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

Phase 2TerminatedNCT02880371

Pfizer82 enrolled

Overview

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).

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Advanced Solid Tumors

Interventions

ARRY-382DRUG

ARRAY-382 will be taken by mouth once daily at a fixed dose.

PembrolizumabDRUG

Pembrolizumab will be administered intravenously over 30 minutes every 3 weeks.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Locations (30)

Outcomes

Primary Outcomes

Phase 1b, Part A: Number of Participants With Dose-Limiting Toxicities (DLT)

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).

Time frame: Cycle 1 (up to 21 days)

Phase 2 Cohorts: Objective Response Rate (ORR)

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.

Time frame: From day of first dose to 30 days after last dose (maximum up to 13.5 months)

Secondary Outcomes

Phase 1b, Part A: Objective Response Rate (ORR)

Data from ClinicalTrials.gov

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Ronald Reagan UCLA Medical Center

Los Angeles, California, United States

UCLA Hematology/Oncology

Los Angeles, California, United States

UCLA Hematology/Oncology - Santa Monica

Santa Monica, California, United States

University of Colorado Denver

Aurora, Colorado, United States

University of Colorado Hospital

Aurora, Colorado, United States

Hem-Onc Associates of Treasure Coast

Port Saint Lucie, Florida, United States

Parkview Cancer Institute

Fort Wayne, Indiana, United States

Parkview Regional Medical Center

Fort Wayne, Indiana, United States

Parkview Research Center

Fort Wayne, Indiana, United States

PPG

Fort Wayne, Indiana, United States

...and 20 more locations

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.

Time frame: From day of first dose to 30 days after last dose (maximum up to 34.7 months)

Phase 1b, Part A and Phase 2 Cohorts: Duration of Response (DOR)

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.

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)

Phase 1b, Part A and Phase 2 Cohorts: Progression-Free Survival (PFS)

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.

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)

Phase 1b, Part A and Phase 2 Cohorts: Overall Survival (OS)

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.

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)

Phase 1b, Part A and Phase 2 Cohorts: Percentage of Participants With Immune-Related Response Rate (irRR)

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.

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)

Phase 1b, Part A and Phase 2 Cohorts: Immune-Related Progression-Free Survival (irPFS)

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.

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)

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

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.

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)

Phase 1b, Part A and Phase 2 Cohorts: Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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.