration of ARRY-382 on Day 1 of Cycle 1 and 2 ]
  Accumulation ratio was calculated and reported for Cmax as RCmax and for AUC as RAUC. RCmax = Cmax at steady-state on Day 1 of Cycle 2 divided by Cmax on Day 1 of Cycle 1. RAUC = AUC from zero to 8 hours after drug administration at steady-state on Day 1 of Cycle 2 divided by AUC from zero to 8 hours after drug administration on Day 1 of Cycle 1.

Original Secondary Outcome Measures (submitted: August 23, 2016)

• (Phase 1b/Part A, Part B) Preliminary antitumor activity of the combination in terms of objective response rate [ Time Frame: Phase 1b is expected to last until disease progression; Duration of Part B is approximately 2.5 years ]
• (Phase 1b/Part A, Part B, Part C) Preliminary antitumor activity of the combination based on immune-related response criteria [ Time Frame: Phase 1b is expected to last until disease progression; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Safety and tolerability of the combination in terms of adverse events and serious adverse events [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Part B) Evaluation of the pharmacodynamics of single-agent ARRY-382 in tumor tissue after 14 days of treatment in terms of immune biomarkers by IHC and/or RNA analysis [ Time Frame: Approximately 14 days ]
• (Phase 1b/Part A, Part B, Part C) Preliminary antitumor activity of the combination in terms of duration of response [ Time Frame: Phase 1b is expected to last until disease progression; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Preliminary antitumor activity of the combination in terms of progression-free survival [ Time Frame: Phase 1b is expected to last until disease progression; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Preliminary antitumor activity of the combination in terms of overall survival [ Time Frame: Duration of Phase 1b is approximately 1 year; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Evaluation of the plasma concentration-time profiles of ARRY-382 and its metabolites in the combination [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Area under the plasma concentration-time curve over the dosing interval (AUCτ) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Maximum plasma concentration (Cmax) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Time of maximum observed plasma concentration (Tmax) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Plasma concentration measured just before the next dose of study drug (Ctrough) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Accumulation ratio based on AUC (RAUC) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Metabolite-to-parent ratio based on AUC (MRAUC) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Metabolite-to-parent ratio based on Cmax (MRCmax) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]
• (Phase 1b/Part A, Part B, Part C) Accumulation ratio based on Cmax (RCmax) of ARRY-382 and its three metabolites [ Time Frame: Phase 1b: Patient safety will be evaluated throughout the treatment period, which is expected to last 6-10 months for each patient; Duration of Part B is approximately 2.5 years; Duration of Part C is approximately 1 year ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of ARRY-382 in Combination With Pembrolizumab for the Treatment of Patients With Advanced Solid Tumors
• Official Title: A Phase 1b/2 Study of ARRY-382 in Combination With Pembrolizumab, a Programmed Cell Death Receptor 1 (PD-1) Antibody, for the Treatment of Patients With Advanced Solid Tumors
• Brief Summary: This is an open-label, multicenter Phase 1b/2 study to determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of ARRY-382 in combination with pembrolizumab in adult patients with selected advanced solid tumors (Part A/Phase 1b); and to estimate the efficacy of the combination in three separate cohorts: 1) patients with advanced solid tumors that have progressed on prior PD-1/PD-L1inhibitors, 2) patients with platinum-resistant ovarian cancer and 3) patients with pancreatic ductal adenocarcinoma (Phase 2).

Detailed Description

ARRY-382 is an inhibitor of CSF1R (colony-stimulating factor-1 receptor).

Each phase of the study consists of a 28-day screening period; 21-day treatment cycles with the combination of ARRY-382 and pembrolizumab until disease progression as determined by the Investigator, unacceptable toxicity, withdrawal of consent, or death (or other discontinuation criteria are met), and a 30-day safety follow-up period. Patients in all cohorts/phases will be monitored for overall survival (OS) until 1 year after the date of the last patient's first visit.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Solid Tumors

Intervention

• Drug: ARRY-382
  ARRAY-382 will be taken by mouth once daily at a fixed dose.
• Drug: Pembrolizumab
  Pembrolizumab will be administered intravenously over 30 minutes every 3 weeks.

Study Arms

• Experimental: Phase 1b/Part A
  Patients in Part A will receive escalating doses of single-agent ARRY-382 in combination with 2 mg/kg pembrolizumab.
  Interventions:

  • Drug: ARRY-382
  • Drug: Pembrolizumab
• Experimental: Phase 2
  Patients in Phase 2 will receive the MTD/RP2D dose of ARRY-382 determined during Part A in combination with 200mg pembrolizumab.
  Interventions:

  • Drug: ARRY-382
  • Drug: Pembrolizumab

• Publications *: Johnson M, Dudek AZ, Sukari A, Call J, Kunk PR, Lewis K, Gainor JF, Sarantopoulos J, Lee P, Golden A, Harney A, Rothenberg SM, Zhang Y, Goldman JW. ARRY-382 in Combination with Pembrolizumab in Patients with Advanced Solid Tumors: Results from a Phase 1b/2 Study. Clin Cancer Res. 2022 Jun 13;28(12):2517-2526. doi: 10.1158/1078-0432.CCR-21-3009.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: March 27, 2020): 82
• Original Estimated Enrollment (submitted: August 23, 2016): 70
• Actual Study Completion Date: October 24, 2019
• Actual Primary Completion Date: September 17, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria

All Study Parts:

• Diagnosis of cancer that has been histologically or cytologically confirmed
• Eastern Cooperative Oncology Group Performance Status of 0 or 1

Part A (1 of the following):

• Ovarian cancer, triple-negative breast cancer, head and neck squamous cell cancer, bladder cancer, metastatic colorectal cancer, pancreatic ductal adenocarcinoma, or gastric cancer that is measurable or evaluable, nonmeasurable as defined by RECIST v1.1 and meets 1 of the following criteria:

  • is refractory to standard of care
  • no standard therapy available
  • patient refuses standard therapy
• Advanced, unresectable, or metastatic melanoma with or without prior treatment and measurable or evaluable, nonmeasurable disease as defined by RECIST v1.1

• Advanced/metastatic PD-L1-positive NSCLC (defined as a tumor proportion score [TPS] ≥ 50%) with measurable or evaluable, non-measurable disease as defined by RECIST v1.1 (1 of the following):

  • 1) No prior systemic chemotherapy if tumor does not have EGFR or ALK genomic aberrations
  • 2) Disease progression on or after platinum-containing chemotherapy;
  • 3) If tumor has EGFR or ALK genomic aberrations, disease progression on an FDA-approved therapy for EGFR or ALK genomic tumor aberrations

Phase 2 (1 of the following):

• Advanced/metastatic solid tumor with PD as defined by RECIST 1.1 or irRC on an anti-PD-1- or anti-PD-L1-containing regimen as their most recent prior therapy
• Advanced/metastatic epithelial ovarian cancer, peritoneal cancer or tubal cancer with measurable disease as defined by RECIST 1.1, that had progressed within 6 months of completing ≥ 4 cycles of platinum-based therapy
• Advanced/metastatic PDA that is locally advanced, unresectable or metastatic with measurable disease as defined by RECIST v1.1 in patients who have received at least one prior line of systemic therapy for their disease

Key Exclusion Criteria

1. Prior treatment as follows:

   • Part A: an immune CPI (e.g., PD-1, PD-L1, or cytotoxic T-lymphocyte antigen 4 [CTLA-4] inhibitor).

   NOTE: For patients with melanoma, prior treatment with ipilimumab is allowed if it was administered as adjuvant therapy and treatment was completed at least 3 months prior to enrollment.

   • Phase 2:

     • A CSF-1R inhibitor or CSF-1 (or MCSF) inhibitor.
     • prOVCA and PDA patients only: an immune CPI (e.g., PD-1, PD-L1, or CTLA-4 inhibitor)
2. Symptomatic brain metastasis at screening
3. Active autoimmune disease, documented history of autoimmune syndrome or disease, or a chronic medical condition that requires chronic steroid therapy or immunosuppressive medication
4. History of pneumonitis or interstitial lung disease
5. Severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient an inappropriate candidate for the study
6. Ocular melanoma

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02880371
• Other Study ID Numbers: ARRAY-382-201; C4261001 ( Other Identifier: Alias Study Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Current Responsible Party: Pfizer
• Original Responsible Party: Array BioPharma
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Array BioPharma
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: May 2022